Lung Cancer
Content
Lung
Hansen
Textbook of
Cancer
Textbook of Lung Cancer, Second Edition, published in association with the European
Society for Medical Oncology, is a comprehensive and multidisciplinary text, which
examines all aspects of this disease, with contributions from a multinational team
of authors on etiology, epidemiology, molecular biology, pathology, smoking,
detection and management, clinical features, staging and prognostic factors, surgery,
radiotherapy and chemotherapy. It provides essential information and guidance for
specialist trainees in oncology, and for the many physicians and specialists involved in
Table of contents
Etiology of lung cancer • Epidemiology of lung cancer • Molecular biology of lung cancer
• Tobacco policy • Smoking cessation programs • Current status of early lung cancer
screening • Histopathology of lung tumors • Clinical diagnosis and basic evaluation
• Staging, classification and prognosis • Treatment of non-small cell lung cancer
• Treatment of small cell lung cancer • Malignant mesothelioma • Summary of treatment
• Therapeutic bronchoscopy for palliation of lung tumors • Complications to lung cancer
• Quality of life and supportive care • The cost and cost-effectiveness of lung cancer
management • The future • Appendix: Chemotherapy
About the editor
Heine Hansen MD FRCP is Professor of Clinical Oncology at the Finsen Center,
National University Hospital, Copenhagen, Denmark.
Also available:
ESMO Handbook of Cancer Prevention
Edited by Schrijvers, Senn, Mellstedt, Zakotnik (ISBN: 9780415390859)
ESMO Handbook of Principles of Translational Research
Edited by Mellstedt, Schrijvers, Bafaloukos & Greil (ISBN: 9780415410915)
Lung Cancer – Translational and Emerging Therapies
Edited by Pandya, Brahmer & Hidalgo (ISBN: 9780849390210)
Image-Guided Radiotherapy of Lung Cancer
Edited by Cox, Chang & Komaki (ISBN: 9780849387838)
Lung Cancer
the field of lung cancer.
Textbook of
Second Edition
Cancer
Second Edition
Edited by
Heine Hansen
Textbook of Surgical Oncology
Edited by Poston, Beauchamp & Ruers (ISBN: 9781841845074)
Lung Cancer Therapy Annual 6
Edited by Hansen (ISBN 9780415465458)
Second
Edition
www.informahealthcare.com
Lung
Textbook of
Published in association with
the European Society for Medical Oncology
Textbook of Lung Cancer
Textbook of Lung Cancer
Second Edition
Edited by
Heine Hansen MD FRCP
Finsen Center
National University Hospital
Copenhagen
Denmark
© 2008 Informa UK Ltd
First published in the United Kingdom in 2000
Second edition published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ.
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Library of Congress Cataloguing-in-Publication Data
Data available on application
ISBN-10: 0 415 38510 5
ISBN-13: 978 0 415 38510 7
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Contents
List of Contributors
vii
Preface
xi
Color plate
1. Etiology of lung cancer
Aage Haugen, Steen Mollerup
xiii
1
2. Epidemiology of lung cancer: a century of great success and ignominious failure
Peter Boyle, Sara Gandini, Nigel Gray
10
3. Molecular biology of lung cancer
Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot
20
4.
35
Tobacco policy
Nigel Gray
5. Smoking cessation programs
Philip Tønnesen
41
6. Current status of lung cancer screening
James L Mulshine
53
7. Histopathology of lung tumors
Elisabeth Brambilla, Sylvie Lantuejoul
61
8. Clinical diagnosis and basic evaluation
John J Mullon, Eric J Olson
75
9. Staging, classification, and prognosis
Michael Dusmet, Peter Goldstraw
97
10. Treatment of non-small cell lung cancer
10.1 Treatment of NSCLC: surgery
Robert J Korst
123
10.2 Treatment of NSCLC: radiotherapy
Merideth MM Wendland, William T Sause
136
vi Contents
10.3 Treatment of NSCLC: chemotherapy
Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias
147
11. Treatment of small cell lung cancer
12.
11.1 Treatment of SCLC: surgery
Hisao Asamura, Riken Kawachi
170
11.2 Treatment of SCLC: radiotherapy
Christopher M Lee, William T Sause
177
11.3 Treatment of SCLC: chemotherapy
Heine H Hansen, Morten Sørensen
184
Malignant mesothelioma
Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney
190
13. Summary of treatment
Heine H Hansen
207
14. Therapeutic bronchoscopy for palliation of lung tumors
Paul WA Kunst, Pieter E Postmus, Thomas G Sutedja
210
15. Complications of lung cancer
Vincenzo Minotti, Michele Montedoro, Maurizio Tonato
218
16. Quality of life and supportive care
Jean-Paul Sculier, Anne–Pascal Meert, Marianne Paesmans, Thierry Berghmans
236
17. The cost and cost-effectiveness of lung cancer management
William K Evans, Christopher J Longo
247
18.
The future
Giovanni Selvaggi, Giorgio Vittorio Scagliotti
264
Appendix: Chemotherapy
275
List of drugs
331
Index
333
Contributors
Sophia Agelaki MD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Hisao Asamura MD
Division of Thoracic Surgery
National Cancer Center Hospital
Tokyo
Japan
Thierry Berghmans MD
Department of Critical Care and
Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Peter Boyle MD
International Agency for Research on Cancer
Lyon
France
Elisabeth Brambilla MD PhD
Deptartment of Pathology
Michallon Hospital
CHRU Grenoble
National Institute for Health and
Medical Research
University Fourier Grenoble
Grenoble
France
Jenette Creaney MD
School of Medicine and Parmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Michael Dusmet MD FMH
Department of Thoracic Surgery
Royal Brompton Hospital
London
UK
Williams K Evans MD FRCPC
Department of Oncology
McMaster University
Hamilton, Ontario
Canada
Sara Gandini MD
Division of Epidemiology and Biostatics
European Institute of Oncology
Milan
Italy
Vassilis Georgoulias MD PhD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Peter Goldstraw MD
Department of Thoracic Surgery
Royal Brompton Hospital
London
UK
viii List of Contributors
Nigel Gray AO MBBS FRACP FRACMA
Tobacco Unit
International Agency for Research on Cancer
Lyon
France
Christopher J Longo PhD MSc BA
DeGroote School of Business
McMaster University
Hamilton, Ontario
Canada
Heine H Hansen MD
The Finsen Center
National University Hospital
Copenhagen
Denmark
Anne–Pascal Meert MD
Department of Critical Care and
Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Aage Haugen PhD
Department of Chemical and Biological
Working Environment
National Institute of Occupational Health
Oslo
Norway
Vincenzo Minotti MD
Department of Medical Oncology
Santa Maria Della Misericordia Hospital
Perugia
Italy
Riken Kawachi MD
Division of Thoracic Surgery
National Cancer Center Hospital
Tokyo
Japan
Steen Mollerup PhD
Department of Chemical and Biological
Working Environment
National Institute of Occupational Health
Oslo
Norway
Robert J korst MD
Daniel and Gloria Blumenthal Cancer Center
Valley Health System
Valley Hospital
Paramus, NJ
USA
Michele Montedoro MD
Department of Medical Oncology
Santa Maria Della Misericordia Hospital
Perugia
Italy
Peter WA Kunst MD PhD
Department of Pulmonary Diseases
HAGA Hospital
The Hague
The Netherlands
Sylvie Lantuejoul MD PhD
Department of Pathology
Michallon Hospital
CHRU Grenoble
National Institute for Health and Medical Research
University J. Fourier Grenoble
Grenoble
France
Christopher M Lee MD
Department of Radiation Oncology
University of Utah School of Medicine
Huntsman Cancer Hospital
Salt Lake City, UT
USA
John J Mullon MD
Division of Pulmonary and Critical Care Medicine
Mayo Clinic College of Medicine
Rochester, MN
USA
James L Mulshine MD
Rush University Medical Center
Chicago, IL
USA
Anna Nowak MD
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Eric J Olson MD
Division of Pulmonary and Critical Care Medicine
Mayo Clinic College of Medicine
Rochester, MN
USA
List of Contributors ix
Marianne Paesmans MSc
Data Center
Institut Jules Bordet
Brussels
Belgium
Athanasios G Pallis MD PhD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Helle Pappot MD
Department of Oncology
Copenhagen University Hospital
Copenhagen
Denmark
Pieter E Postmus MD PhD
Department of Pulmonary Diseases
Vrije Universiteit University Medical Center
Amsterdam
The Netherlands
Hans Skovgaard Poulsen MD DMSc
Department of Radiation Biology
Copenhagen University Hospital
Copenhagen
Denmark
Thomas Tuxen Poulsen MSc
Department of Radiation Biology
Copenhagen University Hospital
Copenhagen
Denmark
Bruce WS Robinson MBBS MD FRACP
FRCP DTM&H FCCP
National Research Centre for Asbestos
Related Diseases
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Cleo Robinson MD
National Research Centre for Asbestos
Related Diseases
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
William T Sause MD
LDS Hospital Radiation Center
Salt Lake City, UT
USA
Giorgio V Scagliotti MD
Department of Clinical and Biological Sciences
University of Turin
Orbassano, Turin
Italy
Jean-Paul Sculier MD PhD
Department of Critical Care and Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Giovanni Selvaggi MD
Department of Clinical and Biological Sciences
University of Turin
Orbassano, Turin
Italy
Morten Sørensen MD
The Finsen Center
National University Hospital
Copenhagen
Denmark
Tom G Sutedja MD PhD
Department of Pulmonary Diseases
Vrije Universiteit University Medical Center
Amsterdam
The Netherlands
Maurizio Tonato MD
Regional Cancer Center
Poloclinico Hospital
Perugia
Italy
Philip Tønnesen MD
Department of Pulmonary Medicine
Gentofte University Hospital
Hellerup
Denmark
Merideth MM Wendland MD
Department of Radiation Oncology
Huntsman Cancer Hospital
University of Utah
Salt Lake City, UT
USA
Preface
Since the publication of the first issue of this textbook
in 2000, the epidemiologic features of smoking have
undergone continuous changes and the worldwide
intensification of the battle against tobacco consumption is changing the geographic pattern. In the USA,
some western European countries, and Australia, the
incidence of lung cancer is decreasing among males,
while the disease continues to increase among females.
In the southern and eastern parts of Europe, lung cancer is on a rapid rise, and a similar pattern is seen in
highly populated countries like China, Indonesia, and
Japan. Other regions of the world, such as the Middle
East, Africa, and South America, show the same dismal
picture.
Worldwide, the annual number of new cases of lung
cancer is estimated at more than one million and is
expected to increase to ten million in 2025. Fortunately,
the political efforts to reduce the use of tobacco are
getting increasing attention in many countries and the
statistics are now showing the first positive results.
Among the epidemiologic changes we also see a
change in the histopathologic pattern, with a relative
decrease in squamous cell carcinoma and a rise in adenocarcinoma. Lately, important new information as
regards the biology of lung cancer is emerging, including new treatment approaches. The result is a slow, but
steady improvement of the overall management of lung
cancer based on an increasing use of combined modality therapy, consisting of surgery, chemotherapy, and
radiotherapy applied concurrently or sequentially in
early stage disease. Furthermore, new techniques are
gaining ground, both within surgery and radiotherapy,
and targeted medical therapy is being offered to more
and more patients.
The textbook brings up-to-date information about
lung cancer, based on worldwide experience, for the
use of the many physicians involved in this field.
Heine H Hansen
Color Plates
(a)
(c)
(b)
Figure 8.5
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma in the left upper lobe (a), with contralateral hilar metastasis
(b). (c) Coronal 18F-FDG-PET without CT fusion, demonstrating no extrathoracic involvement. Transbronchial needle aspirate of the right
hilar lymph node confirmed metastatic adenocarcinoma with stage IIIB NSCLC assigned.
xiv Color Plates
(a)
(c)
(b)
Figure 8.6
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma involving the left upper lobe with ipsilateral mediastinal
lymph node metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without CT fusion demonstrating mediastinal and
extrathoracic (left adrenal) involvement. CT-guided biopsy of the left adrenal confirmed metastatic adenocarcinoma with stage IV NSCLC
assigned.
Color Plates xv
Figure 9.13
The nodal chart established by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC)
in 1997.3
Figure 11.2.2
Anterior-posterior digitally reconstructed radiograph (DRR) illustrating a typical radiation portal which includes the primary tumor mass
and adjacent hilar/mediastinal lymph nodes.
xvi Color Plates
Figure 11.2.3
Conformal radiotherapy planning techniques allow escalated radiation doses to be delivered safely with simultaneous sparing of
surrounding critical structures. In this example, a combination of anterior-posterior and oblique fields (four fields in total) are utilized to
decrease radiation dose to the nearby spinal cord.
Figure 11.2.4
Right lateral digitally reconstructed radiograph (DRR) illustrating a typical portal used for prophylactic cranial irradiation.
1
Etiology of lung cancer
Aage Haugen, Steen Mollerup
Contents Introduction • Carcinogens in tobacco smoke • Environmental tobacco smoke • Air pollution,
radon, workplace exposure, and viruses • Genetic susceptibility and lung cancer etiology • Females and
lung cancer susceptibilty
INTRODUCTION
Lung cancer, which was rare at the beginning of the
20th century, is now a global problem. It is the most
frequent cancer in the world.1 Presently, 1.2 million
people die of lung cancer each year and the global incidence of lung cancer is increasing. A major contribution to this trend comes from the former socialist
economies and developing countries where smoking
rates are still high. Consequently, lung cancer will
remain a major cause of cancer death worldwide in the
21st century even though the prevalence of tobacco use
has declined in many high-income countries.
That carcinogens in tobacco smoke play a major
role in lung cancer is unquestionable. About 85–90%
of lung cancer patients are smokers.2 However, lung
cancer also occurs in people who have never smoked,
and this implies that factors such as environmental
tobacco smoke (ETS), environmental and domestic
air pollution, work-related risk factors, radon exposure,
and viruses may also have an impact on lung cancer
incidence rates. In addition, since fewer than 20% of
smokers will develop lung cancer in their lifetime, inherited predisposition may be an important component.
CARCINOGENS IN TOBACCO SMOKE
Lung carcinogenesis is mediated through an interaction
between several putative carcinogens. A smoker inhales
gas-phase smoke (so-called ‘mainstream smoke’) as well
as particulates (tar). Cigarette smoke is a complex mixture of compounds and more than 4000 compounds
have been identified in tobacco mainstream smoke3–7
(Table 1.1). Studies have led to the identification of
60–70 carcinogens: polycyclic aromatic hydrocarbons
(PAHs), heterocyclic hydrocarbons, N-nitrosamines,
aromatic amines, N-heterocyclic amines, aldehydes,
various organic compounds, inorganic compounds such
as hydrazine and some metals, and free radical species.
Table 1.2 lists likely causative agents for lung cancer.
Available evidence indicates that carcinogenic PAH
compounds and the tobacco-specific carcinogen NNK
(4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone)
are of major importance in lung cancer induction in
smokers.8 Most studies on tobacco smoking genotoxicity in the lung have focused on these compounds. They
are strong carcinogens and tobacco contains relatively
high amounts of PAHs and N-nitrosamines. However,
compounds such as aldehydes, butadiene, and benzene, which appear to have lower carcinogenic potential, are found in much higher quantities in tobacco
smoke.
PAHs are formed by incomplete combustion of
tobacco during smoking. PAHs, particularly benzo(a)
pyrene, induce tumors of the lung in laboratory animals by various routes of administration. Furthermore,
studies have demonstrated that human lung tissue can
metabolize PAHs to reactive metabolites that can interact with DNA, forming mutagenic DNA adducts.9 DNA
adduct formation is thought to be the primary initiating
event in carcinogenesis and may be predictive of
lung cancer risk.10,11 PAH–DNA adducts have been
detected in human lung samples, and increased levels
of PAH–DNA adducts in human lung tissue of smokers
and ex-smokers relative to non-smokers have been
reported in several studies.9 The major adduct formed
by activated benzo(a)pyrene, the (+)-anti-benzo(a)
pyrene-guanine adduct, is premutagenic, mispairing
with A and generating primarily G-to-T transversions.
The role of PAHs in lung cancer is consistent with data
on mutational analysis of the TP53 gene with the demonstration of a large number of G-to-T transversions at
certain bases (hotspots) in this gene in smokers’ lung
tumors.12 In vitro studies have shown a direct molecular link between benzo(a)pyrene and the development
of lung cancer. Exposure of human epithelial cell cultures to the reactive diol epoxide metabolites of this
carcinogen resulted in the formation of adducts and
TP53 hotspot mutations, similar to that observed in
lung tumors in smokers.13
2 Textbook of Lung Cancer
Table 1.1 Carcinogens in cigarette smoke
Agent
Amount in mainstream
cigarette smoke
IARC evaluation of
carcinogenicity
In animals
Polynuclear aromatic hydrocarbons
Benzo[a]anthracene
20–70 ng
Benzo[b]fluoranthene
4–22 ng
Benzo[j]fluoranthene
6–21 ng
Benzo[k]fluoranthene
6–12 ng
Benzo[a]pyrene
8.5–11.6 nga
Dibenz[a,h]anthracene
4 ng
Dibenzo[a,i]pyrene
1.7–3.2 ng
Dibenzo[a,e]pyrene
Present
Indeno[1,2,3-cd]pyrene
4–20 ng
5-Methylchrysene
ND-0.6 ng
Heterocyclic hydrocarbons
Furan
20–40 µgb
Dibenz(a,h)acridine
ND–0.1 ng
Dibenz(a,j) acridine
ND–10 ng
Dibenzo(c,g)carbazole
ND–0.7 ng
Benzo(b)furan
Present
N-Nitrosamines
N-Nitrosodimethylamine
0.1–180 ngb
N-Nitrosoethylmethylamine
ND–13 ng
N-Nitrosodiethylamine
ND–25 ngb
N-Nitrosopyrrolidine
1.5–110 ngb
N-Nitrosopiperidine
ND–9 ng
N-Nitrosodiethanolamine
ND–36 ngb
N′-Nitrosonornicotine
154–196 nga
4-(Methylnitrosamino)110–133 nga
1-(3-pyridyl)-1-butanone
Aromatic amines
2-Toluidine
30–200 ngb
2,6-Dimethylaniline
4–50 ng
2-Naphthylamine
1–22 ngb
4-Aminobiphenyl
2–5 ngb
N-Heterocyclic amines
A-α-C
25–260 ng
MeA-α-C
2–37 ng
IQ
0.3 ng
Trp-P-1
0.3–0.5 ng
Trp-P-2
0.8–1.1 ng
Glu-P-1
0.37–0.89 ng
Glu-P-2
0.25–0.88 ng
PhIP
11–23 ng
In humans
IARC group
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2A
2B
2B
2B
2A
2A
2B
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2B
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2A
2B
2A
2B
2B
2B
2Bc
2Bc
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
Sufficient
Sufficient
2A
2B
1
1
2B
2B
2A
2B
2B
2B
2B
2B
(Continued)
Etiology of lung cancer 3
Table 1.1 Continued
Agent
Amount in mainstream
cigarette smoke
Aldehydes
Formaldehyde
10.3–25 µga
Acetaldehyde
770–864 µga
Phenolic compounds
Catechol
59–81 µga
Caffeic acid
<3 µg
Volatile hydrocarbons
1,3-Butadiene
20–40 µgb
Isoprene
450–1000 µg
Benzene
12–50 µgb
Nitrohydrocarbons
Nitromethane
0.5–0.6 µg
2-Nitropropane
0.7–1.2 ngc
Nitrobenzene
25 µg
Miscellaneous organic compounds
Acetamide
38–56 µg
Acrylamide
Present
Acrylonitrile
3–15 µg
Vinyl chloride
11–15 ng
1,1-Dimethylhydrazine
Present
Ethylene oxide
7 µg
Propylene oxide
0–100 ng
Hydrazine
24–43 ng
Urethane
20–38 ngb
Metals and metal compounds
Arsenic
40–120 ngb
Beryllium
0.5 ng
Nickel
ND–600 ng
Chromium (hexavalent)
4–70 ng
Cadmium
41–62 ngb
Cobalt
0.13–0.20 ng
Lead (inorganic)
34–85 ng
Radio-isotope polonium-210
0.03–1.0 pCi
IARC evaluation of
carcinogenicity
In animals
In humans
IARC group
Sufficient
Sufficient
Limited
2A
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2B
Limited
Sufficient
2A
2B
1
Sufficient
Sufficient
Sufficient
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2A
2B
1
2B
1
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
1
1
1
1
1
2B
2A
1
Modified from Hoffmann and Hoffmann,4 this table shows components of unfiltered mainstream cigarette smoke, with amounts given per cigarette.
Virtually all these compounds are known carcinogens in experimental animals. In combination with data on cancer in humans and – in some cases –
other relevant data, IARC Monograph classifications for these agents have been established as Group 2B (possibly carcinogenic to humans), Group 2A
(probably carcinogenic to humans), or Group 1 (carcinogenic to humans).
Abbreviations: ND, not detected; A-α-C, 2-amino-9H-pyrido[2,3-b]indole; IQ, 2-amino-3-methylimidazo-[4,5-b]quinoline;
Trp-P-1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b]indole; Glu-P-1, 2-amino6-methyl[1,2-a:3′2″-d]imidazole; Glu P-2, 2-aminodipyridol[1,2-a:3′,2″-d]imidazole; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine;
pCi, picoCurie.
a
Data from Swauger et al (2002) (for ‘full-flavor’ cigarettes).5
b
Data from US Department of Health and Human Services (1989).6
c
Corrected value (see Fowler and Bates, 2000).7
4 Textbook of Lung Cancer
Table 1.2 Causative agents in cigarette smoke
Carcinogens
Major risk factors
PAHs
Nitroso compounds
Tumor promoters/
co-carcinogens
Catechol
Phenol
Aldehydes
Oxidative radicals
Minor risk factors
Polonium-210
Aldehydes
Butadiene
Ni, Cd, Cr
Oxidative radicals
The concentration of nitrosamines found in tobacco
products is relatively high, and except for some occupational exposure situations, heavy smokers have the
highest exposure to N-nitroso compounds. The socalled tobacco-specific N-nitrosamines (TSNAs), principally the nicotine-derived NNK, are the strongest
respiratory carcinogens identified in tobacco products.
Adenocarcinoma of the lung is the main type of lung
cancer induced by NNK, and both benign and malignant tumors are formed in rats, mice, and hamsters.14
Moreover, human lung tissue metabolically activates
NNK, although less effectively than rodent lung tissue.
This activation is mediated by P450 monooxygenases,
cyclooxygenases, and lipooxygenases. Metabolites of
NNK have been reported in urine from smokers, and
NNK and N′-nitrosonornicotine (NNN)-specific DNA
adducts have been reported at increased levels in the
lungs of smokers.8,15 A high frequency of G-to-A transitions in the TP53 gene is consistent with the mutational
spectrum expected from NNK.12 NNK might also exert
its biologic activity through cell surface receptors such
as nicotine acetylcholine receptors (nAchRs) and
β-adrenergic receptors.16 Adenocarcinoma has now
overtaken squamous cell carcinoma as the most common lung cancer type, consistent with the role of NNK
in lung carcinogenesis. NNK concentrations in mainstream smoke have increased while those of benzo(a)
pyrene have decreased since the 1960s.
There are relatively high levels of metals in cigarette
smoke (Figure 1.1). At least 30 metals have been
identified.3,4 The contribution of these metals to increased
lung cancer risk is poorly understood. Experimental evidence indicates that many metals are effective initiators
of the carcinogenic process, but can also be potential
promoters during carcinogenesis. This is particular true
for tobacco smoke, where exposure to multiple agents
occurs. Cigarette smoke contains a substantial amount
of chromium, cadmium, and nickel. It is known that
chromium accumulates in the lung and tobacco smoking is the main source of cadmium exposure in humans.
It has been reported that chromates are carcinogenic in
rats, inducing lung tumors after instillation.17 Cadmium
chloride aerosols produce lung adenocarcinoma and
squamous cell carcinoma in rats,18 and nickel subsulfide yields lung cancer in rats upon inhalation.19 Because
of their relatively high levels in cigarette smoke, these
metals may play a role in lung carcinogenesis. They are
likely to contribute to lung cancer induction by multiple mechanisms such as inducing DNA damage (single
strand breaks, cross-linking of DNA and proteins), and
they could potentiate the genotoxicity of other DNAdamaging agents and enhance mutagenesis. Many studies have demonstrated that reactive oxygen species are
implicated in metal carcinogenesis.
Table 1.2 lists other constituents of tobacco-smoke
that could be involved in lung cancer induction. However, less importance has been attributed to these compounds in comparison with PAH and NNK. Inhalation
studies of formaldehyde and acetaldehyde have demonstrated that they are respiratory carcinogens in the
rat.20 These compounds are weak carcinogens, but the
levels are relatively high in cigarette smoke.
Polonium-210 (210Po) is a natural constituent of cigarette smoke and will deposit in the lungs of smokers,
emitting alpha particles.21 The content of several carcinogens in tobacco has been reduced due to changes
in tobacco processing methods and new cigarette filters, but this is not the case with the 210Po concentration, neither in tobacco nor in tobacco smoke. Radiation
exposure may induce lung cancer both alone and in
interaction with other carcinogens in tobacco. Animal
studies have shown that 210Po is a strong pulmonary
carcinogen in rats and Syrian golden hamsters.22
Cigarette smoke contains large amounts of free radicals and is known to induce oxidative damage. Both gas
and particulate phases are highly oxidized, and damage
the lung. Alkenes (i.e. unsaturated aliphatic hydrocarbons), nitrosamines, aromatic and heterocyclic hydrocarbons, amines, and catechol and hydroquinone are
all well known sources of reactive oxygen species such
as hydroxyl radicals, superoxides, and peroxides.23 Damage can also result from the activation of phagocytic cells
that generate reactive oxygen species (ROS).24 Cigarette
smoke is a strong inflammatory stimulus that induces
Etiology of lung cancer 5
Causative agents in cigarette smoke:
PAH, NNK, 210Po, Cr, Cd,
Ni, aldehydes, oxidative radicals
Phase 1
(activation)
Susceptibility:
Variation in
metabolism and
DNA repair
Nutrition
Immunologic
status
P 450
DNA-damaging
metabolites
Chronic exposure
DNA
repair
Days
DNA
repair
10–30 years
Excretion
Synergistic effect:
Asbestos
Chloromethyl ethers
Mustard gas
Radioactive ore
Preneoplastic
cells
Initiated cells
Normal cells
Phase 2
(detoxification)
Progression
Lung
cancer
DNA
repair
Months
Genetic changes:
TP53, KRAS, EGFR, inactivation of FHIT/RASSF1/SEMA3B (3p), INK4, RB
Activation of CCDN1; MYC1 - amplification
LOH (2q, 5q, 9q, 18q, 22q)
Figure 1.1
Lung carcinogenesis.
proinflammatory cytokines and recruits activated macrophages and neutrophils to lung tissue.25 Neutrophils
play an important role in the defense of the lung through
a variety of activities and generate oxidative radicals
when exposed to PAHs and aromatic amines. The oxidative capacity of neutrophils is therefore important
as a potential cause of oxidative damage to the lung.
Several epidemiologic studies have associated lung
inflammatory diseases such as asthma, bronchitis, and
chronic obstructive pulmonary disease (COPD) with an
increased risk of lung cancer development.
DNA is an important target for ROS. In order for
ROS to induce DNA damage, a sufficient concentration
must be available to overwhelm the antioxidant capacity of the lung. Products that result from oxidative damage to both lipids and DNA have been detected in
smokers at higher levels than in non-smokers. Although
the direct role of such products in carcinogenesis is
unclear, 8-oxoguanine (8-oxo-G), a frequent product of
oxidative damage, has miscoding properties associated
with the cancer induction process.26 Studies indicate
that unrepaired 8-oxo-G gives rise to G-to-T transversions. The most abundant genetic change induced as a
consequence of oxidative damage is GC-to-AT transition. Apart from oxidative modification of DNA bases,
free radicals are also able to induce single strand
breaks.
Nicotine is the agent in tobacco capable of producing
addiction, or nicotine dependence, and exists at high
concentrations in the blood of smokers. Direct involvement of nicotine in the development of lung cancer has
not yet been shown, but nicotine does appear to play an
important role and may have multiple sites of action. It
is absorbed rapidly when smokers inhale. Specific,
high-affinity nAChRs are found on human lung cancer
cells of all histologic types as well as in normal lung
tissue.27 Chronic exposure to nicotine can lead to the
activation of growth-promoting pathways upon its
interaction with nAChRs, and may also affect apoptosis
and angiogenesis.28
ENVIRONMENTAL TOBACCO SMOKE
Environmental tobacco smoke (ETS), or passive
smoking, is a mixture of exhaled mainstream smoke
and sidestream smoke diluted with ambient air. Cigarettes generate a large amount of ETS and affected individuals are exposed to the same carcinogens as an active
smoker. However, the relative proportions of the particular compounds may differ between mainstream and
sidestream smoke. For example, due to filters, concentrations of PAHs such as benzo(a)pyrene and benzo(a)
anthracene in the sidestream are approximately 10-fold
6 Textbook of Lung Cancer
higher than those in mainstream smoke. Benzene, formaldehyde, hydrazine, butadiene, N-nitrosamines, aniline, 2-naphthylamine, and 4-aminobiphenyl may
also be present at higher concentrations in sidestream
smoke.29
Many epidemiologic studies, which were evaluated
by the IARC in 2004,3 have shown an increased lung
cancer risk in never-smokers exposed to ETS. This is
particularly true for spouses of active smokers, where
ETS-exposed never-smoking females and males have an
excess risk of lung cancer in the order of 20 or 30%,
respectively. Never-smokers exposed to ETS in the
workplace may also be at an increased risk (12–19%).
Experimental studies have confirmed the carcinogenic
potential of ETS. Thus, concentrations of tobaccosmoke-related compounds adducted to biologic macromolecules such as proteins, and to a lesser extent DNA,
have been found to be increased in individuals exposed
to ETS.3 Also, lung tumors from ETS-exposed nonsmoking individuals show TP53 and KRAS mutations
similar to those found in tumors from smokers, although
at a lower frequency.30,31
AIR POLLUTION, RADON, WORKPLACE EXPOSURE,
AND VIRUSES
The different incidence rates for lung cancer among
non-smokers in different countries suggest that environmental agents can modify the risk. Air pollution is a
complex mixture of different gaseous and particulate
components that may pose a moderate risk factor for
lung cancer. Numerous air pollutants resulting from
heavy traffic, burning of fossil fuels, and industrial
plants are potential contributors to the incidence of
lung cancer. These include PAH, formaldehyde, benzene, ethylene oxide, petroleum vapors, and metals. An
association between lung cancer and air pollution has
been reported in studies from cities. Urban residents
with the highest exposure levels seem to have an
increase in lung cancer in the range of 1.5 times that of
rural residents.32 In a large European prospective study,
it was found that residence in proximity to heavy-traffic
roads or exposure to NO2 concentrations greater than
30 µg/m3 can increase the risk of lung cancer.33 In the
case of NO2, the lung cancer risk ratio has shown an
exposure–response relationship.34 In other studies, particulate matter (fine particles), SO2, and black smoke
have all been associated with a moderate increase in the
risk of lung cancer. However, analysis is complicated
due to the fact that air pollution is a complex mixture,
with numerous air pollutants that vary during the year
and over time. Since the lung has a large respiratory
volume (500–600 liters of air/h) with a large surface
area (75–85 m2), and a large blood perfusion, exposure
to toxic compounds in the ambient air could lead to
lung toxicity and lung cancer development even at low
levels.
Radon, a naturally reactive but chemically inert gas
found ubiquitously in the environment, emanates as a
toxic gas from the soil and from building material of
terrestrial origin, such as stone, bricks, and concrete.
High levels of radon exposure occur in occupational
settings, particularly in uranium mines. People are also
subjected to residential radon exposure, which may be
increasing due to the tendency to reduce ventilation
rates in indoor air. The carcinogenicity of radon is
attributable mainly to its short-lived, radioactive, alphaemitting daughters, polonium-214 and polonium-218.35
In miners, increasing risk of lung cancer is associated
with increasing cumulative exposure to radon.36 There
is also compelling evidence that indoor radon is an
important contributor to the risk of lung cancer.37 The
dose–response relation between residential radon exposure and excess risk of lung cancer appears to be linear
with no threshold. Overall estimates have been made
that radon may contribute to 9% of all lung cancers,
and the available data suggest that the risks of lung
cancer from exposure to radon and smoking are at least
additive.
Workplace exposure plays an important role in the
causation of lung cancer. The evidence for lung cancer
induction by occupational exposure to metals such as
beryllium, chromium, nickel and arsenic is convincing
and well documented.38 High exposure to PAH occurs
in several occupations, such as those involved in aluminium production, coke production, and coal gasification, iron and steel workers, bus drivers (because of
diesel engine exhaust), roofers, and asphalt workers.
The lung is the major target organ among PAH-exposed
workers.39 Although occupational exposure to asbestos
is no longer an issue in most developed countries, in
several developing countries exposure is widespread
and may be a significant etiologic factor for lung cancer.
As in most other exposure scenarios, tobacco smoking
is the main cause of lung cancer in asbestos-exposed
workers, and the relative risk seems to be higher among
non-smokers compared to smokers.40 Crystalline silica,
which may be inhaled in occupational settings, has been
classified as a lung carcinogen, with an apparent linear
dose–response relationship without any threshold.41
It is important to note, however, when assessing the
Etiology of lung cancer 7
etiology of lung cancer associated with occupational
exposure, that a significant confounder to be considered is tobacco smoking.
Oncogenic viruses may be involved in the etiology of
lung cancer. Some evidence has been provided for the
involvement of human papilloma viruses, but detection
rates of the viruses in bronchial carcinomas are highly
variable, ranging from 0 to 100% in different studies.42
Regarding other oncogenic viruses such as Epstein–
Barr virus, human cytomegalovirus, human herpes
virus-8, and simian virus 40, the evidence is scarce.43
repair genes involved in different repair pathways show
associations.
There is increasing knowledge of the genetic defects
that give rise to the observed variation in, and, more
importantly functional significance of these allelic variants. However, there are numerous conflicting reports
on the association between different polymorphisms
and lung cancer risk. Larger studies are needed in
this area.
FEMALES AND LUNG CANCER SUSCEPTIBILITY
GENETIC SUSCEPTIBILITY AND LUNG
CANCER ETIOLOGY
Host factors may influence individual susceptibility to
tobacco smoke. This may be illustrated by the fact that
only 1 in 10 lifetime smokers will develop lung cancer.
Several epidemiologic studies have indicated that there
are genetic factors modifying the risk of individuals to
lung cancer. Some degree of familial aggregation of lung
cancer is evident in most family studies. One study has
reported linkage to chromosome 6q in lung cancer families, strongly supporting the existence of a gene for
lung cancer.44 The human genome project has resulted
in increasing information becoming available on the
existence of polymorphisms in human genes. Susceptibility to lung cancer may be modulated by host-specific
factors including differences in carcinogen metabolism
and detoxification, DNA repair, cell cycle control, cell
signaling, apoptosis, and inflammation pathways. Several studies have been designed to evaluate a large
number of sequence variants among multiple genes
of drug-metabolizing enzymes.45 Procarcinogens in
tobacco smoke are activated by several forms of cytochrome P450 (phase I) and detoxified by glutathione
S-transferase (GST), NADPH:quinone oxidoreductase
(NQO), N-acetyl-transferase (NAT), and others (phase
II). Many of these genes exhibit allelism and there is
accumulating evidence that some CYP, GST, NQO, and
NAT genotypes are associated with an altered risk of
lung cancer.
The removal and repair of DNA damage plays a key
role in protecting the integrity of the genome from the
insults of genotoxic agents such as PAH and NNK found
in tobacco smoke. Lung cancer patients were reported
to have a lower DNA repair capacity, and recent studies
have assessed the relationship between single nucleotide polymorphisms (SNPs) in several DNA repair
genes and the risk of lung cancer.45–47 Several DNA
The relative lung cancer burden from women is
increasing, partly due to their changing smoking
habits. Although controversial, the increase in lung
cancer among females is possibly also partly due to a
higher susceptibility to tobacco smoke carcinogens.
Several studies have reported the relative risk of lung
cancer among females to exceed that of males by a
factor of 1.5 to 2.5.48–50 Although not all epidemiologic
studies have been able to confirm that females are at
increased risk,51,52 it is clear that biologic factors
involved in lung cancer development differ between
the sexes. Experimental studies have indicated sex
differences in PAH metabolism, DNA repair capacity,
and cell proliferation potential that may support this
hypothesis.
By analyzing the TP53 gene mutational spectra in a
large number of lung cancer cases, G:C-to-T:A hotspot
mutations were found at a higher frequency among
female smokers compared to female never-smokers.
Similar differences were not found among males.53
Since G:C-to-T:A transversions are associated with
exposure to PAH, this indicates a specific role for PAH
in generating this particular signature mutation in
women. Women have also been reported to have
increased levels of pulmonary tobacco-smoke-induced
DNA damage in the form of PAH-related adducts.54 The
DNA-adduct level may be a predictor of cancer risk.55
Higher DNA-adduct levels among females coincide
with a higher level of expression of the smoking-induced
cytochrome P450 1A1 (CYP1A1), which is an important
gene in the metabolic activation of PAH.56 Estrogens
and their receptors have been hypothesized to be
involved in these sex differences by interfering with the
transcription-activating activity of the aryl hydrocarbon
receptor (AHR). AHR is a ligand-activated transcription
factor with high affinity for PAH. In studies with lymphocytes isolated from lung cancer patients, it was
found that females might also have a lower capacity to
8 Textbook of Lung Cancer
repair DNA damage,57 which may result in increased
susceptibility to the manifestation of mutations.
One report has indicated that pulmonary expression
of the gastrin-releasing peptide receptor (GRPR), which
is involved in lung development during fetal stages, is
more frequent among women than men.58 The GRPR
gene is induced by smoking and is located on a region
of the X-chromosome that appears to escape X-chromosome inactivation in females. Activation of the GRPR has
been associated with an increased proliferative response
in human airway epithelial cells. Thus, this represents a
model where smoking may induce the gene to a higher
extent among women.
In summary, tobacco smoking (active smoking or
exposure to environmental tobacco smoke) plays a
major etiologic role in lung carcinogenesis. More than
60 compounds in tobacco smoke have been identified
as carcinogenic. Other etiologic factors of minor, but
still significant importance for the disease are air pollution, radon, workplace exposure, and viruses. Genetic
differences in susceptibility to lung cancer are apparent
and sex differences may be involved.
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2
Epidemiology of lung cancer: a century of
great success and ignominious failure
Peter Boyle, Sara Gandini, Nigel Gray
Contents Introduction • Phase I: public health success, 1930s onwards • Phase II: understanding
etiology, losing ground in incidence and mortality • Phase III: descriptive epidemiology of
lung cancer • Phase IV: public health failure, 1960s onwards
INTRODUCTION
The present century has witnessed a remarkable
epidemic of lung cancer. The words of Adler,1 published in 1912, today make salutary reading:
Is it worthwhile to write a monograph on the subject of primary malignant tumours of the lung? In
the course of the last two centuries an ever-increasing literature has accumulated around this subject.
But this literature is without correlation, much of it
buried in dissertations and other out-of-the-way
places, and, with but a few notable exceptions, no
attempt has been made to study the subject as a
whole, either the pathological or the clinical aspect
having been emphasised at the expense of the other,
according to the special predilection of the author.
On one point, however, there is nearly complete
consensus of opinion, and that is that primary malignant neoplasms of the lungs are among the rarest
forms of the disease. This latter opinion of the
extreme rarity of primary tumours has persisted for
centuries.
Lung cancer is currently the most common form of
cancer worldwide. It is the most common cause of cancer
death in men in North America and in virtually all
European countries, west and east, and it is increasingly
common as a cause of death in developing populations
in Asia, Latin America, and Africa, although comparable high-quality data are not available from many of
these populations. From being virtually an unknown
and rare disease at the beginning of the last century,
public health has documented the development of a
true epidemic of lung cancer through the 20th century,
and has failed to alleviate the situation by positive
actions. Knowing the cause, which has been the case for
lung cancer since at least the middle of the last century,
has been of little value in public health terms, since
there has been no real action taken to reduce the impact
of this serious disease.
In viewing the century of lung cancer epidemiology,
there are a number of distinct phases that can be identified. Initially (phase I), there was the great success of
epidemiology, the basic science of public health, in establishing the causal link between cigarette smoking and
lung cancer risk. Following this period, from the mid1950s onwards, there was a period (phase II) where
there was an increasing understanding of the etiology of
lung cancer, and simultaneously public health began
losing ground as smoking rates led to great increases in
the incidence and mortality of the disease, particularly
among men in developed countries. The association
between tobacco smoking and lung cancer became
widely known, and many groups actively took up the
movement towards tobacco control. During this period
(phase III), the situation stabilized while activists and
scientists united to try to bring the adverse effects of
tobacco smoking to general attention and thereby to
take actions designed to reduce smoking and its harmful side-effects. It quickly became clear that a great deal
of ground had been lost, and during phase IV large
increases in lung cancer among women became apparent, indicating the great failure of public health to curb
the development of the habit among women.
PHASE I: PUBLIC HEALTH SUCCESS, 1930s ONWARDS
The association between tobacco smoking and the
development of lung cancer appears to have been
suggested in the UK in 1927.2 The first interview study
on tobacco smoking and lung cancer seems to have
been reported from Vienna,3 where lung cancer rates
Epidemiology of lung cancer: a century of great success and ignominious failure 11
had risen dramatically. Fleckseder3 found 51 smokers
among 54 patients with lung cancer. Thirty-seven of
these smoked between 20 and 90 cigarettes daily, while
excessive smoking of pipes, cigars, or both was rarer.
The same association was alluded to in a report from
the USA4 on a study primarily of a series of
79 patients treated by total pneumonectomy. A report
from Cologne followed one year later,5 based on the
postmortem records of 96 patients. The patients (or
more usually the relatives of fatal cases) were interviewed as to patient’s occupation, tobacco consumption, and exposure to specific ‘inhalants’.
Reanalysis of Muller’s5 data shows a relative risk of
3.1 among moderate smokers, 2.7 among heavy smokers,
16.8 among very heavy smokers, and 29.16 among
excessive smokers. Within the limitations of the study
(e.g. small numbers, especially among non-smoking
cases, and possible inaccuracies in elucidation of precise smoking histories), these results were noticeably
similar to results obtained from later case–control studies in the USA and, apart from a lack of increase among
heavy smokers, there is the possible appearance of a
dose–response relationship.
A study of smoking habits and occupation based on
195 postmortem records of lung cancer cases from the
Pathology Institute at Jena for the years 1930–1941 was
reported: usable replies were obtained from relatives of
93 men and 16 women. Of the women, 13 were nonsmokers.6 The authors attempted to collect control
information by interviewing 700 men in Jena between
the ages of 53 and 54, the average age of the lung cancer
patients at death (53.9 years). This was a study performed
in Germany towards the end of the Second World War,
and only 270 men from Jena responded to the questionnaire. The authors showed great insight in concluding that wartime conditions (particularly the rationing
system) may have favored results from non-smokers.
They reported a statistically significant difference
between non-smokers and heavy smokers among lung
cancer patients on the one hand and normal patients on
the other. Realizing the possible errors on their material, they concluded that there was a considerable probability that lung cancer was far more frequent among
non-smokers than expected. Their data are such that an
approximate relative risk can be calculated: the risk
relative to non-smokers was 1.90 among light smokers,
9.05 among moderate smokers, and 11.34 among
heavy/excessive smokers. Again there appears to be a
moderate dose–response relationship.
The rapid escalation in lung cancer during the 1940s
reached a level that permitted more and larger studies
to be conducted and, in 1950, five major contributions
were made to the literature.7–11
The data presented by Wynder and Graham10 are
capable of transformation to calculate the relative risks
(the concept of which was unknown for a few more
years). Setting the risk among non-smokers at 1.0, there
is to some extent or other a dose–response relationship
with increasing levels of smoking in all age groups.
Together with the study of Wynder and Graham,10 the
fifth paper published on this subject during the year
represented a significant contribution not only to knowledge about smoking and cancer but also to the methodology of retrospective epidemiologic studies.11
This well-planned, controlled, and well-conducted
study was initially reported,11 and completed and published more extensively two years later. It is this latter
report12 that we shall discuss here. Doll and Hill12 did
not discuss cigar smoking, but calculated that use of
one ounce of pipe tobacco was the equivalent of 26.5
cigarettes, and one ounce per week was equivalent to
smoking four cigarettes per day. Non-smokers were
defined as people who had never consistently smoked
as much as one cigarette per day for as long as one
year.11
The strongest difference between cases and controls
(for both males and females) was found to be the average amount smoked daily over the 10 years preceding
the patient’s illness. Qualitatively similar results were
also obtained using the amount smoked immediately
before the patient’s illness, the maximum amount ever
smoked regularly, the total smoked since smoking began,
and the average amount smoked daily over the 10 years
preceding the patient’s illness, over the penultimate 10
years and over the whole of the patient’s life since the
age of 15 (even after allowance had been made for
recorded changes in smoking habit).
Patients who recognized that they inhaled were found
no more frequently in the lung cancer group than in the
control group, although those cases with growths of
central origin inhaled less frequently than normal. It
also appeared that lung cancer patients more frequently
had a history of preceding pneumonia or chronic bronchitis, while other respiratory illnesses were referred to
with approximately equal frequency by the two
groups.
Doll and Hill’s reports11,12 contained a remarkable
amount of information, but the fundamental finding in
men was a highly significant difference between the
proportions of non-smokers and of smokers in the disease group and in the control group. A less marked
series of differences was reported for women. Highly
12 Textbook of Lung Cancer
significant differences were also shown between the proportions of both groups smoking different average
amounts, i.e. between heavy and light smokers, and this
result held for males and females. It is apparent from
the raw data that there is a dose–response relationship
present.
Less marked but nevertheless distinct differences
were found when the duration of smoking was considered rather than the amount smoked. Lung cancer
cases, as a group, began to smoke earlier; they continued to smoke longer and gave up less often and, when
they did, did so for shorter periods. In males, all these
differences were statistically significant, but, although
the differences were in the same direction in women,
they did not reach the commonly accepted (5%) level
of statistical significance.
These five studies,7–11 but mainly the impact of
two,10,11 alerted the medical and scientific community
to the serious health hazards associated with cigarette
smoking. Once alerted, the public response to these
studies was a significant, but brief, drop in the per
capita consumption of cigarettes in both the USA and
the UK.
PHASE II: UNDERSTANDING ETIOLOGY, LOSING
GROUND IN INCIDENCE AND MORTALITY
Throughout the 1950s, a mass of information was
published demonstrating the association between lung
cancer and cigarette smoking, using data derived
from retrospective studies. Many concentrated on inhalation and, while some studies demonstrated a higher
occurrence of inhalation among lung cancer patients
than among controls, others failed to detect this
association.
The US Surgeon General was moved by the weight of
evidence associating smoking with cancer of the lung,
as well as of other sites, to produce an official statement
on ‘Smoking and Health’ on behalf of the US Government.13 This created a worldwide reaction, since it
implicated a frightening link between cigarette smoking
and a variety of fatal diseases in a document of impeccable scientific authority.
This report weighed the available evidence, and considered that it had been established that cigarette smoking was causally related to lung cancer in men, and judged
cigarette smoking in the USA a sufficiently important
health hazard to warrant remedial action.
In the 15 years that passed from that initial report,
the body of evidence increased, and extended to include
women,14 in whom lung cancer had increased fivefold
in two decades in the USA. The Secretary for Health of
the time (Mr Joseph Califano) concluded ‘that smoking
is the largest preventable cause of death in America’.
An important factor in the causal relationship between
smoking and lung cancer is the demonstrated dose–
response relationship. In epidemiologic studies, the dose
has been measured by:
•
•
•
•
•
•
•
•
•
the number of cigarettes smoked per day at interview;
the maximum number of cigarettes smoked per
day;
the age when smoking commenced;
the degree of inhalation of tobacco smoke;
the total number of years smoked;
the total lifetime number of cigarettes smoked;
the tar and nicotine levels of the brand of cigarettes
used;
the number of puffs per cigarette;
the length of the unburned portion of cigarette.
A variety of combinations of these variables can be
converted into dosage scores.
Lung cancer mortality ratios exhibit an inverse relationship with the age of initiation of the smoking habit.
Those who develop the habit at school have a much
higher risk of lung cancer than those who begin smoking at age 25+, in whom the risk is only four to five
times that of non-smokers.
Available data show a strong dose–response relationship between self-reported inhalation of cigarette smoke
and lung cancer mortality. Those who inhale deeply
have risks double those of smokers who do not. The
American Cancer Society 25 State Study15 reported a
mortality ratio among non-smokers of 1.0, a mortality
ratio of 8.0 among smokers who stated that they did
not inhale, and elevations in this risk among those who
inhaled slightly (8.9), moderately (13.1) and deeply
(17.0). Similar results were reported from a Swedish
study:16 although the mortality ratios among nonsmokers (1.0), non-inhalers (3.7), light inhalers (7.8),
and deep inhalers (9.2) were smaller in magnitude, the
same steady pattern was found.
Although it has been suggested for some time that
the risk of developing lung cancer increases with the tar
and nicotine content of cigarettes there has not been
any substantial evidence to suggest that individuals
who switch to lower-tar and lower-nicotine cigarettes
experience less lung cancer mortality.17 It has been proposed that, if the tar and nicotine contents of tobacco
Epidemiology of lung cancer: a century of great success and ignominious failure 13
were reduced, smokers might increase the number of
cigarettes smoked per day and effectively vitiate any
benefit. On the other hand, those who switch to low-tar
and low-nicotine brands might inhale smoke more
deeply than smokers of high-tar and high-nicotine cigarettes, and thus exposure to tar and nicotine might be
reduced.
The relationship of tar and nicotine was carefully
examined with respect to lung cancer in a major study,18
in which 897 825 men and women were classified by
levels of tar and nicotine smoked. Brands were considered to be high in nicotine if they contained between
2.0 and 2.7 mg of nicotine and high in tar if they contained between 25.8 and 35.7 mg of tar. The medium
levels of tar and nicotine were set at 17.6 and 25.7 mg
and at 1.2 and 1.9 mg, respectively. Low tar and nicotine levels were all those below these limits.
The risk in the high-tar and high-nicotine group of
makes was set at 1.0, and the relative risks in the
medium group (risk ratio, RR = 0.95) and low group
(RR = 0.81) were appreciably lower. Similar results were
found for females: high (RR = 1.0), medium (RR = 0.79),
and low (RR = 0.60). These results take into account the
daily cigarette consumption.
In other words, for men smoking the same number of
cigarettes per day, there appears to be an almost 20%
reduction in the risk of developing lung cancer with the
use of cigarettes low in tar and nicotine. In females,
keeping the number of cigarettes smoked per day constant, there appears to be a 40% reduction in risk. The
amount of tar and nicotine taken into the body per day
obviously depends on the number of cigarettes smoked
as well as on the tar and nicotine content of individual
cigarettes. Hammond therefore performed a second
analysis comparing subjects who smoked 1–19 high-tar
and -nicotine cigarettes per day with those who smoked
20–39 low-tar and -nicotine cigarettes per day. Setting
the risk to be 1.0 among the high categories of both
males and females, Hammond found risks of 1.6 (males)
and 2.1 (females) among the groups who smoked
20–39 low-tar and -nicotine cigarettes. He concluded
that the number of cigarettes smoked per day was relatively more important than the tar and nicotine
content.15,18
All these early observations were regarding forms of
cancer and forms of tobacco smoking that were the
most common at the period. Cigarette smoking
increased heavily in Europe during the last years of
Napoleon,19 and the habit spread during the Crimean
War, accelerated around 1900 and reached many men,
and increasingly women, during the First World War
(1914–1918). In many countries, such as the USA and
the UK, women began to reach the same smoking levels
as men during the Second World War (1939–1945).
Subsequent to this period, cancer was becoming
more frequent, and was developing into an international disease that was to become, by the latter part of
the 20th century, a significant global public health
problem. An increasing number of forms of cancer
became linked with cigarette smoking: initially oral
cancers, then lung cancer, bladder cancer, laryngeal
cancer, esophageal cancer, pancreatic cancer, acute
myeloid leukemia, cervical cancer, kidney cancer, and
gastric cancer. Several of these are of unusually high
frequency in international populations.20
PHASE III: DESCRIPTIVE EPIDEMIOLOGY
OF LUNG CANCER
The main tobacco-related site is the lung. Lung cancer
rates in self-reported non-smokers from various studies
are of the order of only 10–15 per 100 000. The IARC
monograph Tobacco Smoking21 gave estimates of the
proportions of lung cancer deaths attributable to
tobacco smoking in five developed countries (Canada,
England and Wales, Japan, Sweden, and the USA):
these ranged between 83% and 92% for males, and
between 57% and 80% for females.
The most recent, international, cancer incidence data
are available for the period around 1990. The highest
incidence rate in men is recorded among the AfroAmerican population of New Orleans in the USA, where
the average, annual, age-standardized rate per 100 000
person-years is 110.8 (Table 2.1). Other Afro-American
populations in the USA also have remarkably high lung
cancer rates in men. Rates are also high among the
Maori population of New Zealand, where the incidence
rate is 99.7 per 100 000 (Table 2.1). The incidence rate
is high in Lower Silesia (Poland) and in the west of
Scotland (Table 2.1). There are virtually no regions of
the world where the annual incidence rates are low: the
lowest incidence rates are reported from a variety of
population groups from the developing world
(Table 2.2).
Among women, the highest rates are found in
the Maori population group of New Zealand (72.9 per
100 000) (Table 2.3). High rates are also found among
a variety of populations of North America – both AfroAmerican and Caucasian. Notably high rates are
reported from the west of Scotland, where incidence
rates are high in men as well as in women (Table 2.3).
14 Textbook of Lung Cancer
Table 2.1 Highest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990
Registry
Cases
ASRa
USA, New Orleans: Black (1988–1992)
USA, Central Louisiana: Black (1988–1992)
USA, Detroit: Black (1988–1992)
USA, San Francisco: Black (1988–1992)
New Zealand: Maori (1988–1992)
USA, SEER:b Black (1988–1992)
USA, Atlanta: Black (1988–1992)
Poland, Lower Silesia (1988–1992)
Canada, Northwest Territories (1983–1992)
UK, Scotland, west (1988–1992)
USA, Los Angeles: Black (1988–1992)
USA, Connecticut: Black (1988–1992)
Italy, Ferrara (1991–1992)
USA, New Orleans: White (1988–1992)
Italy, Trieste (1989–1992)
842
172
2263
1003
387
4964
892
7213
126
8877
1925
422
597
1707
897
110.81
105.62
103.23
101.49
99.73
99.11
97.26
95.52
90.26
88.90
88.74
86.15
85.73
84.01
82.73
a
Average, annual, age-standardized rate per 100 000 person-years.
Surveillance Epidemiology and End Results Program (National Cancer Institute).
b
Table 2.2 Lowest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990
Registry
Cases
ASRa
India, Karunagappally (1991–1992)
Thailand, Kohn Kaen (1990–1993)
Peru, Lima (1990–1991)
Costa Rica (1988–1992)
India, Bombay (1988–1992)
Singapore: Indian (1988–1992)
India, Madras (1988–1992)
Peru, Trujillo (1988–1990)
India, Trivandrum (1991–1992)
USA, New Mexico: American Indian (1988–1992)
Ecuador, Quito (1988–1992)
India, Bangalore (1988–1992)
Mali, Bamako (1988–1992)
Uganda, Kyadondo (1991–1993)
India, Barshi, Paranda and Bhum (1988–1992)
58
355
635
686
1867
83
789
47
69
24
172
495
38
20
11
17.04
17.02
15.89
15.63
14.48
14.33
12.64
11.93
10.63
10.32
10.13
8.06
5.28
4.24
1.26
a
Average, annual, age-standardized rate per 100 000 person-years.
The finding of the incidence rate among women in
Tianjin, China, among the 15 highest incidence rates
recorded, is the first clear indication of the rising epidemic of lung cancer, and other cancers, resulting from
the increasing prevalence of cigarette smoking during
recent decades (Table 2.3). There are some regions of
the world where the incidence rate among women is
still truly low (Table 2.4).
In men in all European countries, except Portugal,
lung cancer is now the leading cause of cancer death. In
the USA (and in all European countries except a few
Scandinavian countries), it is also the commonest tumor
Epidemiology of lung cancer: a century of great success and ignominious failure 15
Table 2.3 Highest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990
Registry
Cases
ASRa
New Zealand: Maori (1988–1992)
Canada, Northwest Territories (1983–1992)
Canada, Yukon (1983–1992)
USA, San Francisco: Black (1988–1992)
USA, Detroit: Black (1988–1992)
USA, New Orleans: White (1988–1992)
USA, San Franciso: non-Hispanic White (1988–1992)
USA, Detroit: White (1988–1992)
USA, Central California: non-Hispanic White (1988–1992)
USA, Los Angeles: non-Hispanic White (1988–1992)
UK, Scotland, west (1988–1992)
USA, SEER:b Black (1988–1992)
USA, Hawaii: White (1988–1992)
USA, Seattle (1988–1992)
China, Tianjin (1988–1992)
326
80
39
562
1213
1115
3906
4772
2267
6674
5086
2558
340
4413
3870
72.93
65.56
47.62
44.33
42.02
41.19
40.42
40.17
39.48
38.58
38.47
38.46
37.94
37.62
37.00
a
Average, annual, age-standardized rate per 100 000 person-years.
Surveillance Epidemiology and End Results Program (National Cancer Institute).
b
Table 2.4 Lowest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990
Registry
Cases
Malta (1992–1993)
France, La Réunion (1988–1992)
France, Tarn (1988–1992)
Spain, Albacete (1991–1992)
Spain, Tarragona (1988–1992)
Algeria, Setif (1990–1993)
Spain, Granada (1988–1992)
Spain, Zaragoza (1986–1990)
India, Karunagappally (1991–1992)
India, Madras (1988–1992)
India, Trivandrum (1991–1992)
India, Bangalore (1988–1992)
Mali, Bamako (1988–1992)
Uganda, Kyadondo (1991–1993)
India, Barshi, Paranda and Bhum (1988–1992)
18
46
60
19
72
33
92
116
10
142
14
103
13
4
3
ASRa
3.35
3.34
3.19
3.14
3.09
2.88
2.71
2.66
2.59
2.37
1.89
1.67
1.53
0.41
0.33
a
Average, annual, age-standardized rate per 100 000 person-years.
in terms of incidence (although the recent inflation of
prostate cancer incidence figures with very early detection of cases is taking prostate cancer above lung cancer
in terms of the incidence of the disease). The range of
geographic variation in lung cancer mortality in Europe
is threefold in both sexes – the highest rates being
observed in the UK, Belgium, the Netherlands, and the
former Czechoslovakia, and the lowest rates being
reported in southern Europe and in Norway and Sweden.22 This overall pattern of age-standardized lung
cancer mortality rates does not reveal the important
and diverging cohort effects occurring in various countries: for instance, some of the countries in which there
are now low rates, such as those in southern Europe
16 Textbook of Lung Cancer
and parts of eastern Europe, experienced a later uptake
and spread of tobacco use, and now appear among the
most elevated rates in the younger age groups. This
suggests that these same countries, including Italy,
Greece, France, Spain, and several countries in eastern
Europe, will have the highest lung cancer rates in men
at the beginning of the next century, in the absence of
rapid intervention.
The importance of adequate intervention is shown
by the low lung cancer rates in Scandinavian countries,
which have adopted, since the early 1970s, integrated
central and local policies and programs against
smoking.23,24 These policies may have been enabled by
the limited influence of the tobacco lobby in these
countries. The experience in Finland provides convincing evidence of the favorable impact, after a relatively
short delay, of well-targeted large-scale interventions on
the most common cause of cancer death and of premature mortality in general.
With specific reference to women, current rates in
most European countries (except the UK and Ireland)
are still substantially lower than in the USA, where lung
cancer is now the leading cause of cancer death in
females. In several countries, including France, Switzerland, Germany, and Italy, where smoking is now
becoming commoner in young and middle-aged
women, overall national mortality rates are still relatively low, although appreciable upward trends have
been registered over the last two decades. This is particularly worrisome in perspective, since smoking prevalence has continued to increase in subsequent
generations of young women in these countries. Thus
the observation that lung cancer is still relatively rare in
women, with smoking at present accounting for only
approximately 40–60% of all lung cancer deaths, cannot
constitute a reason for delaying efficacious interventions
against smoking by women. The currently more favorable situation in Europe compared with the USA,
together with the observation that smoking cessation
reduces lung cancer risk after a delay of several years,
should, in the presence of adequate intervention, enable
a major lung cancer epidemic in European women to
be avoided.
A proportion of lung cancers, varying in various
countries and geographic areas, may be due to exposures at work, and a small proportion to atmospheric
pollution.25 The effect of atmospheric pollution in
increasing lung cancer risk appears to be chiefly confined to smokers. Lung cancer risk is elevated in atomic
bomb survivors,26 in patients treated for ankylosing
spondylitis,27 and in underground miners whose bron-
chial mucosa was exposed to radon gas and its decay
products: this last exposure was reviewed and it was
concluded that there was ‘sufficient evidence’ that this
occupational exposure caused lung cancer.28 A greater
risk of lung cancer is generally seen for individuals who
are exposed at an older age. Investigation of the interaction with cigarette smoking among atomic bomb survivors suggests that it is additive,29 but the data from
underground miners in Colorado are consistent with a
multiplicative effect.30
In conclusion, the overwhelming role of tobacco
smoking in the causation of lung cancer has been
repeatedly demonstrated over the past 50 years. Current lung cancer rates reflect cigarette smoking habits of
men and women over past decades,31–33 but not necessarily current smoking patterns, since there is an interval of several decades between the change in smoking
habits in a population and its consequences on lung
cancer rates. Over 90% of lung cancer may be avoidable
simply through avoidance of cigarette smoking. Rates
of lung cancer in central and eastern Europe at present
are higher than those ever before recorded elsewhere;
lung cancer has increased tenfold in men and eightfold
in women in Japan since 1950; there is a worldwide
epidemic of smoking among young women,34 which
will be translated into increasing rates of tobacco-related disease, including cancer, in the coming decades;
there is another epidemic of lung cancer and tobaccorelated deaths building up in China as the cohorts of
men in whom tobacco smoking became popular reach
ages at which cancer is an important hazard.35 Many
solutions have been attempted to reduce cigarette
smoking, and increasingly many countries are enacting
legislation to curb this habit.36
PHASE IV: PUBLIC HEALTH FAILURE, 1960s
ONWARDS
Thus it has been clear for the entire second half of the
20th century that cigarette smoking causes lung cancer.
Current low levels of smoking among physicians and
research scientists in many countries have led many of
them unconsciously to overlook tobacco smoking as an
important cause of cancer.37 There is, however, a very
substantial body of evidence from many sources that
indicates the carcinogenicity of tobacco smoking. Not
only does cigarette smoking greatly increase the risk of
lung cancer in smokers, but the risk of oral cavity cancer, laryngeal cancer, esophageal cancer, bladder cancer, pancreatic cancer, and kidney cancer is also
Epidemiology of lung cancer: a century of great success and ignominious failure 17
increased. The risk of cancer of the cervix and stomach
may also be increased, although the evidence for this is
much less consistent.38 These forms of cancer can be
expected to rise in women as a result of their increased
levels of cigarette smoking.
There is at present a worldwide epidemic of tobaccorelated disease: not only does smoking cause increased
levels of many different common forms of cancer, it
also increases the risk of cardiovascular disease. As
mentioned in the previous section, deaths from lung
cancer, the tumor most strongly linked to cigarette
smoking, have increased in Japan by a factor of 10 in
men and 8 in women since 1950. In central and eastern
Europe, more than 400 000 premature deaths are currently caused each year by tobacco smoking. In young
men in all countries of central and eastern Europe, there
are current levels of lung cancer that are greater than
anything seen before in the Western countries, and
these rates are still rising. In Poland – a country severely
hit by the tobacco epidemic – the life-expectancy of a
45-year-old man has been falling for over a decade now
owing to the increasing premature death rates from
tobacco-related cancers and cardiovascular disease.39
Tragically, cigarette smoking is still increasing in central
and eastern Europe and also in China, where an epidemic of tobacco-related deaths is building up quickly.
Tobacco smoking is also the most easily avoided risk
factor for cancer.
The most important determinant of risk of lung cancer is the duration of smoking: long-term cigarette
smokers have a 100-fold increased risk compared with
never-smokers. The content of cigarettes (low tar) produces only a threefold variation in risks between the
extremes. (‘Low tar’ is frequently taken to include a
number of features, including filter-tips as well as the
active tar yield.) Lung cancer is the major tobacco-related tumor and the leading cause of cancer death in
men in almost every developed country. Incidence rates
are around 10–15 per 100 000 in non-smokers and
between 80 and 100 per 100 000 in the highest-incidence population groups such as Afro-Americans, and
rates exceeding 200 per 100 000 have been reported in
cities of central and eastern Europe. Since lung cancer
is frequently fatal, mortality rates are high, and consequently so are the social costs.
Women around the world have taken up the cigarette smoking habit with gusto. For many years, it
appeared that their lung cancer rates were low and that
tobacco was not having the same effect as on men. This
complacency, which crept in during the two decades
from the mid-1960s especially, is now exposed as false:
nor is there evidence that the effect of cigarette smoking
on lung cancer risk is greater in women than in men.
The dominance of the effect of duration of smoking
means that a long period of time will pass between the
exposure (large numbers of women smoking) and the
effect (high levels of lung cancer). Lung cancer now
exceeds breast cancer as the leading cancer cause of
death in women in the USA, Canada, Scotland, and several other countries. In Canada, breast cancer mortality
has remained at least constant for nearly four decades,
while lung cancer death rates have increased between
three- and fourfold during the same period. While the
higher case-fatality of lung cancer may be one factor in
the mortality rates overtaking breast cancer, there is,
increasingly, evidence that there are regions of the
world where the gap in the incidence rate is now closing. For example, in Glasgow, an area where lung cancer has been historically high, by 1990 the incidence
rate for lung cancer (115 per 100 000) exceeded that
for breast cancer (105 per 100 000) in 1990.40 Among
international cancer registries, there are some where the
incidence of lung cancer now exceeds the incidence of
breast cancer, and others where there is still a gap. In
the SEER (Surveillance Epidemiology and End Results)
Program of the US National Cancer Institute, the incidence of lung cancer in both Black and White women
increased by over 90% between 1973–1977 and 1988–
1992: the increase in the incidence of breast cancer was
around 25% in both racial groups (comparison made
between incidence rates age-adjusted using the 1970
US population). It is a great worry that there does not
appear to be any end in sight to this increase in lung
cancer risk internationally: it is programmed to continue for several decades to come.
Part of the complacency over the effect on women
was also due to the strong tendency for women to
smoke brands of cigarettes that were lower in tar and
nicotine content than those smoked by men: it was
assumed that these would have less of a risk for lung
cancer than the higher-tar cigarettes that men generally
smoked. Marked changes in the rates of the major histologic cell types of lung cancer can now
be seen, with particular increases in the risk of
adenocarcinoma.41,42 The changes seen are compatible
with increased risk of adenocarcinoma due to increasing
levels of smoking of ‘light’ cigarettes (low-tar, low-nicotine). It appears that abandoning high-tar cigarettes
(15–45 mg tar) may have some impact on reducing
squamous-cell carcinoma risk, but this is now being
balanced by ‘light’ cigarettes increasing the risk of adenocarcinoma.
18 Textbook of Lung Cancer
Cigarette smoking kills half of all those who
adopt the habit, with 50% of these deaths occurring in
middle age and each losing an average of 20 years of
non-smoker’s life expectancy.43 It kills in over 24 different ways, with the lung being the commonest cancer
site.43 Lung cancer rates have been declining in men
and increasing in women: cigarette smoking in men has
been declining while it has been increasing in women.
These two trends are closely related. The move to ‘light’
cigarettes, which is increasingly common, now appears
to be linked to increases in adenocarcinoma of the lung,
and shows no sign of being linked to a reduced risk
overall. There is no such thing as a ‘safe cigarette’.
Smokers should be urged and helped to stop smoking;
children and young adults should be convinced not to
smoke. Tobacco can become an addictive drug: it
should be left alone.20
ACKNOWLEDGMENTS
It is a pleasure to acknowledge that this work was conducted within the framework of support from the Associazione Intaliana per la Ricerca sul Cancro (Italian
Association for Research on Cancer).
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11. Doll R, Hill AB. Smoking and carcinoma of the lung. BMJ 1950;
ii: 739–48.
12. Doll R, Hill AB. A study of the aetiology of carcinoma of the
lung. BMJ 1952; ii: 1271–86.
13. US Public Health Services, Smoking and Health. Report of the
Advisory Committee to the Surgeon General of the Public
Health Service. US Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, DHEW
Publication 1103: Washington, DC, 1964.
14. United States Surgeon General, Smoking and Health. A Report
of the Surgeon General. US Department of Health, Education
and Welfare, Public Health Service, DHEW Publication (PHS)
79-50066: Washington, DC, 1979.
15. Hammond EC. Smoking in relation to death rates of one million
men and women. Natl Cancer Inst Monogr 1966; 19: 127–204.
16. Cederlof R, Friberg L, Hrubec Z, Lorich U. The Relationship of
Smoking and Some Social Covariates to Mortality and Cancer
Morbidity. A Ten Year Follow-up in a Probability Sample of
55,000 Swedish Subjects Age 18–69, Parts 1 and 2. Stockholm:
Karolinska Institute, 1975.
17. Bross IDJ, Gibson R. Risks of lung cancer in smokers
who switch to filter cigarettes. Am J Publ Health 1968; 58:
1396–403.
18. Hammond EC, Garfinkel L, Seidman H, Lew EA. Some recent
findings concerning cigarette smoking. In: Hiatt HH, Watson
JD, Winsten JA, eds. Origins of Human Cancer. Book A: Incidence of Cancer in Humans. New York: Cold Spring Harbor
Laboratory, 1977; 101–12.
19. Bouisson J. Du cancer buccal chez les fumeurs. Montpellier
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Eur J Cancer 1995; 9: 1395–405.
21. IARC (International Agency for Research on Cancer), Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol
38. Tobacco Smoking. Lyon: IARC, 1986.
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and mortality in Europe. Sozial-Präventivmedizin 1989; 34
(Suppl 2): 1–84.
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Peto R, eds. Tobacco: A Major International Health Hazard.
Lyon: IARC, 1986; 285–98.
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effectiveness of tobacco-control legislative policies in European
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25. Tomatis L. Air Pollution and Human Cancer. European School
of Oncology Monograph. Berlin: Springer-Verlag, 1990.
26. Shimizu Y, Kato H, Schull WJ et al. Life Span Study Report 11,
Part 1: Comparison of Risk Coefficients for Site Specific Cancer
Mortality Based on the DS86 and T65DR Shielded Kerma and
Organ Doses. Radiation Effects Research Foundation Technical
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44. Alcohol Drinking. Lyon: IARC, 1988.
Epidemiology of lung cancer: a century of great success and ignominious failure 19
29. Kopecky KJ, Yamamoto T, Fujikura T et al. Lung Cancer, Radiation Exposure and Smoking Among A-Bomb Survivors, Hiroshima and Nagasaki, 1950–1980. Radiation Effects Research
Foundation Technical Report 13–86. Hiroshima: Radiation
Effects Research Foundation, 1987.
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uranium miners: a reappraisal. J Natl Cancer Inst 1983; 71:
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Epidemiol 1987; 125: 731–44.
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period–cohort effect on the incidence of histologic types of
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309: 901–11.
3
Molecular biology of lung cancer
Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot
Contents Introduction • Growth signals and lung cancer • Apoptosis in lung cancer • Aberrant
anti-growth signaling • Replicative potential and telomerases • Angiogenesis • Tissue invasion
and metastasis • Conclusion
INTRODUCTION
It becomes more and more important to understand the
biology of lung cancer as new therapeutic agents are
emerging in the field of clinical oncology. These agents
are often referred to as targeted therapy or biologic
therapy. New advances in molecular technologies are
providing insight into the pathobiology of lung cancer
development. It is now known that clinical lung cancers have accumulated numerous clonal genetic and
epigenetic alterations as a multistep process.1 In many
research laboratories molecular studies are these days
performed in an integrated approach with clinical
investigators to find new ways for early diagnosis, risk
assessment, prevention, and treatment for this frequent
and deadly disease. In the following, the spectrum of
molecular alterations in lung cancer are described as
hallmarks of cancer, subdivided as suggested by Hanahan and Weinberg:2
•
•
•
•
•
•
abnormalities in self-sufficiency
signals;
evading apoptosis;
insensitivity to anti-growth signals;
limitless replicative potential;
sustained angiogenesis;
tissue invasion and metastasis.
of
growth
GROWTH SIGNALS AND LUNG CANCER
In tumor cells, activated (proto)oncogenes often encode
molecules involved in aberrant growth factor signaling,
either by directly promoting cell growth, by mimicking
other growth factors, or by neutralizing growth inhibitory signals. Growth factors are proteins that bind to
receptors (usually on the cell surface) and trigger
activation of cellular proliferation and/or differentiation.
Normal cells depend on external growth stimulating
signals to proceed from quiescence to proliferation
and these growth stimuli are often provided by neighboring cells in the immediate microenvironment,
for instance by release of diffusible growth factors
or expression of cell adhesion molecules. These interrelations between the cell and its environment allow
for establishment of normal tissue homeostasis with
a tight regulation of tissue modeling, growth, and
regeneration.
Tumor cells have lost their dependency on growth
stimulatory signals from the external environment and
are fully capable of proliferating independently. This
phenotype of growth autonomy is attained by a variety
of molecular changes and gene mutations within the
cell, typically characterized by a state of growth factor
self-sufficiency, where the cell itself produces the
required growth factors and receptors, resulting in a
self-stimulatory autocrine signaling loop. Aberrant
expression and signaling by a number of growth factors
and cognate receptors have been identified, which
increase the cellular proliferative potential in lung cancer. In non-small cell lung cancer (NSCLC) these
include upregulation/mutation of certain receptor
tyrosine kinases (RTKs), in particular the epidermal
growth factor receptor (EGFR, ErbB1) and other members of the ErbB RTK family. In small cell lung cancer
(SCLC) overexpression of insulin-like growth factor I
(IGF-I) and its receptor as well as a number of neuronal
growth stimulators is frequently observed.
An overview of the changes in expression and signaling of central growth factors and receptors, signal transducers, and transcription factors in lung cancer is
presented below and summarized in Table 3.1. The
section will conclude with a presentation of related
experimental therapeutic strategies developed to target
these mediators for future treatment of lung cancer.
Molecular biology of lung cancer 21
Table 3.1 Growth signals and lung cancer
Signaling mediators involved in activating growth signaling in lung cancer
Aberrant activation/mutation frequency
Oncogene
NSCLC (%)
SCLC (%)
References
EGFR
HER2-Neu
IGF-I
C-Kit/C-Met
K-ras
Neuropeptides
C-myc
50–90
∼30
—
—
∼20–30
16–47
up to 50
—
—
>95
Up to 70
—
All
10–40
3, 4
33
9
12, 13
15
17
23, 24
Epidermal growth factor receptor overexpression
and signaling in NSCLC
Overexpression of EGFR occurs in 50–90% of all
NSCLC and is particularly common in squamous cell
carcinoma,3,4 whereas EGFR overexpression is rare in
SCLC. The receptor is membrane associated and contains three main regions: an extracellular ligand binding
domain, a hydrophobic membrane spanning region,
and a cytoplasmic part holding the catalytic tyrosine
kinase activity. Upon ligand binding, EGFR undergoes
a conformational change, leading to dimerization of the
receptor and activation of the intracellular catalytic
domain by phosphorylation of tyrosine residues. The
phosphorylated tyrosine residues serve as binding sites
for a number of different downstream signaling molecules and adaptors within the cell. Three major signaling pathways downstream of EGFR are outlined
in Figure 3.1. One of the most intensively studied
cascades is the Ras/Raf/ERK pathway (the right-hand
pathway in Figure 3.1). The effects of this pathway are
diverse (for a review see reference 5), with a large number of Ras effectors, but in general Ras signaling upon
EGF stimulation has been associated with increased cell
growth and proliferation. One of the three ras genes,
Kirsten-ras (K-ras, p21-ras), is mutated in ∼30% of
NSCLC. The oncogenic impact of this mutation in lung
cancer is discussed further below.
Another central pathway in EGFR signaling involves
activation of PI3-kinase and AKT (PKB). This pathway
generally serves to promote cell survival, by inhibition
of various cell cycle regulators such as glycogen synthase kinase 3 (GSK3) and the pro-apoptotic protein
BAD (Figure 3.1, the middle pathway).
A final key pathway activated by EGFR involves
the activation of phospholipase C-γ (PLC-γ), resulting
in hydrolyzation of phosphoinositide 4,5-bisphosphate
(PIP-2) to generate inositol-3-phosphate (IP3) and
diacylglycerol (DAG) (Figure 3.1, the left-hand pathway). This results in the release of calcium ions from intracellular stores, which affects cell motility and migration
by interfering with the activity of actin-modulatory
proteins. The activation of PLC-γ also activates
protein kinase C (PKC), which causes attenuation of
EGFR signaling by a negative feedback mechanism.
The different pathways by which activated EGFR
exerts its proliferative, migratory, and anti-apoptotic
effects, and the fact that many of the involved signaling
modulators have been found to cross-react between
pathways, provide a central, yet complex, role for EGFR
in cell transformation. In NSCLC, increased EGFR signaling is obtained by an increased gene copy number
and by activating mutations within the EGFR gene.6
One mutated EGFR variant termed EGFRvIII, commonly found in various malignancies including ∼16%
of NSCLC, has gained increasing interest in recent
years. EGFRvIII lacks the extracellular ligand-binding
domain, rendering the receptor incapable of binding
any ligands, yet the receptor is constitutively active
and fully capable of activating downstream modulators.7 In recent years, novel activating mutations within
the tyrosine kinase domain of EGFR have been identified in NSCLC. These mutations have gained massive
interest, since they have been found to correlate with
increased response to treatment with EGFR tyrosine
kinase inhibitors.8
Another member of the ErbB family is HER2-Neu
(ErbB2), which is overexpressed in ∼30% of NSCLC.
No ligands for Her2-Neu have yet been identified but
the receptor is a central dimerization partner for the
other RTKs of the ErbB family. To date, results are
22 Textbook of Lung Cancer
EGFR dimer
EGF
EGF
Membrane
DAG
PKC
PIP2
Raf
IP3
Ras
PLC-γ
TK
TK
PI3K
SOS
SHC
Ca2+
MEK
GRB2
AKT
Ca2+
Ca2+
Ca2+
Cytosol
GSK3
BAD
ERK
Nucleus
Altered gene expression
- Increased cell growth and proliferation
- Downregulation of apoptotic response
- Increased cell motility/migration
Figure 3.1
EGFR signaling. Upon ligand binding EGFR dimerizes, resulting in a complex signaling response within the cell. Oncogenic EGFR signaling
occurs through three major pathways: the Ras/ERK (right-hand), the PI3-kinase AKT (middle), and the phospholipase C-γ (left-hand)
pathways, resulting in an increased malignant potential of the cells. For further explanation see text.
conflicting with regard to Her2-Neu overexpression
and prognosis in NSCLC.
Overexpression of other growth factor receptors
and ligands
The expression level of the mitogen IGF-I is elevated in
the majority of SCLC, resulting in a self-stimulatory
autocrine loop involving the IGF-I receptor which is
commonly co-expressed in this malignancy.9 IGF signaling proceeds through binding of IGF ligands (IGF-I
and II) to cell surface RTKs (IGF-IR and -IIR). The biologic activity of the signaling system is modulated by
binding of IGF binding proteins present in the extracellular fluids and serum to the IGF ligands. As for EGFR,
activated IGF-IR signaling is complex but primarily
occurs through the Ras/Raf/ERK and the PI3-kinase/
AKT pathways. A correlation between significantly
elevated IGF-I serum levels and lung cancer risk has
been reported, but results of other studies are
conflicting.10,11
The RTK c-Kit and its ligand stem cell factor (SCF) is
another receptor/ligand system, upregulated in more
than 80% of SCLC tumors.12 A study of c-Kit expression in SCLC patients identified c-Kit as a marker for
Molecular biology of lung cancer 23
increased survival13 – an observation which appears
contradictory to the oncogenic properties of c-Kit signaling. However, the patients enrolled in this study were
receiving chemotherapy targeting actively dividing
cells, and since activation of c-Kit induces cell proliferation, the active receptor may render the malignant
cells more susceptible to cytotoxic treatment, thereby
improving overall survival.
c-Met is yet another RTK often overexpressed in
SCLC. Signaling through this receptor system has
been reported to be associated with tumor growth and
metastasis. In contrast to the c-Kit/SCF system, the
c-Met ligand hepatocyte growth factor (HGF) is rarely
co-expressed with the receptor in SCLC,12 but is
expressed and secreted from surrounding normal lung
fibroblasts. This observation indicates a paracrine rather
than autocrine activating loop of c-Met expression in
lung cancer. The importance of paracrine c-Met signaling for lung cancer pathogenesis has been investigated
further in a study where c-Met-expressing lung cancer
cells were transplanted into HGF-overexpressing
mice, resulting in increased metastatic potential of the
transplanted cells.14
Activating Ras mutations
As mentioned, mutations of the intracellular membraneassociated signaling mediator Ras (Figure 3.1, green
pathway) with a high overrepresentation of mutations
in the K-ras gene are detected in up to 30% of NSCLC,15
but rarely in SCLC patients. Ras protein becomes
activated by the binding of guanine triphosphate (GTP),
allowing for transmission of growth stimulatory signals
to the cell nucleus. Downregulation of Ras signaling
occurs by hydrolysis of GTP to GDP, mediated by the
GTPase-activating protein (GAP). In NSCLC and other
malignancies, activating point mutations in the K-ras
gene result in resistance to GAP activity, thereby trapping the Ras protein in a constitutively active state,
capable of continuous growth promoting signaling.
Controversy exists as to whether K-Ras mutations serve
as a marker for poor prognosis in lung cancer, but a
global meta-analysis correlated the presence of pointmutated constitutively active Ras in NSCLC with a poor
prognosis.16
G-protein-coupled receptors, resulting in activation of
various downstream signaling pathways including PLC,
PI3-kinase, and certain kinases, involved in cellular
focal adhesion. Gastrin releasing peptide (GRP) signaling via the GRP receptor (GRP-R) has become one of
the most intensively studied neuropeptide signaling
pathways in SCLC, since different studies have shown
that blocking GRP or GRPR activity inhibits SCLC cell
growth in vitro and in vivo, whereas GRP addition
to SCLC cells induces cell proliferation.18,19 The concentration of the GRP precursor pro-GRP is highly elevated in the majority of SCLC patients and levels
decrease upon tumor resection, indicating that proGRP serum levels may serve as a detection and monitoring marker for patients with this disease. Other
neuropeptides highly expressed in lung cancer include
bradykinin, neuron specific enolase and L-Dopa decarboxylase. Whether these molecules play an oncogenic,
growth-promoting role in lung cancer and/or whether
they may potentially serve as clinical markers remains
controversial.
In recent years, the expression of the neuroendocrine
transcription factor Achaete–Scute homolog 1 (ASH1)
in SCLC has gained increased attention. ASH1 is normally expressed in neuronal progenitor cells during
early fetal development of various tissues including the
central nervous system and the lung. Expression is virtually absent in the normal adult organism, but ASH1
is reactivated and highly expressed in SCLC and in
other lung tumors with a neuroendocrine phenotype,
including a minority of large cell and adenocarcinomas.
High expression of ASH1 seems to correlate with poor
differentiation of these lung tumors, since expression is
virtually absent in fully differentiated carcinoid tumors.20
Furthermore, ASH1 expression is tightly linked to classic neuroendocrine markers including L-Dopa decarboxylase. Although future research is clearly necessary
to clarify the role of ASH1 in lung cancer pathogenesis,
many studies suggest ASH1 expression as a critical
pathogenic factor in neuroendocrine lung tumors. The
overexpression of ASH1 induces lung tumors and cell
hyperplasia in mouse models,21 and one study reported
significant inhibition of SCLC cell growth after ASH1
knock out in vitro and in vivo.22
Overexpression of neuropeptides
Highly elevated expression of different neuropeptides
is a hallmark of SCLC and many of these markers
have also been detected in some (mainly poorly differentiated) NSCLC tumors.17 Neuropeptides exert their
effect via binding to seven transmembrane (7TM)
Amplification of myc
Members of the c-myc, N-myc, and L-myc (proto)oncogene family are commonly amplified in SCLC and
NSCLC, resulting in overexpression of Myc transcription factors.23,24 Myc protein competes with other transcription factors to bind Max, resulting in activation
24 Textbook of Lung Cancer
and repression of a number of genes. Although the contributions of myc amplification to lung cancer pathogenesis remain to be elucidated, recent studies point to
a role for myc in promoting cell cycle progression by
activation of key cell cycle molecules responsible for
entry into the S-phase of the cell cycle (for a review of
myc signaling in lung cancer see reference 25). In combination with loss of tumor suppressor genes such as
Rb (the properties of which will be discussed in a later
section), myc has been shown to significantly contribute to decreased cell cycle arrest and deregulated tumor
growth.26
Experimental therapeutic targeting of growth
factors and oncogenes in lung cancer
In the previous sections, a number of different growth
factors and oncogenes of importance for lung cancer
biology have been presented. Knowledge gained about
the properties of these molecules has allowed for
the development of novel therapeutics targeting
key activating, growth promoting, and tumorigenic
pathways.
A research area of major focus in recent years has
been therapeutic targeting of EGFR in NSCLC. There
are two general strategies for inhibiting signaling via
EGFR. One is to prevent binding of ligand by blocking
the ligand binding site (commonly with a monoclonal
antibody) and the other is to directly inhibit receptor
signaling by blocking activity of the cytoplasmic tyrosine
kinase domain. Belonging to the first group, cetuximab
is a humanized monoclonal EGFR antibody, which is
presently under development and testing for treatment
of NSCLC. The results of a recently published phase
I/II clinical trial have shown an effect of cetuximab
in combination with chemotherapy of NSCLC,27 and
further clinical studies are ongoing at present.
The two most clinically advanced RTK inhibitors
are erlotinib and gefitinib, and erlotinib recently
obtained FDA approval for second-line treatment
of NSCLC. As previously mentioned, a number of
mutations in the RTK domain of EGFR have been
identified in NSCLC.8 Importantly, the presence of
RTK mutations seems to correlate positively with the
response to treatment with gefitinib, suggesting that
these mutations may serve as classifiers for selecting the
patients who will benefit from EGFR-RTK inhibiting
treatments.
As previously mentioned, the gene encoding the
growth promoting Ras protein is mutated in up to 30%
of NSCLC, making this protein a potential target for
therapeutic intervention. Cytoplasmic Ras protein is
inactive and must be associated with the plasma membrane to contribute to cell signaling. For this association
to occur, synthesized Ras protein is post-translationally
modified by addition of a farnesyl group. Farnesylation
is mediated by a specific enzyme – the farnesyl
transferase – and targeting this reaction with farnesyl
transferase inhibitors has been investigated clinically
for treatment of lung cancer and other malignancies.
Despite promising preclinical data and reported
responses in patients with breast cancer and certain
leukemias, the results of the use of farnesyl transferases
for treating lung cancer have been disappointing, with
lack of tumor regression in all of the clinical studies
reported to date.28
The monoclonal antibody imatinib targets a number
of RTKs including c-Kit and has been evaluated in two
recent phase II studies for treatment of SCLC. Disappointingly, both studies report no inhibitory effect on
tumor growth, even in patients with c-Kit-positive
tumors.29,30 Apart from the clinical studies reported to
date, a number of preclinical investigations have shown
promise for anti-growth-signaling targeted therapy
of lung cancer. Therapeutic blockade of IGF-I signaling
by an IGF-IR-specific tyrosine kinase inhibitor has
been reported to enhance the sensitivity of SCLC cells
to chemotherapy in vitro, correlating with inhibition of
the anti-apoptotic PKB signaling pathway.31 Finally,
therapeutics have been developed which target neuronal markers overexpressed in lung cancer, primarily
SCLC. However, a phase I clinical trial using an antibody targeting GRP in patients with SCLC reported no
significant therapeutic response.32 In contrast, recent
pre-clinical data showed growth suppression of SCLC
cells after knockout of ASH1 in vitro and in vivo.22
APOPTOSIS IN LUNG CANCER
Apoptosis is a morphologically and biochemically
distinct form of cell death that occurs under various
physiologic and pathologic conditions triggered by
extrinsic and intrinsic cellular and molecular damage. It
is characterized by the activation of a specific event of
molecular processes followed by certain morphologic
changes such as shrinkage of the cell, condensation
of chromatin, and disintegration of the cell into small
fragments.
Today many of the key players in cellular apoptosis
regulation have been identified and activators and
inhibitors have been characterized and can therefore be
targeted by therapeutic agents. Apoptosis is activated
Molecular biology of lung cancer 25
by a family of intracellular cysteine proteases called caspases. They are synthesized as zymogens and activated
by proteolytic cleavage. They are divided into two distinct classes, initiator caspases, which include caspases
P8, P9, and P10, and effector caspases, which include
caspases P3, P6, and P7.
Current knowledge suggests that there are two separate pathways of caspase activation. One starts with
binding of an extracellular ligand to its cell surface
receptor. The ligands are TNF, FasL, and Trail, and
their respective receptors are TNFRI, FAS, and DR4 and
DR5. The ligand binding triggers initiator caspase activation through a death inducing signaling complex
(DISC), resulting in caspase-P8 activation of effector
caspases, either directly or through BCL-2 interacting
domain (BID)-mediated release of cytochrome c from
mitochondria (Figure 3.2). The other caspase activation
pathway starts with release of cytochrome c from the
intermembrane space of mitochondria. Two proapoptotic family members, BAX and BAK, appear to facilitate cytochrome c release by participating in the
Death
ligand
Death receptor
pathway
Mitochondrial
pathway
Membrane
Death receptor
PROCASP 8/10
FADD
Mitochondria
BID
BID
DISC
Cytochrome c
CASP 8 (CASP10)
PROCASP 9
EXECUTIONER PATHWAY
CASP3,6,7
APOPTOSIS
CASP 9
APAF1
Apoptosome
Figure 3.2
Apoptosis. Major pathways to apoptosis: two pathways lead to
apoptosis, an extrinsic pathway through death receptors and an
intrinsic pathway through the mitochondria. The two pathways
overlap and interact.
formation of a pore that releases mitochondrial intermembrane space proteins. After its release, cytochrome
c binds to apoptotic protease activating factor-1 (APAF-1).
APAF-1 binds to procaspase-9 forming a multiprotein
complex, called an apoptosome, which activates effector caspases through caspase-9 (Figure 3.2).
Anti-apoptotic factors such as Bcl-2-related proteins
antagonize BAX and BAK. In addition, IAP (inhibitor of
apoptosis protein) binds and inhibits apoptosomerelated caspases. However, this inhibition can be
relieved by the release of another mitochondrial protein, called Smac/Diablo, which binds to the IAP and
releases active caspases. The most widely studied IAP
is survivin. Activators and inhibitors are influenced
by several other proteins including p53, RB, PTEN,
Raf-ERK, PI3K-PKB, and Hsp70.33,34
The apoptotic pathways and possible defects have
not been studied much in human lung cancer, and
therefore only sporadic, non-conclusive data are available. However, recently it has been shown that DR4
and DR5 are upregulated in NSCLC, and overexpression of DR5 correlates with a poor prognosis in patients
with NSCLC. Bcl-2 expression is higher in SCLC compared with NSCLC. Furthermore, data have indicated
that the BAX:Bcl-2 ratio might be of importance for
resistance to apoptosis. Caspase-8 and caspase-10 might
be deregulated, and differences in deregulation in SCLC
compared with NSCLC especially concerning caspase-8
have been observed, resulting in deregulation of DISC.
Others have found that the apoptosome signaling might
be blocked. In addition, it has been indicated that
downregulation of caspase-3 is correlated with a poor
prognosis in patients with NSCLC.33,35
Survivin is increased in most NSCLC and it has been
shown that absence of its expression might be associated with improved prognosis. In addition, previously
unpublished microarray data show that survivin is
upregulated in SCLC in human cell lines, xenografts,
and resected tumors from patients (Figure 3.3)36
(Poulsen HS, unpublished data).
Targeting apoptotic pathways
Treatment with TNF has been undertaken. However,
due to pronounced general toxicity, its potential as a
therapeutic drug is limited. Recently TRAIL agonists
have been approved for clinical trials but no data are
presently available.
Small molecule inhibitors of Bcl-2 have been developed and are at the moment being tested in preclinical
trials. In addition, antisense constructs against survivin
have been produced and tested in phase I clinical trials.
26 Textbook of Lung Cancer
250
Microarray signal
200
150
100
50
Normal tissues
SCLC cell lines and xenografts
SCLC tumor 1
SCLC tumor 2
SCLC tumor 3
SCLC tumor 4
SCLC tumor 5
SCLC tumor 6
CPH 54A
CPH 54A Xeno
CPH 54B
CPH 136A Xeno
GLC 2
GLC 3
GLC 3 Xeno
GLC 14
GLC 14 Xeno
GLC 16
GLC 19
GLC 26
GLC 28
DMS 53
DMS 79
DMS 92
DMS 114
DMS 153
DMS 273
DMS 273 Xeno
DMS 406
DMS 456
H69
H69 Xeno
NCI 417
NCI 417 Xeno
MAR H24
MAR H24 Xeno
MAR 86H
Fetal brain
Brain
Adrenal gland
Colon
Heart
Kidney
Liver
Lung
Pancreas
Prostate
Salivary gland
Skeletal muscle
Small intestine
Spleen
Stomach
Testes
Thyroid
Trachea
0
Tumors
Figure 3.3
Survivin in SCLC. Survivin mRNA expression in SCLC cell lines, xenografts, and resected patient tumors compared with normal tissue.
In addition, an adenovirus-based gene therapy approach
targeting survivin is under development.37
ABERRANT ANTI-GROWTH SIGNALING
A review of key tumor suppressors, frequently
mutated in lung cancer is presented below and summarized in Table 3.2, followed by an update within the
field of tumor suppressor reactivation in experimental
lung cancer therapy.
Apart from upregulation of growth stimulatory signaling, cancer cells often lack expression of a number of
tumor suppressors. In contrast to oncogenes, tumor
suppressor genes act to prevent and control cell growth,
often via tight control of cell cycle progression. Full
inhibition of tumor suppressor activity often requires
inactivation of both alleles of a tumor suppressor gene
in the cancer cell. This dual inactivation is frequently
accomplished by a two-step process, involving a chromosomal translocation or deletion resulting in loss of
heterozygosity (LOH), followed by an inactivating point
mutation of the remaining allele. In lung cancer cells,
LOH of distinct chromosomal regions is frequently
detected and many of these regions harbor genes encoding central tumor suppressors, known or speculated to
be involved in cancer pathogenesis. Tumor suppressor
activity may also be inhibited by dominant negative
mutations, which actively inhibit the activity of wildtype protein binding partners within the cell. Finally,
epigenetic alterations (i.e. mutation-independent mechanisms) have in recent years gained increased attention
in the regulation of tumor suppressor knock-down.
Tp53 mutations
The transcription factor p53 is one of the most intensely
studied tumor suppressors. The Tp53 gene is located
within a region of chromosome 17 (17p13), which is
mutated or altered in the majority of lung cancers with
a specifically high prevalence in SCLC and squamous
cell carcinoma.38,39 The types of Tp53 alterations observed
in lung cancer range from gross chromosomal changes
such as LOH, homozygous deletions, and DNA rearrangements, to local point mutations,40 all of which
contribute to Tp53 malfunction or inactivation.
The p53 protein is a key player in the cellular
response to stress, acting as a gatekeeper of the cell
cycle. Activation of p53 signaling in normal cells generally occurs in response to different types of cellular
stress including DNA damage, aberrant oncogenic
growth factor signaling, and exposure to extracellular
factors such as chemotherapeutics and UV light. The
level of p53 protein and activity within the cell is regulated at the level of degradation rather than the level of
synthesis and, under normal conditions, the protein is
rapidly degraded within the cell. The cellular enzyme
Molecular biology of lung cancer 27
Table 3.2 Aberrant anti-growth signaling
Tumor suppressor gene mutations/inactivations and LOH in lung cancer
Mutation/inactivation frequency
Tumor suppressor gene
Chromosome location
NSCLC (%)
SCLC (%)
References
Tp53
RB
p16INK4a
TGFbRII
LOH 3p
17p13
13q14
9p21
3p22
3p regions
∼50
∼30
∼70
∼44
70–100
∼80
∼90
∼10
<75
>90
43
44, 61
45, 61
48, 62
51, 52
MDM2 plays an important role in the downregulation
of p53. MDM2 serves as a p53 binding partner, which
facilitates the attachment of ubiquitin tags to p53,
thereby targeting it for degradation. Furthermore,
MDM2-bound p53 activates transcription of the MDM2
gene, resulting in increased MDM2 levels, p53 ubiquitinylation, and degradation. Upon lowering of the p53
concentration, fewer MDM2–p53 complexes are
formed, resulting in reduced MDM2 transcription and
decreased p53 degradation. As such, the MDM2–p53
interaction generates an oscillating feedback loop of
p53 and MDM2 degradation and synthesis within the
cell (Figure 3.4).
Activation of p53 requires post-translational modifications (such as acetylation, glycosylation, and addition
of phosphate groups), some of which may inhibit p53
degradation by inhibiting its binding to MDM2. This is
the case upon DNA damage, where activation of different proteins such as ATM-kinase and DNA-dependent
kinase facilitates the phosphorylation of p53 at sites
involved in the interaction with MDM2, resulting in
p53 activation (Figure 3.4).
Active p53 regulates transcription of a number of
genes involved in cell cycle control (such as cyclindependent kinase inhibitors), resulting in cell cycle
arrest, thus allowing for repair of damaged DNA by the
cellular repair machinery. Activation of p53 also induces
apoptosis via activation of a number of apoptotic mediators (including Bax) and inhibits blood vessel formation by activation of genes encoding anti-angiogenic
factors.
A frequent observation in lung cancer cells with
mutated p53 is accumulation of p53 within the
cell, due to increased stability of the mutated protein.41
A number of studies have investigated the prognostic
role of p53 mutations in lung cancer patients, and
although the results are somewhat conflicting, accumulating evidence suggests that p53 mutations result in a
poorer prognosis in NSCLC. Given the high abundance
of p53 mutations in SCLC patients, the limited number
of patients with intact p53 signaling limits prognostic
studies in this malignancy. For a detailed review of p53
mutations in lung cancer, and the clinical impact of
these aberrations, see reference 42.
Mutated RB and p16INK4a
A central tumor-suppressing signaling cascade, frequently altered in human lung cancer, is the p16INK4a/
CDK-cyclin-D/Rb pathway. The retinoblastoma (RB)
tumor suppressor gene located at 13q14 encodes a
transcription factor involved in the regulation of G1
to S-phase transition in the cell cycle. The tumorsuppressing activity of Rb depends on its level of phosphorylation. In its hypophosphorylated state, Rb binds
to and inhibits the activity of different binding partners,
including members of the E2F family of transcription
factors. Upon phosphorylation of Rb, E2F is released
and activated, resulting in transcription of genes responsible for G1 to S-phase cell cycle progression (Figure 3.5). Consequently, Rb in its hypophosphorylated
state serves as a tumor suppressor. Phosphorylation of
Rb is mediated by different complexes of cell cycle proteins such as cyclin D and CDK4 and 6. The formation
of these complexes is inhibited by p16INK4a, which
thereby serves as a tumor suppressor upstream of Rb by
indirectly inhibiting its phosphorylation and thereby
promoting Rb association with its binding partners
(Figure 3.5).
Inactivation of the RB gene by LOH and/or mutation
is observed in 90% of SCLC tumors,43 whereas the
p16INK4a gene is frequently inactivated in NSCLC,44
resulting in lack of activity of the Rb tumor suppressor
pathway in virtually all lung cancers. These findings
indicate that inactivation of this pathway is a mandatory step in the pathogenesis of pleural malignancies.
The p16INK4a gene locus is located at chromosome 9p21,
28 Textbook of Lung Cancer
DNA damage
p14ARF
Decreased
p53 activity
MDM2 p53
ATM-kinase/DNA
dependent kinase
INCREASED
MDM2-SYNTHESIS
MDM2
p14ARF MDM2
ACTIVE
p53
Altered gene expression
- Cell cycle arrest
- Apoptosis
- Anti-angiogenesis`
Figure 3.4
p53 signaling. In normal cells p53 plays a key role in regulation of
the cellular response to a number of stress factors, but the p53
protein is frequently mutated in lung cancer and other malignancies. Under normal conditions p53 activity is inhibited by the
binding of MDM2 to the protein. Upon cellular exposure to
stress, cellular proteins such as p14ARF and specific kinases (i.e.
ATM-kinase and DNA-dependent kinase) release p53 from MDM2
inhibition, resulting in activation of p53. This again may result in
cell cycle arrest, apoptosis, and anti-angiogenic signaling.
which is a region frequently subjected to LOH in NSCLC.45
Apart from p16INK4a, the same locus also encodes the
tumor suppressor p14ARF through an alternative reading
frame. The p14ARF protein is known to bind to MDM2,
thereby inhibiting ubiquitinylation and degradation of
p53 (Figure 3.4). Furthermore, E2Fs are known to activate p14ARF transcription, providing a functional link
between the Rb and p53 tumor suppressor pathways.
Aberrant TGFβ signaling
The transforming growth factor β (TGFβ) receptor
system is also commonly altered in lung cancer. In
contrast to the growth factor receptor systems described
in previous sections, the effects of signaling by TGFβ
are mostly associated with inhibited cellular proliferation in many cell types. TGFβ signaling is mediated via
serine-threonine-kinase receptors that can be divided
into two subgroups termed TGFβRI and II. Lack of
response to TGFβ (termed TGFβ resistance) in SCLC
has been correlated with lack of TGFβRII,46,47 and this
association was recently confirmed by the introduction
of functional TGFβRII into receptor-negative lung cancer cells, resulting in restored sensitivity to TGFβ.48
TGFβ signaling is associated with a number of cellular
functions, the best described of which relate to inhibition of the cell cycle. Growth inhibitory effects of TGFβ
signaling have been associated with inhibition of expression and assembly of some of the cyclin/CDK components responsible for Rb activation.49
Loss of chromosome 3p and related genes
Probably the most frequent chromosomal abnormality
in lung cancer is loss of regions within chromosome
3p. LOH at chromosome 3p has been reported in
70–100% of all NSCLC and more than 90% of SCLC.50,51
A number of genes within this region have been suggested as putative tumor suppressors.
The loss of the fragile histidine triad (FHIT) gene
located at position 3p14.2 is frequent in lung cancer,
with more extensive genetic lesions occurring in highergrade tumors compared with low-grade and premalignant
lesions.52 Accumulating evidence points to a role of
FHIT as a tumor suppressor. Expression of FHIT protein in NSCLC cell lines and mouse xenograft models
has been shown to suppress tumor growth and induce
apoptosis,53 and recently FHIT has been found to stabilize p53 presumably by interaction with MDM2, which
thereby becomes incapable of binding and ubiquitinylating p53.54 This points to a functional role of FHIT in
apoptotic signaling, although the exact function of
FHIT remains to be fully elucidated.
RASSF1A is a different candidate tumor suppressor
gene residing at chromosome 3p (position 3p21). This
gene is inactivated in virtually all SCLC and more than
60% of NSCLC.55,56 Apart from allelic loss, the RASSF1A
gene has been found to be inactivated by epigenetic
mechanisms and hypermethylation of distinct regions
(so called CpG islands) within the promoter of the
RASSF1A gene, which inhibits gene transcription.
Reintroduction of RASSF1A has been found to reduce
colony formation, suppress anchorage-independent
growth, and inhibit tumorigenicity of NSCLC cells in
vitro and in nude mice.55 Furthermore, RASSF1A has
been shown to associate with microtubules, and recently
overexpression of RASSF1A has been reported to inhibit
motility of NSCLC cells and increase cell adhesion, suggesting a role for RASSF1A in cell migration and metastasis.57 Several other genes reside at the frequently
deleted regions of chromosome 3p but much remains
to be learned about the role of these genes in tumor
suppression. For a review of candidate tumor suppressor
Molecular biology of lung cancer 29
CDK4/6
CYCLIN D
p16INK4a
Rb
E2F
Rb
CDK4/6 CYCLIN D
P
ACTIVE
E2F
Altered gene expression
- Cell cycle progression
- Cell proliferation
- Anti-apoptosis
Figure 3.5
Rb signaling. The Rb–p16INK4a–tumor suppressor pathway, which is
frequently mutated in lung cancer, acts by inhibiting the
activation of the E2F family of transcription factors responsible for
growth promoting and anti-apoptotic signaling within the cell.
p16INK4a, which is frequently mutated in NSCLC, acts by inhibition
of the cyclin-CDK4/6 complex responsible for release of E2F from
Rb inhibition. In SCLC, Rb itself is frequently mutated, rendering
the protein incapable of inhibiting E2F signaling. The high
frequency of Rb and p16INK4a mutations in SCLC and NSCLC,
respectively, suggests that inhibition of this pathway is
0mandatory in the development of pleural malignancies.
genes residing at chromosome 3p which may play a
role in lung cancer pathogenesis see reference 58.
Experimental treatments: reintroduction of tumor
suppressors
Since the loss of activity of certain tumor suppressor
pathways is a distinctive characteristic of human lung
cancer, reintroduction of tumor suppressor activity is
an attractive strategy for therapeutic intervention. For
this purpose, replacement gene therapy by
delivery of lost tumor suppressor genes to cancer cells
has become increasingly attractive. Most reports of
tumor suppressor replacement gene therapy of lung
cancer involve reintroduction of TP53 in NSCLC, where
a number of clinical trials have been published. In general, the treatment has been found to be well tolerated
and responses have been observed in terms of tumor
regression and disease stabilization in some of the
enrolled patients. However, the limiting factor of gene
therapy today remains poor delivery of the therapeutic
gene to the cancer cells. The clinical studies performed
to date have all used modified viruses for gene delivery.
Although the delivery rates using viral systems have
been improved, a major drawback of using viruses for
gene delivery is the induction of immune responses
against the virus in the patients. This results in the production of antibodies which target the virus for degradation and limit the efficiency of repeated treatments.
Novel non-viral delivery vehicles are being developed,
which may in the future provide a potent alternative to
viral gene therapy. The status within the field of replacement gene therapy for lung cancer and delivery vector
development has recently been reviewed.59
Reintroduction of other tumor suppressor genes in
lung cancer has been evaluated in preclinical studies.
Co-delivery and expression of FHIT and TP53 have
been reported to provide a synergistic tumor-suppressing
effect in NSCLC in vitro and in vivo.54 Future studies
will be necessary to assess the potential of these strategies for treatment of lung cancer patients.
REPLICATIVE POTENTIAL AND TELOMERASES
When cultures of differentiated somatic cells are established in vitro they have a well-defined potential for cell
division. After a number of divisions, the cells are predetermined to enter crisis, a state characterized by
extensive cell death and chromosomal aberrations. This
phenomenon has been termed the mitotic clock and is
part of the tight regulation of normal cell growth. In
contrast, cancer cells propagated in culture have an
unlimited potential for continuous cell division and are
said to be immortalized.
The molecular explanation for the mitotic clock
resides in the chromosomal structure and mechanism
of DNA replication. Upon cell division, the cell initiates
DNA replication which proceeds to produce new leading and lagging strands from the DNA double helix.
Since DNA replication can only proceed in one direction (3′–5′), only the leading strand of the double helix
is continuously synthesized, whereas the new lagging
strand is assembled by ligation of smaller DNA fragments. The discontinuous replication of the lagging
strand results in a gap at the 5′ end of the newly synthesized DNA strand, resulting in loss of chromosomal
material during each mitotic cycle.
The chromosomal ends are termed telomeres
and are composed of six nucleotide repeats. The telomeres are involved in the correct orientation of the chromosomes during cell division. Due to the continuous
shortening of telomeric DNA following cell division,
30 Textbook of Lung Cancer
lack of telomere maintenance ultimately results in chromosomal degradation and end-to-end chromosome
fusion, exemplified by the massive cell death observed
during the crisis state of untransformed cells cultured
in vitro. In order to overcome the limitation of telomere
shortening, cancer cells activate a program for telomere
maintenance, which is normally shut down in fully differentiated normal cells. Most frequently, this is accomplished by activation of an enzyme complex known as
telomerase, but a subset of cancer cells lacks telomerase
activity and are immortalized by a process known as
alternative lengthening of telomeres (ALT). The implications of the telomere-activating machinery in lung
cancer and the development of therapeutic strategies
targeting telomere maintenance are discussed below.
Telomere maintenance in lung cancer
The core telomerase enzyme comprises an RNA
subunit (hTERC) which provides the template for synthesis of new telomeric DNA facilitated by the catalytic
subunit human telomerase reverse transcriptase
(hTERT). The RNA component hTERC is ubiquitously
expressed in many cells, whereas hTERT expression is
normally confined to undifferentiated cells such as
germ line cells and bone marrow stem cells, identifying
the enzyme moiety as the limiting factor for telomere
maintenance. Indeed, the great majority of SCLC and
NSCLC expresses the enzyme hTERT,60 whereas hTERT
expression and telomerase activity has been found to be
repressed in the majority of lung carcinoids, a malignancy which is also associated with a longer-term survival.61 A number of studies have shown that increased
telomerase activity and increased levels of hTERT
mRNA are mainly found in patients with poorly differentiated tumors (such as SCLC) and advanced disease
and correlate with poor survival, suggesting telomerase
activity as an important prognostic marker for patients
with lung cancer.62,63
A number of alternative splice variants of hTERT mRNA,
many of which lack enzymatic activity, have been identified, but the prognostic value and molecular role of these
mutations in lung malignancies remain to be clarified.
As previously mentioned, a small subset of cancer
cells acquires telomere maintenance without activation
of telomerase by a process termed ALT. Although this
phenomenon remains to be fully elucidated, ALT appears
to involve recombination of chromosome ends in a
mechanism associated with DNA replication.64 No studies reporting ALT in lung cancer have been published
to date, and whether ALT plays a role in lung cancer
cell immortalization therefore remains to be elucidated.
Experimental therapeutic targeting of telomerase
in lung cancer
Due to the central role of telomerase in the transformation of lung cancer cells, and the lack of telomere maintenance in normal tissues, blocking the activity of this
enzyme appears an intriguing target for therapeutic
intervention.
A number of small molecular inhibitors of telomerase
activity have been developed and some of these agents
have been reported to inhibit the growth of NSCLC
cells in vitro, albeit with a delay in growth inhibition of
several months after the initiation of treatment.65
The compound GRN136L is a lipid-modified oligonucleotide, which binds to the hTERC subunit of telomerase with high affinity, thereby inhibiting reverse
transcription by blocking access of hTERT to its RNA
template. GRN136L has recently been reported to successfully inhibit telomerase activity, leading to telomere
shortening and resulting in decreased growth of adenocarcinoma cells in vitro and effective prevention of
tumor metastasis in a xenograft mouse model.66
Another strategy involves activation of an immune
response towards telomerase by administration of a vaccine composed of hTERT-derived peptides. Recently a
clinical phase I/II study investigating the effect of treatment with two hTERT peptides in patients with
advanced NSCLC was published,67 reporting the treatment to be well tolerated and detecting immune responses
towards telomerase in 11 and tumor response to treatment in 2 of 24 patients. A new clinical trial is being
planned, aiming to investigate the effect of telomerase
immunogenic peptides in combination with chemo- and
radiotherapy.
ANGIOGENESIS
The vasculature is crucial for cell function and survival
in all tissues, since oxygen and nutrients are supplied
by the vessels. The growth of new blood vessels, called
the process of angiogenesis, is a normal physiologic
process taking place under organogenesis, which under
these conditions is transitory and carefully regulated.2
In a similar way tumors must develop angiogenic ability
to progress. This ability appears by activating the angiogenic switch. The activation is probably a result of the
change in the balance of angiogenesis inducers and
countervailing inhibitors, e.g. by altered gene transcription. Angiogenesis can be described as a result of a
dynamic balance between pro-angiogenic factors and
anti-angiogenic factors.68 Once a tumor has activated its
Molecular biology of lung cancer 31
angiogenic switch it becomes able to grow; in the
absence of this activation the tumor remains in a dormant state and is unable to grow in size beyond a few
millimeters. Angiogenesis, however, involves more
components than pro- and anti-angiogenic factors only.
For succesfull angiogenesis, interactions between tumor
cells, activation of the endothelial cells and mature vessels, degradation of the surrounding basement membrane, and invasion and migration of endothelial cells
into the surrounding connective tissue are needed.
Hereby tumor-associated neovascularization can take
place by establishing continuity with the systemic circulation, allowing tumor survival and growth and, more
seriously, facilitating further metastatic spreading.
Many different pro- and anti-angiogenic factors have
been identified. The angiogenesis-initiating signals
are exemplified by vascular endothelial growth factor/
vascular permeability factor (VEGF/VPF) and acidic
and basic fibroblast growth factors (FGF1/FGF2), which
all bind to transmembrane tyrosine kinase receptors
displayed by endothelial cells.69 The typical angiogenesis inhibitor is thrombospondin-1, which binds to
CD36, a transmembrane receptor on endothelial cells
coupled to intracellular Src-like tyrosine kinases.70 In
total there are up to nearly one hundred different proand anti-angiogenic factors. These include platelet-derived endothelial cell growth factor (PE-ECGF),
platelet-derived growth factor (PDGF), EGF, angiogenin, angiotensin II, platelet-activating factor (PAF),
and the inhibitor angiostatin. Most of the molecules
involved in angiogenesis are not specific to vascular
endothelial cells, but have a broad spectrum of target
cells, except from VEGF, which activates only endothelial cells. VEGF is a heparin-binding glycoprotein, which
binds selectively to two high-affinity tyrosine kinase
cell surface receptors: VEGFR1 and VEGFR2. These
receptors are found in blood vessels within or near
tumors, and the expression is found to be upregulated
in most cancers including lung cancer. VEGF has been
demonstrated to be an important predictor of poorprognosis in NSCLC.71
Targeting angiogenic factors
Inhibiting angiogenesis through anti-angiogenic and/or
vascular targeting agents seems logical, as new anti-cancer
treatment strategies. In particular, much attention has
focused on targeting VEGF and VEGFR. Compounds
currently under investigation in cancer therapy include
anti-VEGF/VEGFR antibodies, small molecule VEGFR
tyrosine kinase inhibitors, antisense suppression of
VEGF, immunotherapy, viral-directed targeting of
VEGFR signaling, ribozymes, and various toxin conjugates.72 Furthermore, blocking angiogenesis may
enhance conventional anti-cancer treatments such as
radiation therapy in situations where tumors are unresponsive to current anti-growth factor efforts, and the
benefits of combining angiogenic inhibitors with radiation are being explored. Recent clinical trials have
shown that the anti-VEGF antibody bevacizumab, combined with standard first-line chemotherapy in NSCLC,
provided a statistically and clinically significant survival
advantage with tolerable toxicity.73 In addition, more
recently tested compounds characterized as antivasculature agents have been shown to be effective
against mutiple targets; the efficiency of such compounds is currently being investigated in clinical trials
for NSCLC.
TISSUE INVASION AND METASTASIS
As mentioned above, cancer cells and tissues often have
dysregulation of crucial processes and factors, such as
apoptosis, growth factors, angiogenesis, replication
potential, sensitivity to anti-growth signaling, and
invasion and metastasis. Many of these processes are
dependent on proteases, making proteases an interesting target for new anti-cancer treatments. Proteases
(proteolytic enzymes) are highly involved in invasion
and metastasis by degradation of the extracellular
matrix, e.g. basement membranes. Proteases are involved
in both extra- and intracellular protein degradation.
Under normal conditions proteolysis is a physiologic
process leading to, for example, wound healing, but in
the malignant tumor proteolysis becomes a harmfull
factor enabling tumor cells to move out, invade adjacent tissues, and thence travel to distant sites where
they may succeed in founding new colonies, metastases
(Figure 3.6), which are the cause of 90% of human
cancer deaths.74 Thus, based on the degradation of
extracellular proteins and basement membranes by
proteolytic enzymes, increased invasion and metastasis
can take place in malignant diseases. The major components of the basement membrane and the extracellular
matrix are type IV collagen, laminin, fibronectin, vitronectin, and proteoglycans. Tumor cells can produce
a number of proteolytic enzymes which can degrade
these protein structures, including matrix metalloproteinases (MMPs), collagenases, urokinase plasminogen
activator (uPA), plasmin, cathepsins, and others. MMPs
are known to play a functional role in the metastatic
spread of lung cancer.75 Different MMPs are active in
32 Textbook of Lung Cancer
Extravasation
Intravasation
Regional lymph
node metastasis
Survival in
circulation
Growth in new
environment
Figure 3.6
Metastasis. This diagram illustrates the importance of proteolysis in cancer, leading to tissue degradation, invasion, and metastasis.
different steps of the invasive and metastatic process,
and a better understanding of the involvement of MMPs
in the invasion and regulation of growth of both primary and metastatic tumors may help to implement
these as anti-cancer therapy targets. Cathepsins have
been demonstrated to have a prognostic value in NSCLC
and levels of the receptors for uPA (uPAR) and other
components of the plasminogen activation system are
associated with survival in NSCLC.76
Targeting proteases and the metastatic process
It is expected that inhibition of the metastatic potential
of a tumor by interaction with extracellular protein degradation could be an important target, especially during
early tumor development. Drugs targeting MMPs have
been in clinical trials, but have shown little or no activity in lung cancer. Inhibition of MMPs has especially
been focused on targeting MMP-2 and -9. In studies on
cell lines and xenografts, the MMP inhibitor batimastat
has shown an ability to decrease the invasion of cancer
cells and to prolong survival in the treated animals.
However, these finding have been most consistent in
pancreatic cancer. The efficacies of batimastat and
another MMP inhibitor marimastat have been tested in
different solid tumor types, but the studies have been
limited by toxicity. In the clinical phase I and II studies
performed to date, little or no activity has been reported
in lung cancer. At the moment new MMP inhibitors
such as CP-471,358 are being evaluated in phase I and
II studies in a number of malignancies including lung
cancer.77
CONCLUSION
As is evident from the preceding sections, major advances
in molecular biologic research during recent decades
have resulted in a substantial insight into important
signaling pathways and mediators contributing to lung
cancer pathology. Recently, the first novel therapeutic,
which directly targets growth-promoting pathways, was
approved for treatment of lung cancer and many other
drugs are presently under clinical investigation. However, although some patients respond well to the new
treatments, it has become evident that further insight
into the mechanism of action of many of these novel
agents must be gained, in order to better individualize
the targeted treatments to the patients who will benefit.
Gaining further knowledge into the complexity of
molecular lung cancer biology, correctly applying this
knowledge in the development of novel therapeutics,
and optimization of presently available agents therefore
represent important challenges in lung cancer research
and clinics for the years to come.
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4
Tobacco policy
Nigel Gray
Contents Introduction • Basic policy • Developing countries • The future
INTRODUCTION
The single global public health objective in this field is
to reduce consumption of tobacco by all possible means
as quickly as possible. Major successes such as the
decline in British consumption and mortality are currently matched by the steep ascent of these two indices
in developing countries, particularly China,1 which
illustrates the urgency of policy action.
It is reasonable to assert that implementation of
policy lags, sometimes decades, behind policy development, which lags similarly behind the development of
knowledge. In a number of sophisticated countries,
among which are the UK, Norway, Sweden, Australia,
Canada, and the USA, the proportion of the population
which continues to smoke has fallen from over a half to
about a quarter. Mortality declines have usually followed, but at very different rates. So it is wrong to be
pessimistic but important to be impatient. Pressing for
activist policies, on the grounds that outcomes take a
long time, seems to be an integral part of the duty of the
health professions.
Comprehensive tobacco policy has been well established and understood since the mid-1970s.2 The recommendations in this chapter are informed by long
experience of successful and unsuccessful policies in
many diverse countries. Many of the important policy
issues and outcomes have never been the subject of refereed articles in the technical press, so the reader must
be satisfied with basic references and must be willing to
search newspaper archives for historic detail.
Tobacco use has been, and is, perhaps the most difficult issue faced by public health workers in the 20th
century. Historic diseases such as smallpox, polio, measles, diphtheria, tetanus, whooping cough, rubella, and
scarlet fever were conquered in developed countries
within a decade or so of the arrival of effective control
systems. When vaccines and antibiotics worked, they
were used. Failures in developing countries relate to the
failure of national and international social organization
and rarely to organized opposition. The reappearance
of malaria and tuberculosis, depressing though it is, is
partly due to these factors and partly due to the lack of
really effective means of control.
The singular feature of the tobacco problem is that
someone is selling it. No one is selling tuberculosis. To
this can be attributed the fact that, five decades after
discovering its carcinogenicity, tobacco consumption
worldwide is falling very slowly. Comparisons with the
other industries selling toxic products are unsatisfactory. There is no pretence that asbestos does not cause
asbestosis, nor that drunken driving is merely a pleasurable habit. The international tobacco industry is
unique in its stubborn refusal to concede the sideeffects of its product, despite revelations3 which make
it clear that the industry knew of the carcinogenic and
addictive properties of tobacco some decades ago. Once
having retreated into its legal bunker it is now in the
difficult position of facing enormous legal and financial
consequences if it makes concessions or tells the truth.
Thus the forces of public health and the global tobacco
industry are locked in continuous warfare and prospects for peace are slight.
While no form of tobacco use has been discovered to
be safe, the cigarette is the most ubiquitous, widely
used, and best-studied product. The myriad forms of
tobacco use seen in India and other parts of Asia are
carcinogenic in many different ways and, being personally grown or based on cottage industry production,
each poses specific individual problems. Certainly it is
easier to develop policies to control cigarette smoking
than tobacco/betel chewing as the product is factory
made, taxed, exported and imported, and often the
subject of retail licensing.
The unrepentant nature of the global tobacco industry, which is controlled by relatively few major manufacturers, is reflected in the sales statistics. Sales are in
decline in the most developed countries and the
expected indices follow. Lung cancer in males, especially younger ones, is declining, as is heart disease.1
By contrast, tobacco exports from the USA are climbing
and the antique tobacco monopolies of the previously
36 Textbook of Lung Cancer
communist world are being replaced by modern mass
production systems owned by the same people. Marketing measures forbidden in the USA, UK, and Europe
are rampant in many developing countries.
Consideration of tobacco policy may conveniently
focus first on the cigarette. Such consideration should
take note that smoking is a learned habit which is initiated by social forces but sustained by the development
of addiction in persistent users.
•
BASIC POLICY
This is theoretically simple:
•
•
•
•
change the cultural background;
change the smoker;
change the cigarette;
protect the children.
Changing the cultural background
The cultural background against which tobacco smoking must be considered is a mixture of community law
and community norms. Laws usually arise as a result of
public opinion at a point in time and are an important
reflection of community norms, although they do not
always mirror public opinion in those countries where
the tobacco industry is strongest. The failed battle to
introduce strong tobacco legislation in the USA in 1998
shows the difficulties in the path of lawmakers that are
posed by the organized and well-funded opposition of
tobacco manufacturers. This situation, while obvious in
the USA, arises in most countries when tobacco policy
requires lawmaking, although the opposition may be
less obvious and behind the scenes.
An important element in the interaction between
government, parliaments, and popular opinion may be
non-government organizations. Policy frequently arises
in the non-government sector, as may the drive for legislation. Thus the interactive process of introducing legislation may be an important part of providing a driving
force for implementation. Popular laws are more likely
to be implemented. Opposition to standard comprehensive laws is to be expected and is routinely led by
those with vested interests, supported by the industry,
using arguments now outdated and often ugly when
exposed to public gaze.
•
•
•
Model legislation
•
•
Health warnings These should state government
policy and the facts. Rotating, explanatory warnings
are the first step. Warnings researched for understandability and offering a telephone number to an
information service are better. Warnings with
graphic pictures are even better.
Packet labeling There is a powerful case for generic
packaging as a way of interfering with global brand
advertising. Packaging should declare yields of
known major carcinogens and other substances,
which may be specified as knowledge develops.
Packet inserts are a way of providing the sort of
comprehensive information that is given with such
substances as aspirin. Tobacco industry claims for
the right to compete for adult markets are specious
as adults and children co-exist in society and measures to protect or attract children often impinge
on adults and vice versa.
Abolition of promotion – in every form Tobacco brand
names need to be forbidden in advertisements for
any other product. Direct and indirect advertising
needs to be specifically addressed. This issue
remains difficult because of the cross-border abilities of satellite media. It should be understood that
there is no case which can be made in favor of
tobacco promotion as the product is seriously and
chronically toxic when used as the manufacturers
intend. Evasion of promotional restrictions is the
profession of a large number of people, all of whose
arguments should be ignored. Even at point of sale,
advertisement should be forbidden.
Availability Sales to children, defined as 16–18 in
most countries, need to be prohibited and the prohibition policed. Such legislation is widespread,
but policing is not. Vending machine sales need to
be supervised in places inaccessible to children, or
forbidden. This policy measure is widely adopted
but almost nowhere has policing been tried. Until
that experiment is done and shown to fail this
issue remains high on the agenda for developing
countries.
Smoke-free environments These need encouragement for exemplary as well as risk-avoidance reasons. Schools, hospitals, workplaces, and public
transport should be smoke-free, as a minimum.
Smokers in many countries have been remarkably
accepting of this policy. It is an important downward pressure on smoking rates in all age groups,
and probably reduces daily dose as well as encouraging quitting.
Tax This should be high in the context of individual
income and should be regularly increased; a set
proportion should be allocated to health purposes
Tobacco policy 37
•
including tobacco education.4 Tobacco tax is among
the only taxes demonstrated to be popular. There is
good reason why the price of a packet of cigarettes
should be several times that of a hamburger.
Regulation of the product It is unacceptable that a
product as dangerous as tobacco should be unregulated. Additives need to be demonstrated to be
non-toxic in both burnt and unburnt form; and
upper limits should be set, and continuously
reviewed, for major carcinogens and toxins. Public
health advisors and departments have been slow to
act in this field, possibly because of perceived
complexities. However, the establishment of upper
limits for cigarette emissions is relatively straightforward and is in need of urgent implementation.
The importance of legislation is underlined by the
experience of Norway, the pioneer, in 1975, of comprehensive tobacco legislation. Tobacco consumption
peaked in the mid-1970s, having risen by about 25%
between the mid-1950s and mid-1970s. Since then it
has declined by approximately the same amount. The
original legislation in Norway was from a unanimous
parliament, but was surrounded by much discussion
and public interaction. This early legislation did not
include severe workplace and public place restrictions,
and Norwegian prices have risen only slightly, in real
terms, since the 1980s.5 While it is possible to argue
over the potential benefits of more aggressive pricing,
public education, and smoking opportunity restrictions, the Norwegian experience is a testimony to the
efficacy of good legislation as the basis for a comprehensive anti-tobacco program.
Community norms are usually well reflected in public opinion. A comprehensive tobacco policy would
include regular surveys of tobacco consumption, public
opinion, relevant attitudes among smokers and nonsmokers, and evaluation of education programs. Opinion may move slowly, but it does move with time and
in the presence of well-directed education programs. It
is both logical and true that parental attitudes and
example flow through to youth behavior, so changing
the cultural background implies measuring beliefs and
recruiting all the potential role models of society as well
as removing the tobacco industry’s ability to promote
its product. It is also logical to believe that education
programs work better without opposition, further
underlining the importance of complete eradication of
promotion.
In summary, changing the cultural background
requires an activist and persistent approach to legislation
and community involvement. This means that a wellorganized and co-ordinated anti-smoking movement is
a necessary basis. Such movements are not always large;
efficiency and co-ordination are the keys.
Changing the smoker
Changing the smoker to become a non-smoker
is a complex multifaceted process requiring analysis of
individual society’s smoking patterns. It is accepted
that addiction to tobacco is the major force in maintaining smoking status. Progress towards becoming a nonsmoker may be generally and simply summarized:
Rational information → dissonance → attempts to quit →
success → maintenance
Dissonance may be defined as dissatisfaction with
one’s own smoking behavior, and affects a majority of
smokers in the USA, for example, but probably a minority in less well-informed societies. Clearly dissonance is
more likely to occur if the victim/person is well
informed, so the place of varied education programs,
targeted to the subgroups as well as the totality of smokers, cannot be doubted, but is country-specific, at least
to a degree. Other factors can be expected to stimulate
dissonance: the smoke-free workplace and public
places; peer group and family pressure; negative peer
group experiences such as deaths or disease; societal
attitudes and levels of information. Such factors reflect
the cultural background and vary from country to
country.
Attempts to quit occur frequently in sophisticated
countries and policy should encourage and provide
support for smokers who make them.
The role of nicotine replacement therapy (NRT) is
crucial and in need of considerable development. Its
value is well established although results are generally
disappointing by comparison to expectations. Better
products are needed as is greater availability and more
support services. It is bizarre that cigarette content is
virtually unregulated while bureaucratic restrictions on
alternative sources of clean nicotine are widespread.
The general global failure of health professionals,
especially physicians, in support of patients and provision of therapy is a disturbing reflection of health priorities, which at least means there is hope for potential
improvement.
The debate over nicotine addiction6 per se ought not
to hold back development of better products and services. Tobacco is a uniquely toxic way of delivering the
desired dose of nicotine while NRT appears to be safe
or relatively so. Up to this time there is no evidence of
38 Textbook of Lung Cancer
mass addiction to nicotine chewing gum, although the
lack of competitive products which will deliver the
quick, efficient, ‘fix’ of the cigarette might well explain
this. Nevertheless, policy should be aimed at providing
support, NRT, and whatever other pharmaceutical aids
may be developed, since the status quo is an ongoing
disaster which justifies greater effort than it receives.
Continuing use of NRT in smokers who cut down but
do not abstain is a sensible form of harm reduction,
although the obvious goal is abstinence.
Policy makers should note that the costs of helping
smokers are infinitely less than those of treating them
and that, while the most immediate mortality, morbidity, and cost benefits are achieved by attention to longduration heavy smokers, every smoker is at risk sooner
or later, and early intervention is always best.
learned in reducing vehicle emissions to the cigarette,
and to base regulations upon it.
It is known8,9 there is great diversity in the levels
of major carcinogens in mainstream smoke yields on
the world market, so the evidence that cigarettes
with lower carcinogen levels can be made and sold is
indisputable – cigarettes low in nitrates and nitrosamines are made and sold.
The policy issues then become the following:
•
•
•
Changing the cigarette
The cigarette is a uniquely efficient nicotine delivery
device which has so far escaped significant production
controls worldwide. This is in contrast to motor vehicles, pharmaceuticals, food, houses, and even sewage
systems. While the reasons for this disparity are interesting, as they include corruption on a global scale,
there can be no excuse for continuing to allow the
tobacco industry alone to decide what will go into the
product, and therefore what is present in mainstream
smoke.
First it is necessary to state that the policy of
the 1960s, which favored reduction of tar and nicotine
levels over time, has not produced the benefits anticipated. Changes in cigarette design7 have brought about
reductions in some carcinogens and increases in others.
Mortality benefit, if present, is small, and adenocarcinoma has increased in the USA and elsewhere. Since tar
measurement takes no account of the qualitative changes
which have occurred in smoke it is misleading. Over the
same time, bioavailability of nicotine has been increased
and, together with compensatory smoking, means
the machine-measured levels of nicotine are also misleading.
It can therefore be unequivocally stated that tar and
nicotine measures as currently used should be abolished – the policy question is what they should be
replaced with?
It must be recognized that cigarette design is best
understood by the tobacco industry and is clouded by
commercial secrecy, and that no governments have
applied the necessary research resources to know enough
to tell manufacturers how to make their product. However, it is certainly possible to apply the principles
•
•
•
•
Governments must claim power to regulate the
content of cigarette smoke – this power exists in
some countries.
Health authorities require suitable advisory systems involving independent scientists and with
mandatory access to industry information.
Initially, major carcinogens such as benzo(a)pyrene,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK), and N-nitrosonornicotine (NNN) should
be targeted. Market analysis would show the range
of yields. Those cigarettes yielding above the median
should be removed from the market, or modified,
within a standard period such as 12 months.
Over time this process would allow progressive
reduction in carcinogens and other toxins, since
the starting point is a level found to exist on the
market and already achieved by at least some
manufacturers.
Nicotine needs special treatment. The first essential
is a new measurement system. However, a measure
which measures smoke content will not accurately
reflect what gets into the smoker’s bloodstream, as
it cannot control for compensatory smoking practices. Therefore, while control of smoke yield can
be exerted by a measure such as nicotine content
per liter of smoke, the decision-making process
which sets the yield levels needs to be informed by
behavioral experiment and analysis.
The ultimate policy decision – whether mass weaning of nicotine-dependent populations should be
attempted by regulatory reduction of dose per cigarette – cannot be made in the light of knowledge
in 2007. However the goal of reduction in the
addictiveness of the cigarette is a proper one and
should be pursued as a matter of policy.
In facing the decision to control nicotine yields,
policy makers must understand that the rise of
cigarette smoking was a vast unplanned experiment performed by the tobacco industry, initially
ignorant of its product’s toxicity. Long-term decisions on nicotine policy will require similarly large
Tobacco policy 39
•
experiments based on sensibly considered probabilities. The decision to reduce tar and nicotine
was sensible when conceived but subverted by
industry manipulation. This mistake should not be
made again but should not prevent innovative regulatory policies.
New products containing tobacco ought also to be
regulated and only tested in situations similar to
those which are used for the testing of new pharmaceuticals. So far the tobacco industry has not
produced a successful alternative to the standard
cigarette. They should not be discouraged from
doing so but should not receive marketing advantages over NRT and other nicotine alternatives.
ongoing smokers need to be related to those of children
to a smoke-free and promotion-free environment.
Policy is not only about prohibitions and restraints.
There is a clear need for experimentally based, expensive, education programs aimed at children. The fact
that few of these have been developed outside a few
richer countries, and even fewer adequately funded, is
not an excuse for failure to change. Every society which
spends money on treating sick smokers would be well
advised to spend funds of the sort spent on promotion
of cola drinks on campaigns aimed at discouraging
smoking.
DEVELOPING COUNTRIES
Protecting the children
As social norms and fashions have changed over time,
so have the specific stimuli which trigger or contribute
to initiation of the smoking habit. Age of onset of initiation varies around the world, beginning earlier in
developed countries. Cultural differences play an important role, as exemplified by the great diversity in smoking rates between men and women in countries such as
China. Whereas the factors which contribute to initiation in particular societies differ, the policy question is
what can be done to interfere with the pressures toward
initiation – or in simple terms, what can be done to
protect the children?
The first policy approach is to remove or reduce all
the pro-smoking pressures which can be controlled.
Formal and informal promotion of tobacco has been
dealt with above. Nevertheless, it must be re-emphasized that children are extremely sensitive to promotional pressures and that any presentation of a tobacco
brand name needs to disappear from the social environment. This has been substantially achieved in a number
of countries, but has been subverted to a variable degree
by cross-border advertising of events such as motor
races and cricket matches sponsored by tobacco interests. Global control of this phenomenon will not be
achieved easily, but the battle, slowly being won in
developed countries, needs to be fought in developing
countries as the industry seeks to source such events
from them.
Local social pressures need policy attention. The role
of parents, siblings, peer groups, and local and international role models should be the subject of education
programs and local campaigns, with the specific objective of reducing initiating pressures wherever they exist.
What happens in schools, homes, workplaces, and public places needs detailed consideration. The rights of
Tobacco use is already built in to many developing
countries and takes many forms. No form of tobacco
use has been shown to be free of risk and the fact that
snuff use in Sweden is less hazardous than tobacco/
betel chewing in India is not sufficient to allow fantasies
of safe tobacco products to intrude on public policy.
The principles set out above are applicable to some
degree with most forms of tobacco use. However, local
cultures in which the many and strange variants of
tobacco smoking and chewing persist need to be considered individually. The broad-brush weapons of education, warning labels, taxation, and restriction where
relevant can be considered by policy makers, and locally
suitable policies developed and tried. The after-effects
of tobacco use as known are such that no variant of use
can be neglected.
The reappearance of the cigar as a social status
symbol in the USA should warn against complacency.
THE FUTURE
The basic principles of tobacco policy discussed here
have been tested and appraised in real societies and
shown to work to a greater or lesser degree. The degree
usually depends on the enthusiasm with which policies
are implemented. The force of the vested interests of
the tobacco industry has been able to slow policy implementation, but the fact remains that tobacco use in
developed countries had declined substantially and the
tobacco industry is now seeking to replace its lost,
dying, and dead smokers in developed countries with
new users in the poor and developing world.
The political battle over the proposed tobacco settlement in the USA in 1998, although seemingly lost at
40 Textbook of Lung Cancer
that time, is a serious and important indication of the
degree to which the international tobacco industry has
declined in power and influence. It is to be expected
that the public health principles espoused here will be
applied progressively and more rapidly over the next
decade. The result can only minimize the tobacco mortality epidemic already set in train by past events, but
while tobacco remains one of the largest causes of
avoidable death and disease, it remains one of the major
global public health targets for all countries.
REFERENCES
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2.
Peto R, Lopez AD, Boreham J et al. Mortality from smoking
world-wide. Br Med Bull 1996; 52: 12–21.
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8.
9.
Glantz SA, Slade J, Bero LA et al. The Cigarette Papers. Berkeley: University of California Press, 1996.
Manley M, Glynn TJ, Shopland D. The Impact of Cigarette
Excise Taxes on Smoking Among Children and Adults: Summary Report of a National Cancer Institute Expert Panel.
Bethesda MD: National Cancer Institute, 1993.
Bjartveit K, Lund KE. The Norwegian Ban on Advertising of
Tobacco Products. Has it Worked? Oslo: Norwegian Cancer
Society, 1996.
Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. N Engl J Med 1994; 331: 123–4.
Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995.
J Toxicol Environ Health 1997; 50: 307–64.
Fischer S, Speigelhalder B, Preussmann R. Tobacco specific
nitrosamines in commercial cigarettes; possibilities for
reducing exposure. Relevance to Human Cancer of NNitroso Compounds, Tobacco Smoke and Mycotoxins.
International Agency for Research on Cancer. Monograph 105.
Lyon: 1991 489–93.
Gray N, Boyle P, Zatonzki W. Tar concentrations in cigarettes
and carcinogen content. Lancet 1998; 352: 787–8.
5
Smoking cessation programs
Philip Tønnesen
Contents Introduction • Clinical approach • Stages of motivation • Carbon monoxide in expired air
• Nicotine replacement therapy • Varenicline • BupropionSR • Other drugs • New drugs • Alternative
therapies • Smoking reduction • Special considerations for lung cancer patients who smoke
• Weight gain • Conclusions
INTRODUCTION
This chapter focuses on the proper use of nicotine
replacement therapy (NRT), varenicline, and bupropionSR, golden rules in smoking cessation, predictors of
success, and the concept of smoking reduction. It should
be remembered that cigarette smoking is an addiction,
and for that reason smoking cessation cannot be compared with treatment of other medical conditions. NRT
will produce low success rates when used without
adjunctive behavioral support; however, since most
smokers quit on their own and using over-the-counter
(OTC) NRT, even these low success rates will have an
important influence on public health. The degree of
supportive adjunctive behavioral therapy parallels the
actual success rate, while the relative success rate (i.e.
the odds ratio between NRT and placebo) remains more
or less unchanged at around a factor of two.1
As a preventive tool, smoking cessation is very costeffective. Smoking cessation with NRT or bupropionSR
is approximately eight times more cost-effective per
saved year compared with 300 medical treatments.2
Also, smoking is the most important etiologic factor in
the development of lung cancer, accounting for almost
85% of all lung cancer cases, and has been strongly correlated with other cancers, including oral, laryngeal,
and bladder cancer. Around one-third of all cancer
deaths are attributed to tobacco.3 Also, tobacco use is a
major contributor to chronic obstructive pulmonary
disease (COPD) and coronary arteriosclerosis – diseases
that often prevent lung cancer patients from undergoing curative surgery.
CLINICAL APPROACH
When a health care provider, i.e. a physician, nurse,
dentist, or pharmacist, meets with a smoking patient,
he or she has a responsibility to interfere and discourage
tobacco use.4,5 The first thing is to ask whether or not
the patient is a smoker. Already, by asking, one shows
to the patient that one cares about smoking and that
smoking might be of importance in relation to health.
It is important that the patient’s smoking be handled in
a neutral way without anger or condemnation. The
smoker should be informed about the risks of smoking,
and the information should be individualized for the
particular patient.
STAGES OF MOTIVATION
Some smokers are contented smokers: they do not consider quitting and do not think about the dangers of
smoking. But many smokers would like to quit. Motivation to do so can be regarded as a cyclic process of
changes, as described by Prochaska and Goldstein.6
However, these stages do not correlate well with success in quitting. It is much more important for patients
with smoking-related diseases such as lung cancer to
quit compared with ‘healthy smokers’. Continued smoking in lung cancer patients has a negative effect on the
outcome of surgery, chemotherapy, and radiation therapy, and increases the risk of secondary primary lung
cancers in long-term survivors.
The therapist’s approach to the smoker depends on
the motivation to quit. Use of the questions in Table 5.1
is an easy and quick way to classify the motivational
stage of the individual smoker and then to apply the
right treatment approach. If the smoker wants to quit
you should support with advice about NRT and the
golden rules of smoking cessation, use NRT, varenicline, or bupropionSR, clinician-provided assistance
and skills training, and follow-up visits.7 If the smoker
is only interested in cutting down, the smoking reduction concept should be applied. Patients who declare
42 Textbook of Lung Cancer
Table 5.1 Assessment of motivation to quit smoking or to
reduce
1.
Will you participate in a smoking cessation
course now?
Answer ‘Yes’: Start smoking cessation
‘No’: Continue to 2
2. Will you try to cut down your daily number of
cigarettes now?
Answer ‘Yes’: Start smoking reduction
‘No’: Recommend cessation and give
brochures
3. How motivated are you to quit on a scale from
0 to 10?
(0 = not at all motivated;
10 = extremely motivated)
Answer _______ score (0–10)
4. How motivated are you to reduce on a scale
from 0 to 10?
(0 = not at all motivated;
10 = extremely motivated)
Answer _______ score (0–10)
no interest in smoking cessation or reduction should
receive brochures and other self-help material about
smoking or smoking cessation. More detailed guidelines for smoking cessation have been published by the
Agency for Health Care Policy and Research in the USA
and by NICE in the UK.8,9
However, there are some basic principles related to
successfull smoking cessation that are important for the
therapist to consider: smokers must stop smoking completely at quit day (even one or two cigarettes per day
during the first one or two weeks of cessation are usually followed by relapse):
•
•
•
•
•
the use of NRT, varenicline and bupropionSR
lessens withdrawal symptoms and improves cessation outcome;
for lung cancer patients aggressive use of NRT,
varenicline, or bupropionSR should be used;
follow-up should be arranged to prevent relapse
(which is highest during the first three to six
weeks, then gradually declines, similarly to other
addictions);
smoking reduction might be a gateway to smoking
cessation in smokers low in motivation to quit;
if the patient relapses, he or she should be encouraged to make another attempt to quit later on and
then receive retreatment (‘recycling’).
CARBON MONOXIDE IN EXPIRED AIR
In most smoking cessation studies, sustained abstinence
is used as the outcome measure. It consists of the
smoker’s statement of not smoking now and not having
smoked since the last visit, together with biochemical
verification by carbon monoxide (CO) in expired air.
CO measurement is an easy and inexpensive way to
verify abstinence biochemically. The half-life of CO
varies between four and six hours, and the cut-off value
between non-smokers and smokers is usually 10 parts
per million (ppm). Most non-smokers attain CO values
of 1–4 ppm, and some use a cut-off value of 6 ppm.
Subjects exposed to passive smoking might attain values
of 6–9 ppm.
CO levels are most often measured with a portable
CO monitor (Bedfont Monitor, Sittingbourne, UK) in
expired air after a 15 s breathhold, with a CO value of
less than 6–10 ppm verifying abstinence.10 The result is
displayed immediately. Calibrations have to be performed at least every six months using a 50 ppm CO
test gas. False-positive values might be observed in subjects with lactose malabsorption. Although an ethanol
filter is present, high ethanol concentrations in the
breath might interfere with measurements. Drifting of
the zero-point might be observed if many smokers
are tested consecutively. Without CO monitoring, up
to 10% of failures might state that they do not smoke.
Plasma, saliva, or urinary cotinine levels are another
biochemical way to verify smoking abstinence.
NICOTINE REPLACEMENT THERAPY
The rationale for nicotine substitution is as follows.
When quitting smoking, the administration of nicotine
decreases withdrawal symptoms in the first months,
thus allowing the subject to cope with the behavioral
and psychologic aspects of smoking (Table 5.2).
Table 5.2 The principle of nicotine replacement
therapy (NRT)
•
•
•
•
•
Principle: quit cigarettes
Use NRT to reduce withdrawal
Break the psychologic addiction
After two to four months, stop NRT
Some might need NRT for longer periods
Smoking cessation programs 43
Withdrawal symptoms (craving for cigarettes, irritability, anxiety, depression, drowsiness, difficulty in
concentrating, restlessness, headache, hunger, sleep
disturbances) are usually assessed on a four-point scale
(0 = not at all; 1 = mild; 2 = moderate; 3 = severe).11,12
Withdrawal symptoms often appear four to eight hours
after quitting, peak during the first week (days 3–5),
and then gradually decline over the next two to four
weeks. Nicotine dependence is measured by the Fagerström test of nicotine dependence (FTND), with a possible scoring of 0–10 (most dependent)13 (Table 5.3).
With the nicotine replacement products used today,
lower nicotine levels are attained compared with smoking
(i.e. the high peak plasma levels of nicotine reached
during smoking are not achieved) (Figure 5.1). Patients
are weaned off nicotine replacement products (usually
over two to six weeks) when withdrawal symptoms are
lessened owing to decreased dependence. The average
12-month success rate reported in most studies is about
15–25%.8,9 Predictors that correlate with a lower success rate are higher nicotine addiction, lower age, no
previous quit attempts, previous depression, suffering
from COPD and cardiovascular disease, a smoking
spouse, and low motivation to quit.
Nicotine is the drug of choice to assist smoking
cessation. Results reported in a Cochrane meta-analysis
Table 5.3 Fagerström test for nicotine dependence (FTND)
Item
1.
How soon after you wake up do
you smoke your first cigarette?
2.
Do you find it difficult to refrain from
smoking in places where it is forbidden, i.e.
in church, at the library, in the cinema, etc.?
3. Which cigarette would you most hate most
to give up?
4. How many cigarettes per day do you smoke?
Do you smoke more frequently during the first
hours after waking than during the rest of the day?
6. Do you smoke if you are so ill that you are in bed
most of the day (or absent from work)?
Plasma nicotine concentrations (ng/ml)
5.
35
Answer
Score
Within 5 min
6–30 min
31–60 min
61 min or more
Yes
No
3
2
1
0
1
0
The first one in the morning
Any others
1–10
11–20
21–30
31 or more
Yes
No
Yes
No
Total score
1
0
0
1
2
3
1
0
1
0
0–10
Figure 5.1
Plasma nicotine levels during cigarette smoking, nicotine nasal
spray (NNS) use, and 4-mg nicotine chewing gum use.
30
25
20
Cigarettes
15
NNS
4-mg gum
10
5
0
8
9
12
16
20
Time (hours)
24
4
8
44 Textbook of Lung Cancer
of 105 trials with 39 503 subjects, who received various
forms of NRT (gum, patch, spray, inhaler, and sublingual/lozenge), indicated that NRT almost doubled
long-term (6–12 months) quit rates.14 The odds ratio
for success of NRT compared with controls was 1.8
(95% confidence interval, CI, 1.7–1.9). The odds ratios
for the different nicotine replacement products were
1.6 for gum, 1.8 for patch, 2.4 for nasal spray, 2.1 for
inhaler, and 2.1 for sublingual/lozenge (Table 5.4).
Overall, there was no statistical difference between the
different forms of NRT and this has also been found in
comparative studies.
The nicotine products described above are self-dosing systems to be used ad libitum, in contrast to the
patch, which ‘infuses’ about 1 mg of nicotine per hour
at a constant rate.
There are six different formulations of nicotine
replacement products (Table 5.5) and the determination of the most appropriate product should be according to patient preference, cost, nicotine dependence,
and number of daily cigarettes (Tables 5.6–5.9).
Nicotine chewing gum
Gum users should only chew a piece five to ten times
until they can taste the nicotine, then let the gum rest
in the cheek for a few minutes, and then chew again
to expose a new surface of the gum. Free nicotine can
then be absorbed and reduce side-effects due to
swallowed nicotine. The gum can be chewed for about
20–30 minutes. About 0.8–1.2 mg of nicotine is absorbed
from a piece of 2-mg nicotine gum, and 1.2–1.5 mg
of nicotine from a 4-mg piece15 (Table 5.5). With use
of nicotine gum throughout the day, blood levels of
one-third (for 2-mg gum) and two-thirds (for 4-mg
gum) of the nicotine obtained through smoking are
achieved.16,17
A basic advantage of gum is the possibility of
self-titrating the dose, in contrast to the patch, which
delivers a fixed dose. Thus it is possible to use a piece of
gum whenever it is wanted or needed during the day.
The principal disadvantage of gum use is potential
underdosing, which might explain the lack of effect in
several trials. The approximate dose equivalent for most
nicotine patches is approximately 20 pieces of the 2-mg
Table 5.5 NRT formulations
Gum
2 and 4 mg content: 0.8–1.2 mg and 1.2–1.5 mg
absorbed, respectively
Patch
15 mg/16 h; 21 mg/24 h
Inhaler
10 mg in one container: 4–5 mg released (2–3 mg
in clinical use)
Nasal spray
0.5 mg/dose in each nostril
Sublingual tablet
2 mg content: 0.8–1.2 mg absorbed
Lozenge
1 mg and 2 mg content: 0.5 and 0.8–1.2 mg
absorbed
Table 5.6 NRT use: 1
1–9 cigarettes/day (not-evidence based)
• 2-mg gum
• Inhaler
• 1-mg lozenge
7–9 cigarettes/day
• As above, or
• Patch 10-mg/16 h or 7-mg/24 h
Table 5.4 Efficacy of NRT
Table 5.7 NRT use: 2
•
•
•
10–20 cigarettes/day
• Patch: 15-mg/16 h or 14-mg/24 h
• Gum 2- or 4-mg
• Inhaler
• 2-mg lozenge or 2-mg sublingual
•
•
•
•
•
Meta-analysis controlled trials
Success rates sustained for one year
Odds ratio
1.77 (95%
CI 1.67–1.89)
Gum:
1.66
Patch:
1.81
Nasal spray:
2.35
Inhaler:
2.14
Sublingual/lozenge:
2.05
15–20 cigarettes
• As above, or
• NNS
Smoking cessation programs 45
Table 5.8 NRT use: 3
21+ cigarettes/day
• Patch: 25-mg/16 h or 21-mg/24 h
• Gum: 4-mg
• NNS
• Inhaler
• Sublingual 2-mg or lozenge 2-mg
• Gum as rescue in relapse situations
• NRT as long-term use if needed
• Combination of patch and one of the other
NRTs
• NRT in combination with bupropionSR
Table 5.9 NRT use: 4
•
•
•
•
•
Use of NRT in smokers as withdrawal
suppressor
Meetings, workplaces, travel
Few hours: gum, inhaler
6 or more hours: gum, inhaler, patch
Instruct smoker to try a piece of
gum/inhaler before travel starts
Table 5.10 Varenicline use
10+ cigarettes/day
• Varenicline 0.5 mg in morning days 1–3; then
0.5 mg b.i.d. days 4–7
• Quit smoking after 1 (–2) week
• Varenicline 1 mg b.i.d.
• Duration: 12 weeks
• In quitters after 12 weeks eventually continue
with varenicline up to 6 months
• Side-effects: mild nausea (30%), vomiting (2%)
• Contraindications: severe renal failure
gum, whereas the mean number of pieces of gum consumed daily is only around five to six in most studies.
Thus underdosing is a plausible explanation for lack of
efficacy in several studies.18,19
From these observations, it would be logical to
attempt to raise the consumed dose either by increasing
the number of pieces of gum chewed or by using the
higher-dose (4-mg) gum. In four studies comparing
the 4- and 2-mg gums, the 4-mg gum was superior to
the 2-mg gum for short-term outcome. Another way to
increase the amount of consumed gum might be to
administer it in fixed-dosage schedules as shown by
Killen et al.20
Side-effects of gum consist mainly of mild, transient,
local symptoms in the mouth, throat, and stomach due
to swallowed nicotine (i.e. nausea, vomiting, indigestion,
and hiccups). After adequate instruction, most smokers
can learn to use the gum properly. However, without
instruction many will discontinue use or underdose
themselves.
In the Lung Health Study, among 3094 smokers who
were followed for five years, the use of the 2-mg gum
appeared safe and did not produce cardiovascular
problems or other adverse events, even in subjects who
continued to smoke and still used nicotine gum.21
It is suggested that smokers be instructed to stop
smoking completely, use the nicotine gum on a fixed
schedule (i.e. every hour, from early morning, for at
least 8–10 hours), and to use extra pieces of gum whenever needed.
The optimal duration of treatment is not known;
however, in most studies, the gum has been used for at
least 6–12 weeks and up to one year. Individualization
of treatment duration is recommended.
Nicotine transdermal patch
The nicotine patch is a fixed nicotine delivery system
that releases about 1 mg of nicotine per hour for 16
hours (daytime patch) or for 24 hours (24-hour patch).
Nicotine substitution is about 50% of the smoking level
(21-mg patch/24 h and 15-mg patch/16 h) (Table 5.5).
The nicotine curve attained in plasma with patches is
flat, without the high peaks attained by cigarette
smoking. It is much easier to administer the patch and
to use it compared with gum, but it is not possible to
self-titrate.22 The recommended treatment duration is
8–12 weeks.
In a multicenter smoking cessation trial from the
USA, examining the effect of 0, 7-mg, 14-mg, and
21-mg nicotine patches, a dose–response effect of
increasing nicotine dosages was reported.23 Two large
placebo-controlled trials with 600 and 1686 smokers
have been published.24,25 The one-year success rate was
9.3% in the active patch group versus 5.0% in the placebo patch group in the first study,24 and 9.0% versus
6.3% in the other study.25 Among 19 studies examining
long-term (i.e. 6–12 months) smoking cessation success, 10 showed a significant outcome in favor of the
nicotine patch.22 The pooled success rate was 15.8% for
active patches versus 8.8% for placebos (odds ratio
1.98; 95% CI 1.70–2.30).
46 Textbook of Lung Cancer
Side-effects are mainly mild local skin irritation,
occurring in 10–20% of subjects. In only 1.5–2.0% of
subjects was the patch terminated owing to more persistent and severe skin irritation at the patch location.22
Because of its ease of use, the patch may be the first
choice of nicotine delivery system today. Transdermal
nicotine replacement does increase success in smoking
cessation with minimal adjunctive support.
Nicotine inhaler
An inhaler consists of a mouthpiece and a plastic tube
with a porous plug impregnated with nicotine, which
releases nicotine vapor when air is drawn through the
plug. Most of the nicotine is absorbed through the
mouth and throat. Each inhaler contains 10 mg of nicotine (Table 5.5). In clinical use, each inhaler releases
approximately 2–3 mg of nicotine, and the number of
inhalers used daily averages five or six. Thus, nicotine
levels comparable to those found during use of the
2-mg nicotine gum are attainable (i.e. relatively low
concentrations).
Few controlled trials have been conducted with nicotine inhalers. The efficacy and safety of the nicotine
inhaler were examined in a double-blind, clinical,
smoking cessation trial.26 The first published study was
a one-year, randomized, double-blind, placebo-controlled trial that enrolled 286 smokers. The success rates
for smoking cessation were 15% and 5% at 12 months
(p < 0.001) for active and placebo, respectively. The
mean nicotine substitution based on determinations
after one to two weeks of therapy was 38–43% of smoking levels. The treatment was well accepted, and no
serious adverse events were reported. Three other studies have confirmed the above finding, with odds ratios
in favor of active treatment of 1.6, 2.2, and 1.6.27 The
inhaler may replace some of the habit patterns associated with smoking (e.g. oral and handling reinforcement), along with providing nicotine replacement. At
least four inhalers should be used per day, the optimal
number being 4–10 per day and the duration of use
three months, with another 3–9 months of use and
downtitration if needed. With rapid and frequent puffing, it is possible to increase the dose.
Nicotine nasal spray
The nicotine nasal spray (NNS) consists of a multidose,
hand-driven, pump spray with nicotine solution. Each
puff contains 0.5 mg nicotine; thus a 1-mg dose is delivered if both nostrils are sprayed as recommended
(Table 5.5). The NNS is a strong and rapid means of
delivering nicotine into the body with a pharmacokinetic
profile closer to cigarettes. After a single dose of 1 mg
nicotine, the peak level is reached within 5–10 minutes,
with average plasma trough levels of 16 ng/ml. Three
published studies with the NNS indicate that the
one-year success rates for active NNS versus placebo,
respectively, were 26% and 10%, 27% and 15%, and
27% and 17%.28,29
This strong spray induces localized side-effects, such
as sneezing, nasal secretion and irritation, and congestion, watery eyes, and coughing. Up to 5% of subjects
rate these side-effects as unacceptable; however, most
symptoms decrease within a few days after the spray is
initiated. Highly nicotine-dependent smokers might be
the target group for this delivery mode of nicotine.
The NNS should be used for three months, but has
been used for up to one year in some studies. The dose
is from 10 to 40 puffs in each nostril per day.
Nicotine sublingual tablet/lozenge
The 2-mg sublingual tablet should be placed under the
tongue, where it will disintegrate within 20 minutes.
The 1-mg and 2-mg lozenges should be sucked at until
a strong taste appears, they should then rest in the
cheek for a few minutes and then the cycle is repeated
for 15–20 minutes. The nicotine released from the tablet will be absorbed through the oral mucous membrane and the dose delivered is comparable with the
2-mg nicotine chewing gum.30 Side-effects are similar
to those from the nicotine gum. Many subjects with
dentures who cannot use nicotine gum can use tablets
or lozenges.
The tablet/lozenge should be used for three months,
but duration of treatment should be individualized
for up to one year or longer. One tablet per hour is
the recommended dosage up to 20/day, with a maximum dose up to 40 tablets/day in highly dependent
smokers.
Combination of two different NRTs
Relatively few studies have been published about the
combination of two NRT products. A short-term
increase in success has been observed in some, and a
trend towards a statistically significant 12-month
increase has been found in meta-analysis.14
A dose–response effect has been observed with both
the nicotine gum and patch. Even 22- and 44-mg
patches have been tested with promising results after
four weeks of treatment, i.e. success rates of 45% and
68%. In two studies the degree of nicotine substitution
was compared to outcome and in both higher success
rates were found with increasing degree of substitution.
Smoking cessation programs 47
In the CEASE study comprising 3575 subjects, a higher
success rate was achieved with 25-mg 16-hour patches
compared with 15-mg nicotine patches.31
Overall, in clinical use the combinations of different
NRT administration forms seem safe with few sideeffects. Also, concomitant use of NRT and cigarette
smoking seems safe, with nicotine concentrations similar
to those found during normal cigarette smoking.
VARENICLINE
Varenicline affects the central nicotine receptors by
binding to the nicotine receptor as an agonist with some
antagonist action. This means that varenicline mimicks
the effect of nicotine, but also prevents the pleasure
from cigarette smoking by preventing nicotine from
binding to the receptor. In two studies with 1025 and
1027 smokers with similar design, varenicline 1 mg bid
was compared with bupropionSR 150 mg bid versus
placebo for three months.32,33 The quit rate after 1 year
was 22% and 23% for varenicline, 16.4% and 15% for
bupropionSR, and 8.4% and 10.3% for placebo, i.e.
there were significantly higher quit rates for varenicline
versus placebo and bupropionSR.
A relapse prevention study reported that, in subjects
who had quit after 3 months, prolongation of varenicline use for another three months resulted in a higher
quit rate after one year.34 The major side-effect was
nausea in approximately 30% of cases, with 2–3% discontinuing the drug due to nausea and vomiting. However, in most subjects the nausea was not a major
problem. No drug interactions have been found, and
no significant contraindications have been reported,
except severe renal failure. Varenicline has no effect on
post-cessation weight gain.
Overall, varenicline is a new, effective, and safe agent
for smoking cessation. Also, varenicline tends to be more
effective than bupropionSR. Varenicline should be considered a first-line drug in lung cancer patients.
The dosing should be varenicline 0.5 mg a.m. for
3 days, 0.5 mg bid for another 3 days, then quit cigarettes from day 7 and continue with 1 mg varenicline
bid for 12 weeks and, if needed, up to six months.
of 19 placebo-controlled studies reported a doubling of
quit rates with an odds ratio of 2.06 (95% CI 1.8–2.4)
in favor of bupropionSR.35
The recommended dosing for bupropionSR is
150 mg a.m. for one week prior to the quit date, in order
to establish adequate blood levels. Therapy should then
continue with 150 mg bid for 7–12 weeks.
Common adverse events from bupropionSR are
insomnia (up to 40%) and dry mouth. These sideeffects usually decline during the first week of therapy.
In clinical trials the treatment was stopped due to
adverse events in 10–12% of subjects. The most serious
adverse event was epileptic seizures, which were
reported in 0.1% of patients, and allergic reactions
(1–2%), with 0.1% cases of serious hypersensitivity.35,36
The formulation is slow release to prevent high peak
concentrations as seizures are concentration-dependent.
BupropionSR is contraindicated in individuals with an
increased risk of seizures (e.g. epilepsy, earlier head
trauma, anorexia nervosa). A reduced dose – that is,
one tablet daily – is recommended in patients with
severe liver impairment. As bupropionSR is metabolized in the liver, interactions occur with several drugs.
Similarly, it is important not to increase the dose above
300 mg, and to administer the daily dose in divided
form, with an interval of at least eight hours. The last
dose should not be taken later than 6 p.m. if insomnia
is a problem. Post-cessation weight gain is reduced by
2–3 kg during the drug treatment period.
There are few studies comparing bupropionSR
with NRT or looking at the combination effect; however,
the combination seems safe and is recommended for
hard-core smokers such as lung cancer patients.
BupropionSR is of similar efficacy to NRT and is
generally well tolerated in smoking cessation. As bupropionSR has a more severe side-effect profile, more contraindications, and is only available on prescription,
I regard NRT as first-line medication and bupropionSR
as a second-line drug, but this is a matter of personal
judgment and in most guidelines bupropionSR is a
first-line medication. The dosing should be bupropionSR 150 mg a.m. for 6 days, then quit cigarettes from
day 7 and continue with 150 mg bid for 7–12 weeks
and, if needed, up to six months (see Table 5.11).
BUPROPIONSR
OTHER DRUGS
BupropionSR, an amino-ketone, is an antidepressant that
differs from tricyclic antidepressants and serotonin reuptake inhibitors, and the effect on smoking is not coupled to the antidepressive effect per se. A meta-analysis
Nortriptyline, a tricyclic antidepressant, has been shown
to be as effective as NRT and bupropionSR in smoking
cessation. A meta-analysis of four trials found an odds
48 Textbook of Lung Cancer
Table 5.11 BupropionSR use
10+ cigarettes/day
• BupropionSR 150 mg in the morning
for 7 days
• Quit smoking after 7 days
• Increase dose: bupropionSR 150 mg b.i.d.
• Duration: 7–12 weeks
• Side-effects: sleep disturbances, seizures in
1:2000
• Contraindications: epilepsy, increased risk of
seizures, impaired liver function
It might be used as a secondary drug, especially in
smokers afraid of or not accepting weight gain. Rimonabant has been marketed as a weight-reducing agent due
to the low efficacy in smoking cessation.
Several nicotine vaccines are under development.
The principle is to produce antibodies in the blood that
prevent most of the inhaled nicotine from cigarettes
from reaching the brain. Phase II studies have found
that it is possible to induce a long-term antibody level
in humans with a safe vaccine and that high antibody
response is associated with smoking cessation.40
ALTERNATIVE THERAPIES
ratio of 2.8 (1.7–4.6) for one-year quit rates for nortriptyline versus placebo at a dose of 50–75 mg daily.37
There are contraindications, common anticholinergic
side-effects, and particularly cardiac conduction disturbances and a decrease in orthostatic blood pressure.
However, at the relatively low dose used for smoking
cessation, nortriptyline seems to be relatively well tolerated and is a second-line agent or even first-line agent,
especially in countries that cannot afford the more
expensive first-line drugs or where they are not marketed. Several other antidepressants including selective
serotonin re-uptake inhibitors have not been found to
be effective in smoking cessation, e.g. doxepin, fluoxetine, sertraline, moclobemide, and venlafaxine.
Clonidine, an α2-noradrenergic agonist, has been
used as a smoking cessation agent. Six studies were
included in a meta-analysis comprising 722 subjects,
and the odds ratio of success with clonidine versus placebo was 1.89 (95% CI 1.30–2.74).38 However, a high
incidence of adverse effects (median 71%) occurred
(e.g. dry mouth, sedation, dizziness, and symptomatic
postural hypotension). In my opinion – due to the high
incidence of adverse events – clonidine is an obsolete
drug in this area.
NEW DRUGS
Rimonabant is a cannabinoid type 1 receptor antagonist
with a central action and has been tested in smoking
cessation trials. Preliminary results showed an increased
three month quit rate with rimonabant, with relatively
low absolute abstinence rates.39 Rimonabant more or
less prevents post-cessation weight gain; however,
when the drug is ceased weight increases. The role
of rimonabant in smoking cessation has to be defined.
Other ‘popular’ interventions often used are acupuncture and hypnosis. However, there is no evidence to
support an effect from hypnosis or other alternative
therapies. A meta-analysis comparing active versus
control acupuncture found that acupuncture was no
more effective than placebo.41 One study reported no
effect for laser therapy in 320 adolescents.42
SMOKING REDUCTION
Many smokers would prefer to reduce the number of
cigarettes smoked daily instead of quitting completely.
The aim of smoking reduction is to widen access to cessation by including smokers not currently able or willing to stop abruptly, wanting to reduce smoking, or
unable or unwilling to quit. As shown below, by the
concept of smoking reduction it is possible to recruit a
new segment of smokers who are not interested in
abrupt cessation. The reduction process should be
looked at as a gateway to complete cessation.
The definition of smoking reduction is a decrease in
the number of cigarettes (or tobacco) smoked daily. A
50% reduction or more in daily cigarettes has been
chosen arbitrarily in most studies.43,44
Several randomized controlled trials have been published. In eight studies, two using nicotine inhalers
and six using nicotine chewing gum for half to one
year, comprising 2424 smokers, a reduction (>50%)
was reported in 15.9% of smokers using nicotine products compared with a reduction in 6.7% of placebo
users.45 Surprisingly, after one year a smoking cessation
rate of 8.4% was found among nicotine users versus
4.1% in placebo users. A reduction of more than 50%
after 3–4 months had a strong predictive value for
quitting at one year. Also, participation in reduction
Smoking cessation programs 49
trials increased the motivation to quit smoking,
thus not undermining the motivation to stop smoking
completely.
Another way to attain smoking reduction and reduce
the harm of smoking could be through tobacco product
modification.46 For the group of smokers not motivated
to quit smoking a less hazardous cigarette might be an
advantage. Also, smokeless tobacco (chewing tobacco
and snuff) might be an alternative with tobacco smoking,
with fewer health risks compared with smoking.47 Epidemiologic studies in Sweden have found much less
harm in snuff users compared with cigarette smokers.48
The smoking reduction concept should be offered to
smokers who are not motivated to quit. They should be
prescribed NRT – nicotine gum or inhaler – for three
months and recommended to reduce the number of
cigarettes by at least 50% during the first 1–2 weeks
and then to try to reduce further. If the smoker has not
reduced by more than 50% after three months, NRT
should be stopped as the chance of quitting then is low.
In smokers who have reduced by more than 50%, NRT
should be continued for up to one year, and after six
months they should be recommended to try to stop
smoking completely.
In summary, smoking reduction seems to have a role
for smokers not motivated or able to quit, as a gateway
to complete cessation. There is limited evidence that
smoking reduction is followed by an improvement in
health, in contrast to the use of smokeless tobacco
products.
SPECIAL CONSIDERATIONS FOR LUNG
CANCER PATIENTS WHO SMOKE
In this group of patients as many as 80% quit smoking
during the time of diagnosis.49 However, up to 50% of
patients undergoing curative surgery for lung cancer
relapse and smoke after five years, thus increasing the
risk of a secondary primary lung cancer.50,51 In healthy
smokers a high relapse rate is observed during the first
month after quit day, in contrast to cancer patients
where most relapses occur between one and six months
after quit day.52,53
An increasing proportion of lung cancer patients
undergo chemotherapy and this proportion will probably further increase during the next decade due to
increased public focus on this disease. Thus, in the
future most patients will undergo treatment with surgery and/or chemotherapy. The importance of smoking
cessation is due to a decreased complication rate after
surgery and during chemotherapy and radiation therapy if the patient has stopped smoking.
The period of diagnosis and therapy might elicit
depressive reactions and put a heavy strain on the
patient’s and family’s mental and social situations. Many
family members of lung cancer patients are often smokers and do not quit spontaneously during this period.54
It might also be that lung cancer patients are more
nicotine dependent.55 Overall, this calls for a more
intensive and aggressive effort to get these patients to
successfully quit smoking. A nurse-managed program
reported an abstinence rate of 40% after six weeks.54 A
combination of nicotine patch with another NRT product should be the rule, and also a longer duration of
treatment with the possibility to continue long term
with NRT. A combination of NRT and bupropionSR
might also be an option. However, as many of these
smokers have tried NRT previously, varenicline might
be the right option for these dependent smokers. Scheduled visits with smoking cessation counseling and
support are important, to be combined eventually with
telephone calls.
In healthy smokers higher quit rates have been
obtained if spouses are also enrolled in the same program and quit smoking, and this might also prove to be
the case for lung cancer patients. For the small fraction
of lung cancer patients with the lowest performance
status, where only supportive therapy is prescribed and
who have an expected short survival time, I would not
actively suggest smoking cessation.
The clinics involved with the diagnostics and therapy
of lung cancer should be able to cover smoking
cessation, and the health-care workers should have an
adequate knowledge about smoking cessation.52 It is
important that a specific budget is allocated to each
clinic for a smoking cessation service.
WEIGHT GAIN
A weight gain of 3 to 6 kg for abstainers after one year
is found in most studies.56,57 In 10% of males and 13%
of females the weight increase is more than 14 kg, i.e.
they are ‘supergainers’. About half of the participants
are afraid of gaining weight and it may be a more
significant problem for females. Weight gain can be
regarded as a withdrawal symptom due to increased
hunger and increased caloric intake. NRT products are
only partially able to reduce the post-cessation weight
gain while bupropionSR has a slightly greater effect, i.e.
a reduction in post-cessation weight gain of 2–3 kg.57
50 Textbook of Lung Cancer
For lung cancer patients the increase in weight might
be an advantage if they are underweight. The increase
in appetite might also be an advantage for patients with
decreased appetite.
CONCLUSIONS
In summary, NRT, varenicline, and bupropionSR
almost double the one-year cessation outcome, and,
combined with counseling and behavioral strategies,
are important adjuncts for maintaining long-term smoking cessation. Nicotine gum, patch, and inhaler are first
line drugs, while NNS nasal spray is for the more heavily dependent smokers. The patch might not be the first
choice for heavily dependent smokers. The duration of
NRT treatment is approximately three months, with
individual variations.
NRT is a very cost-effective treatment compared with
several other medical treatments, and should be much
more widely implemented in the future. If the smoker
has failed using NRT, varenicline or bupropionSR is the
choice.
As lung cancer patients might be more nicotinedependent and have more difficulty in stopping smoking, a more aggressive therapeutic approach should be
used, i.e. higher doses of NRT, a combination of two
NRT formulations, varenicline, bupropionSR plus NRT,
a longer duration of therapy (6–12 months), and more
support visits. Family members who smoke should also
be enrolled in a cessation program.
Most lung cancer patients have used NRT previously,
varenicline seems to be the drug of choice as it seems
more effective than bupropionSR, with fewer adverse
effects and almost no contraindications or interactions.
Also, varenicline tends to be more effective when compared with bupropionSR.
Physicians and other health-care providers have
an obligation to discourage tobacco use in their
patients and to deliver up-to-date assistance in smoking cessation.
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6
Current status of lung cancer screening
James L Mulshine
Contents Introduction • Current evidence • Technical innovations with CT imaging • Recommendations
from professional societies • Recent developments • Conclusion
INTRODUCTION
Lung cancer screening is the crucible where providing
an expensive new service with the potential for harm in
vast numbers of variably at-risk individuals collides
with the consequences of the world’s most lethal cancer. With over 160 000 annual deaths, lung cancer
accounts for 30% of cancer deaths in the USA.1 Regional
or distant metastatic spread is evident in at least threequarters of lung cancer cases at time of initial diagnosis
resulting in a 5-year survival rate of 15%. For surgically
resected cancer, the 5-year survival rate exceeds 60%.
By comparison, localized breast and prostate cancer are
detected at rates of 63 and 82%, so correspondingly
their 5-year survival rates are much better at 87 and
98%, respectively. For women, there has been a 600%
increase in the frequency in lung cancer over the last
eighty years, and lung cancer death rates in United
States women are the least favorable in the world.2 Unlike
cardiovascular disease, the risk of developing lung
cancer remains elevated after smoking cessation.3–5
Lung cancers are being diagnosed at least as frequently
in the over 45 million former smokers as in current
smokers,3 and smoking cessation strategies are of no
utility in the growing cohort of former smokers. The
progress in cardiovascular disease has not been matched
in lung cancer outcomes, so this cancer has recently
emerged as the dominant cause of death in tobaccoexposed individuals.6 Tobacco-related diseases are the
leading cause of premature death and account for half
of health-care costs in our society, so better approaches
to lung cancer management are critical.7
Promising reports with high-resolution computed
tomography (CT) detection have renewed interest in
early lung cancer screening.4,8–11 No major lung cancer
screening trial has been completed here in decades and
the recent United States Preventive Services Task Force
(USPSTF) analysis acknowledges the methodologic limitations of the previous chest X-ray screening trials.12–14
Lingering debate about those earlier trials has fostered
concern about CT-based lung cancer detection being not
only prohibitively expensive but possibly dangerous.15–17
Against this charged back drop, it is timely to review the
status of early lung cancer detection.
CURRENT EVIDENCE
A number of CT screening pilot studies have been
reported over the last few years (Table 6.1). While there
are different eligibility criteria and case work-up
approaches, these single-arm studies have been consistent for several critical parameters. Frequency of stage I
detection with CT screening is about 80%, which is
considerably higher than the national experience of
17%.1 This published experience is too recent to have
long-term clinical outcomes except for a recently presented Japanese series. From 1975–1993, the Anti-lung
Cancer Association performed 26 338 screening chest
X-rays,18 and in the detected cases 42% were stage I
lung cancer with an average primary size of 3 cm and
33% were stage III/IV. During 1993, this group began
using CT and, by 2002, 15 342 scans had been performed. With CT screening, 78% of the detected cases
were stage I with a mean diameter of 1.5 cm and the
rate of detection for stage III/VI disease had decreased
to 14%. With this transition, the overall 5-year survival
improved from 49% with chest X-ray-detected cases to
84% with CT-detected cases. This experience is consistent with the early reports from the International-Early
Lung Cancer Action Project (I-ELCAP), whose screening experience with current and former smokers was
presented with prevalence evaluation of over 26 000
subjects and follow-up incidence data from 19 700
subjects.19,20
The critical endpoint of a randomized trial is significant cancer-related mortality reduction in the
screened population compared to a control population.
The randomized trial design addresses the potentially
confounding influence of overdiagnosis. The term
54 Textbook of Lung Cancer
Table 6.1 Distillation of the pilot CT screening results for non-small cell lung cancer
No of subjects
Prevalence
cohorts8,37,38,67,71
Incidence
cohorts33,37,38,67,71
Number of CT-detected
lung cancers tumors
Mean size of
primary (mm)
Percent stage I
cancers
13 122
112
16.5
79
9 401
54
14.8
81
‘overdiagnosis’ refers to clinical outcome events not
adjusted for disease that would remain clinically covert
until death from other causes. If there is considerable
overdiagnosis, an apparently favorable screening result
in regard to stage or 5-year survival would not lead to
a significant lung cancer mortality reduction in the
screened arm. With current information it is not possible to establish a reliable estimate of the magnitude of
overdiagnosis, but emerging clinical and biologic information suggests that these small screen-detected lung
cancers may behave like symptom-detected lung
cancers.21,22
Furthermore, the term ‘overdiagnosis’ is used loosely
and may be construed to include the situation where a
clinically aggressive lung cancer is detected by CT
screening. However, in certain situations overdiagnosis
also refers to the patient who expires first of a co-morbid
condition related to tobacco yeast. In the decades since
the last major NCI-sponsored lung cancer screening trials, the influence of competing risks has diminished
related to both improved coronary artery disease outcomes and the increasing number of former smokers
perhaps mitigating the influence of overdiagnosis.6,23–25
Finally, overdiagnosis could also be construed as cases
where lethal iatrogenic complications occur in the course
of clinical management of screen-detected lesions.26
Overtreatment refers to the use of an intervention that
may entail greater morbidity than benefit of screening
that may be accrued to an individual choosing to undergo
lung cancer screening.
The best clinical management for small CT-detected
primary cancers is emerging to be different from the
standard management recommended for a chest X-raydetected lung cancer.27,28 For example, an anatomic
lobectomy with mediastinal dissection is the appropriate operation to manage a chest X-ray-detected lung
cancer, but is it the best way to remove a 7 mm peripheral primary lung cancer? Since even with subcentimeter screen-detected primary cancers, the frequency of
regional nodal involvement remains around 10%, the
optimal size range for finding lung cancers before lymphatic dissemination must be even smaller. Nevertheless, the evidence for more favorable outcomes in
managing smaller primary lung cancers is growing.29–36
From the experience in Tokyo, Rochester (MN), New
York City, and Milan, it is evident that centers of excellence can deliver high-quality lung cancer screening
care and measures reducing the number of invasive
diagnostic procedures improve cost efficiencies.8,33,37–40
Professional groups such as the Society for Thoracic
Surgery have developed national registries as a tool
for improving quality outcomes in thoracic surgery
(http://www.sts.org/doc/8406), and these measures may
allow favorable management outcomes to become more
generalized.4,41 Currently, the best approach to reducing
overtreatment, and with it the morbidity and mortality
of screening case management, is an area of uncertainty,
but clear research opportunities exist and preliminary
studies in this regard are being undertaken.42–45
An important finding at both Mayo Clinic and Cornell is that smoking cessation counseling in the setting
of lung cancer screening is associated with favorable
quit rates.46,47 Tobacco control has been the dominant
public health response for improving lung cancer outcomes.48 Linking smoking cessation with early detection research efforts may improve the cost economy of
lung cancer screening.
In light of the reports suggesting spiral CT can detect
small, early lung cancer, the NCI rapidly initiated the
National Lung Cancer Screening Trial (NLST) to evaluate whether CT screening leads to a significant improvement in lung cancer-related mortality. This urgency
was heightened by the concern that widespread ad hoc
CT screening, despite being a non-reimbursed service,
could preempt the opportunity for conducting a formal
randomized trial. Based on favorable initial data, many
people believe that lung cancer screening will be a
sensitive test for early disease. While this may be true
for many individuals, from a public health policy perspective it is also necessary to place emphasis on the
Current status of lung cancer screening 55
specificity of a screening test. The specificity of the
screening test will affect the resultant costs to society, in
terms of morbidity and dollars, in regard to overdiagnosis, overtreatment, false positives, and adverse events
associated with appropriate treatment. Conventional
wisdom is that these factors can only be assessed in a
prospective, randomized trial with a control group and
a lung cancer mortality endpoint.
The NLST, which has already completed full accrual,
uses multi-detector-row scanners (at least four rows)
for the 25 000 volunteers on the CT arm of that trial.
The control group of 25 000 receives annual chest X-ray
screening. The NLST subjects will receive annual
screening for three years, and follow-up will continue
for a few years until a mortality endpoint is reached.
The Dutch national randomized CT screening trial will
use 16-detector scanners and computer-assisted-detection (CAD) tools for their entire study population and
compare outcomes with a standard care control arm.
Other European trials including studies in France and
Italy are coming online. Investigators from the American and European trials will have periodic meetings to
standardize elements of data acquisition so that comparison of results from the various trials may be more
productive.
While breast cancer screening trials were conducted
over several decades with relative stability of the imaging detection tool,49 the dynamic pace of innovation
with spiral CT and its consequences have imposed an
unprecedented challenge to the randomized trial design
concept.50,51 Thoughtful analysis of the relative utility of
different trial designs, large databases, and other
resources in permitting adaptive public health progress
is a profound strategic challenge, but one that merits
more serious attention.19,41
TECHNICAL INNOVATIONS WITH CT IMAGING
Over the last decade, there have been substantial
improvements in the speed and quality of CT imaging.
Ten years ago, a typical single-detector CT scanner
acquiring one centimeter thick views (slices) along the
entire axial length of the thorax took several minutes
and consequently the respiratory motion of chest structures seriously compromised image resolution. Since
then there have been several generations of multi-detector CT scanners; the latest 64-detector-row scanners
will image the entire thorax using 0.625 mm slice thicknesses in several seconds. This thinner slice thickness
may allow for markedly better image resolution, but the
amount of data generated in this process is daunting.
Currently, the average size of incident primary cancers
detected at one center is under 1.0 cm.27,52,53 The gap
between the technical capabilities of the hardware in
acquiring vast amounts of imaging data and the availability of validated software to harness this improved
imaging capability highlights the importance of research
into CAD for early cancers. A potential benefit of higher-resolution imaging is that the evaluation may be
more sensitive in finding smaller primary cancers. This
size reduction may further decrease the frequency of
metastatic disease as well as interval-detected cancer.27–
32
A particular problem in this regard is the reliable
detection of curable small cell lung cancer cases.
CAD has not had a major clinical impact on breast
cancer imaging,54 but this is a two-dimensional data situation. With the anatomically more precise, three-dimensional spiral CT, this situation could be different for lung
cancer. The additional information provided by the third
dimension greatly improves the precision of measurement and of volume comparisons across time.55–57
If CT screening is validated to be effective, many
more lung CT scans will be performed. Even with
screening high-risk cohorts, the frequency of cancer in
a high-risk population will typically be about 1% or
less, so software to allow efficient work flow is essential
to leveraging the productivity of thoracic radiologists.
However, to reliably establish clinically relevant features such as the irregular boundary of small pulmonary lesions abutting normal adjacent structures, the
amount of imaging information required by a CAD system may exceed the amount of imaging information
that it is reasonable to expect a radiologist to review.
This disconnection will be most evident when CAD is
being applied to evaluate very small lesions, where
human vision has limited capabilities and determining
the ‘ground truth’ will be problematic. Therefore, developing and validating CAD applications for cancer
screening are great challenges, but standardized image
evaluation tools may prove essential in moving population-based lung cancer screening into routine care
settings.54,58–60 For this reason, the NCI developed the
Lung Image Database Consortium (LIDC) to accelerate
the maturation of image-processing tools for CAD. The
key aspect of this cooperative group is to create a large,
well-characterized database of images and clinical outcomes data for CAD algorithm research and validation.
This resource could expedite such projects as the utility
of volumetrically determined growth rates for identifying potential cancerous pulmonary nodules53,61 or
studies on the natural history of newly reported
56 Textbook of Lung Cancer
ground-glass opacities (or non-solid nodules).39,42,62
Rapid progress with CT-based imaging is expected to
continue. To extract clinically significant information
from such a detail-rich image, computer-assisted tools
will be crucial. The further pragmatic issues encountered in the breast cancer screening efforts in regard to
radiologists’ workload, reimbursement, and professional liability may also be ameliorated if validated
computer-aided diagnosis methods are developed.63,64
A major concern about widespread CT screening
relates to its cost, especially in light of one study which
projected enormous costs from models assembled using
assumptions based on early screening reports.15 More
extensive use of non-invasive imaging techniques in the
work-up of screen-detected lesions may explain why
the cost features of some screening management
approaches are less expensive.65 Only 13% of the
screened cases require further follow-up, with most of
those cases evaluated by serial CT imaging for nodule
growth rate.52,53,61 Further potential for cost savings and
morbidity reductions can be achieved by carefully
defining the risk features of the screened cohort,66
by reducing the screening intensity in following up
screen-negative populations,67 as well as from further
innovation with the imaging technology.
RECOMMENDATIONS FROM PROFESSIONAL
SOCIETIES
The American Cancer Society (ACS) updated its statement on testing for early lung cancer and recommended
against testing for early lung cancer in the asymptomatic population of at-risk individuals.68 However, this
revised statement recommends that individuals at high
risk for lung cancer, due to significant exposure to
tobacco smoke or occupational exposure, should discuss with their physician the potential benefits and
harm to inform their testing decision. ACS further recommends that such testing be done only in experienced
centers linked to multidisciplinary specialty groups for
diagnosis and follow-up.69
Table 6.2 Points to consider for clinicians in discussing lung cancer screening and its implications with individuals considering
spiral CT screening
•
•
•
•
•
•
•
•
•
•
•
The risk and benefits of lung cancer screening should be discussed, including potential morbidity,
mortality, and associated medical costs
No data are available from the two randomized trials evaluating for improvement in lung cancer-related
mortality and results are expected in several years
Results from observational studies of CT screening among high-risk patients (i.e. those with a history of
heavy smoking) indicate a high rate of diagnosis of lung cancer in stage I (a relatively curable stage)
The risk:benefit issues around lung cancer screening may be different for current smokers compared to
former smokers.
• For current smokers, smoking cessation remains the single most important measure to improve one’s
overall but especially cardiovascular health prospects
• For former smokers, the elevated risk of developing lung cancers persists for the rest of their lives
CT screening reveals many non-calcified nodules, only a fraction of which will be found to be lung cancer
The approach to diagnostic evaluation of suspicious nodules should be refined to maximize information
yield from non-invasive procedures while minimizing iatrogenic risk
Referral to a facility that is experienced and committed to providing high-quality integrated screening care
is essential. At such a facility there would be experienced and credentialed clinicians from
multidisciplinary fields (including thoracic surgeon, pathologist, pulmonologist)
The surgeon selected to perform the lung cancer operation should not only be specifically trained to
provide such care but should also perform lung cancer operations frequently
Facilities providing lung cancer screening care should provide objective information about the quality of
their outcomes
There is a persistent increased risk of subsequent lung cancers after curative resection of lung cancer, so
ongoing surveillance is essential
Participation in research to optimize CT screening management should be strongly encouraged
Current status of lung cancer screening 57
The conclusions from the USPSTF analysis, based on
a review of the literature published as of January 2003,
(http://www.ahrq.gov/clinic/uspstf/uspslung.htm) are as
follows:
The USPSTF recommends neither for nor against
using chest x-ray, computed tomography (CT scan),
or sputum cytological examination to look for lung
cancer in people who have no symptoms to suggest
the disease. If screening is being considered, doctors
and patients should discuss the pros and cons of
screening before going ahead with x-ray, CT scan, or
sputum cytologic examination to screen for lung
cancer. Patients should be aware that there are no
studies showing that screening helps people live longer. They should also know that false-positive test
results are common and can lead to unnecessary
worry, testing, and surgery.12
This statement represents a change from their previous
recommendation against screening and this reflects the
accumulation of more persuasive though not yet definitive data regarding the utility of lung cancer screening.
As a reflection of the extraordinary pace of this field, a
number of relevant reports have been published since
the completion of the USPSTF literature review on new
cohorts,18,38,39 efficiency of the diagnostic work-up,27,53,70
outcomes,72,73 and cost-effectiveness.45,65
In this dynamic setting, clinicians have a major challenge in staying abreast to provide current information
to their patients. Issues to consider in discussion with a
patient who may be considering lung cancer screening
are complex. In light of recent reports about health literacy there is a major communications challenge in responsibly educating about lung cancer screening (see
http://www.iom.edu/report.asp?id=19723 and http://
www.ahrq.gov/clinic/epcsums/litsum.htm).
Since the clinical management for lung cancer screening has a higher probability of morbid and mortal complications than cancer screening for other organs, a
mortality reduction benefit found by the NLST may not
result in improved national outcomes with lung cancer
if screening care delivery systems for early lung cancer
are not in place.41 The choice is between organized
screenings, where screening services are provided in
centers committed to excellence in early cancer management, or ad hoc screening, where the specifics of
screening care are left to be refined by market forces.
We recently tried to organize a series of issues that
should help physicians organize their dialog with
subjects considering lung cancer screening.72
RECENT DEVELOPMENTS
The New England Journal of Medicine recently published
a landmark experience in using spiral CT in over 31 000
individuals at risk for lung cancers from 38 institutions
across three continents.73 Over the last 15 years, the
group at Cornell, together with their collaborators, has
systematically explored the best approach to finding
and operating on early lung cancer. In a series of peerreviewed publications they have defined innovative
uses of spiral CT, image processing techniques, and
internet-based clinical trial co-ordination, driving progress in the detection and management of early lung
cancer. There is controversy about the benefit of CTbased screening for lung cancer, but there should be no
argument about the core strategy of attempting to
improve our ability to routinely find early, localized
lung cancer.
In community-based populations, finding early lung
cancer is a daunting process since disease prevalence is
relatively low. Finding economic approaches to detect
and confirm the occurrence of lung cancer in this setting is a critical public health challenge. The Cornell
group has described a successful approach to this and
has integrated minimally invasive diagnostic and surgical techniques as feasible for early lung cancer management. In addition, they have worked with a number of
the most respected thoracic pathologists in the world
(mostly from IASLC) to review these cases and, in their
recent publication, reported that the cases found by CT
screening fulfill standard criteria for fully fledged aggressive lung cancers.74 This supports recent tumor biology
information suggesting that these screen-detected
tumors behave like routinely detected lung cancers.22
Of the more than 400 cancers recently reported in the
Cornell study, 85% of the detected cases were stage I.
The 10-year survival analysis, after three years of median
follow-up, shows that over 90% of the people undergoing operations were projected to be alive and lung cancer free. All eight individuals who for personal reasons
declined surgery died of lung cancer.
A key enabler of this large study consortium was the
use of a web-based early lung cancer management system developed by the Cornell group which allowed
research to go on in the setting of clinical care. The current I-ELCAP results convincingly demonstrate that
systematic efforts to find early lung cancer can be associated with very favorable outcomes and their organizational process accelerates early lung cancer research. A
challenging debate is proceeding about the sufficiency
58 Textbook of Lung Cancer
of the I-ELCAP data to change national health-care
policy on lung cancer screening. This is a profoundly
important scientific, medical, and political process.
However, the IASLC could play a pivotal role in generating the research data to inform the process. There are
many steps in moving to responsible management of
early lung cancer and we need better information about
all of them. How do we identify the optimal cohort,
how do we do the diagnostic work-up, how do we do
the most appropriate removal of the primary cancer,
how frequently do we do follow-up CT scans to find
synchronous primaries, etc. These and many more
issues need to be addressed with research using stateof-the-art imaging tools. Since the progress in improving imaging tools is moving so fast, it is a major challenge
for our research processes. This is a part of the discussion about early detection research that merits much
more serious and urgent research attention. The contentious discussion surrounding screening trial design
has distracted us from a profound emerging opportunity to much more successfully manage lung cancer.
CONCLUSION
CT screening for lung cancer detection has considerable promise. Yet many individuals seeking lung cancer
screening services, such as the lower-risk subject outlined in the introductory vignette, may have a greater
chance of iatrogenic harm that screening benefit. While
definitive trials are in progress, the opportunity should
not be lost to conduct further essential research to generalize a potential mortality reduction benefit evident in
a lung cancer screening trial to routine care settings.
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7
Histopathology of lung tumors
Elisabeth Brambilla, Sylvie Lantuejoul
Contents Introduction • Squamous cell carcinoma • Adenocarcinoma • Small cell carcinoma
• Large cell carcinoma • Adenosquamous carcinoma • Sarcomatoid carcinoma
• Typical and atypical carcinoid • Conclusions
INTRODUCTION
With 169 500 new cases per year in the United States
and 182 000 new cases per year in Europe, lung cancer
is the most common worldwide diagnosed cancer and
the major cause of mortality,1 with157 400 cancer
deaths2 in the USA and 190 000 cancer deaths in the
European Union in 2001. Although cancer incidence
began to decline in men in the USA from 1980,3 its rate
is increasing in women,2 as a consequence of the
increasing proportion of women who smoke.
The international standard for histologic classification of lung tumors is that proposed by the World
Health Organization (WHO) and the International
Association for the Study of Lung Cancer (IASLC;
Table 7.1).4 The four major histologic types of lung
cancer are squamous cell carcinoma, adenocarcinoma,
the incidence of which is increasing at the expense of
squamous cell carcinoma, small cell carcinoma (SCLC),
and large cell carcinoma. These major types have been
subclassified into subtypes, the clinical significance of
which might be extremely important, such as the bronchioloalveolar carcinoma (BAC) as a variant of adenocarcinoma.4
Although lung cancer can be divided into many subtypes, the most important distinction is between SCLC
and non-small cell lung carcinoma (NSCLC). Clinical
importance has been given to this distinction because
of the major clinical differences in presentation, metastatic spread, and response to therapy of SCLC. However, this is an extremely simplistic means of distinction
between these subtypes which is not recommended
because it may override the clinical significance of specific subtypes like BAC. Histologic heterogeneity is an
important feature of the pathology of lung cancer,
which consists of a mixture of histologic types that represent a derivation of lung cancer from a pluripotent
stem cell.5–10 This histologic heterogeneity is apparent
on light microscopic examination in at least 30% of
lung cancers, and is even more frequently seen by
electron microscopy.
SQUAMOUS CELL CARCINOMA
A malignant epithelial tumor showing keratinization
and/or intercellular bridges that arises from bronchial
epithelium.11
Squamous cell carcinoma (SCC) accounts for approximately 30% of all lung cancers in the United States12
and 45% in Europe. Twenty years ago it was the most
frequent histologic type of lung cancer in Europe, and
it has progressively decreased, while adenocarcinoma
has increased in incidence. Over 90% of SCC occurs in
cigarette smokers. Two-thirds of SCCs present as central tumors, whereas one-third present as peripheral
tumors, although the primary bronchial site may be
easily detected at histology.13,14 The morphologic features that characterize squamous differentiation include
intercellular bridging and keratinization (or individual
cell keratinization or squamous pearl formation). These
differentiated features are readily apparent in well-differentiated tumors, and are difficult to detect in poorly
differentiated ones.15 However, this spectrum of differentiation has not been demonstrated to correlate with
prognosis in lung SCC. Segmental bronchi more often
than lobar and mainstem bronchi are the primary site
of SCC.16
Variants described in the WHO classification include
papillary, clear cell, small cell,17 and basaloid subtypes.4
This last variant has a dismal prognosis as compared to
poorly differentiated SCC.18,19 In a recent evaluation of
a large series of cases where basaloid carcinoma appeared
to have a shorter survival than other types of NSCLC
(p = 0.005) the basaloid variant of SCC did not differ
from pure basaloid cases with regard to survival.20
Papillary SCC often shows a pattern of exophytic endobronchial growth.21,22
62 Textbook of Lung Cancer
Table 7.1 WHO histologic classification of tumors
of the lung
Table 7.1 Continued
Malignant epithelial tumors
Squamous cell carcinoma
Papillary
Clear cell
Small cell
Basaloid
8070/3
8052/3
8084/3
8073/3
8083/3
Small cell carcinoma
Combined small cell carcinoma
8041/3
8045/3
Adenocarcinoma
Adenocarcinoma, mixed subtype
Acinar adenocarcinoma
Papillary adenocarcinoma
Bronchioloalveolar carcinoma
Non-mucinous
Mucinous
Mixed non-mucinous and
mucinous or indeterminate
Solid adenocarcinoma with mucin
production
Fetal adenocarcinoma
Mucinous (‘colloid’) carcinoma
Mucinous cystadenocarcinoma
Signet ring adenocarcinoma
Clear cell adenocarcinoma
8140/3
8255/3
8550/3
8260/3
8250/3
8252/3
8253/3
8254/3
Large cell carcinoma
Large cell neuroendocrine carcinoma
Combined large cell
neuroendocrine carcinoma
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Large cell carcinoma with
rhabdoid phenotype
8012/3
8013/3
8013/3
Adenosquamous carcinoma
8560/3
Sarcomatoid carcinoma
Pleomorphic carcinoma
Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
8033/3
8022/3
8032/3
8031/3
8980/3
8972/3
Carcinoid tumor
Typical carcinoid
Atypical carcinoid
8240/3
8240/3
8249/3
8230/3
8333/3
8480/3
8470/3
8490/3
8310/3
8123/3
8082/3
8310/3
8014/3
(Continued)
Salivary gland tumors
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma
Preinvasive lesions
Squamous carcinoma in situ
Atypical adenomatous hyperplasia
Diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia
Mesenchymal tumors
Epithelioid hemangioendothelioma
Angiosarcoma
Pleuropulmonary blastoma
Chondroma
Congenial peribronchial
myofibroblastic tumor
Diffuse pulmonary lymphangiomatosis
Inflammatory myofibroblastic tumor
Lymphangioleiomyomatosis
Synovial sarcoma
Monophasic
Biphasic
Pulmonary artery sarcoma
Pulmonary vein sarcoma
Benign epithelial tumors
Papillomas
Squamous cell papilloma
Exophytic
Inverted
Glandular papilloma
Mixed squamous cell and glandular
papilloma
Adenomas
Alveolar adenoma
Papillary adenoma
Adenomas of the salivary gland type
Ta
Mucous gland adenoma
Pleomorphic adenoma
Others
Mucinous cystadenoma
Lymphoproliferative tumors
Marginal zone B-cell lymphoma
of the MALT type
Diffuse large B-cell lymphoma
8430/3
8200/3
8562/3
8070/2
9133/1
9120/3
8973/3
9220/0
8827/1
8825/1
9174/1
9040/3
9041/3
9043/3
8800/3
8800/3
8052/0
8052/0
8053/0
8260/0
8560/0
8251/0
8260/0
8140/0
8940/0
8470/0
9699/3
9680/3
(Continued)
Histopathology of lung tumors 63
Table 7.1 Continued
Lymphomatoid granulomatosis
Langerhans cell histiocytosis
Miscellaneous tumors
Harmatoma
Sclerosing hemangioma
Clear cell tumor
Germ cell tumors
Teratoma, mature
Immature
Other germ cell tumors
Intrapulmonary thymoma
Melanoma
Metastatic tumors
9766/1
9751/1
8832/0
8005/0
9080/0
9080/3
8580/1
8720/3
From WHO Classification of Tumors, 2004.
Behavior is coded /0 for benign tumors, /3 for malignant tumors, and /1
for borderline or uncertain behavior.
ADENOCARCINOMA
A malignant epithelial tumor with glandular differentiation
or mucin production, showing acinar, papillary, bronchioloalveolar, or solid with mucin growth patterns, or a mixture
of these patterns.
Adenocarcinoma can be classified into:
•
•
•
•
•
•
•
•
•
adenocarcinoma mixed subtype;
acinar adenocarcinoma;
papillary adenocarcinoma;
bronchioloalveolar carcinoma;
– non-mucinous
– mucinous
– mixed non-mucinous and mucinous
– solid adenocarcinoma with mucin production.
Variants are:
fetal adenocarcinoma;
mucinous (‘colloid’) carcinoma;
mucinous cystadenocarcinoma;
signet ring adenocarcinoma;
clear cell adenocarcinoma.
Adenocarcinomas account for about 30% of lung
cancers in Europe and the USA.12 Most primary pulmonary adenocarcinomas, in contrast with metastases, are
highly heterogeneous and consist of a mixture of histologic subtypes. Most adenocarcinomas are histologically heterogeneous, consisting of two or more of the
histologic subtypes and whilst a majority of the lung
adenocarcinomas diagnosed are classified today into
the mixed subtype. For this reason the adenocarcinoma
mixed subtype was moved to the top of the list of adenocarcinoma subtypes in the 2004 WHO classification,
although it was not recognized in the 1981 WHO
classification.23 The acinar and papillary subtypes are
recognized by their architectural pattern of tumor cell
growth and invasion. A substantially different definition has been given to bronchioloalveolar carcinoma
(BAC subtype), which should be restricted to tumors
that grow in a purely lepidic fashion without invasion
of stroma, blood vessels, or pleura. The solid type is a
poorly differentiated carcinoma presenting intracytoplasmic mucins that should be of at least five mucin
droplets in two different high-power fields. Mucin
stains recommended are PAS (periodic acid–Schiff)
with diastase digestion and Kreyberg staining with
alcian blue.
Several additional unusual variants have also been
recognized, such as well-differentiated fetal adenocarcinoma,24 mucinous (‘colloid’) adenocarcinoma,25 mucinous cystadenocarcinoma,26–28 signet ring carcinoma,29
and clear cell adenocarcinoma.4 Two unusual gross
patterns of adenocarcinoma include the endobronchial
polypoid adenocarcinoma30 and pseudomesotheliomatous adenocarcinoma.31–33
Bronchioloalveolar carcinoma is uncommon, and
probably restricted to fewer than 5% of all lung malignancies.12 In the new 1999 WHO/IASLC classification,
BAC is defined as a tumor showing lepidic growth
along pre-existing alveolar septa with intact elastic and
basal lamina frames, without invasive growth. It should
be noticed that some increased fibrotic collagen deposit
of alveolar walls is accepted, as long as no myofibroblastic proliferation is visible. The lack of invasive
growth is added as an essential criterion4 based on clinico-pathologic data indicating that in patients with less
than a 2 cm tumor, BAC may be curable by economic
surgical resection.34 As a result of the narrow criteria for
BAC, the term ‘adenocarcinoma, mixed subtype’ is used
for tumors that have BAC and an invasive component.
In such cases the invasive patterns present (acinar, papillary, or solid) should be mentioned. It is common to
observe central scars in pulmonary adenocarcinoma
that contain invasive components and a focal BAC-like
pattern at the periphery of the tumor.
As a consequence of this revised definition of BAC,
the literature dealing with these tumors need complete
re-evaluation. Indeed, previous to the last classification,
BAC included tumors with obvious invasive growth.23,35,36
More than 50% of tumors previously classified as BACs
presented focal central desmoplastic scarring tissue or
64 Textbook of Lung Cancer
intra-alveolar complex papillary growth while the lepidic
growth started around the edge of the scar.37 For tumors
showing malignant tumor cell nests in a desmoplastic
stromal reaction, the diagnosis is adenocarcinoma mixed
subtype and the various subtypes present should be
mentioned (such as acinar, papillary, or BAC). These are
no longer considered as pure BAC.13,37 In addition, filling of alveolar lumens by papillary or micropapillary
structures is considered to be papillary adenocarcinoma,
but not bronchioloalveolar carcinoma.
BAC has two major cytologic subtypes, non-mucinous
and mucinous,4 and are rarely mixed, consisting of an
association of mucinous and non-mucinous cells.4 The
majority of BACs are mucin-producing, followed by the
non-mucinous type, while about 12% are a mixture of
both.37,38
Non-mucinous BACs consist of Clara cells and type
II pneumocytes; the latter cell type is a common stem
cell for distal bronchioles and alveoli identified in fetal
lung and is nowadays considered as the lung adenocarcinoma stem cell.39 The non-mucinous BACs are more
likely to be solitary38 than the mucinous type. These
tumors are composed of cuboidal cells proliferating
along alveolar septa and showing a hobnail appearance.
Specific nuclear inclusions are patent in half of the nonmucinous tumor cells that are stained with diastasedigested PAS and immunohistochemically for surfactant
apoprotein. On electron microscopy, these inclusions
form a network of 40-nm diameter microtubules.40,41
The mucin-producing BACs tend to be more multicentric and characteristically have mucin production.38
They may cause lobar consolidation resembling pneumonia on gross examination. Histologically, these
tumors consist of tall columnar cells with abundant apical cytoplasmic mucin and small, basally oriented, regular bland nuclei lining thin alveolar septa. Alveolar and
bronchiolar spaces are filled with abundant mucin.
According to the 1999 WHO/IASLC classification, a
final diagnosis of BAC can only be achieved on examination of a surgical resection specimen. Small biopsies
obtained by bronchoscopy or fine needle sampling may
show a lepidic growth pattern suggesting the possibility
of BAC, but are not sufficient to exclude the presence of
an invasive growth.
Pathoradiologic correlations
There are several growth presentations for the most
common adenocarcinoma mixed subtype with BAC:
•
•
a solitary nodule;
multiple nodules;
•
•
lobar consolidation;
diffuse (pseudopneumonic) consolidation pattern.
The typical radiologic appearance of BAC (pure BAC
or BAC component) is the ground glass pattern by CT
and an ill-defined, aerated, spongy density on gross
examination. In contrast, a grossly circumscribed nodule at growth examination and a pure solid appearance
on CT is typical of purely invasive adenocarcinoma
(acinar, papillary, solid). In between, a mixture of
these growths and CT appearances is seen in mixed
subtype adenocarcinoma with both invasive (often centrally located) components and BAC component (often
peripheral). When BAC and other adenocarcinomas
present with multiple nodules they can be unilateral or
bilateral. Unilateral nodules are classified as T4 by the
TNM classification and multiple nodules in another
lobe are classified as M1. Lobar consolidation and diffuse pseudopneumonic condensation patterns are difficult to distinguish grossly or radiologically from
infective pneumonia. All cases of adenocarcinoma
presenting with a diffuse or pseudopneumonic consolidation pattern have been shown to correspond to
mixed subtype adenocarcinoma with BAC component.
They are more frequently of the mucinous cell type,
with varying amounts of acinar, papillary, and solid
components.
Prognostic correlations with solitary small
peripheral lung nodules
Several important clinico-pathologic studies have
shown the clinical significance of BAC.34,42,43 Noguchi
et al34 reported that, in a large series of 236 peripheral
lung adenocarcinomas less than 2 cm in size, the
patients achieved 100% 5-year survival. These were
pure BACs, in contrast to patients with ‘invasive BAC’
who experienced higher mortality and a 5-year survival
of 75%, while the purely invasive form had a 5-year
survival of 52%. Suzuki et al42 demonstrated that the
size of the fibrotic scar was correlated with survival in
a series of 100 peripheral adenocarcinomas less that
3 cm in size: a 5-year survival of 100% was recorded
for patients with a scar size of 5 mm or less, in contrast
to 70% for patients with scars 5 to 15 mm in size
and 40% for patients with a central scar greater than
15 mm. In this study, the size of central fibrosis was
an independent prognostic factor on multivariate analysis (p = 0.01), as significant as vascular invasion
(p = 0.024) and lymph node metastasis (p = 0.024).
Yokose et al43 studied multiple pathologic factors for
prognostic assessment in 200 patients: 100% 5-year
Histopathology of lung tumors 65
survival was associated with at least one of the following
features:
•
•
•
a pattern of lepidic growth of more than 75%;
a central scar measuring 5 mm or less;
lack of destruction of the elastic fiber framework
by tumor cells.43
The most significant determinants of shorter survival
in the multivariate analysis were vascular invasion
(p < 0.001) and more than 25% papillary or invasive
growth (p = 0.043). Size and grade/pattern of stromal
invasion44,45 also influence survival. This has practical
consequences: all small (≤3 cm) tumors with a predominant BAC component should be entirely sampled serially, and included so that potential foci of invasion are
detected.
BAC is not a unique feature for lung adenocarcinoma
since about 15% of digestive mucinous carcinoma
metastases might mimic the histologic appearance of
BAC. Thyroid transcription factor-1 (TTF-1) immunostaining restricted to primary lung adenocarcinoma is
of great help in this distinction.
SMALL CELL CARCINOMA
A malignant epithelial tumor consisting of small cells with
scant cytoplasm, ill-defined cell borders, finely granular
nuclear chromatin, and absent or inconspicuous nucleoli.
The cells are round, oval, and spindle-shaped.
SCLC accounts for 25% of all lung cancers in
the USA as well as in Europe.12 Two-thirds of SCLCs
are proximal and present as a perihilar tumor. They
occur in a bronchial location, infiltrating the bronchial
submucosa and subsequently leading to bronchial
obstruction by circumferential compression. SCLCs are
not commonly observed on a surgical specimen since
extensive lymph node metastasis is common and the
tumor is not surgically curable. Macroscopically the
tumor is soft, friable, white-tan, and extensively necrotic.
Extensive lymph node metastasis is very frequent and
less than 5% of cases present as a solitary coin
lesion.46,47
The 1999 WHO/IASLC classification presents only
two types of SCLC: SCLC (with pure SCLC histology)
and combined SCLC (combined with any non-small cell
type) (see Table 7.1).4 The two subtypes oat cell carcinoma and intermediate cell type, that were proposed
in the 1981 WHO classification, as well as the category
of mixed small cell, large cell, proposed in 1988 by
the IASLC, were discarded from the new classification
because of difficulties in reproducibility of these subtypes and lack of confirmation that these patients have a
different prognosis.48,49
SCLC has a distinctive histologic appearance. The
tumor cells have a small size, not exceeding that of
three lymphocytes. They have a round or fusiform
shape, scant cytoplasm with a nuclear to cytoplasmic
ratio of 9 to 10, a finely granular nuclear chromatin
(‘salt and pepper’ appearance), and absent or inconspicuous nucleoli.4 Owing to the scarcity of cytoplasm,
nuclear molding and smearing of nuclear chromatin is
frequent, caused by crush artifacts. There is usually
extensive necrosis and a mitotic rate exceeding 20 and
reaching 100 mitoses per 2 mm2 area. Most often, the
growth pattern consists of diffuse sheets, although
endocrine differentiations with rosettes, palisading, ribbons, and organoid nesting might be seen.50 Basophilic
encrustation of vessel walls is known as the Azzopardi
effect in necrotic areas.50
Depending on the biopsy specimens, the tumor cell
size of SCLC might appear larger, which is often the
case in well-fixed open biopsies.
Fine needle aspiration (FNA) biopsy and core biopsy
may provide excellent material for assessment of the
diagnosis of SCLC, essentially because cytologic features of SCLC have a high diagnostic value and the
architecture is not critical for the diagnosis. The small
cell proliferation, with nuclear moulding, the very high
nuclear to cytoplasmic ratio, and the ‘salt and pepper’
quality of chromatin are extremely useful for this diagnosis on FNA. The diagnostic markers (NE markers,
TTF-1, absence of CK34βE12 expression) are of primary help in the diagnosis of SCLC. There is an excellent yield of these markers on FNA and/or biopsy.
Combined small cell lung cancer
The frequency of combined SCLC depends on the
extent of histologic sampling, and the extent of the
associated component. Combined SCLC represents
about 10%49 of SCLC if small biopsies are considered.
However, in a recent study on surgically treated SCLC,
using a conservative estimate of 10% of tumors showing associated NSCLC for subclassifying a tumor as a
combined variant of SCLC, 28% of the cases of SCLC
showed a combination with NSCLC, more commonly
with large cell lung carcinoma followed by adenocarcinoma and squamous cell carcinoma.48,49,51–53 SCLC can
also be associated, although rarely, with spindle cell
carcinoma,54,55 giant cell carcinoma,54 and carcinosarcoma.56 Immunohistochemistry might help to differentiate associated components, such as cytokeratin antibody
66 Textbook of Lung Cancer
cocktails, which tend to stain NSCLC components, a
good example of which is cytokeratin 1, 5, 10, 14 recognized by 34βE12.57 However, evidence is lacking
that pure and combined SCLC behaves differently with
regard to prognosis and response to therapy.51 Following chemotherapy, a mixture of large cells, squamous
cells, adenocarcinoma or giant cells with SCLC may be
seen in 15 to 45% of the cases.52,58–60
Differential diagnosis
Because SCLC has distinctive clinical properties with
an aggressive clinical course, frequent widespread
metastasis of presentation, common paraneoplastic
syndrome, and responsiveness to chemotherapy, histologic classification of lung cancer often is simplified
into SCLC versus NSCLC. A constellation of criteria is
applied for the distinction between SCLC and large
cell neuroendocrine carcinoma (LCNEC) including cell
size, nucleoli, nuclear-to-cytoplasmic ratio, nuclear
chromatin pattern, nuclear molding, cell shape (fusiform versus polygonal), and Azzopardi phenomenon
(Table 7.2).4,23,61,62
Disagreement among expert lung cancer pathologists
over this distinction occurs in up to 10% of cases,10,63
owing to the fact that sometimes LCNEC may adopt the
nuclear features of SCLC. With the new description of
LCNEC, the main differential resides in the distinction
of SCLC from LCNEC (Table 7.2). Crush artifact is
common in small biopsy specimens owing to scarcity of
stromal protection; this can also be seen in carcinoid
tumors, lymphocytic infiltrates, or poorly differentiated
NSCLC. In these cases, cytology specimens might be
helpful because the morphology may be more diagnostic than on a small biopsy specimen. Immunohistochemistry for neuroendocrine differentiation, keratins,
and common leukocyte antigen (lymphoid marker) can
be useful in marking SCLC versus lymphoid cells,
respectively.64 TTF-1 has been shown to be of great
help in distinguishing between SCLCs, which are 85%
positive for TTF-1 nuclear staining, and other proliferating small cells such as the small cell variant of
squamous cell carcinoma and basaloid carcinoma, both
of which are always TTF-1 negative.57,65 The most useful and specific neuroendocrine markers for distinction
of SCLC in formalin-fixed, paraffin-embedded tissue
sections are chromogranin A, synaptophysin, and neural cell adhesion molecule, especially the 123C3 clone
and CD56.61,66–70 Keratin (AE1/AE3) and epithelial
membrane antigen (EMA) as well as TTF-1 stain virtually all SCLCs in open lung biopsy and transbronchial
biopsy specimens.57,61,65,66 In contrast, a specific set of
cytokeratins never expressed in neuroendocrine proliferations (CK 1, 5, 10, 14) called 34βE12 is always absent
in pure SCLC. In the cases where common cytokeratins
Table 7.2 Light microscopic features for distinguishing small cell carcinoma and large cell neuroendocrine carcinomaa
Histologic feature
Small cell carcinoma
Large cell neuroendocrine
carcinoma
Cell size
Larger
Nuclear/cytoplasmic ratio
Nuclear chromatin
Smaller (less than diameter
of 3 lymphocytes)
Higher
Finely granular, uniform
Nucleoli
Absent or faint
Nuclear molding
Fusiform shape
Polygonal shape with
ample pink cytoplasm
Nuclear smear
Basophilic staining of
vessels and stroma
Characteristic
Common
Uncharacteristic
Lower
Coarsely granular or vesicular,
less uniform
Often (not always) present,
may be prominent or faint
Less prominent
Uncommon
Characteristic
Frequent
Occasional
Uncommon
Rare
a
From Travis WD, Linnoila RI, Tsokos MG, et al.61 Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma.
An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15: 529–533, 1991; with permission.
Histopathology of lung tumors 67
Table 7.3 Histochemical differential diagnosis between
small cell lung carcinoma (SCLC), basaloid carcinoma, and
large cell neuroendocrine carcinoma (LCNEC)
SCLC
Basaloid
carcinoma
LCNEC
NE markers
TTF-1
Cytokeratins
1, 5, 10, 14
+
−
+
−
−
+
+
+/−
−
are negative in a suspected SCLC, the pathologist
should exclude other possibilities such as chronic
inflammation, lymphoma (CD45 positive), primitive
neuroectodermal tumor, or small cell round sarcoma.
One difficulty resides in the fact that about 25% of
SCLCs express the antigen CD99/MIC-2, as do primitive neuroectodermal tumors and small round cell sarcoma. It is important to recognize that this distinction
is based primarily on light microscopy (Table 7.2).4
Since no single monoclonal antibody can reliably
distinguish SCLC from NSCLC,70,71 a set of reliable
markers should be considered (Table 7.3).
LARGE CELL CARCINOMA
Large cell carcinoma is a tumor that shows no differentiation pattern to allow classification into squamous cell
carcinoma, adenocarcinoma, or small cell carcinoma.
These poorly differentiated tumors most often arise in
the lung periphery, although they may be located centrally. They frequently appear at gross examination as
large, necrotic tumors. Histologically, these consist of
sheets or nests of large polygonal cells with vesicular
nuclei and prominent nucleoli.23 Although they are
undifferentiated by light microscopy, features of
squamous cell or adenocarcinoma might be found on
electron microscopy examination.6,7,72
There are several variants of large cell carcinoma, some
of which have high clinical significance, recognized in
the new WHO/IASLC histologic classification of lung
cancer (Table 7.1).4 These include LCNEC,4,61,73 basaloid
carcinoma,18,19,74 lymphoepithelial-like carcinoma,75–77
clear cell carcinoma,78 and large cell carcinoma with
rhabdoid phenotype.79 Lymphoepithelial-like carcinoma is described as an EBV (Epstein–Barr virus)
dependent epithelial proliferation more commonly seen
in the upper respiratory tract.
Because lung cancers are classified according to the
best differentiated component, areas of large cell carcinoma are frequently observed in poorly differentiated
adenocarcinoma or squamous cell carcinoma, and due
to the common heterogeneity of these cancers it is difficult to specifically and appropriately classify many
lung cancers in which only small pieces of tissue are
available. In such cases, the best diagnosis might be
‘non-small cell carcinoma’ and specification of the most
obvious component.5,80,81
Large cell neuroendocrine carcinoma
LCNEC is a variant of large cell carcinoma. It is a highgrade non-small cell neuroendocrine carcinoma that
differs from atypical carcinoid and small cell carcinoma.
Histologic criteria include:
(1) neuroendocrine morphology (organoid, palisading,
trabecular, or rosette-like growth patterns;
(2) non-small cell cytologic features (large size, polygonal shape, low nuclear to cytoplasmic (N/C) ratio,
coarse or vesicular nuclear chromatin, and obvious
nucleoli);
(3) high mitotic rate (≥11 per 2 mm2) with a mean of
60 mitoses per 2 mm2;
(4) frequent necrosis; and
(5) at least one positive neuroendocrine immunohistochemical specific marker or neuroendocrine
granules by electron microscopy.4,61
It is difficult to diagnose LCNEC based on small
biopsy specimens because of frequent lack of neuroendocrine morphology without a substantial sampling of
the tumors. Some criteria have been proposed based on
cytology.82
The term combined LCNEC is used for tumors associated with other histologic types of NSCLC, such as
adenocarcinoma or squamous cell carcinoma (Table 7.1).4
Any combination of LCNEC with SCLC is diagnosed as
SCLC combined.4 A variety of criteria must be used to
separate SCLC from LCNEC (Table 7.2).
Differential diagnosis
In 10% of the cases of NSCLC lacking neuroendocrine
morphology, immunohistochemical neuroendocrine
markers or neuroendocrine granules by electron microscopy can be demonstrated. Such tumors are called nonsmall cell carcinomas (adenocarcinoma, squamous cell
carcinoma, or large cell carcinoma) with neuroendocrine
differentiation (NSCLC-NED).4,61 Although Iyoda et al83
found that the tumor size of large cell carcinoma with
68 Textbook of Lung Cancer
neuroendocrine differentiation was significantly larger
than that for LCNEC, the survival was not different
in this series from patients with LCNEC. At the present
time, the clinical significance of the diagnosis of NSCLCNED is not known. Whether these tumors are responsive
to SCLC chemotherapy regimens84–86 or whether expression of neuroendocrine markers may be an unfavorable
prognostic factor87–94 remains to be determined.
show no staining in small cell, large cell and LNEC
whereas it stains quite all basaloid carcinoma. TTF-1 is
never present in basaloid carcinoma, but is present in
the majority of SCLC and LCNEC (Table 7.3).57,95 p63
is expressed in most cells of all basaloid carcinomas.
Basaloid carcinoma
Basaloid carcinoma is the most prominent variant of
large cell carcinoma after LCNEC.4,18,74 Basaloid carcinoma represents 3 to 4% of NSCLCs in Europe, almost
always occurs in males, and most of these tumors
develop in proximal bronchi where they frequently
have an endobronchial component. Two-thirds of these
tumors arise from long areas on the bronchial mucosa
and show prolonged and laterally extended in situ carcinoma. About half of the tumors present with a pure
basaloid pattern that belongs to a variant of large cell
carcinoma. The remaining cases have minor (less than
50%) components of squamous cell carcinoma or, more
rarely, adenocarcinoma and are thus classified as
squamous cell carcinoma (basaloid variant) or adenocarcinoma, respectively. These tumors consist of a lobular, trabecular, or palisading gross pattern of relatively
small monomorphic cuboidal to fusiform cells with
moderately hyperchromatic nuclei, finely granular
chromatin, absent or only focally conspicuous nucleoli,
scant cytoplasm but a nuclear to cytoplasmic ratio lower
than that of SCLC, and a high mitotic rate from 20 to
100 mitoses per 2 mm2. Neither intercellular bridges
nor individual cell keratinization are present which
allows them to be distinguished from poorly differentiated squamous cell carcinoma. Patients with basaloid
carcinoma have a significantly shorter survival than
those with poorly differentiated squamous cell carcinoma which deserves this differential diagnosis.18,19,74
Adenosquamous carcinoma accounts for 0.6 to 2.3% of
all lung cancers96–100 and is defined as a lung carcinoma
having at least 10% of squamous cell or adenocarcinoma components.4 Adenosquamous carcinoma should
not be confused with mucoepidermoid carcinoma, a
malignant epithelial tumor characterized by the presence of squamoid cells, mucin-secreting cells, and cells
having intermediate type, identical to the same tumors
encountered in the salivary glands. Mucoepidermoid
carcinoma of high-grade malignancy is differentiated
from adenocarcinoma by a variety of features including
a mixture of mucin-containing cells and squamoid cells,
transition areas from classic low-grade mucoepidermoid carcinoma, and lack of keratinization.
Differential diagnosis
Since comedo type necrosis is common, palisading is a
characteristic feature of basaloid carcinoma, and rosettes
can be identified in about one-third of cases, the main
differential diagnosis resides in separation from LCNEC.
Immunohistochemical stains for neuroendocrine markers are negative in basaloid carcinoma and positive in
LCNEC. No secretory granules have been seen by electron microscopy in basaloid carcinoma. Two antibodies
are helpful to make the distinction on small biopsies
between basaloid carcinoma, SCLC, and LCNEC. The
specific cytokeratins 1, 5, 10, 14 recognized by 34βE12
ADENOSQUAMOUS CARCINOMA
SARCOMATOID CARCINOMA
This group of lung carcinomas is poorly differentiated
and expresses a spectrum of pleomorphic, sarcomatoid,
and sarcomatous elements. They express the features and
the biological behavior of epithelial cells that adopt an
epithelial to mesenchymal transition in certain conditions of culture in vitro. Pleomorphic carcinomas tend
to be large peripheral tumors invading bronchial
lumens, forming endobronchial growth. They often
invade the chest wall and are associated with a poor
prognosis.54 Because of the characteristic histologic heterogeneity of this tumor, adequate sampling is required
and should consist of at least one section per centimeter of the tumor diameter. To enter in this category a
pleomorphic carcinoma should have at least a 10%
component of spindle or giant cells associated with, but
distinctly identifiable from, other histologic types
such as adenocarcinoma or squamous cell carcinoma.4
A few giant cells disseminated in an otherwise recognizable squamous cell adenocarcinoma or SCLC have no
value for classification in the category of sarcomatoid
carcinoma.
Rarely carcinomas present with a pure giant cell or
spindle cell pattern and deserve the terms giant cell or
spindle cell carcinoma. Giant cell carcinoma consists of
Histopathology of lung tumors 69
huge, bizarre, pleomorphic and multinucleated tumor
cells that engulf numerous inflammatory cells, particularly polymorphonuclear leukocytes, in their cytoplasm.101–
103
They are discohesive and separated by significant
infiltration of inflammatory cells. This tumor is defined
as a carcinoma by light microscopy, but immunohistochemical and epithelial markers such as keratins
are also quite helpful in confirming their epithelial
nature.4
Carcinosarcoma
Carcinosarcoma is a tumor composed of a mixture of
carcinoma and sarcoma. A heterologous component
should be demonstrated such as cartilage, bone, or
skeletal muscle – heterologous elements which do not
display cytokeratin staining.4 Experience proves that
these cases are extremely rare while observations of
pseudochondromatous or pseudo-osseous patterns in
sarcomatoid carcinoma are frequent: in these cases the
pseudosarcomatous components also express keratins.
Pulmonary blastoma
Pulmonary blastomas are defined as biphasic tumors
consisting of an association of a glandular component
that resembles well-differentiated fetal adenocarcinoma
and a primitive sarcomatous or mesenchymal component.4 Well-differentiated fetal adenocarcinoma is no
longer regarded as the epithelial pattern of monophasic
pulmonary blastoma but, rather, as a variant of adenocarcinoma.4
TYPICAL AND ATYPICAL CARCINOID
Carcinoid tumors accounts for 1 to 2% of all invasive
lung malignancies.12 The majority of patients are
asymptomatic at presentation.104 Symptoms include
hemoptysis, postobstructive pneumonitis, dyspnea, paraneoplastic syndromes including carcinoid, Cushing’s
syndrome,104–106 and acromegaly.107 There is no gender
predilection.104,108 There is no association with smoking
since 40% of patients with carcinoid are non-smokers,
which is the proportion within the normal population.
The mean age is 55 years, with a range up to 82 years.104
This is the most common lung tumor in childhood.109
The treatment of choice of pulmonary carcinoids is
surgical resection.104,110 Patients with typical carcinoid
(TC) have an excellent prognosis and rarely die from
their tumors.104,111 However, metastases do not disqualify the diagnosis of typical carcinoid. Five to ten percent
of TCs have regional lymph node involvement that does
not affect their clinical outcome.13 Compared with TC,
atypical carcinoid (AC) presents with a larger tumor
size, higher rate of metastases, and a significantly
reduced survival. Most series where the diagnosis was
based on actual accepted criteria reported a mortality of
27 to 47%.104,112–114
Carcinoid tumors are most often centrally located
with a polypoid endobronchial obstructive component.
When peripheral carcinoids occur they are more often
of the spindle cell type. Both TC and AC are characterized histologically by an endocrinoid, organoid growth
pattern and uniform cytologic features, consisting of
moderate eosinophilic, finely granular cytoplasm, a
nucleus with a finely granular chromatin (Table 7.4),
and inconspicuous nucleoli that can be discretely more
prominent in AC. A variety of histologic patterns may
occur in AC and TC, including trabecular, palisading,
rosette-like, papillary, sclerosing papillary, glandular,
paragangliomatous, spindle cell, and follicular patterns.61 More rarely, the tumor cells of pulmonary carcinoid tumors may have oncocytic, acinic cell-like, signet
ring, mucin-producing, or melanocytic features.61
The most distinguishing feature between typical carcinoid and atypical carcinoid is the rate of mitosis and
the presence or absence of necrosis. Typical carcinoids
show less than 2 mitoses per 2 mm2 area of viable tumor
(per 10 high power field) and no necrosis. The presence of between 2 and 10 mitoses per 2 mm2 or necrosis73 defines the diagnosis of atypical carcinoids. The
presence of features such as cell pleomorphism, vascular invasion, and increased cellularity are of no help in
separating TC from AC and in allowing stratification of
patients for prediction of survival.73 TC may well show
focal cytologic pleomorphism, as do paragangliomas in
the head and neck area.61,112 The necrosis in AC usually
consists of small foci centrally located within organoid
nests of tumor cells.
Immunohistochemistry
Nearly 80% of TC and AC stain for pancytokeratins and, as other pulmonary neuroendocrine
tumors, they always express cytokeratins 8, 18, and
19.115 From a more practical standpoint, expression of
cytokeratins 1, 5, 10, and 14 has never been observed
along the whole spectrum of neuroendocrine tumors of
the lung.116
Neuroendocrine markers are present in all carcinoids. Chromogranin A is present in neurosecretory granules and synaptophysin is contained in synaptic
vesicles.68 They all express CD 56/NCAM, which belong
to the immunoglobulin superfamily of transmembrane
70 Textbook of Lung Cancer
Table 7.4 Typical and atypical carcinoid: distinguishing features
Histologic or clinical feature
Typical carcinoid
Atypical carcinoid
Histologic patterns: organoid,
trabecular, palisading, and
spindle cell
Mitoses
Characteristic
Characteristic
Absent or <2 per 2 mm2 area
of viable tumor (10 high power
fields on some microscopes)
Absent
2–10 per 2 mm2 or area of viable
tumor (10 high power fields
on some microscopes)
Characteristic, usually focal or
punctate
Often present
Necrosis
Nuclear pleomorphism,
hyperchromatism
Regional lymph node
metastases at presentation
Distant metastases at
presentation
Survival at 5 years
Usually absent, not sufficient
by itself for diagnosis of AC
5–15%
Disease-free survival
at 10 years
40–48%
Rare
20%
90–95%
58%
90–95%
35%
adhesion molecules, and to date, as for other neuroendocrine tumors of the lung, NCAM remains the most
useful immunohistochemical marker, even on crushed
biopsies or small specimens, in the differential diagnosis with papillary adenocarcinoma and sclerosing
hemangioma. In contrast, as widely reported, NSE
immunostaining is of little help in the diagnosis of
neuroendocrine tumors in general because of its lack of
specificity.69,117
TTF-1 expression was demonstrated to be negative
in the spectrum of neuroendocrine hyperplasia, tumorlets, and typical and carcinoid tumors.118 However,
other authors have reported some TTF-1 expression in
nearly one-third of TC and AC,119,120 predominantly in
a peripheral location.121 This discrepancy could be
related to differences in immunohistochemical techniques or in assessing the threshold of positivity. TTF-1
expression has not been demonstrated in cDNA expression profiling, whereas it is in high-grade NE tumors of
poor prognosis.122
Concerning the proliferation antigen Ki 67 in carcinoids, staining is observed in less than 10%, and an index
higher than 4%, more frequently observed in AC, seems
to be related to a shorter survival.123,124
Differential diagnosis
Carcinoids differ from tumorlets by the size of the latter,
which do not exceed 5 mm in diameter. Sclerosing
hemangiomas may resemble carcinoids, especially with
a papillary or pseudoglandular pattern. The demonstration of neuroendocrine markers and absence of TTF-1
expression distinguish carcinoids from sclerosing
hemangiomas.124 Carcinoids may be confused with
paragangliomas, but this lesion remains very rare in the
lung, and the lack of cytokeratin expression in the latter
has a discriminative feature. Glomus tumors and other
smooth muscle tumors may mimic carcinoids, from
which they are distinguished by the presence of smooth
muscle actin and the absence of neuroendocrine markers. Adenocarcinoma enters the differential diagnosis
because a gland-like pattern occurs in carcinoids. Mucin
production is not a definitive distinguishing feature
since carcinoids may disclose mucin formation. TTF-1
expression and the absence of neuroendocrine markers
in adenocarcinoma are of great help. The solid type
adenoid cystic carcinoma may be mistaken for carcinoid, but is negative for neuroendocrine markers.
CONCLUSIONS
Histologic subclassification of lung tumors is essentially
based on light microscopy in order to achieve the widest application through the world and assume comparability and consistency of data. However, techniques
including immunohistochemistry, electron microscopy,
Histopathology of lung tumors 71
tissue culture, and molecular biology might provide
valuable information on carcinogenesis, histogenesis,
and differentiation. It is well recognized that immunohistochemistry and electron microscopy may detect
differentiation, specifically regarding the histologic
heterogeneity of lung cancer, that cannot be seen by
routine light microscopy. However, these techniques
are occasionally required for precise classification.
An example of this is LCNEC and malignant mesothelioma, which require appropriate immunohistochemical and/or electron microscopic findings to confirm the
diagnosis.
15.
16.
17.
18.
19.
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8
Clinical diagnosis and basic evaluation
John J Mullon, Eric J Olson
Contents Introduction • History • Physical examination • Imaging • Diagnostic techniques
• Overview of basic evaluation • Future developments
INTRODUCTION
HISTORY
Lung cancer is the most lethal of all malignant diseases
worldwide and remains the leading cause of cancerrelated death in the United States.1 Lung cancer is
responsible for the overall increase in cancer mortality
noted over the second half of the 20th century in
the USA, which since 1999 has exceeded heart disease
as the leading cause of death in those less than 85 years
of age.1 Although the overall death rates due to lung
cancer have decreased in the USA and western Europe
since 1991, largely due to reductions in tobacco
smoking,2,3 global lung cancer incidence and mortality
rates are expected to continue to rise as a result of
the ongoing tobacco use in countries with developing
or transitional economies.4 Three- to five-year diseasefree rates for resected stage I lung cancer as high as
60 to 90% are reported, but less than 20% of all
lung cancers are stage I at the time of diagnosis and
five-year survival rates for all stages of lung cancer
remain approximately 15%.1 It is imperative that
clinicians be familiar with the evaluation of lung
cancer given its tremendous worldwide public health
impact and the prognostic importance of early cancer
detection.
Lung cancer outcome depends on the cell type
and stage of disease at presentation based on the
TNM classification. Accordingly, the essential aspects
of lung cancer evaluation are the histologic distinction
of small cell (SCLC) and non-small cell (NSCLC) types
and accurate determination of the extent of disease so
that appropriate treatment can be initiated. The evaluation of lung cancer begins with a careful history and
physical exam, followed by testing to obtain a tissue
diagnosis and stage the extent of disease. This chapter
will review aspects of clinical presentation, imaging,
and diagnostic testing for bronchogenic carcinoma.
Details regarding staging are discussed elsewhere in
this text.
Lung cancers are clinically silent for the majority of
time as they theoretically grow from a single malignant
cell to a potentially detectable lesion. The vast majority
of patients diagnosed with lung cancer are symptomatic
at the time of diagnosis. In only about 10% of cases is
lung cancer discovered incidentally in an asymptomatic
patient, for instance as a solitary pulmonary nodule on
a routine chest radiograph. Smoking history,5 concurrent chronic obstructive pulmonary disease (COPD),6
and previous exposures to certain environmental and
occupational carcinogens,7 including environmental
tobacco smoke,8 predict a higher risk for bronchogenic
carcinoma. Ethnic and racial differences also contribute
to the smoking-related risk of lung cancer, with African
Americans and native Hawaiians within the USA at
higher risk.9 Local tumor growth, regional extension,
metastases, paraneoplastic phenomenon, or a combination of mechanisms may cause tumor-associated symptoms (Table 8.1). There are no characteristics of clinical
presentation which absolutely distinguish NSCLC and
SCLC.
Local effects
The most common initial symptom of lung cancer is
cough, which occurs in 45–75% of patients,10 and may
be productive in up to 27%.11 Bronchorrhea, the expectoration of large-volume, thin, mucoid secretions, may
be seen with advanced bronchioloalveolar carcinoma
(BAC), but is rare. Due to the location of vagal afferent
cough receptors, which principally line the airway
mucosa, cancer types with a predilection for central airway involvement (notably SCLC or NSCLC in the form
of squamous cell carcinoma) may cause cough earlier in
their course, whereas peripherally located tumors such
as adenocarcinoma or large cell carcinoma may only
cause cough as a late symptom. In addition to bronchial
mucosa tumor invasion, causes of cough may include
76 Textbook of Lung Cancer
Table 8.1 Aspects of lung cancer presentation
Asymptomatic
Symptomatic
Effects of local tumor growth
Cough
Bronchorrhea
Fever, chills, purulent sputum
production (postobstructive pneumonitis)
Dyspnea
Hemoptysis
Chest pain
Wheeze
Stridor
Effects of regional tumor extension
Hemidiaphragm paralysis
Hoarseness
Dysphagia
Bronchoesophageal fistula
Pericardial effusion/tamponade/
tachyarrhythmias
Lymphangitic carcinomatosis
Pulmonary nodules
Tumor microembolism
Pleural effusion
Superior vena cava syndrome
Pancoast syndrome
Metastatic effects
Adrenal
Liver
Central nervous system
Bone
Paraneoplastic effects
See Table 8.2
postobstructive pneumonitis/atelectasis, tumor cavitation, or pleural effusion. Although cough is a nonspecific symptom frequently present in patients with
co-existent smoking-related airways disease, a change
in the character of a chronic cough, such as new hemoptysis or co-existent fever and chills, should raise suspicion of an additional process such as lung cancer. Lung
cancer is overall an unusual cause of chronic cough,
occurring in less than 2% of patients,12 and is even less
likely in the setting of a normal chest radiograph.13
One-third to one-half of patients initially report dyspnea that may arise from large airway obstruction,
postobstructive pneumonitis/atelectasis, pleural effusion, lymphangitic metastases, pericardial effusion, or
concurrent illnesses such as COPD. Dyspnea in a lung
cancer patient with a normal chest X-ray may be due to
pulmonary thromboembolism or, less commonly,
tumor microembolism. Lung cancer presents with
hemoptysis in many patients as a result of tumor necrosis, mucosal ulceration, tumor erosion into pulmonary
vasculature, postobstructive pneumonia, and pulmonary thromboembolism. Retrospective studies reveal
that bronchogenic carcinoma accounts for 19–29% of
cases of hemoptysis.14,15 In patients with a normal chest
radiograph and hemoptysis, only 2–9% are subsequently found to have lung cancer.16 Hemoptysis is
commonly blood-streaked sputum, although large central tumors may lead to massive hemoptysis that can
result in death by asphyxiation. Tumor involvement of
the parietal pleura, chest wall, and mediastinum leads
to chest pain as an initial complaint in 25–50% of
patients.17 Other causes of pain include rib cage metastases, pulmonary embolism, and postobstructive pneumonitis. Pneumothorax is a rare cause of chest pain and
dyspnea in lung cancer patients.
Regional extension effects
Direct mediastinal extension by lung cancer or metastases to mediastinal lymph nodes can lead to a variety of
presentations due to the diversity of adjacent structures.
Phrenic nerve involvement by tumor may cause ipsilateral diaphragmatic paralysis demonstrated on chest
X-ray by hemidiaphragm elevation often in the setting
of a centrally located mass. If lung cancer is not initially
identified as the etiology of diaphragm paralysis, it is
unlikely to become the explanation over time.18 Hoarseness, a finding at presentation in 5–18% of lung cancer
patients,17 is usually attributable to unilateral left vocal
paralysis resulting from damage to the left recurrent
laryngeal nerve anywhere along its intrathoracic course.
Extrinsic esophageal compression by tumor or metastatic lymph nodes may cause dysphagia. Postprandial
coughing raises the possibility of bronchoesophageal
fistula. Pericardial involvement, which may be present
in 20% of patients,17 occurs by hematogenous, lymphatic, or direct extension routes, and may cause
asymptomatic pericardial fluid/thickening detected
radiographically, tachyarrhythmias, or pericardial tamponade.
In addition to its characteristic tendency to spread to
hilar and mediastinal lymph nodes, lung cancer may
metastasize within the lung in several patterns. One
type is lymphangitic carcinomatosis, which usually
appears on chest radiography as focal or diffuse reticular or reticulonodular interstitial infiltrates and Kerley B
lines, possibly combined with central adenopathy and
Clinical diagnosis and basic evaluation 77
pleural effusions. By high-resolution chest computed
tomography (CT), this process characteristically appears
as irregular nodular thickening along bronchovascular
bundles and interlobular septa, consistent with the role
of lymphatics in this form of dissemination.19 Intrapulmonary metastases may also appear as single or multiple nodules/masses in one or both hemithoraces. A
management dilemma occurs in patients with otherwise resectable lung cancer who have one or more
radiographically indeterminate lung nodules. The differential diagnosis is broad, but includes synchronous
lung cancers, granulomatous processes, silicotic nodules, metastatic extrapulmonary malignancies, Wegener’s granulomatosis, and others. An individualized
approach to these situations is generally recommended.
Lung cancer microembolism to the pulmonary arterial
system, a rare form of intrathoracic metastasis, produces dyspnea and is very difficult to diagnose antemortem. Diagnosis has been occasionally accomplished
by cytologic examination of blood drawn through a
wedged pulmonary artery catheter.
Pleural effusion
Ten percent of all lung cancers metastasize to the pleura,
with adenocarcinoma being the most common.17,20
Malignant pleural effusions due to lung cancer are generally on the same side as the main tumor. They may be
moderate to large in size, bloody, and recurrent following thoracentesis. Pleural effusions develop in the setting of malignancy from local effects of the tumor
(pleural metastases, lymphatic obstruction, bronchial
obstruction with pneumonia or atelectasis, chylothorax), systemic effects (pulmonary thromboembolism,
hypoalbuminemia), or as complications of therapy. The
main mechanism for malignant pleural effusion formation is altered lymphatic drainage. Metastatic tumor
implants on the pleural surface may alter capillary
permeability and further increase pleural fluid formation. In most cases, metastatic involvement of the pleura
is thought to begin with hematogenous seeding of the
visceral pleura followed by subsequent movement
and attachment of tumor cells to the parietal pleural
surface.
Malignant effusions are usually exudative (effusion
meets at least one of the following criteria: pleural fluid/
serum total protein ratio >0.5, pleural fluid/serum lactate dehydrogenase [LDH] ratio >0.6, or pleural fluid
LDH > two-thirds of the upper limits of normal of the
serum). The fluid may appear serous, serosanguinous,
or frankly bloody. The initial thoracentesis of a malignant effusion reveals malignant cells 50% of the time.
The cytologic yield increases to 65% and 70% on the
second and third attempts, respectively. Pleural fluid
cytology is more sensitive than closed pleural biopsy,
primarily because pleural metastases tend to be focal
and percutaneous biopysy is performed blindly. Pleural
biopsy adds very little to the overall diagnostic yield
when combined with cytology.21 Therefore, a second
thoracentesis is usually performed rather than closed
pleural biopsy if malignant effusion is suspected. Low
pleural fluid pH (<7.30) and glucose (<60 mg/dl) values predict higher pleural fluid cytology yields, but also
predict poor response to pleurodesis and short survival
time.22
Malignant cells in pleural fluid indicate T4 or stage
IIIB disease in NSCLC and this eliminates further consideration of surgical resection. It is important to
remember, however, that the mere presence of a pleural
effusion does not categorically preclude surgery for
NSCLC. Other conditions that can cause pleural fluid
without direct tumor involvement of the pleura include
postobstructive pneumonitis/atelectasis, pulmonary
embolism, or illnesses unrelated to the tumor, such as
congestive heart failure, non-obstructive pneumonia,
and cirrhosis. Therefore, the physician must thoroughly
evaluate pleural effusion in NSCLC patients with otherwise potentially resectable disease. Unfortunately, series
have demonstrated that only 5–10% of lung cancer
patients with cytologically negative pleural effusions are
ultimately found to have operable disease.23
Superior vena cava syndrome
Several well-known syndromes result from regional
growth of lung cancer. Obstructed venous flow due to
extrinsic compression of the superior vena cava (SVC)
by adjacent bronchogenic carcinoma causes the SVC
syndrome.24 Overall, approximately 2–4% of patients
suffering from bronchogenic carcinoma will develop
the SVC syndrome;25 however occurrence is as high as
20% in those with SCLC due to its propensity to develop
in the central airways.26 Clinical manifestations result
from venous hypertension above the level of the obstruction. Symptoms and signs typically include headache
and facial fullness (which may be worse in the recumbent position), swelling and ruddiness of the face, neck,
and upper extremities, distended neck veins, and
prominent/tortuous collateral venous drainage over the
upper torso (Figure 8.1). Chest radiography may reveal
mediastinal widening or a right perihilar mass. The differential diagnosis also includes lymphoma, metastatic
extrathoracic malignancies, granulomatous mediastinal
inflammation/fibrosis, postirradiation fibrosis, and aortic
78 Textbook of Lung Cancer
Figure 8.1
Tortuous, prominent, collateral venous drainage over the upper
torso in superior vena cava syndrome. (Courtesy of JH Ryu MD,
Mayo Clinic, Rochester, MN.)
imaging (MRI) in staging is recommended and is superior to CT in determining the extent of local invasion.33
A magnetic resonance angiogram (MRA) is likewise
superior to both MRI and CT in assessing vascular
involvement.34 The majority of cases of Pancoast’s syndrome are due to NSCLC, but SCLC, metastatic extrapulmonary cancer, and infectious conditions (bacterial,
mycobacterial, and fungal) have also been implicated.
Tissue diagnosis is recommended and transthoracic
needle aspiration is frequently and successfully employed
in this regard. Pancoast’s tumors are generally found to
be stage IIB, IIIA, or IIIB lesions.
aneurysms. Although the treatment goal remains
prompt initiation of palliative chemotherapy or radiation, SVC syndrome is no longer regarded as a medical
emergency.27 Diagnostic studies can be safely executed
and a tissue diagnosis should be obtained before starting therapy. Overall treatment with radiation and/or
chemotherapy is effective in approximately 60% of
cases of SVC syndrome due to NSCLC; however recurrence occurs in almost 20%.28 The presence of SVC
syndrome is a poor Prognostic indicator for patients
with NSCLC, with a median survival of five months.29
Metastatic effects
Approximately 40–50% of NSCLC patients present with
metastatic disease that precludes surgical resection. SCLC
has an even greater propensity to metastasize earlier in
its course. Consequently, SCLC is considered a systemic
disease at time of diagnosis, even if it appears limited to
the chest. Lung cancer dissemination may occur via lymphatic, hematogenous, or interalveolar routes. Metastases to nearly every organ have been described, but the
most common sites of involvement are the lung, adrenals,
liver, central nervous system, and bone. Clinical manifestations depend upon the extent of specific organ dysfunction induced by metastases. Quoted frequencies of
metastases differ depending upon whether initial presentation or autopsy series are cited.
Pancoast’s syndrome
Pancoast’s syndrome is characterized by a tumor situated in the extreme apical region of the hemithorax
called the superior sulcus, in conjunction with ipsilateral shoulder and medial scapular discomfort. Pancoast
initially described the syndrome of shoulder and arm
pain in the distribution of the eighth cervical and first
and second thoracic nerve trunks, Horner’s syndrome,
and ipsilateral hand atrophy and weakness associated
with superior pulmonary sulcus tumors.30 Most patients
do not have all of these signs and symptoms until late
in the course of the disease. Tumor invasion of the
adjacent chest wall, brachial plexus, and sympathetic
ganglion is the cause for the clinical manifestations.
The clinical findings vary depending on the extent to
which the adjacent structures are involved. Shoulder
pain is the most common symptom, occurring in up to
88% of patients, with arm weakness noted in 40% and
Horner’s syndrome in 30%.31 Superior sulcus tumors
may manifest on chest radiography as unilateral apical
thickening (>5 mm), an apical mass (Figure 8.2), or
bony destruction.32 The use of magnetic resonance
Adrenal
Adrenal metastases are common in lung cancer. They
are usually asymptomatic and initially detected as unilateral adrenal gland enlargement on staging chest CT
extended to the upper abdomen. In two series totaling
576 NSCLC patients, 4–7.5% were found to have an isolated unilateral adrenal mass, and approximately 30–40%
of the adrenal lesions were found to be malignant.35,36
Adrenal adenomas occur in 2–10% of the general population and typically appear on CT as homogeneous,
low attenuation (due to fat content), well-circumscribed
lesions <3 cm in diameter.37 The differential diagnosis
for benign adrenal enlargement includes adrenal adenomas, nodular hyperplasia, and hemorrhagic cyst.
Chemical shift MRI has been shown to be 96% sensitive
and 100% specific for distinguishing adenomas,38 and
more recently 18F-fluoro-2-deoxy-D-glucose positron
emission tomography (18F-FDG-PET) has been shown
to be 93% sensitive and 90% specific for detecting adrenal metastases in patients with known lung cancer.39
A positive result on 18F-FDG-PET, although highly
suspicious, does not confirm the presence of adrenal
Clinical diagnosis and basic evaluation 79
(a)
(b)
Figure 8.2
(a) Posteroanterior and (b) lateral chest radiographs, and (c) CT appearance of a large right
superior sulcus tumor in a 52-year-old smoker
who presented with right shoulder pain.
Transthoracic needle aspiration revealed
squamous cell carcinoma.
(c)
metastasis, which must be further proven by CT or
endoscopic ultrasound-guided needle biopsy before
withholding potentially curative resection.
Liver
Metastatic involvement of the liver is common and
usually clinically silent early in the course of disease.
Liver metastases are particularly common with SCLC.
History and physical exam do not dependably detect
liver metastases. Liver involvement may be suggested
by abnormalities on the initial staging CT or by elevated
liver test values. Advanced liver involvement may be
associated with systemic symptoms, such as anorexia,
weight loss, and jaundice.
Central nervous system
Lung cancer is the most common cause for brain metastases, accounting for approximately 70% of cases.40 Clinical and autopsy data indicate that approximately 40% of
lung cancer patients will develop brain metastases.17 Small
cell and adenocarcinoma are the most common histologic
types of lung cancer to cause brain metastases. Although
occasionally asymptomatic, brain metastases usually cause
either non-focal symptoms, such as headache (most common), nausea, and vomiting, or focal abnormalities,
including seizures, hemi-sensorimotor changes, and cranial nerve deficits. Neurologic symptoms precede lung
cancer symptoms in most patients with concurrent disease. Metastases develop more commonly in the cerebral
hemispheres, particularly in the parietal and frontal lobes,
than in the cerebellum.41 Metastatic lesions are detected
by CT or MRI. Central nervous system metastases signal
stage IV disease and generally herald an ominous prognosis, but neuro- and radiosurgical advances have resulted
in successful treatment of brain metastases leading to
improvements in neurologic status and survival.41,42 In
SCLC the brain is a common site of relapse and prophylactic cranial irradiation is shown to confer a significant
3-year survival benefit to those patients who experience a
complete initial response.43
Other forms of central nervous involvement by metastatic lung cancer include spinal cord metastases and
80 Textbook of Lung Cancer
leptomeningeal carcinomatosis. Intraspinal lesions
usually cause back pain that is worsened by movement,
straining, and supine positioning. Neurologic deficits
from spinal cord compression, such as sensory defects
at or below the level of the lesion, paraparesis or paraplegia, and bowel/bladder incontinence tend to develop
quickly, progress rapidly, and be irreversible. In this
event, spinal metastases become a medical emergency
for which steroids should be starting pending definitive
therapy. Leptomeningeal carcinomatosis is uncommon
and uniformly predicts a short survival time. Neurologic symptoms may also result from a number of paraneoplastic syndromes, which are discussed below.
Bone
Skeletal metastases occur in approximately 25–30% of
lung cancer patients and are typically found as osteolytic lesions in the vertebral bodies, ribs, and long
bones of the arms and legs.17 These lesions usually produce pain or elevations of calcium or alkaline phosphatase.37 Twenty percent of SCLC patients may also
have bone marrow involvement, which may not initially
be accompanied by clinical or laboratory abnormalities.
Bony metastases may be detectable on plain radiographs.
If these are negative or non-diagnostic, a planar bone scan,
single photon emission computed tomogram (SPECT),
or 18F-FDG-PET scan should be obtained. Of these
three, 18F-FDG-PET is the most sensitive, but is associated with greatest expense and is not universally
available.44,45 Directed MRI of the culprit region remains
an alternative as MRI is highly sensitive and specific for
bony metastasis, although it has not yet been systematically compared to 18F-FDG-PET in this regard.
Paraneoplastic effects
Bronchogenic carcinomas are associated with paraneoplastic syndromes more than any other tumor. Ten to
twenty percent of lung cancer patients will develop
paraneoplastic syndromes.46 These diverse phenomena,
most of which are more common with SCLC, result
from effects of lung cancer on other organ systems
beyond those related to the physical presence of the
primary or metastatic lesions. The clinical manifestations are frequently non-specific and are mediated by
the ectopic production of biologically active peptides,
cytokines, and antibodies. An awareness of the paraneoplastic syndromes is important since they may be
the presenting feature of an otherwise difficult to detect
lung cancer in its earlier or recurrent stages. With the
clinically frustrating exception of the neurologic syn-
dromes, the course of most paraneoplastic syndromes
is analogous to that of the underlying lung cancer.
Table 8.2 lists the paraneoplastic syndromes associated
with lung cancer. The most common paraneoplastic
syndromes are discussed below.
Hypercalcemia
Hypercalcemia is the most frequently encountered paraneoplastic syndrome, occurring in up to 12.5% of patients
with lung cancer.47 Lung cancer is the most commonly
responsible malignancy, with squamous cell the usual
histologic type. Hypercalcemia generally results from
tumor production of parathyroid hormone-related peptide (PTHrP).48 Rarely, hypercalcemia is due to osteolytic
bony metastases or aberrant elaboration of other cytokines. PTHrP mimics the actions of endogenous parathyroid hormone (PTH), so hypercalcemia results from
heightened osteoclastic bone breakdown, decreased bone
formation, and decreased renal calcium excretion. The
manifestations of hypercalcemia are malaise, weakness,
fatigue, abdominal pain, constipation, anorexia, polydipsia, polyuria, confusion, hyporeflexia, and shortened QT
interval on electrocardiogram. Coma and death are late
manifestations. Diagnosis is made by demonstrating a
combination of increased serum ionized calcium level
(or disproportionate increase in total serum calcium
relative to the serum albumin), normal or low PTH level
by immunoassay (to rule out primary hyperparathyroidism), and exclusion of other causes of hypercalcemia
(granulomatous disorders such as sarcoidosis, hyperthyroidism, adrenal insufficiency, acute renal failure,
Paget’s disease, and medications such as thiazide diuretics and vitamin D). It is also very important to rule out
bony metastases. PTHrP is detectable by radioimmunoassay. Treatment strategies are volume repletion with normal saline, increased urinary calcium excretion with a
loop diuretic such as furosemide, decreased bony resorption with bisphosphanates, calcitonin, or gallium, and
treatment of the underlying malignancy. A novel therapeutic approach inhibiting osteoclast activity through
the use of an immunologically mediated tumor necrosis
factor receptor blockade has effectively inhibited hypercalcemia in a murine model.49 This therapeutic approach
has yet to be fully investigated. Hypercalcemia in the setting of lung cancer is generally a late complication occurring in the setting of advanced disease. The median survival
after onset of hypercalcemia is two to three months.
Syndrome of inappropriate antidiuretic hormone
The cardinal manifestation of the syndrome of inappropriate antidiuretic hormone (SIADH) is hyponatremia
Clinical diagnosis and basic evaluation 81
Table 8.2 Paraneoplastic syndromes associated with lung
cancer
Endocrine/metabolic
Hypercalcemia
Syndrome of inappropriate antidiuretic hormone
Cushing’s syndrome
Gynecomastia
Galactorrhea
Acromegaly
Carcinoid syndrome
Hyperthyroidism
Hypercalcitoninemia
Hyperglycemia
Hypoglycemia
Hypouricemia
Cachexia/anorexia
Cutaneous
Clubbing/hypertrophic osteoarthropathy
Dermatomyositis
Acanthosis nigricans
Erythema gyratum repens
Hyperpigmentation
Urticaria
Vasculitis
Pruritis
Basex’s syndrome (acrokeratosis)
Tylosis
Erythroderma
Acquired ichthyosis
Erythema annulare centrifugum
Sign of Leser–Trelat
Musculoskeletal
Polymyositis
Myopathy
Neurologic
Lambert–Eaton myasthenic syndrome
Peripheral neuropathy
Cerebellar degeneration
Limbic encephalitis
Polyradiculopathy
Myelopathy
Opsoclonus/myoclonus
Dysautonomia
Retinopathy
(Continued)
Table 8.2 Continued
Hematologic
Anemia
Polycythemia
Hypercoagulable state
Migratory thrombophlebitis
Disseminated intravascular coagulation
Non-bacterial thrombotic endocarditis
Leukocytosis/leukemoid reaction
Dysproteinemia
Eosinophilia
Thrombocytopenia purpura
Renal
Glomerulonephritis
Tubulointerstitial disorders
Nephrotic syndrome
Modified from references 37 and 46.
due to the inappropriately sustained ectopic production of arginine vasopressin (AVP; antidiuretic hormone), which acts on the distal renal tubule to promote
free-water conservation. Small cell is almost always the
underlying lung cancer histologic type.50 SIADH can
occur with equal frequency in limited and extensive
SCLC and may produce symptoms in 5% of patients.46
What, if any, prognostic significance SIADH may have
is unclear, although a recent study suggested a slightly
worse survival in those patients with limited stage SCLC
and SIADH when compared with those without SIADH.51
This is in contrast to earlier studies that found no difference in responsiveness to chemotherapy or survival
in patients with SCLC and SIADH in comparison to
those without SIADH.50,52 Clinical manifestations of
hyponatremia are due to cerebral edema and occur
more in relation to the rate of fall of the serum sodium
rather than to the absolute serum sodium level. Because
the hyponatremia usually develops slowly in SIADH,
many patients are asymptomatic at presentation. Early
symptoms include fatigue, weakness, nausea, and
anorexia. The diagnostic criteria for SIADH are hyponatremia, serum hypoosmolality (<275 mosm/kg), inappropriately increased urine osmolality (>200 mosm/kg),
natriuresis (urine sodium >20 mEq/l), clinical euvolemia,
and the absence of renal, adrenal, and thyroid dysfunction. Central nervous system disorders, other pulmonary lesions (notably pneumonia), and drugs (including
cyclophosphamide, tricyclic antidepressants, thiazide
diuretics, morphine, and vincristine) can also cause
SIADH.
82 Textbook of Lung Cancer
Asymptomatic or mildly symptomatic patients may
be treated with restriction of water intake to less than 1
liter per day (although sustained compliance is difficult) and demeclocycline (which gradually blocks the
action of AVP on the kidney). More serious symptoms,
such as seizures, cognitive decline, and mental status
changes, or more profound hyponatremia (serum
sodium <120 mEq/l), should be treated with normal
(0.9%) saline and a loop diuretic. Use of normal saline
alone may actually decrease the serum sodium concentration so a loop diuretic must be added. The use of
hypertonic (3%) saline is rarely indicated. The goal
should be to raise the serum sodium at a maximum rate
of 2 mEq/l/hour (maximum 20 mEq/l/day) to a target of
120–125 mEq/l. More aggressive sodium correction
may theoretically result in central pontine myelinolysis,
a devastating central neurologic insult usually resulting
in death.
Ectopic adrenocorticotropic hormone syndrome
Cushing’s syndrome describes a constellation of
findings due to excess glucocorticoid production.
Approximately 80% of adrenocorticotropic hormone
(ACTH)-dependent cases of Cushing’s syndrome are
due to Cushing’s disease – an ACTH-secreting tumor of
pituitary origin. The remaining cases are due primarily
to ectopic ACTH or corticotropin-releasing hormone
(CRH) production, usually by bronchial carcinoid
tumors, but also occurring as a result of thymic carcinoid, gastrinoma, pheochromocytoma, and small cell
carcinoma.53 Ectopically produced ACTH directly stimulates adrenal glucocorticoid release, while CRH triggers ACTH release from the pituitary. Slowly growing
carcinoid tumors may be accompanied by the classic
features of Cushing’s syndrome, including truncal
weight gain, moon facies, hypertension, purplish cutaneous striae, hirsutism, glucose intolerance, and proximal muscle weakness. Cushing’s manifestations in more
rapidly growing SCLC are usually limited to weight
loss, hypertension, edema, weakness, poor skin integrity, hypokalemic alkalosis, and glucose intolerance.
Overall, less than 5% of SCLC patients develop Cushing’s syndrome46 and its occurrence predicts a shorter
survival time, perhaps due to the co-morbidities induced
by glucocorticoid excess. An elevated 24-hour urinary
free cortisol level (four or more times the upper limit of
normal) and failure to suppress cortisol during lowdose dexamethasone challenge generally confirm the
presence of Cushing’s syndrome. Late-night salivary
cortisol levels have been shown to have high diagnostic
sensitivity and specificity for Cushing’s syndrome and
may in the future replace urinary free cortisol or lowdose dexamethasone suppression as a first-line screening test.54 The diagnosis is at times problematic as
tumors responsible for Cushing’s syndrome may have
variable secretory activity and, especially pulmonary
carcinoids, may be suppressible with low-dose dexamethasone. Treatment options include resection (carcinoidtumors),chemotherapy(SCLC),bilateraladrenalectomy,
or medical suppression of adrenal glucocorticoid production with ketoconazole, aminoglutethimide, etomidate, or metyrapone.
Neurologic syndromes
There are several stereotypic neurodegenerative syndromes that occur primarily in SCLC patients. These
paraneoplastic syndromes are distinct from the nonfocal neurologic dysfunction induced by systemic effects
of cancer. They are felt to be sequelae of autoimmune
phenomena that can involve any level(s) of the nervous
sytem (brain, cranial nerves, spinal cord, peripheral
nerves, neuromuscular junction, and muscle). The proposed pathogenetic sequence begins with the ectopic
expression by tumor cells of antigens similar to those
normally expressed in the nervous system. The shared
antigen is sensed as foreign and an immune response
ensues, causing nervous system injury and clinical
deficits.55,56 In support of this mechanism are the observations that these syndromes are associated with specific detectable antibodies, nervous system injuries are
strikingly limited to specific cell types, deposits of
immunoglobulin have been demonstrated in areas of
neuronal cell loss, and the characteristic antibodies are
made in the central nervous system by autoreactive
lymphocytes. The prototypic process of the autoantibody pathogenetic mechanism is the Lambert–Eaton
myasthenic syndrome (LEMS). However, not all patients
with clinically similar syndromes have detectable
autoantibodies, attempts to induce similar syndromes
in animals with passive immunoglobulin transfer or
immunization with the culprit antigen have been largely
unsuccessful, and immunosuppressants are not usually
effective treatments. Our understanding of these syndromes continues to evolve.
Lambert–Eaton myasthenic syndrome
Proximal muscle weakness, hyporeflexia, and autonomic dysfunction (dry mouth, erectile dysfunction,
constipation, blurred vision) characterize LEMS. The
pathognomonic electromyographic finding is a marked
increase of the compound muscle action potential following high rates of nerve stimulation. Similarly, augmented strength and reflexes can be demonstrated on
Clinical diagnosis and basic evaluation 83
physical exam after maximal contraction of the involved
muscle groups. Clinical manifestations are due to antibodies to P/Q type voltage-gated calcium channels
expressed on the presynaptic cholinergic synapses of
peripheral nerves that interfere with the release of acetylcholine.57 These voltage-gated calcium channels
also appear on SCLC cells. Treatments of potential
benefit include 3,4-diaminopyridine (increases presynaptic calcium influx), pyridostigmine (inhibits acetylcholinesterase), oral immunosuppressive agents such as
corticosteroids, plasma exchange, intravenous immunoglobulin, and treatment of the underlying tumor.
Approximately one-third to one-half of LEMS patients
will improve with treatment of the underlying SCLC.
However, not all patients with LEMS have an identifiable underlying malignancy.
Antineuronal nuclear autoantibodies-1-associated
(ANNA-1) syndromes
ANNA-1, also known as anti-Hu antibodies, are IgG
antibodies that recognize a family of nuclear mRNA
binding proteins expressed in SCLC cells and neurons
of the central and peripheral nervous systems. These
antibodies are distinct from the autoantibodies of systemic lupus erythematosis, and whether ANNA-1 antibodies have a pathogenetic role in the neurologic
manifestations remains unclear. Seropositivity for
ANNA-1 is associated with a diverse set of neurologic
disorders that can occur in varying combinations.58
Lucchinetti and colleagues59 reported on the wide spectrum of neurologic and oncologic findings in 162
ANNA-1 seropositive patients. Twice as many women
were afflicted as men. By the end of follow-up, a malignancy had been detected in 142 patients (88%), with
81% having SCLC. Of the patients with SCLC, 17
developed at least one other malignancy. Neurologic
signs associated with ANNA-1, in decreasing frequency,
were neuropathy (sensory > mixed somatic > autonomic
> motor), cerebellar ataxia, limbic encephalitis (neurocognitive and neurobehavioral deficits), polyradiculopathy, LEMS, myopathy, myelopathy, opsoclonus/
myoclonus, motor neuronopathy, brachial plexopathy,
and aphasia. Gastrointestinal dysmotility occurred
in 38 (28%) patients, as manifested primarily by gastroparesis and intestinal pseudoobstruction due to
involvement of the myenteric plexus. The neurologic
manifestations preceded the cancer diagnosis in 96% of
patients, and usually progressed in a subacute manner.
None of the 49 patients who received immunosuppressant therapy (steroids, plasma exchange, intravenous
immunoglobulin, or cyclophosphamide) experienced
neurologic improvement. Somewhat ironically, ANNA-1
seropositivity is associated with more limited stage
SCLC at presentation, higher complete tumor response
to chemotherapy, and longer survival.60 Patients with
unexplained neurologic findings, ANNA-I positivity,
and a history of smoking should undergo a thorough
search for SCLC, including a chest CT with contrast. If
evidence of SCLC is not clearly identified by CT the
addition of an 18F-FDG-PET scan should be considered as the combination of CT and 18F-FDG-PET has
been shown in one small series to be 100% sensitive for
tumor detection.61 Five to fifteen percent of SCLC patients
may be ANNA-1 seropositive without neurologic
findings.
Other neurologic paraneoplastic syndromes
Type 2 antineuronal nuclear autoantibodies (ANNA-2),
also known as anti-Ri antibodies, are linked with
opsoclonus/myoclonus (opsoclonus are involuntary,
conjugate, arrhythmic high-amplitude, saccadic eye
movements) in breast cancer. Paraneoplastic cerebellar
degeneration is associated with a specific anti-Purkinje
cell antibody called anti-Yo (PCA 1) in females with
breast and gynecologic malignancies. Similar syndromes
can occur in SCLC and NSCLC, but lung cancer patients
are typically, although not always, ANNA-2 or anti-Yo
seronegative. Cancer-associated retinopathy is a rare
complication of SCLC, felt to be due to detectable antibodies directed at the retinal photoreceptor layer or
ganglion cells. SCLC is also strongly associated with
other antineuronal autoantibodies such as collapsing
response-mediating protein-5 (CRMP-5), which has yet
to be directly associated with a discrete clinical syndrome. It has been suggested that abnormalities identified on autoantibody paraneoplastic panels may serve
best to predict the underlying neoplasm rather than a
specific neurologic syndrome.62
Other paraneoplastic syndromes
Clubbing of the fingers and toes is characterized by loss
of the angle between the base of the nail bed and cuticle, rounded nails, and enlargement of the digit tips.
Hypertrophic osteoarthropathy (HPO) is a painful, proliferative periostitis that classically involves long bones
of the arms and legs. The affected bones reveal periosteal
new bone formation on plain radiographs and increased,
symmetric uptake on radionuclide studies. Clubbing
and HPO are rare entities that can occur together or as
isolated findings. The cause(s) remains unknown; however recent data suggest that platelet microthrombi with
subsequent release of platelet-derived and vascular
84 Textbook of Lung Cancer
endothelial growth factors may play a role in the development of clubbing.63 Clubbing and HPO can occur in
conjunction with bronchogenic carcinoma, as well as a
variety of cardiopulmonary suppurative processes
(bronchiectasis, cystic fibrosis, empyema, subacute
bacterial endocarditis), usual interstitial pneumonitis/
idiopathic pulmonary fibrosis, pulmonary arteriovenous
malformations, congential cyanotic heart disease,
inflammatory bowel disease, and cirrhosis. The potential association between the inflammatory myopathies
and lung cancer remains to be fully defined.64 Similarly,
it is unclear how thoroughly the physician should
search for malignancy in patients with unexplained
venous thromboembolism. A prospective randomized
trial of 201 patients with idiopathic venous thromboembolism65 identified a 10% incidence of occult
malignancy in the extensively screened cohort. Over a
two-year follow-up, 9.8% of patients in the control
group subsequently developed symptomatic malignancy. Overall malignancies were detected earlier and at
an earlier stage in the extensively screened group,
although a significant survival benefit could not be
demonstrated. Currently no professional organization
recommends extensive screening for malignancy in the
setting of idiopathic venous thromboembolism. A prudent strategy may be to maintain a low threshold of
suspicion for malignancy when venous thromboembolism develops without conventional risk factors, and to
proceed with additional testing as directed by history,
physical exam, and routine initial investigation.
PHYSICAL EXAMINATION
A careful physical exam is a vital component of the lung
cancer evaluation as it may provide important diagnostic, prognostic, and staging clues. General appearance
may be normal or may reveal debilitation, cachexia,
lethargy, pallor, jaundice, fever, or significant comorbidities. Blood pressure irregularities can be seen in
conjunction with neurologic or adrenal paraneoplastic
phenomena. Hoarseness suggests recurrent laryngeal
nerve compromise.
Respiratory system examination should be conducted
in an orderly manner. On inspection, tachypnea may
signal painful rib metastases, pleural effusions, or postobstructive pneumonia, while expiratory prolongation
is consistent with underlying COPD. Signs of venous
hypertension limited to the head, neck, and arms are
seen with SVC syndrome, while jugular venous hypertension and pulsus paradoxus are signs of pericardial
tamponade from metastatic disease. Pain may cause the
patient to favor the upper extremity ipsilateral to a
superior sulcus tumor. Neck palpation may yield evidence of spread to supraclavicular lymph nodes. Focal
rib tenderness implies metastases. Direct extension of
lung cancer to the chest wall is rarely palpable. The
combination of percussible dullness, diminished breath
sounds, and reduced fremitus suggests pleural effusion,
hemidiaphragm dysfunction due to phrenic nerve
entrapment, or postobstructive pneumonitis/atelectasis.
Bronchial breath sounds and increased fremitus indicate consolidation with patent proximal airways. Focal
wheezing is detected with central airway compromise
by an endobronchial tumor or extrinsic compression,
generalized wheezing with COPD. Concurrent interstitial lung diseases, such as asbestosis, may be heralded
by characteristic Velcro-type inspiratory crackles.
Depending on their distribution, rubs may be due to
venous thromboembolic events or metastatic pericardial or pleural involvement.
The remainder of the exam is equally important. Pertinent skin findings include cutaneous metastases, typically over the torso and scalp, and Basex’s syndrome,
which is hyperkeratosis of the acral regions. Acanthosis
nigricans, brown velvety plaques of the groin, back of
neck and axillae, may be paraneoplastic phenomena,
but are more commonly seen with obesity and diabetes.
The differential diagnosis for bony pain in the cancer
setting includes skeletal metastases and HPO. Liver
metastases may be palpable. A thorough nervous system examination is crucial, especially in patients with
headache, sensorimotor complaints, and back pain.
Unilateral lower extremity swelling, tenderness, and
erythema may accompany deep venous thromboses.
The history and physical exam findings can be combined to estimate general health status, such as by the
Karnofsky (Table 8.3) or Eastern Cooperative Oncology
Group (ECOG, Table 8.4) performance scores.66,67
These clinical indices provide a convenient framework
to rate the impact of the lung cancer and comorbidities on the patient. Performance status has been
reproducibly shown to be an important prognostic variable in NSCLC and SCLC, and usually influences treatment decision-making.
IMAGING
Standard chest radiograph
The standard posteroanterior and lateral chest radiograph is usually the first test to suggest bronchogenic
Clinical diagnosis and basic evaluation 85
Table 8.3 Karnofsky Performance Scale (modified from Mor et al66)
Definition
Percent
Able to carry on normal activity
and to work; no special care
needed
100
90
80
Unable to work; able to live at
home; cares for most personal
needs; a varying amount of
assistance is needed
70
60
50
Unable to care for self; requires
equivalent of institutional or
hospital care; disease may be
progressing rapidly
40
30
20
10
Criteria
Normal; no complaints; no evidence of disease
Able to carry on normal activity; minor signs or symptoms of
disease
Normal activity with effort; some signs or symptoms of disease
Cares for self; unable to carry on normal activity
or to do active work
Requires occasional assistance but is able to care for most of
needs
Requires considerable assistance and frequent medical care
Disabled; requires special care and assistance
Severely disabled; hospitalization is indicated, although death
may not be imminent
Very sick; hospitalization necessary; active supportive
treatment necessary
Moribund; fatal processes progressing rapidly
Table 8.4 Eastern Cooperative Oncology Group Performance Scale (from Oken et al67)
Performance status
Definition
0
1
Fully active; no performance restrictions
Strenuous physical activity restricted; fully ambulatory and able to carry out light
work
Capable of all selfcare but unable to carry out any work activities.
Up and about >50% of waking hours
Capable of only limited selfcare; confined to bed or chair >50% of waking hours
Completely disabled; cannot carry out any selfcare; totally confined to bed or chair
2
3
4
carcinoma, and it helps to assess the intrathoracic extent
of cancer, guides subsequent work-up, and identifies
simultaneous thoracic disease.68 The spectrum of possible findings is broad, but the most common are a
localized opacity (nodule or mass), pleural effusion,
infiltrate, atelectasis, and adenopathy. Certain radiographic appearances may suggest histologic types of
lung cancer, but these generalizations are not absolute.
Squamous cell carcinoma usually presents as a large
mass centered at or near the hilum, that may cavitate.
Due to the central airway origin, up to 50% of patients
with squamous cell carcinoma will present with endobronchial obstruction with postobstructive pneumonia
or atelectasis.69 SCLC may also present as a rapidly
enlarging central mass with contiguous hilar and mediastinal involvement. Only 5–10% of SCLCs present as
peripheral lung lesions. Adenocarcinoma typically arises
peripherally as a solitary nodule or mass. Large cell carcinoma is characteristically a large peripheral mass. BAC
may appear as a nodule or an alveolar infiltrate that can
be diffuse. The drawbacks of plain chest radiography
include lack of specificity and resolution limitations.
Lesions smaller than 2–3 mm are not reliably detectable
and the miss rate for lesions less than 2 cm may exceed
50%.70 Regions obscured by the heart, clavicles, and
diaphragm may be particularly difficult to interpret.
Estimates are that chest radiography is 70–80% accurate in the overall detection of lung cancer, 50–60%
sensitive in the detection of hilar adenopathy, and less
than 50% sensitive in the detection of mediastinal adenopathy.71 Studies using commercially available computer-aided diagnostic software to improve the sensitivity of
digital chest radiographs show modest improvements
in nodule detection.72
86 Textbook of Lung Cancer
Computed tomography
CT greatly enhances the imaging of bronchogenic carcinoma by providing further definition of the primary
lesion’s appearance, detecting concurrent parenchymal
or pleural disease missed by plain chest radiography,
demonstrating lymphangitic spread of malignancy,
guiding diagnostic maneuvers, and evaluating hilar and
mediastinal lymph node metastases. CT also helps in
the evaluation of distant metastases by the routine practice of extending the examination to include the liver
and adrenals. The delineation by CT of the relation of
bronchogenic carcinoma to surrounding structures is
particularly important since these findings significantly
influence prognosis and, in the case of NSCLC, surgical
options. However, the resolution limitations of CT in
this regard must be acknowledged. Consensus calls for
intrathoracic lymph nodes larger than 1 cm in the short
axis dimension to be considered abnormal by CT; however, using this criterion CT is only 57% sensitive and
82% specific in identifying hilar and mediastinal lymph
metastases.73 The sensitivity of CT suffers from microscopic lymph node metastases, while the specificity is
influenced by benign causes for lymphadenopathy,
such as reactive hyperplasia, granulomatous inflammation, and anthracosis. CT also has difficulties in accurately diagnosing chest wall or mediastinal structure
invasion, detecting endobronchial lesions, and differentiating tumor from adjacent atelectasis or pneumonia. Hence, CT is not a substitute for histologic
information and patients must not be denied surgery
for NSCLC simply on CT findings without tissue confirmation.
Solitary pulmonary nodule
Solitary pulmonary nodule (SPN) is a common clinical
radiologic dilemma. Defined as a singular rounded
lesion entirely surrounded by normal lung parenchyma
and without associated lymphadenopathy, an SPN may
be caused by malignant and benign processes
(Table 8.5).74 The majority of SPNs are benign. Most
malignant SPNs are clinical stage I bronchogenic carcinomas. SPNs are usually incidental findings on plain
chest radiographs or CTs obtained for other purposes.
The questions become whether the SPN is benign or
malignant, and whether it should be observed, biopsied, or removed. The evaluation begins, if possible,
with review of previous chest radiographs. A nodule
that has been radiographically stable for at least two
years is by definition benign, and no further maneuvers
are necessary. A steadily growing nodule is considered
malignant and should be immediately resected. When
Table 8.5 Causes of solitary pulmonary nodules (from
Midthun et al74)
Infectious granuloma
Tuberculosis
Histoplasmosis
Coccidiomycosis
Bronchogenic carcinoma
Metastatic cancer
Breast
Head and neck
Colon
Renal cell
Sarcoma
Germ cell
Bronchial carcinoid
Hamartoma
Organizing pneumonia/abscess
Wegener’s granulomatosis
Rheumatoid nodule
Arteriovenous malformation
Pulmonary infarction
Bronchogenic cyst
Lipoma
Amyloidoma
comparison studies are insufficient, the next step is to
assess for calcification in the nodule with CT. Central,
concentric, or popcorn calcification patterns are reliable indicators of their benign nature. Eccentric calcification does not rule out malignancy. Thin-section CT
images may also detect fat within the nodule, indicative
of a hamartoma, which is always benign. Taking advantage of the differences in vascular supply between
benign and malignant nodules, Swensen and colleagues75 demonstrated that the level of nodule enhancement detected by thin-section CT after injection of
intravenous contrast reliably differentiated benign versus malignant lesions (Figure 8.3). Using 15 Hounsfield
units as the threshold for enhancement, sensitivity of
this technique for malignancy was 98%. Specificity was
just 58%, since some inflammatory and infectious
lesions may enhance. The negative predictive value was
96% – if a nodule does not enhance, it is almost always
benign. Recently 18F-FDG-PET was compared to nodule enhancement CT and found to have similar sensitivity and superior specificity in differentiating malignant
from benign pulmonary nodules, although noduleenhancement demonstrated a negative predictive value
Clinical diagnosis and basic evaluation 87
(a)
Figure 8.3
CT images demonstrating enhancement
of 87 Hounsfield units (HU) of a left lung
nodule after injection of iodinated
contrast (31 HU on the precontrast image
versus 118 HU on the postcontrast
image). The circle within the nodule
circumscribes the region used to
measure enhancement.
(b)
HU= 31
of 100%.76 The authors concluded that 18F-FDG-PET
is preferable to nodule-enhancement CT in evaluating
indeterminate pulmonary nodules; however noduleenhancement CT remains a useful tool due to its very
high negative predictive value, convenience, and lower
cost. If radiologic studies are inconclusive, clinical factors which predict a higher risk of malignancy include
advanced age of the patient, smoking history, prior
malignancies, and larger nodule size. The patient’s
wishes must be considered in the decision-making process. Lesions ≥3 cm in size are malignant in over 90%
of cases and should not be observed. If a lesion is not
removed and is indeterminate, then it must be observed.
Observation typically involves obtaining serial chest CT
scans every three months for the first six months, and
then every six months for the remainder of two years.77
Serial plain chest radiographs do not reliably detect
enlargement of small nodules. If the nodule grows, it
must be resected. If the nodule is stable for two years,
it is safe to assume that it is benign.
With the introduction of helical and multi-detector
row CTs the detection of nodules as small as 1–2 mm
is becoming common. The Mayo Clinic CT Screening
Trial demonstrated that less than 1% of nodules <5 mm
in size in patients without a history of cancer proved to
be malignant.78 Henschke and colleagues79 further demonstrated that the follow-up interval for nodules <5
mm in size at initial detection could safely be extended
to 12 months. The likelihood that an incidentally
detected nodule is malignant also depends on known
risk factors such as cigarette smoking, as well as radiographic characteristics such as density. With this in
mind the Fleischner Society80 has endorsed a statement
recommending variable follow-up of small nodules
(<8 mm) identified incidentally based on patient risk
factors and nodule size at the time of detection. Included
in this is a provision for no follow-up of incidentally
detected nodules less than or equal to 4 mm in size in
low-risk patients.
HU= 118
Ground-glass opacities
Recent advances in CT screening for lung cancer (discussed below) have led to increased detection of focal
ground-glass opacities (GGOs). A GGO is defined as a
hazy area of increased lung attenuation with preserved
bronchial and vascular margins (Figure 8.4).81 These
features may be the result of interstitial thickening, air
space filling or partial collapse, or increased capillary
blood flow; alternatively they may be seen as a feature
of normal exhalation. As such, GGO is a non-specific
finding which may be caused by a variety of infectious,
inflammatory, and neoplastic processes.82,83 A recent
series84 demonstrated that GGOs with no concomitant
solid component will represent malignancy approximately 20% of the time; however with serial follow-up
almost 40% will regress or disappear spontaneously. In
the same series, GGOs with a concomitant solid component represented malignancy approximately 30% of the
time; however up to 50% regressed or disappeared spontaneously. Regression, when present, occurred within
the first 90 days of follow-up in the vast majority of cases.
Malignant and premalignant lesions are most commonly
BAC, adenocarcinoma, and atypical adenomatous hyperplasia.85 Female gender, spiculated border, a concomitant solid component, and size greater than 1 cm appear
to be risk factors for malignancy, whereas an elevated
serum eosinophil count may predict a benign etiology.
When malignant, tumor doubling times vary widely and
may be as long as 1486 days for some BACs.86 Frequent
spontaneous regression, relatively high malignancy rates,
and long doubling times all make management decisions
for GGOs problematic, and currently no specific guidelines exist for the follow-up or management of GGOs.
Based on available data it may be reasonable to biopsy
GGOs that persist beyond 90 days and are greater than
1 cm in size or have other concerning characteristics.
Serial follow-up, if elected, should continue beyond five
years before determining that an identified GGO does
not represent malignancy.
88 Textbook of Lung Cancer
18
Figure 8.4
Chest CT demonstrating a ground-glass opacity measuring
12 × 7 mm (circled). Note the preservation of underlying vascular
and interstitial structures.
CT lung cancer screening
Five-year survival for stage I lung cancer approaches
70%; however <20% of lung cancers are detected at
this early stage. That the vast majority of these early
stage lung cancers are asymptomatic and identified
incidentally on a radiograph or CT obtained for other
purposes has raised tremendous interest in devising a
rational method to screen for lung cancer radiographically, similar to the way a mammogram is used to screen
for breast cancer. Early screening trials conducted in
the 1970s using chest radiography and sputum cytology demonstrated a higher incidence rate, resectability,
and survivorship among the intensively screened group,
but failed to show a mortality benefit (summarized in
reference 87). A number of more recent studies investigating the use of low-dose CT have shown an ability
to detect earlier stage cancers; however, they have also
shown high false-positive rates with indeterminate nodules identified in up to 70% of participants.88,89 Recent
five-year prospective data collected on over 1500 highrisk participants suggest that overdiagnosis rather than
earlier diagnosis may be playing a role in the use of CT
screening, and did not demonstrate a mortality benefit.90 Conversely, a recently reported multicenter study91
enrolling over 31 000 patients over ten years identified
484 lung cancers, 85% of which were stage I. For those
patients diagnosed at stage I, the estimated ten-year
survival rate was 88%, and 92% for those who underwent surgical resection within one month of diagnosis.
At this time no professional organization recommends
screening for lung cancer.
F-fluoro-2-deoxy-D-glucose positron emission
tomography
Accurate staging of NSCLC is essential to determine
appropriate therapy and estimate prognosis. Evaluation
of mediastinal nodal disease and extrathoracic metastasis is crucial in this regard due to their impact on operative candidacy and potential surgical cure. As discussed
above, the accuracy of CT for predicting mediastinal
nodal metastasis is not ideal. 18F-FDG-PET is a radionuclide test that involves injection of the radioisotope
18
F-fluorodeoxyglucose (18F-FDG). Tissues with high
metabolic activity, such as high-grade neoplasms,
demonstrate increased glucose uptake relative to normal tissues and will show increased isotope deposition.
A meta-analysis of 18 studies found 18F-FDG-PET
to have a sensitivity of 84% and specificity of 89%
when investigating the mediastinum for metastases
(Figure 8.5).73 In lymph nodes smaller than 1 cm specificity may be as high as 95%, although sensitivity is
lower.92 18F-FDG-PET also increases detection of extrathoracic metastases (Figure 8.6), identifying unsuspected distant metastases in as many as 28% of patients
with stage III disease in one series,93 and reducing by
20% non-therapeutic thoracotomies in a series enrolling
patients with stages IA–IIIA NSCLC.94 18F-FDG-PET
imaging has been shown to be superior to conventional
imaging for identifying tumor recurrence.95 False-positive results may be seen with various inflammatory and
infectious processes such as sarcoidosis, pulmonary
Langerhans cell histiocytosis, and mycobacterial and
fungal diseases. False-negative results may occur
with low-grade neoplastic processes such as BAC and
bronchial carcinoid tumors. Because of the occasional
false-positive findings potentially metastatic sites should
be proven by biopsy when clinically and technically
feasible.96
Magnetic resonance imaging
MRI does not have a routine role in the evaluation of
lung cancer. However, its superiority over CT in distinguishing tumor abutment versus invasion of chest wall,
vertebral, and mediastinal structures makes MRI a useful adjunct in situations such as superior sulcus tumors
and possible neuroforaminal encroachment. The magnetic resonance angiogram (MRA) is the study of choice
to investigate vascular invasion.
Other nuclear medicine studies
In NSCLC patients with marginal pulmonary function,
quantitative ventilation-perfusion (V/Q) lung scans
can be used to assess candidacy for lung resection.
Clinical diagnosis and basic evaluation 89
(a)
(c)
Figure 8.5
18F-FDG-PET scan with CT fusion
demonstrating a primary adenocarcinoma in the left upper lobe (a), with
contralateral hilar metastasis (b).
(c) Coronal 18F-FDG-PET without CT
fusion, demonstrating no extrathoracic
involvement. Transbronchial needle
aspirate of the right hilar lymph node
confirmed metastatic adenocarcinoma
with stage IIIB NSCLC assigned. (See color
plate section, page xiii)
(b)
The fraction of total ventilation or perfusion from the
contralateral lung is multiplied by the preoperative
forced expiratory volume in 1 second (FEV1) to predict
postoperative FEV1 for patients undergoing pneumonectomy. A postoperative FEV1 of 40% of predicted
suggests the patient should tolerate resection from a
pulmonary perspective.97 Bone scan and 18F-FDG-PET
are useful in investigating bony metastases in patients
with bone pain, hypercalcemia, increased alkaline
phosphatase, and/or pathologic fractures. Of these three
techniques, 18F-FDG-PET is the most sensitive and
has the additional advantage of identifying other areas
of intra- and extrathoracic metastases. Abnormalities
identified with these techniques will require further
evaluation by plain radiography or MRI, and, under
appropriate clinical circumstances, biopsy.
DIAGNOSTIC TECHNIQUES
An accurate tissue diagnosis is an essential early step in
the management of lung cancer because of its therapeutic
and prognostic import. Biopsy procedures are not always
required before surgical therapy, but are conducted in
most patients suspected of lung cancer since clinical and
radiographic findings are not uniquely assigned to SCLC
or NSCLC. Various techniques are available to obtain
tissue for cytologic and histopathologic analysis.
90 Textbook of Lung Cancer
(a)
(c)
Figure 8.6
18F-FDG-PET scan with CT fusion
demonstrating a primary adenocarcinoma involving the left upper lobe with
ipsilateral mediastinal lymph node
metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without
CT fusion demonstrating mediastinal and
extrathoracic (left adrenal) involvement.
CT-guided biopsy of the left adrenal
confirmed metastatic adenocarcinoma
with stage IV NSCLC assigned. (See color
plate section, page xiv)
(b)
Sputum examination
Sputum cytology
Sputum cytology is a non-invasive method to obtain a
diagnosis in appropriate situations.98 The yield depends
on the ability of the patient to produce acceptable sputum, tumor size, location of the tumor in relation to
major central airways, and the skills of the cytopathologist. The average sensitivity is approximately 65%, with
sensitivities ranging from 22 to 98% reported.99 Most
studies, although not all, show decreased sensitivity for
the diagnosis of peripherally based nodules and masses,
with an overall sensitivity of 71% for central and 49%
for peripheral lesions.99 The appropriate number of
specimens to collect remains unclear, but one to three
consecutive early morning samples or a three-day pooled
sputum specimen are generally recommended.100 A sputum sample can be obtained spontaneously or induced,
and is considered representative if bronchial epithelial
cells or alveolar macrophages are present. Overall diagnostic yield appears highest with specimens collected
spontaneously, except in the setting of peripherally
based cancers where induced specimens appear more
informative.101,102 Abnormal findings may also result
from concurrent pulmonary infections (false-positives)
or unsuspected head and neck cancers.
Sputum cytometry
Recent data suggest that the yield of sputum cytology
may be improved through the use of molecular, genetic,
Clinical diagnosis and basic evaluation 91
and immunocytochemical markers of malignancy.
Studies evaluating archived sputum specimens collected
as part of lung cancer screening programs have shown
that abnormal cells may be identified as early as twenty
months prior to the diagnosis of lung cancer using these
techniques. Xing and colleagues103 further demonstrated a twenty-fold improvement in sensitivity over
sputum cytology alone using automated cytometric
techniques. They were able as well to detect severe dysplasia/carcinoma in situ lesions and correctly identified
over 70% of peripherally based cancers. A sensitivity of
75% and specificity of 98% has been shown for semiautomated sputum cytometry in the diagnosis of lung
cancer in a multinational study.104 These results have
sparked interest in the implementation of this technique as part of a co-ordinated lung cancer screening
process.
specimens. TBNA should be obtained before sampling
other endoscopically visible lesions to avoid false-positive
results. Bleeding is a very infrequent complication of
TBNA. Autofluorescence bronchoscopy exploits the
difference in fluorescence properties between normal
bronchial mucosa and that of invasive and pre-invasive
disease. The best-known device uses a helium-cadmium
laser (442-nm wavelength) and an optical multichannel
analyzer in place of the standard white light source,
with normal mucosal surfaces having a green coloration
whereas premalignant and malignant lesions appear
reddish in color. A prospective, multicenter trial demonstrated an increase in the detection of preinvasive
disease with the use of autofluorescence by a factor of
2.1 when compared to white light bronchoscopy
alone.110 Bronchoscopy in COPD patients confers only
a slightly increased risk if obstruction is severe.
Flexible fiberoptic bronchoscopy
Flexible fiberoptic bronchoscopy is commonly used for
diagnostic and staging purposes. Endoscopically visible
abnormalities are approached with traditional biopsy
forceps, brushings, and washings. Transbronchial needle aspirations (TBNAs) may also be performed on submucosal tumors or those causing extrinsic bronchial
compression. The yield from an endoscopically visible
lesion should be in excess of 80%. Peripheral lesions
are sampled with fluoroscopically guided transbronchial biopsies, brushings, and washings. Lesion size is
the primary determinant of outcome, with yields of
25% reported for malignant lesions under 2 cm, 60–70%
for lesions >2cm, and 80% for lesions >4 cm.105
Yield, particularly for lesions <2 cm, may be increased
with the use of electromagnetic navigation bronchoscopy, with a recent study demonstrating 74% diagnostic yield for peripheral lesions in this size range.106
Transbronchial lung biopsies should detect lymphangitic spread of malignancy. For staging purposes, bronchoscopy may occasionally detect synchronous lesions,
assess proximal extent of tumor, and facilitate sampling
of paratracheal, subcarinal, and hilar lymph nodes by
TBNA.
Traditional TBNA sensitivity is 50%, with a specificity
of 90% for mediastinal staging.107 However, guidance
using endobronchial ultrasound (EBUS) increased the
sensitivity to 94% in one study of 500 patients.108 EBUS
also appears superior to CT in differentiating airway
tumor infiltration from extrinsic compression.109 Chest
CT should be obtained before TBNA to help guide the
attempts. Use of 19-gauge needles improves sensitivity
by allowing procurement of cytologic and histologic
Transthoracic needle aspiration
Peripheral lesions or those with extension to the mediastinum, chest wall, or pleura may also be sampled by
fluoroscopically or CT-guided transthoracic needle
aspiration (TTNA). Suspicious peripheral lesions are
sometimes directly resected for diagnosis and treatment
if surgery would be the anticipated maneuver regardless of TTNA results. However, TTNA may be applied
when a tissue diagnosis is needed but the patient cannot or will not undergo surgery, the patient is
undecided about surgery pending tissue confirmation
of cancer, or fiberoptic bronchoscopy was non-diagnostic.
Yields above 90% have been reported.111,112 Pneumothorax is the main complication, occurring in up to 30% of
cases, yet less than 15% typically require a chest tube.
Tumor seeding of the biopsy tract is a very rare complication. Increased risk situations for TTNA include
bullous emphysema in the region to be biopsied, lesions
located away from the pleural surface, a poorly cooperative patient, and underlying lung disease whose
impact would significantly increase if pneumothorax
developed. There is a substantial false-negative rate
(20–30% of patients with a negative TTNA may have a
malignant lesion)37 so indeterminate or negative TTNA
results must not be interpreted as a diagnostic endpoint. A repeat TTNA is diagnostic in 35–65% of cases.37 Percutaneous radiologic-guided needle aspiration
is used to confirm metastases to liver, bone, and
adrenals.
Endoscopic ultrasound
The linear array echoendoscope was introduced in the
mid-1990s and is gaining popularity due to its ability to
92 Textbook of Lung Cancer
permit fine-needle aspiration of mediastinal abnormalities from a transesophageal approach that are not easily
accessed by bronchoscopy or mediastinoscopy. Endoscopic ultrasound (EUS) easily identifies vascular structures and is useful in sampling tissue from inferior and
posterior mediastinal (station 8, 9), aortopulmonary
window (station 5, 6), and subcarinal (station 7) lymph
nodes. Lobar (station 12), interlobar (station 11), and
anterior tracheal nodes (station 3) are not well evaluated by EUS. In a study of 26 patients undergoing
transesophageal biopsy performed with EUS and fineneedle aspiration the overall sensitivity for the diagnosis of malignancy was 89% and the specificity was 83%,
with a positive predictive value of 100% and a negative
predictive value of 75%.113 Recent studies further suggest that EUS may be superior to CT and PET in establishing mediastinal staging of NSCLC,114,115 and may be
superior to mediastinoscopy in sampling paratracheal
and subcarinal nodes.116
Thoracic surgery techniques
Cervical mediastinoscopy and anterior mediastinotomy have been the traditional routes by which histologic verification of mediastinal metastases has been
obtained. These are safe procedures whose findings
may obviate the need for further surgery in NSCLC
patients. Cervical mediastinoscopy allows sampling of
the right paratracheal and subcarinal nodes, while
anterior mediastinotomy accesses the left paratracheal,
supra-aortic, and aortopulmonary window nodes.37 It
remains controversial whether mediastinal sampling
should be routinely performed before all surgery for
NSCLC. Many surgeons may forego mediastinoscopy
in patients with radiographic T1N0 disease due the
relatively low prevalence (5–15%) of nodal metastases
in this group. 18F-FDG-PET may have a role in these
patients, allowing those without evidence of mediastinal involvement to avoid mediastinal lymph node
sampling, although PET combined with CT may still
miss up to 5% of mediastinal micrometastases.117 Video-assisted thoracoscopic surgery (VATS) is a more
recent, less invasive technique for sampling of indeterminate peripheral nodules, pleural thickening and
effusions, and mediastinal/hilar lymph nodes. Scalene
or supraclavicular lymph node biopsy is an appropriate diagnostic and staging procedure in the setting of
clinically significant enlargement. The patient with a
suspicious lesion (enlarging or spiculated nodule)
without evidence of metastatic disease may go
directly to thoracotomy for definitive diagnosis and
treatment.
OVERVIEW OF BASIC EVALUATION
The purpose of the basic evaluation is to efficiently and
accurately establish the diagnosis and initial extent of
lung cancer. Aspects of this process are influenced by
local practice biases. The core elements include a careful
history and physical exam, posteroanterior and lateral
chest radiographs, and basic blood tests, including complete blood count and chemistry profile (especially electrolytes, serum calcium, alkaline phosphatase,
glutamic-oxaloacetic transaminase, albumin, total bilirubin, and creatinine).36 While the cost-effectiveness of the
blood tests can be debated, they may suggest metastatic
disease, paraneoplastic phenomena, or co-morbidities.
Chest CT with extension to upper abdominal CT is routinely obtained to define the primary lesion and locoregional extent of disease. 18F-FDG-PET scanning plays an
additive role in addressing the solitary pulmonary nodule and should be included when investigating mediastinal and extrathoracic metastases from a known NSCLC.
Testing for extrathoracic metastases is pursued as directed
by the initial information. Biopsy of suspected metastases
may allow simultaneous diagnosis and staging. For
peripheral chest lesions the diagnostic options are TTNA,
bronchoscopy, VATS, or thoracotomy. It is unclear
whether TTNA or bronchoscopy is the better initial
choice. TTNA may enjoy a higher yield for smaller
lesions, but also a higher complication rate. Bronchoscopy allows for endobronchial visualization and would
still be performed at the time of thoracotomy if TTNA
were positive. For central lesions or hemoptysis with
negative chest film, sputum cytology is also an option,
and bronchoscopy is usually favored over TTNA.
Additional pulmonary testing may be necessary if
surgical resection is considered. Given the common
etiologic thread of smoking, it is not surprising that
80–90% of lung cancer patients also have COPD,
20–30% with severe disease.118 Lung resection, incisional pain, medical appliances, and postoperative use
of sedatives and analgesics impact negatively on lung
function and defense. Preoperative spirometry and diffusing capacity (DLCO) should be obtained. Patients with
FEV1 >1.5–2 l, maximal voluntary ventilation (MVV)
>50% predicted, and DLCO >60% predicted can proceed
to thoracotomy. Patients below these values may need
to undergo a more thorough examination that includes
quantitative V/Q lung scanning and/or exercise testing
with evaluation of maximum oxygen uptake. Although
no value categorically precludes surgery, predicted
postoperative FEV1 <40% of predicted, hypercapnia
(PCO2 >45), or maximal oxygen consumption <10 ml/
Clinical diagnosis and basic evaluation 93
kg/min during exercise testing predicts significant postoperative problems.119 The use of VATS and limited
resections have dramatically changed the definition of
inoperability due to pulmonary limitations.
FUTURE DEVELOPMENTS
Given the dramatic differences in overall lung cancer
survival versus those enjoyed with resectable stage I
disease, interest will continue to focus on methods of
earlier lung cancer detection and more accurate staging.
The recent use of spiral CT scanners allows for extremely
rapid thoracic imaging at a reduced radiation dose,
thereby imparting the benefits of CT sensitivity with the
speed and radiation levels of more traditional radiographic imaging. Whether CT screening, alone or in
concert with other screening modalities, results in earlier detection and decreased mortality from lung cancer
remains to be demonstrated and the results of the
National Lung Screening Trial will determine to a great
extent whether CT screening is adopted as a viable
standard screening modality. Sputum cytometry and
autofluorescence bronchoscopy additionally show
promise as methods to identify cancerous and precancerous lesions within the central airways early, when
directed therapy or resection is most successful. Their
role in standardized screening warrants further investigation. In 2007 a five-year randomized surveillance
study funded by Cancer Research UK incorporating
combined techniques of sputum cytology/cytometry,
CT scanning, and autofluorescence bronchoscopy
began enrollment and have helped define the role of
these techniques in screening for lung cancer. Early
reports of serum proteomic patterns being able to distinguish patients with ovarian and prostate cancer from
normal controls are exciting, although preliminary.
What, if any, role proteomic patterns may play in the
detection and diagnosis of lung cancer is one of the
most intriguing new areas of investigation in early
detection. It is hoped that these new techniques combined with greater participation of patients in prospective clinical trials (currently only 1% of lung cancer
patients in the USA are enrolled) will result in improved
lung cancer survival rates.
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9
Staging, classification, and prognosis
Michael Dusmet, Peter Goldstraw
Contents Introduction • The staging system • The staging process • The staging tests • Restaging after
induction chemotherapy • Other prognostic indicators • Prognosis
INTRODUCTION
It is logical that this chapter should fall between the
preceding one on diagnosis and evaluation and those
that follow on the treatment modalities for non-small
cell lung cancer (NSCLC) and small cell lung cancer
(SCLC). At its most simplistic, ‘staging’ is the process by
which the clinician examines and describes the local,
regional, and distant extent of the cancer. This precise
information is then used to determine the appropriate
therapy for a patient diagnosed to have lung cancer.
However, staging should not be thought of as a set of
investigations that are performed between diagnosis
and treatment. Many of the tests that are undertaken to
establish the diagnosis, such as chest radiography,
bronchoscopy, and pleural aspiration cytology, provide
valuable information as to stage. Often the choice of
test by which to establish the diagnosis will be made on
the basis of the clinician’s assessment of the probable
stage of the disease. In this context, obviously taking
into account the financial cost and the potential morbidity of every procedure, it is desirable to undertake
first the test that will prove the highest stage. For example, if a patient has a lung lesion and a probable adrenal
metastasis, biopsy of the adrenal will, if positive, provide both a tissue diagnosis of cancer and the stage
(M1).Tests undertaken to decide stage proceed in parallel with those required to establish the diagnosis and
others to assess patient fitness for possible treatment
options, often interweaving and providing information
across these categories. Tests may have to be repeated
if undertaken without sufficient foresight to look
beyond the diagnosis and consider the consequential
issues of treatment. Sometimes treatment may be recommended after staging and before a firm diagnosis. A
surgeon may ‘stage’ a patient and recommend thoracotomy with only the strong clinical–radiographic suspicion of lung cancer and without pursuing the diagnosis
to a cytologic or histologic conclusion. In such circumstances the surgeon will establish the diagnosis as the
first step at thoracotomy using rapid, ‘frozen section’
histology prior to proceeding with treatment by pulmonary resection.
Thus staging has several objectives, some patient
orientated and some disease centered. Precise staging
will allow the clinician to offer the individual patient
the best treatment, on the basis of the understanding
of prognosis that derives from the stage. Staging
allows clinicians to evaluate the results of different
treatment regimens and to exchange and compare them
between different centers. This also allows new treatment strategies to be assessed. Finally it allows us to
evaluate in an on-going manner the results of staging
modalities.
We will consider the separate aspects of staging: the
‘staging system’, the ‘staging process’, and the ‘staging
tests’.
THE STAGING SYSTEM
The International Staging System (ISS) for lung cancer
is the TNM Classification of Malignant Tumors, administered by the International Union Against Cancer
(UICC).1 This provides a recognized shorthand to
describe the extent of the disease, in which the
T descriptor indicates the extent of the primary tumor,
the N descriptor the extent of lymph node involvement,
and the M descriptor the presence or absence of distant
metastases. For each descriptor, advancing numeric
subscripts are allocated for progressively advancing
disease. The latest revision of the ISS was published in
1997,2,3 and integrated into the sixth edition of the
UICC TNM Classification of Malignant Tumors manual
in 2002.4 The next revision of the staging system is
due to be published early in 2009. The descriptors as
presently defined are listed in Table 9.1. A more precise
definition of the boundaries and definitions can be found
in another article by Dr Mountain.5 The definition
of the great vessels includes the aorta, the vena cava,
98 Textbook of Lung Cancer
Table 9.1 TNM descriptorsa
Primary tumor (T)
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or
bronchial washings but not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence
of invasion more proximal than the lobar bronchusb (i.e. not in the main bronchus)
T2 Tumor with any of the following features of size or extent:
• >3 cm in greatest dimension
• involves main bronchus, ≥2 cm distal to the carina
• invades the visceral pleura
• associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve
the entire lung.
T3 Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors),
diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus <2 cm distal to the
carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the
entire lung
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus,
vertebral body, carina; or tumor with a malignant pleural or pericardial effusion,c or with satellite tumor
nodule(s) within the ipsilateral primary-tumor lobe of the lung
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes
involved by direct extension of the primary tumor
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular
lymph node(s)
Distant metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis presentd
a
Reproduced with kind permission of Dr CF Mountain and the Editor of Chest.2
The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also
classified T1.
c
Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural
fluid show no tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not
related to the tumor, the effusion should be excluded as a staging element and the patient’s disease should be staged T1, T2, or T3. Pericardial effusion is classified
according to the same rules.
d
Separate metastatic tumor nodule(s) in the ipsilateral non-primary-tumor lobe(s) of the lung are also classified M1.
b
and their main intrathoracic branches and tributaries.
The point at which the pulmonary vessels become great
vessels (a T4 descriptor) is the pericardium: the intrapericardial portions of these vessels are considered to
be great vessels. As an example, a tumor of 5 cm in diameter, involving the ipsilateral mediastinal lymph glands
and with an additional pulmonary nodule, believed to
be malignant, in the contralateral lung would be
described as T2N2M1.
For convenience, TNM subsets with similar survival
prospects and for which treatment options would be
similar are combined into stage groups (Table 9.2)
and the example given above would be assigned to
stage IV.
Staging is done at various time points during the
patient’s journey through preliminary investigations
and then treatment. It is important to know when
staging is done so as to compare like with like when
Staging, classification, and prognosis 99
Table 9.2
Stage
0
IA
IB
IIA
IIB
IIIA
IIIB
IV
Stage grouping: TNM subsetsa,b
TNM subset
Carcinoma in situ
T1N0M0
T2N0M0
T1N1M0
T2N1M0
T3N0M0
T3N1M0
T1N2M0
T2N2M0
T3N2M0
T4N0M0
T4N1M0
T4N2M0
T1N3M0
T2N3M0
T3N3M0
T4N3M0
Any T Any N M1
a
Staging is not relevant for occult carcinoma, designated TXN0M0.
Reproduced with the kind permission of Dr CF Mountain and the Editor
of Chest.2
b
evaluating different treatment regimens. The initial, pretreatment, stage is the clinical/evaluative stage, or
cTNM. This may integrate the information obtained
from imaging and bronchoscopy as well as, for example, the histopathology from a fine needle aspiration
biopsy (FNAB) of a distant metastasis. Obviously, with
the addition of information obtained at surgery and the
pathologic examination of the resection specimen, the
postsurgical/pathologic stage known as the pTNM will
be more accurate. (See comments later on ‘stage migration’.) The ‘y’ prefix is used when the patient is restaged
after induction or neo-adjuvant therapy (induction
therapy being a treatment modality aimed at rendering
an inoperable stage tumor operable; the goal of neoadjuvant therapy is to improve the survival rate of an
operable tumor). This can be used in conjunction with
the ‘c’ and ‘p’ prefixes. Thus ycTNM would reflect the
clinical restaging after induction or neo-adjuvant therapy and ypTNM the pathologic (i.e. postsurgical) stage
after similar presurgical chemo- and/or radiotherapy.
The ‘r’ prefix is used for the staging of recurrent tumors
and the ‘a’ prefix for autopsy findings.4
It is important to understand the principle differences the fifth edition of the TNM Classification of
Malignant Tumors brought to the staging system for
lung cancer in 1997 as many studies on induction/
neo-adjuvant therapy were designed and/or implemented before that year. The four main differences are:
(1) that stages I and II were subdivided, respectively,
into stages IA, IB and IIA, IIB; these reflect the
increase in size of the tumor from T1 to T2 (i.e. ≤
or >3cm in diameter);
(2) stage T3N0M0 was moved from stage IIIA to IIB as
the five-year survival is more akin to this latter
stage;
(3) separate nodules within the same lobe were assigned
to the T4 category; and
(4) separate nodules in other, ipsilateral lobes and the
contralateral lung were included in M1 disease.
Many clinicians feel that such detailed staging is
irrelevant for SCLC, and consider that a cruder division
into ‘limited’ and ‘extensive’ disease allows clinical decisions to be made on treatment.6 There are two definitions: from the Veterans Administration Lung Study
Group (VALG) and from the International Association
for the Study of Lung Cancer (IASLC). In the former,
limited disease (LD) is defined as tumor which is
restricted to one hemithorax, often including the ipsilateral supraclavicular fossa, basically a single radiotherapy field, whilst any wider-spread disease, including
distant metastases, is considered as extensive disease.
In the IASLC staging system all patients without distant
metastases are considered to have LD, including those
with a malignant pleural effusion and all patients
with contralateral mediastinal and/or supraclavicular
lymph node metastases to be included in the LD category. It has been shown that the IASLC staging system
is a better discriminator of survival.7 Whilst this distinction is certainly sufficient for the vast majority of
sufferers with this cell type the TNM stage remains relevant for the fortunate patient with unusually localized
disease (stage I essentially, possibly stage IIA) for whom
surgical therapy or multimodality therapy should be
considered.5,8
THE STAGING PROCESS
The clinician is confronted with a bewildering array of
tests which may, when used appropriately, provide
information as to the extent of disease and therefore
permit one to stage the patient and advise on therapy.
The value and place of each test will be discussed in the
100 Textbook of Lung Cancer
next section. The clinician may utilize any and all such
tests to construct a clinical/evaluative TNM stage
(cTNM). Such tests may include surgical exploration
such as mediastinoscopy and video-assisted thoracoscopy (VATS) undertaken prior to a decision to recommend treatment. It is as well to remember that as one
proceeds with this information-gathering exercise, the
tests become increasingly costly and more invasive.
Once sufficient information has been collected as to
permit a decision regarding treatment, then further
tests become obtrusive and unwarranted. The difficulty
for the clinician is to know where to draw the line and
to decide that the evidence is sufficiently reliable as to
make the case for a particular treatment.
There can be no rigid protocol for staging and the
clinician will decide the next step based upon the overall picture as it emerges as each step provides additional
information. For most clinicians the critical point in the
staging process is reached once the patient’s disease has
been shown to be too extensive to permit surgical treatment. The oncologist or radiotherapist might still consider other staging tests to be important in defining the
most appropriate regimen. If the patient comes through
the assessment of the clinician and is still considered
operable, the surgeon may wish to define the stage
more precisely before making a final decision to operate. As this frequently involves a decision as to the
probable extent of resection, and the use of surgical
investigations such as mediastinoscopy, this step should
be left to the surgeon.
The issue as to which tests are considered the minimum necessary to establish cTNM has been considered
by the IASLC, and is one that is regularly updated at
their workshops.9,10 The American Thoracic Society and
the European Respiratory Society have accepted similar
recommendations.11 More recent guidelines have been
published by the American College of Chest Physicians
(ACCP) in 2003,12 and by the National Institute for
Health and Clinical Excellence (NICE) in the UK in
2005.13 A summary of these recommendations is shown
in Table 9.3.
Once a decision has been made as to treatment, the
cTNM assigned to that patient should not be changed
in the records. As alluded to above, additional information will accumulate if the patient proceeds to thoracotomy and pulmonary resection. This will allow the
pTNM to be established. This should be recorded separately, and does not replace the cTNM.
The UICC4 allows and recommends that a record
be made of the assessment of residual disease after
treatment. This is also the recommendation in the
Manual for Staging of Cancer, produced by the American
Joint Committee on Cancer Staging and End Results
Reporting.15 This is most usually done after surgical
resection. The designation R is used to define this. RX
indicates that it is not possible to evaluate the presence
of residual disease. R0 indicates that no residual disease
remains, i.e. that there was a complete resection with all
resection margins through normal, non-tumoral tissues. R1 indicates that microscopic residual tumor
remains and R2 signifies that there is macroscopic
residual tumor after what must be considered an incomplete resection. Most workers interpret the R1 status as
applying to the case where the resection margins are
unexpectedly positive on subsequent histologic examination of the resection specimen. Honest surgeons will
also use this descriptor when tumor tissue has been
cleaved off remaining structures. This classification is
not part of the staging system but represents good practice. The 2005 IASLC guidelines define the requirements
of complete resection.16 These require histologically
proven free resection margins, complete lymph node
clearance (vide infra) with no extracapsular spread in
the nodes, and disease-free highest mediastinal node.
We believe that at least six lymph node stations (three
N1 and three N2) need to be completely resected (as
opposed to sampled) to qualify as lymph node clearance, as specified in the European Society of Thoracic
Surgeons (ESTS) guidelines for intraoperative staging.17
When the resection margins are free but all of these
criteria are not met, or if there is carcinoma in situ at
the bronchial resection margin, or if the pleural lavage
cytology is positive, then the term ‘uncertain resection’
should be used.
As time passes the disease may recur or progress and
additional tests may be indicated to establish a retreatment or rTNM. Some would consider that our ultimate
insight into the extent of disease is realized at autopsy,
when a TNM can be created. However, time is the ultimate test and our understanding of disease progression
is curtailed by death, preventing the development of
clinically relevant disease that could be overlooked at
autopsy.
In summary, the first step in the evaluation of a
patient with suspected lung cancer is to take a very
careful history and perform a thorough physical examination. Chest radiographs and computerized tomographic (CT) scans (chest and abdomen to include the
entire liver and both adrenals) are then obtained. Bronchoscopy will usually be performed at this time, especially if the tumor is centrally located. If there is a
suspicion of brain metastases appropriate imaging will
Staging, classification, and prognosis 101
Table 9.3 Pretreatment minimal staging6,9,11,12
Step 1
Investigation
Clinical history
Weight loss and
performance status
Patient group
All patients
Clinical examination
Chest radiographs
All patients
PA
All patients
Lateral
Blood tests
Hb
All patients
Alk phosphatase
Transaminase
Lactate dehydrogenase
If still thought suitable for curative therapy proceed to Step II
Step II
Investigation
Bronchoscopy
Patient group
All patients with central
tumors or those in whom
central extension is
suspected
All patients if available
Confirmatory tests
As appropriate
As appropriate
Aspiration of any effusion
(considered positive if cytology malignant)
As for high-risk patients in
Step II
Confirmatory tests
The features of proximal, extrinsic
compression are unreliable and require
further evaluation of the mediastinum by
CT and/or mediastinal exploration
Dubious findings confirmed (not
necessarily histologic)
CT chest and upper
abdomen (to lower
pole of kidneys with
iv contrast enhancement
of mediastinal vessels)
Liver ultrasound
High risk groupa if CT
of abdomen not available
Brain assessment by
Advisable in high risk groupa
MRI (or CT if MRI not
available)
a
High risk patients are those having non-specific features identified by Hooper et al.14
• Unexplained anaemia (Hb <11%)
• Unexplained weight loss (>8 lb (3 kg) in 6 months)
• Abnormal alk phosphatase, or transaminase
• Where any clinical suspicion of metastatic disease exists
• Patients with stage III disease
If still thought suitable for curative treatment proceed to Step III
Step III
Investigation
(a) PET-CT
(b) Bone scan only if PET not available
(c) Bronchoscopy if not previously
undertaken
(d) Thoracoscopy (video-assisted)
Patient group
All patients
Skeletal X-rays ± CT/MRI of bone if dubious positive result
All patients
If pleural effusion present and cytology negative but clinical
suspicion remains, do a pleural biopsy
(Continued)
102 Textbook of Lung Cancer
Table 9.3 Continued
(e) Mediastinal exploration
• It is recommended that this
is performed pre-operatively by:
• Transtracheal or transesophageal
aspiration
Patients in whom CT suggests mediastinal
invasion or if CT shows aspiration nodes >1.0 cm in Short
axis diameter
• Cervical mediastinoscopy
Same
• Additional evaluation of the
The above groups with tumors of the left upper
subaortic fossa by left anterior
lobe or left main bronchus if suspicion of station
mediastinotomy or VATS
5 or 6 metastases on CT or PET
• This must be performed
All patients – including those whose
intra-operatively
mediastinum has been assessed preoperatively
• Palpation insufficient
• Careful and extensive mediastinal
dissection (‘systematic nodal
dissection’)
• Separate labeling as per Naruke
or ATS of excised nodes for
subsequent histologic examination
(only N1 nodes on resection
specimen)
• Re-evaluation of T stage:
completion of intra-operative
staging of tumor and pleural
space
Proceed with definitive therapy, which will be surgical resection in all but the most unusual
circumstances
be obtained (preferably magnetic resonance imaging
(MRI) – vide infra). If the patient is a candidate for radical (i.e. ‘curative’) therapy then a positron emission
tomography (PET)-CT should be obtained.13 While this
staging process is being undertaken the functional evaluation of the patient can be carried out so that at the
end of this process a treatment decision can be made. If
the treatment decision is to give the patient induction
therapy this process will need to be repeated at the term
of the induction therapy so as to determine the logical
next step.
THE STAGING TESTS
Lung cancer is dealt with nowadays by teams which
comprise pulmonary physicians, surgeons, oncologists,
radiotherapists, palliative care physicians, radiologists,
pathologists, and numerous support staff. In the UK
this is known as the multidisciplinary team (MDT). In
an age of technologic progress it is often necessary to
remind ourselves of the importance of good clinical
acumen. All of our elaborate scans have to be directed
by clinical assessment and interpreted in the light of
this.
Clinical history and examination
These remain the most basic and most cost-effective
assessments of disease extent. The clinician, whilst
enquiring as to symptoms of the primary tumor, will be
looking to assess performance status and co-morbid
conditions. Watching the patient come into the consultation room and careful enquiry into his/her functional
status and exercise tolerance will determine the patient’s
ability to undergo aggressive treatment, be it surgery,
chemotherapy, or radiotherapy. Investigations may be
curtailed in a very unfit patient because their results
will not influence treatment choices. The performance
status (Table 9.4) of every patient should be recorded
at the first clinical visit.
A few questions are critical to assess stage. The presence of chest wall pain is more accurate at determining
Staging, classification, and prognosis 103
Table 9.4 ECOG performance status142
Grade
ECOG performance status
0
Fully active, able to carry on all predisease
performance without restriction
Restricted in physically strenuous activity
but ambulatory and able to carry out work
of a light or sedentary nature, e.g. light
house work, office work
Ambulatory and capable of all self-care but
unable to carry out any work activities; up
and about more than 50% of waking hours
Capable of only limited self-care, confined
to bed or chair more than 50% of waking
hours
Completely disabled; cannot carry out any
self-care; totally confined to bed or chair
Dead
1
2
3
4
5
chest wall invasion than a CT scan. The presence of
unexplained weight loss should alert the clinician to
the increased possibility of disseminated disease in such
patients. A patient may well dismiss weight loss as
attributable to changes in diet and a deliberate attempt
at weight reduction. Further enquiry may show that
repeated previous attempts at weight reduction have
failed without the assistance of disseminated malignancy! The patient coming to see a chest specialist will
not volunteer the recent onset of bone pain, assuming
it to be degenerative or traumatic in nature, and may
assume that hoarseness is due to the trauma of coughing. Similarly, patients and their relatives may rationalize the change in personality as due to anxiety after
hearing the diagnosis and dismiss neurologic symptoms
as due to minor nerve damage.
A careful examination should focus upon any questions raised in the history and also routinely examine
for cervical lymphadenopathy and hepatomegaly. One’s
ability to detect enlarged neck nodes improves with
practice and this important examination should not be
designated to the most junior member of the team.
Examination of the supra-clavicular fossa with ultrasound (US)-guided FNAB is becoming increasingly
popular and does detect a number of otherwise unsuspected lymph node metastases, which are very important as they are an N3 determinant (stage IIIB). When
reading the literature on routine US screening of the
supra-clavicular fossa it is important to determine
the prevalence of nodal disease, which will be related to
the inclusion criteria for the study (patients with ‘operable’ NSCLC vs all patients with suspected or proven
NSCLC vs patients with suspected N2 disease) as this
has an obvious impact on the incidence of N3 disease
detected by this investigation. Thus in one study of
‘operable’ patients with NSCLC this technique proved
N3 disease by virtue of supra-clavicular lymph node
metastases in 8% of patients, but this led to upstaging
of only 4%.19 In a study of patients with lung cancer at
any stage, 31% were found to have supra-clavicular
lymph node metastases in non-palpable nodes.20 This
was the same frequency as probable or proven adrenal
metastases and the supra-clavicular lymph node metastases were often associated with mediastinal lymphadenopathy and/or other distant metastatic disease. This
study also showed that US was superior to CT in detecting non-palpable supra-clavicular lymph node metastases. Finally, the yield was again very low in otherwise
apparently operable patients with NSCLC. In one study
of patients with NSCLC and probable stage N2 disease,
46% of patients were found to have supra-clavicular
lymph node metastases, and this obviated the need for
other staging procedures in 42%.21 These results have
two implications. First it means that US-guided FNAB
of supra-clavicular lymph nodes will obviate the need
for more invasive staging procedures in a significant
number of patients, sparing them the risks of the procedure and making considerable cost savings for the
health-care economy. Second, it will upstage a significant number of patients, and this can have considerable
therapeutic consequences as in many cases this will
mean a shift from so-called curative treatment modalities to a more palliative approach. However, the yield
and benefit are greatest in patients who are already suspected of having at least stage IIIA disease, and the
yield in patients with stage I and II disease is much more
limited, making its routine application for this subset of
patients much more debatable. This finding was confirmed in another study in which only 3/117 patients
were upstaged by supra-clavicular US-guided biopsy of
non-palpable lymph nodes.22
Chest radiography
This is usually the starting point in further evaluation.
Whilst it usually provides clues as to the diagnosis, it
also gives valuable staging information as to tumor size
and possible local invasion.23 It is as well to check the
radiograph for rib erosion, elevation of the hemidiaphragm, the presence of other lung nodules, or evidence of an effusion (Figure 9.1). The presence of such
features may allow one to cut short the process of
104 Textbook of Lung Cancer
the surgeon will wish to examine the airway with respiration suspended under general anesthesia, often using
the rigid bronchoscope with its wider field of view and
facility for larger biopsies. Bronchoscopy also allows
the clinician to rule out other small endobronchial
tumors and demonstrates anatomic variants of bronchial anatomy to the surgeon.
Figure 9.1
The chest radiograph of a patient with a mass in the right upper
lobe (arrow). The film also shows gross widening of the superior
mediastinum (arrow head), strongly suggestive of mediastinal
nodal disease, but there is also a right pleural effusion. Aspiration
cytology of the effusion gave the diagnosis of adenocarcinoma,
allowed staging of the disease as T4 (stage IIIB), and also showed
the patient to be inoperable.
assessment by establishing the diagnosis and staging
the patient with a single investigation, such as pleural
aspiration cytology. The posteroanterior and lateral
films can also be useful for tumor localization in relation to the fissures.
Hematologic parameters
Parameters such as anemia, disturbance of liver enzymes,
or elevation of serum alkaline phosphatase are reliable
indicators, suggesting a greater probability of distant disease.24 Such tests are inexpensive and widely available,
and should be a routine part of the staging process.
Bronchoscopy
For the patient who remains operable at this point a
wide vista of additional tests may be appropriate. The
diagnosis may be established by sputum cytology, an
underutilized investigation, but for all patients except
those with extensive disease, bronchoscopy will be
undertaken. This provides an opportunity for more
accurate determination of cell type by histologic examination and allows one to assess the proximal extent of
the disease within the tracheobronchial tree. The
fiberoptic bronchoscope is an excellent screening tool
for the respiratory physician, but in borderline cases
Computerized tomography
CT has greatly aided the staging of lung cancer and the
proliferation of CT scanning facilities attests to the
enormous value of this investigation. However, much
depends upon technical aspects of the scanner, the protocol used for the study, and the experience of the radiologist.25 CT scans of the chest provide an enormous
amount of three-dimensional information as to disease
extent. One can analyze the individual components of
the scan, assessing the accuracy with which CT can
detect mediastinal gland involvement, mediastinal invasion, chest wall invasion, the presence of additional
pulmonary nodules, or deposits in the abdominal
organs or brain. However, in reality the value of the
information provided by CT scanning is far greater than
the sum of its component parts. The three-dimensional
construct helps the surgeon anticipate the possible
extent of resection, the technical problems that may be
encountered, and the areas to inspect for possible tumor
extension. The surgeon can use such information in
evaluating the patient’s fitness for such extended surgery, to guide intraoperative assessment, and to plan
the operative strategy to deal with likely areas of extension or concern. It does not matter to the surgeon that
such areas of concern may prove to be fallacious, it is
better to be prepared, but for the clinician the lack of
specificity must be an ever-present concern in evaluating the true extent of disease. One would not want to
deny the patient potentially curative surgery on the
basis of a radiographic feature that lacks accuracy. Confirmatory tests are often necessary, particularly if the
decision hinges upon a single, adverse CT feature.
The significance of additional pulmonary nodules will
depend upon geographic factors such as the local prevalence of benign granulomatous disease. In one study,
two-thirds of such nodules were shown to be definitely
benign, and only 11% were definitely malignant.26 Mediastinal lymph nodes can be seen more easily on CT than
with conventional radiology.27 As the size of such nodes
increases, so does the probability that they contain
metastases. However, there is no size criterion below
which deposits are excluded with certainty, nor above
which deposits are certain to be present (Figure 9.2).
Staging, classification, and prognosis 105
Figure 9.2
A CT scan of the chest with contrast enhancement of the mediastinal vessels. An enlarged node is visible in the right paratracheal
area (arrow). Although this node was larger than 1 cm, it was
shown at mediastinoscopy to be benign, and this was confirmed
at subsequent thoracotomy.
Figure 9.3
A CT scan of a patient with a left upper lobe tumor.
The CT shows unequivocal evidence of irresectable involvement of
the mediastinum with tumor encircling the main pulmonary
artery to its origin. A left anterior mediastinotomy would be
unnecessary unless tissue diagnosis was required.
As one increases the size limit permitted for normality,
those nodes deemed ‘abnormal’ are more likely to contain metastases, and the evaluation gains greater specificity, but at the cost of declining sensitivity. If one
applies a lower cut-off the reverse applies, sensitivity
rises at the expense of falling specificity, and one is
more likely to designate nodes as ‘abnormal’ when they
do not contain metastases.28 This is the dilemma for the
radiologist. The commonest compromise is to report
nodes as abnormal if their short-axis diameter is greater
than 1.0 cm.29 The accuracy of this assessment depends
upon many factors: the speed of the scanner, the use of
contrast to enhance the mediastinal vessels, and the
rigor with which lymph node deposits are sought at
thoracotomy. The reported sensitivity and specificity
fall from 70–80% to 60% when the CT assessment is
subjected to detailed intrathoracic staging.30–32 Abnormal nodes, larger than this, should be examined by
mediastinal exploration to gain histologic confirmation
of their involvement. Such enlarged nodes within the
superior mediastinum are accessible to cervical mediastinoscopy and anterior mediastinotomy (see later).
Enlarged nodes beyond the reach of these techniques
can be accessible to video-assisted thoracoscopy (VATS),33
but such nodes have less impact on the results of surgical treatment and their accurate designation can usually
be left until thoracotomy.
If the CT scan of the chest shows the mediastinal
nodes are within this size limit the surgeon may proceed to thoracotomy without mediastinal exploration.34
However, there are four classic risk factors for false negative mediastinal imaging studies (including position
emission tomography (PET) scanning, which will be
discussed below). These are: large tumors, central
tumors, PET-positive hilar nodes, and cell type of adenocarcinoma or large cell poorly differentiated carcinoma.35 This should be taken into account when deciding
whether invasive mediastinal staging is indicated. Also,
many surgeons will be more cautious (i.e. more extensive in their preoperative staging) when faced with a
higher risk resection (right pneumonectomy, for example) or a high-risk patient, or both together.
Mediastinal invasion may be suggested on CT, but this
assessment is unreliable36 unless there is gross involvement (Figure 9.3). More frequently the CT scan of the
chest will show that the tumor, and the associated
atelectasis or consolidation, is contiguous with the mediastinal outline (Figure 9.4). If CT does not demonstrate
a fat line separating these two opacities the radiologist
will warn that invasion may be present.37 This judgement carries a sensitivity and specificity of around
60%,38 but is imperfect and dependent upon the experience of the radiologist. Such a worry can often be
resolved by mediastinoscopy (Figure 9.5), with the
addition of mediastinotomy in appropriate cases. A
suggestion of mediastinal invasion beyond the reach of
these techniques can be inspected using VATS, but is
usually deferred until thoracotomy when a more determined assessment of resectability can be made without
the danger of massive bleeding. The CT evaluation of
chest wall invasion is similarly imperfect unless rib erosion or extension outside the chest wall can be demonstrated.39 Fortunately, such invasion does not preclude
successful resection with good survival results.40,41
Most clinicians when requesting a CT scan will ask
for the chest study to extend into the abdomen to the
106 Textbook of Lung Cancer
Figure 9.4
A chest radiograph (a) and CT scan (b) of
a patient with a tumor in the right
middle lobe. This was initially deemed
inoperable by another clinician based
on his interpretation of the CT scan. The
appearances are not unequivocal and at
thoracotomy resection of a T2N0 tumor
was possible by bilobectomy. The chest
radiograph (c) was taken 3 years later
and the patient is still well and diseasefree 12 years later.
Figure 9.5
The CT scan of a patient with a tumor in the right upper lobe
encroaching upon the mediastinum and the right main bronchus.
This was evaluated by mediastinoscopy and found to be resectable. The patient underwent right upper lobectomy and sleeve
resection for a T2N1 tumor.
Figure 9.6
The CT of the abdomen suggested a liver metastasis. The
appearances were not clarified by ultrasound and a needle biopsy
showed a benign hemangioma.
lower pole of the kidneys in a search for distant metastases in the liver, abdominal nodes, adrenals, and kidneys. Whilst this is a useful addition to the CT protocol,
an isolated abnormality should not be taken as proof
unless there is confirmatory evidence that such an
abnormality is metastatic (Figure 9.6).42 This may
require CT-guided needle biopsy (Figure 9.7). We have
found this to be a useful role for PET, if this is available
(see later). The addition of CT of the brain is debated.
Undoubtedly the number of unsuspected metastases
discovered is small, around 5%,12,43 but as this has a
profound effect on the advisability of thoracotomy we
routinely undertake CT of the brain, chest, and
abdomen prior to surgery.44 If there is any suspicion of
Staging, classification, and prognosis 107
Figure 9.7
A CT-guided needle biopsy of an indeterminate mass in the right
adrenal gland. It showed the presence of an adenoma.
brain metastases, and indeed for screening purposes,
MRI should always be the preferred brain imaging
modality unless local availability is an issue.45,46
Scintigraphic scans
These are largely obsolete, with the possible exception
of bone scintigraphy.47 This has retained a place in staging if and only if PET is not available. Most clinicians
use bone scans selectively in ‘high-risk’ individuals in
whom distant metastases have been suggested clinically
by symptoms, or the presence of non-specific features
such as weight loss or disturbed blood parameters.48,49
As false-positive bone scans can occur with trauma and
degenerative conditions it is as well to follow up any
abnormality with skeletal radiology, and in doubtful
cases a local CT or MRI of the area.50 However, if a
whole body PET scan is obtained then the bone scan is
redundant. PET has both higher sensitivity and higher
specificity than scintigraphic bone scans.51–53 However,
despite this higher accuracy confirmatory studies
should be performed if there is any doubt about the
diagnosis of metastatic disease.12
Abdominal ultrasound
This is widely available and, in experienced hands, is as
good as CT at detecting metastases in the liver54 or
adrenals.55 If CT is not available, US should be performed in high-risk cases. US is helpful to obtain
additional information to characterize any abdominal
abnormality on CT, and may obviate the need for needle biopsy. It is also a useful guiding technique for the
biopsy, if required.
Mediastinal exploration
This is a fundamental tool to select patients for surgery
because of the strong negative prognostic implication
of N2 and N3 disease. The ESTS has recently published
guidelines on both the pre-operative and the intra-operative lymph node staging.17,35 If it is felt that the
patient would be a candidate for induction (also called
neo-adjuvant) therapy, then it may be desirable to avoid
surgical staging of the mediastinum so that the most
definitive procedure can be carried out in an unoperated and unscarred mediastinum at the end of the
induction therapy (see section below on restaging of
the mediastinum after induction therapy). It can also be
desirable to avoid surgical staging in more frail patients.
Unfortunately, the reliability (the combined sensitivity
and specificity) of all techniques increases with invasiveness. The true gold standard of mediastinal staging
is the systematic nodal dissection done at the time of
thoracotomy. Mediastinoscopy has a false-negative rate
of less than 10%,56 whereas all endoscopic techniques
with FNAB have a false-negative rate of around 15% in
the best of hands. So the decision as to how to proceed
will depend on the clinical indices of suspicion for
mediastinal lymph node involvement as well as the
patient and the planned resection, as it is clearly
desirable to avoid the discovery of false-negative staging at thoracotomy in a high-risk situation. So in most
centers mediastinoscopy is now used selectively to
evaluate the mediastinum when CT has suggested the
presence of enlarged mediastinal nodes or mediastinal
invasion,57 if there are PET-positive nodes in the
mediastinum, or if there are other clinical indices leading to heightened suspicion of mediastinal lymph node
involvement.
Cervical mediastinoscopy58 is undertaken under general anesthesia through a short cervical incision. It
allows inspection and biopsy of lymph nodes in the
paratracheal region to both sides of the trachea, in the
pretracheal area, and below the carina, excluding gross,
often irresectable, nodal metastases. When the nodes
are of a normal size and metastases are small and intranodal there is obviously a risk of sampling error, and
this is the most common cause of false-negative mediastinoscopy. The one area where more overt mediastinal nodal deposits can be missed is classically the
inferior part of station 7 (the subcarinal nodes) as well
as its most posterior aspect. This risk can be minimized
by dissecting station 7 off both left and right main
bronchi, as well as off the pericardium posteriorly prior
to taking biopsies. There are several reports of falsenegative rates of well over 10%. We feel that using a
108 Textbook of Lung Cancer
video mediastinoscope, with its greatly enhanced vision,
this is unacceptable and, if this is the case, the surgeon
should consider taking more care to identify all possible nodes, to dissect them out more so that larger biopsies can be taken safely, and to prepare the subcarinal
fossa as described above so that it can be extensively
biopsied. When the tumor is a left-sided tumor it is the
practice of the authors to do this part of the mediastinoscopy quite aggressively because it then becomes
part of the systematic nodal dissection. Likewise, as it
is extremely difficult to reach L4 and L2 effectively
through a left thoracotomy, it is the practice of the
authors to resect as many nodes as possible at mediastinoscopy, again with the view that mediastinoscopy, if
negative, will then become a seamless part of the operative management of the tumor, fulfilling the philosophy of intraoperative staging as described in the ESTS
guidelines.17
Two more radical methods of mediastinal staging have
been described. These are VAMLA (video-assisted mediastinoscopic lymphadenectomy) and TEMLA (transcervical extended mediastinal lymphadenectomy).59–61 As
the names imply, both techniques aim to perform
a radical mediastinal lymphadenectomy removing all the
para-tracheal nodes as well as emptying out in a radical
manner the subcarinal fossa (and therefore more than
just station 7). TEMLA also aims to remove stations 5,
6, and 8. In experienced hands these techniques can be
performed safely with entirely acceptable morbidity.
However, at the moment experience is limited and they
are only performed in a few centers. Furthermore their
exact place in mediastinal staging remains to be established. First, do we truly want a perfect method to stage
the mediastinum? Patients with true minimal N2 disease (single-station, intracapsular involvement) have a
25–40% five-year survival with surgery alone. It is
uncertain whether it is in these patients’ best interest to
be denied surgery because they are found to have N2
disease. Second, at the end of this chapter we shall
explore the issue of restaging the mediastinum after
induction chemotherapy. It is when the N2 disease has
been eradicated that there is an indication for surgery.
This would be impossible after VAMLA or TEMLA,
making the decision whether to proceed with surgery
more difficult because all that would be left would be
to assess the decrease in the maximal standardized
uptake value (SUV max) of the primary tumor as a
measure of the response to induction chemotherapy.
The major advantage for such techniques at present
would appear to be in allowing the mediastinal component of systematic nodal dissection (see later) to be
performed prior to surgery when video-assisted resection is planned.
Mediastinoscopy can also be very useful to assess
direct mediastinal invasion by right upper lobe tumors,
so in some cases it can also be useful to assess T stage
and thus resectability. When wishing to inspect the
area around the aortic arch and subaortic fossa, as in
patients with tumors arising in the left upper lobe or
reaching the left main bronchus, cervical mediastinoscopy should be supplemented by left anterior mediastinotomy.58 This allows digital examination and, if necessary,
cautious biopsy of disease in this area (Figure 9.8). It is
applied selectively depending upon the CT appearances
in this area of the mediastinum.62 Some surgeons prefer
to use VATS to biopsy stations 5 and 6. Such techniques do not exclude more subtle mediastinal disease
but, with experience, ensure that complete resection is
possible in 95% of negative cases.63,64 The surgeon will
often be encouraged to proceed with thoracotomy and
resection when other, less accurate techniques such as
CT have raised doubts. When the lung cancer is in the
left upper lobe and the CT shows only small-volume
nodes, completely surrounded by fat, in the para- or
subaortic area on CT, some surgeons do not routinely
explore this area preoperatively because the five-year
survival in patients with this pattern of nodal disease
may be equivalent to that of patients with N1 (i.e. stage
II) disease, and not that of patients with N2 (i.e. stage
IIIA disease).65,66
Mediastinal needle biopsy
This can be undertaken through the bronchoscope.67
Suitable target nodes should be identified in the main
Figure 9.8
This patient has a tumor in the left upper lobe and the surgeon is
undertaking evaluation by cervical mediastinoscopy and left
anterior mediastinotomy. After all biopsies have been taken,
bi-digital palpation of the subaortic fossa will exclude invasion or
gross mediastinal gland enlargement in this critical area.
Staging, classification, and prognosis 109
carina or the paratracheal area, usually on CT. This
technique may obtain tissue diagnosis and confirm
irresectability, but there is a small risk of false-positive
samples.68,69 It cannot be considered to be a reliable
alternative to staging the mediastinum by surgical exploration prior to thoracotomy, even with US-guided biopsies. Overall, bronchoscopic FNAB techniques have a
false-negative rate of around 15%, so the main value of
these techniques is when this minimally invasive technique proves mediastinal lymph node involvement.
Transesophageal fine needle aspiration (with
ultrasound guidence)
EUS-FNA has been used to assess the presence of
mediastinal node enlargement, but is limited by the
same size criteria as CT.70 The transesophageal route is
attractive as a conduit to examine the mediastinum
below the carina, beyond the reach of the mediastinoscope, as well as the left para-tracheal area, checking
areas where CT has suggested mediastinal lymph node
involvement or tumor invasion. The results have proven
unreliable,71 being of a similar order of magnitude as
with trans-tracheal biopsies. The same caveats therefore
apply to this technique, even with US guidance. However, it has been shown that EUS-FNA can be used to
improve the yield of mediastinoscopy.69 In this study
there were 36/100 patients who were ultimately proven
to have N2/N3 disease. These were located within reach
of EUS-FNA in 29 patients, and were positive at EUSFNA in 22. Mediastinoscopy detected N2 (17%) or N3
(2%) lymph node metastases in 19 of the 100 patients.
These were located within reach of mediastinoscopy in
29 patients and were confirmed in 19 of these patients.
Lymph node metastases were confirmed in 31 (86%) of
36 patients by either EUS-FNA or mediastinoscopy.
The five lymph node metastases that were missed by
both techniques were located at station 4L in one
patient, 5 in one patient, 7 in two patients, and 8 in one
patient. This study also showed that T4 status can be
correctly assessed by this technique in a number of
cases. Similar results with this combined technique
have been reported by others.72
Positron emission tomography
PET using the 18F-labeled glucose analog fluoro-2-deoxy-D-glucose (FDG-PET) has emerged as an exciting
addition to the staging tests. It is expensive, and in
many areas is still not widely available, and we are still
assessing its cost-effectiveness. It provides an alternative, metabolic search for malignant disease that is independent of the anatomic features of the deposits and is
thus a useful tool to detect and characterize the primary
tumor as well as loco-regional and distant metastases.73
It can characterize the lung lesion reliably in many
cases,74 failing only to detect very small deposits and
more indolent tumors such as broncho-alveolar carcinoma.75 False-positive cases can occur with chronic
inflammatory conditions, most notably tuberculosis
and histoplasmosis. PET may thus have a role in diagnosis and its place relative to bronchoscopy or needle
aspiration is under discussion.76 PET is reliable for
lesions that are over 8–10 mm in diameter, and should
probably not be performed for smaller lesions.12 Interest, however, has focused on the possibility that PET
could aid the non-invasive search for metastatic disease
in the mediastinum and at distant sites.77 Initially it was
said that PET is more accurate in the detection of mediastinal nodal disease than CT and even mediastinal
exploration, with a reported sensitivity of 80–100%
and specificity of 70–100%.78 However, the images
produced by FDG-PET scanners are indistinct and lack
anatomic precision (Figure 9.9). It is difficult to accurately define the margins of hilum and mediastinum. In
many centers this problem has been addressed by concomitant PET and CT scanning in a dedicated PET-CT
scanner. Two studies have shown the superiority of
integrated PET-CT as compared to the combination of
a PET study and a CT with correlation of the images by
the examining physician.79,80 This superiority was found
to be significant for the determination of T stage,
N stage, and M stage. A final caveat regarding PET is that
one study has shown it to be significantly less reliable
in smokers (or recent quitters) than in non-smokers.81
The maximal SUV was also higher in never-smokers,
both in the primary tumor and in mediastinal metastases. This could be due to the fact that the background
FDG uptake is higher in smokers than in never-smokers. Most centers having access to PET continue to rely
upon CT and confirm positive PET findings by mediastinal exploration, thus adding to the expense of staging.82 There is also the philosophical problem as to
whether one wishes to detect all mediastinal nodal
deposits. There are many reports of five-year survival of
20–30% after complete resection in the presence of
truly minimal N2 disease.64,83–85 Mediastinal exploration will miss such subtle N2 disease, perhaps to the
patient’s benefit, encouraging one to proceed with surgery with complete resection in 85% of cases.64 It is
unknown to what extent detection of this minimal N2
burden and induction chemotherapy would alter the
natural history of this entire very small subset of
patients (because induction therapy does not eradicate
110 Textbook of Lung Cancer
Figure 9.9
The chest radiograph (a) of a patient who
presented with a tumor in the left lower
lobe; there is an additional lesion at the
right apex (arrow). The CT scan (b) did
not suggest this additional lesion was a
tumor. An FDG-PET study (c) showed high
uptake in both lesions, and the rightsided lesion was confirmed histologically
to be malignant.
N2 disease in the majority of patients with more bulky
N2 disease). Furthermore, we do not know if the results
of induction chemotherapy would be better, worse, or
the same as adjuvant chemotherapy, which would now
be offered to these patients unless contraindicated.
PET will detect otherwise unsuspected distant metastases in 11–29% of patients otherwise thought suitable
for thoracotomy.86–88 However, the specificity of this
evaluation is not 100%. With regard to distant staging,
the initial enthusiasm for PET needs to be tempered. A
recent study with much larger numbers (350 patients)
demonstrated solitary extrathoracic lesions in 72 patients
(21%). A diagnosis was obtained in 69: 37 were true
metastases, 32 were not. These 32 lesions proved to be
unrelated malignancies in 6 and benign tumors or
inflammatory lesions in 26.89 Similarly, in the study by
Reed et al otherwise unsuspected metastatic disease was
identified in 15/287 (5.2%), as well as three second
primary tumors. However, PET also identified 19
potential areas of M1 disease that were proven not to be
metastases (6.6%). Thus the sensitivity of PET for M1
disease was 83%, the specificity was 90%, the negative
predictive value was 99%, and the positive predictive
value was 36%.90 This underscores the value of the recommendation in the current ACCP12 and NICE13 guidelines for histologic verification of apparent solitary
metastases detected by PET.
Similarly our experience with PET as a staging tool
for the mediastinum has grown and some of the initial
enthusiasm has been tempered by this experience.
There have been many recent studies and all essentially
show similar results to the three published reports.90–92
These studies included between 202 and 400 patients.
The sensitivity of PET ranged from 64 to 71%, the specificity from 77 to 84%, the positive predictive value
from 44 to 56%, and the negative predictive value from
87 to 91% (Table 9.5). An editorial by Kernstine
explains why these values are the best one can expect
with the current technology.93 What these results mean
is that, if one relies exclusively on PET to rule out N2/
N3 disease, between 9 and 13% of patients will be found
at thoracotomy to have unexpected N2 disease which
might have precluded surgery. Putting together what we
know from the CT era and this knowledge it seems reasonable to proceed with thoracotomy for small, peripheral tumors (unless known to be an adenocarcinoma or
Staging, classification, and prognosis 111
Table 9.5 Accuracy of PET-CT for mediastinal staging
Reference
Number of
patients
Sensitivity (%)
Specificity (%)
Positive predictive
value (%)
Negative predictive
value (%)
Reed et al90
Gonzalez-Stawinski
et al91
Cerfolio et al92
303
202
61
64
84
77
56
45
87
88
400
71
67
44
91
poorly differentiated large cell carcinoma) on the basis
of the PET scan alone, provided that the surgeon is prepared to resect unexpected minimal N2 disease if found,
on the basis that surgery alone offers a 20–35% chance
of cure in this situation.35 This might be improved with
adjuvant chemotherapy if the patient is fit for this treatment modality. Otherwise, invasive staging of the mediastinum should be carried out. This does not make PET
useless. First, in the apparent stage I (and possibly II)
patients with peripheral lesions it can allow lung resection to be carried out without surgical staging of the
mediastinum. Second, because it is precisely the patients
with the highest risk of unsuspected mediastinal disease who are also at highest risk of distant metastatic
disease that PET has the highest chance of detecting
otherwise occult stage IV disease.
Integrated PET-CT has been shown to be more accurate than PET alone with correlation to a previously
performed CT;79,80 however not to a degree that fundamentally changes this discussion about the indications
for surgical staging of the mediastinum.
Despite all our improvements in non-invasive staging,
invasive staging remains the closest we have to a prethoracotomy gold standard for the detection of N2 disease. The risk factors for unsuspected N2 disease that
we knew from the CT era of staging are still pertinent
in the PET age. They are tumor size, location, and histology and PET-positive hilar nodes.35 Large tumors,
central tumors and adenocarcinoma/poorly differentiated large cell carcinomas present the greatest risk of
false-negative non-invasive staging. The true gold standard for the precise diagnosis and assessment of N2
disease remains the intra-operative systematic nodal
dissection.17 This is not only a staging tool but could
also have a beneficial effect on outcome.94–97
Magnetic resonance imaging
MRI is little or no more accurate than CT in routine
staging. Some authorities consider that the ability to visualize in planes other than axial gives MRI an advantage
Figure 9.10
An MRI scan of a patient with a right-sided Pancoast tumor. The
scan gives coronal reconstruction of this difficult area, but also
suggested nodes at the main carina, which were confirmed to
contain metastatic disease at mediastinoscopy.
in difficult areas such as the lung apex and lower mediastinum.98 Most would recommend MRI when evaluating Pancoast tumor (Figure 9.10).99 With modern, fast,
multislice CT scanners and the software to do multiplanar reconstructions many of the advantages of MRI
have been obviated. If appropriately thin cuts are
obtained, modern CT scanners have higher spatial resolution than MRI. However, MRI remains of value as a
problem-solving tool looking at the central nervous
system. MRI is more accurate than CT at detecting and
characterizing brain lesions.45,46,100 If there is a clinical
suspicion of brain metastases then MRI should be
obtained unless there are local availability issues. We
would also recommend its use if CT of the brain shows
an abnormality (to rule out multifocal disease) or when
clinical suspicion remains after a negative CT. The routine use of MRI as a screening tool for asymptomatic
brain metastases has not been shown to be of value.
Similarly, if the CT raises doubts as to tumor extension
around the spine and into the spinal canal, MRI will
give clearer definition and valuable information. Whenever a neurosurgical opinion is to be sought, MRI
should be obtained beforehand.
112 Textbook of Lung Cancer
The tests described above should allow one to determine cTNM and, in appropriate cases, recommend thoracotomy. For the surgeon, however, the staging process
does not end there. We have come to appreciate that a
detailed re-evaluation at thoracotomy is a valuable step
prior to proceeding with resection. Intrathoracic staging
will evaluate areas of concern remaining after CT and
subsequent mediastinal evaluation, search for additional pulmonary nodules and pleural deposits not seen
on CT,101 and permit a thorough evaluation of nodal
extent by systematic nodal dissection.102
There is debate as to the value of pleural lavage
cytology as a routine step immediately after opening
the chest. Kondo and his colleagues found positive
pleural cytology in 9% of cases and showed it to be a
strong indicator of poor prognosis.103 Other workers
have confirmed the incidence of positive cytology but
did not find a statistically significant influence on prognosis after resection.104 We have reviewed our experience with pleural lavage cytology. We found malignant
cells in the lavage in 4.5% of the 292 patients studied.
Positive pleural lavage had a statistically highly significant and independent impact on survival: patients with
positive pleural lavage had a median survival of only 13
months, as compared to 49 months for those with a
negative lavage.105
Despite rigorous preoperative staging with CT and,
where appropriate, mediastinal exploration, cTNM has
been shown to be inaccurate in over half of the patients
coming to thoracotomy.106 Whilst occasionally cTNM
will overestimate the extent of disease, in most cases the
disease will be shown to be more extensive. As yet we
do not know precisely how the integration of newer
(a)
STEP 1
(b)
tools such as PET-CT will improve this. It is clearly
important that the surgeon obtains such valuable insight
into the extent of disease before making a decision
whether to proceed with resection, and when judging
the extent of pulmonary resection necessary to achieve
complete resection.
Systematic nodal dissection (SND) begins with the
excision of all mediastinal fat and the lymph nodes contained therein (Figure 9.11). It is recommended that
the nodes be labeled in accordance with an internationally recognized chart such as that proposed by Naruke
(Figure 9.12)107 or that of Mountain and Dressler
(Figure 9.13).3 It is our routine to slice these nodes at
the operating table and examine the internal architecture before deciding whether rapid histologic confirmation is necessary by frozen section analysis. If resection
is deemed possible we proceed to examine the N1
nodes similarly, in a centrifugal fashion, until the extent
of resection has been determined. The only nodes
remaining in the resection specimen can be assumed to
be N1. In such a way the surgeon will ensure complete
resection with the minimum resection of lung parenchyma.
We have shown that SND will disclose N2 disease in
18% of patients coming to thoracotomy without histologic evidence preoperatively, and only 60% of patients
will be shown to be node negative.108 This study confirmed that SND could not be omitted on the basis of
cell type, tumor size, tumor origin, lobe of origin, or by
preoperative mediastinal exploration. As ‘skip’ lesions
to the mediastinal nodes without hilar node involvement were found in 6% of cases, the assessment of the
mediastinum is important irrespective of the findings in
STEP 2
Figure 9.11
An operative specimen showing fat and
lymph node stations removed during the
first step in SND (a). These can be
correlated with the Naruke chart to show
that a complete circumnavigation of the
right side of the mediastinum has been
accomplished. Step 2 of the nodal
dissection (b) removes the nodes from the
fissure and the hila of the individual
lobes.
Staging, classification, and prognosis 113
1
2
1
4
5
10
10
7
13 12
14
2
3 6
10
14
2
3
2
4
1
10
10
10
10
10
11
11
12
11
8
14
13
12
8
13
14
14
14
13
12 13
13 14
13
8
13
13
14
14
9
1
3p
8
9
2 3
4
3a
9
1 Superior mediastinal or highest mediastinal
2 Paratracheal
3 Pretracheal
1
3a anterior mediastinal
3p retrotracheal or
2
3a
3
posterior mediastinal
6
4 Tracheobronchial
5 4
5 Subaoratic or Botallo’s
6 Paraaortic (ascending aorta)
7 Subcarinal
8
8 Paraesophageal
(below carina)
9 Pulmonary ligament
9
10 Hilar
11 Interlobar
12 Lobar … upper lobe
middle lobe and
lower lobe
13 Segmental
14 Subsegmental
Figure 9.12
The nodal chart devised by Naruke. The lymph node stations are
numbered: 1–9 indicate mediastinal nodal stations. (Reproduced
with permission of Dr T Naruke and Mosby Inc from J Thorac
Cardiovasc Surg 1978; 76: 832–9.107)
the hilum. If mediastinal node deposits are discovered
at thoracotomy and yet complete resection has been
confirmed to be feasible, the surgeon must decide
whether to proceed with resection, balancing the
reduced prospects of survival after complete resection
and the added morbidity and mortality of pulmonary
resection. The surgeon will be aware that the patient
has already necessarily incurred the morbidity and
mortality of thoracotomy (annual returns, The Society
of Cardiothoracic Surgeons of Great Britain and Ireland), and will base the decision to resect upon the
patient’s fitness, the extent of resection necessary, the
cell type, and the number and position of positive
nodes. Complete resection will be deemed appropriate
in 85% of cases, although the perioperative mortality is
higher and the five-year survival reduced to around
20–30%.64,83–85
Subsequent histologic examination of lymph node
stations removed at surgery will show metastases that
the surgeon had not appreciated in up to 9% of cases.109
The pathologist will also study the specimen and
attached lymph nodes, looking for the presence of
pleural invasion and satellite lesions that may have
eluded the surgeon. Some authors have suggested that
the use of monoclonal antibody stains will detect nodal
deposits not seen with conventional stains in up to 6%
of lymph nodes in 22% of patients.110 Others have suggested that this is the result of taking additional slices
of the nodes and that the majority of such micrometastases will be found with conventional stains by more
thorough histologic examination.111
To establish the pTNM the clinician will thus have to
scrutinize the operative findings and study the detailed
pathology report. The accuracy of pTNM will depend
heavily on the detailed nature of such reports.
RESTAGING AFTER INDUCTION CHEMOTHERAPY
A full discussion of the place of induction chemotherapy in the management of NSCLC is outside the remit
of this chapter. However, if multimodality therapy is
considered, restaging of the patient prior to surgery is
of paramount importance.
Recently there have been studies that have challenged
the role of surgery in all but true minimal N2 disease
(i.e. intracapsular, single node N2 disease found at
the time of thoracotomy), showing apparently similar
results with radical radiotherapy after induction
chemotherapy.112–114 However, in one of these studies114
there was a significantly improved progression-free survival with surgery and a trend towards increased overall
survival, and the authors concluded that surgery can be
considered in fit patients, especially if a pneumonectomy will not be required. In another,112 the number of
complete responses (only 4% overall) was far less than
usually found and the pneumonectomy rate (50%) was
unusually high, so it does seem fair to consider the
results of the experience to date as inconclusive. The
authors of this European trial112 themselves point out
that we do not know what the outcome would be in the
patients who are now considered to be the appropriate
candidates for surgery, i.e. those who have been downstaged from N2 to N1 or N0. It is interesting to note
that in this same study the locoregional recurrence rate
was much lower in the surgery arm (55% vs 32% in the
radiotherapy arm). Finally, RTOG 89-01 was closed
prematurely to give priority to another trial, which will
114 Textbook of Lung Cancer
Figure 9.13
The nodal chart established by the American
Joint Committee on Cancer (AJCC) and the Union
Internationale Contre le Cancer (UICC) in 1997.3
(See color plate section, page xv)
weaken the conclusions that can be drawn from this
trial.113
With induction chemotherapy, typically 30–50% of
patients will have the N2 nodes cleared of cancer by the
induction therapy. It is interesting to note that, when
there was sequential induction therapy comprising chemotherapy followed by chemoradiation therapy, and
when PET was performed at the outset, after the
chemotherapy and at the end of the induction process
it was the postchemotherapy PET (and not the PET
post-total induction therapy) that was the better predictor of survival.115
If the N2 nodes have been cleared of cancer, the fiveyear survival ranges from 29 to 44%,35,116,117 and if a
pathologic complete response is observed the five-year
survival is estimated to be 54% (median survival not
reached).118 If, on the other hand, this is not the case
then the five-year survival is 7–24%, usually below the
10–15% range in most studies. This is why it is considered essential to restage the mediastinum after induction therapy to avoid futile and potentially dangerous
thoracotomies and resections if there is persistent N2
disease. Unfortunately there is no perfect tool to restage
the mediastinum.35
Repeat mediastinoscopy has been used to restage the
mediastinum. The best results have been published
(and recently updated) by the Antwerp group.119 Over
10 years they had 32 patients who underwent repeat
mediastinoscopy after induction therapy. They were
able to perform the procedure in all patients and had
only five false-negative repeat mediastinoscopies, yielding a sensitivity of 71%, a specificity of 100% and an
accuracy of 84%. De Leyn et al reported the Leuven
experience of 30 prospectively studied patients and, in
their hands, there were only five positive repeat mediastinoscopies. In 18 cases the node which had been
positive at the first mediastinoscopy could not be adequately assessed because of extensive scarring and
fibrosis. All patients underwent thoracotomy and the
systematic nodal dissection revealed persistent N2 disease in 17. Therefore the sensitivity of repeat mediastinoscopy was 29%, its specificity was 100%, and its
accuracy only 60%.120 A Dutch group reported their
experience with repeat mediastinoscopy in 15 patients.
In 6 patients the procedure was considered to be inadequate; there were 9 adequate procedures – 2 were true
positives and 2 were false negatives.121 The conclusion
must be that in the real world repeat mediastinoscopy
Staging, classification, and prognosis 115
is a challenging operation with insufficiently robust
results to recommend its routine use for restaging of the
mediastinum after induction therapy.
CT scanning is even more inaccurate for restaging
than it is for primary staging.35 PET, when used for
restaging the mediastinum after induction therapy, is
less accurate than when used for primary staging, with
a sensitivity of 50–60% and a specificity of 85–90%.35
Fused PET-CT is better that PET alone in this situation
and in one study (with by far the best results) the sensitivity was 77%, the specificity was 92%, and the accuracy was 83%.120 However the results of fused PET-CT
are not usually as good as this.35 Again, a variety of
FNAB techniques have been described, with essentially
the same sensitivity and specificity as when used in the
chemo-naïve setting. Thus restaging of the mediastinum
after induction therapy in N2 disease remains a fraught
subject, often requiring a complex step-wise approach
with CT, PET-CT, trans-tracheal or esophageal FNAB,
and repeat mediastinoscopy, and still with a risk of
false-negative assessment of the mediastinum.35
As we have seen, tissue diagnosis is the ideal restaging
tool, but it is difficult and, even in the best hands, it will
always have a finite false-negative rate; it also requires
heavy use of time and resources, and can submit the
patient to multiple procedures. PET has been shown to
be an alternative, or surrogate way to restage the mediastinum after induction therapy. Cerfolio et al have
published two papers on an overlapping patient population, looking at the change in the SUV max on PET
before and after induction chemotherapy.122,123 In the
first study122 they demonstrated that a drop in SUV max
of 80% in the primary tumor predicted a pathologic
complete response with a sensitivity of 90%, a specificity of 100%, and an accuracy of 96%. These results are
roughly as accurate as the best combined invasive
restaging strategies. In the second study123 they showed
that a drop in SUV max of 75% predicted complete
response. If the SUV max in the mediastinal nodes
decreased by 55% there was a very high chance of being
a partial responder. The median decrease in SUV max
was 100% (range 75–100%) in complete responders,
58% (range 2–100%) in patients who had a complete
response in the N2 nodes but residual viable tumor in
the primary tumor, and 32% (range ⫺5–82%) in patients
with residual N2 disease. In terms of N2 disease,
PET-CT was less reliable. A decrease of SUV max of
>55% had a likelihood ratio of 9.1 in predicting clearance of the N2 nodes, but in reality residual N2 disease
was missed by PET-CT in 13/65 patients (20%). One
group studied the SUV max before and after induction
chemotherapy.124 These patients underwent induction
chemotherapy followed by chemo-radiation therapy
then surgery. A PET-CT was performed at time 0, after
the chemotherapy (t1), and at the end of the induction
process (t2). Patients with either a complete response
or less than 10% viable tumor cells in the tumor had a
drop in SUV max of 67% at t1 and 73% at t2. Follow-up
was short so the survival data are difficult to interpret.
Another group used PET to study the metabolic rate of
glucose.125 The multivariate analysis showed that the
absence of N2/N3 disease at PET had a survival hazard
ratio of 2.33 (95% CI 1.04–5.22; p <0.04). Reading
from the graphs, this translates into a three-year survival of a little under 0.6 for N2/N3 negative patients vs
around 0.25 for those with N2/N3 disease. The hazard
ratio for each 10% drop in the metabolic rate of glucose
was 0.99 (95% CI 0.98–0.99; p <0.01). A residual metabolic rate of glucose after induction of ≤0.13 had a
hazard ratio of 1.95 (95% CI 1.28–2.97; p <0.002).
Again, looking at the graphs this translates into a threeyear survival of around 0.6 vs 0 for a value >0.013.
Restaging with PET may also reveal previously undetected metastases after induction chemotherapy. This
was seen in 9/47 patients in one study,126 and in 10/56
in another.127
The only alternative would be to try to stage the
mediastinum with any of the variety of FNAB techniques, and, if that fails but there is a high index of
clinical suspicion of N2 disease, administer induction
chemotherapy to the patient. This would allow mediastinoscopy to be performed in an unscarred mediastinum, hopefully with a much higher sensitivity. However
this approach is unvalidated at present.
There is one important pitfall with the whole concept
of offering patients induction chemotherapy. The harsh
reality is that only 30–50% of patients will be downstaged and offered surgery, the rest going on to radical
radiotherapy. This means that their chemo-radiation
therapy will be sequential instead of concurrent, and
there is a consensus now that concurrent chemoradiotherapy is the standard of care in stage IIIA and
IIIB disease. The patient needs to be aware of this when
consent is sought for induction therapy.
OTHER PROGNOSTIC INDICATORS
Table 9.6 summarizes known or supposed prognostic
factors in surgically resected NSCLC. Cell type is not per
se a prognostic indicator,128 but as we have discussed
previously certain cell types (adenocarcinoma and large
116 Textbook of Lung Cancer
Table 9.6 Prognostic factors in surgically resected NSCLC
Prognostic factors
Tumor related
Host related
Environment related
Essential
T category
N category
Extracapsular nodal
extension
Superior sulcus location
Intrapulmonary
metastases
Histologic type
Grade
Vessel invasion
Tumor size
Molecular/biologic
markers
Weight loss
Performance status
Resection margins
Adequacy of mediastinal
dissection
Gender
Age
Radiotherapy dose
Adjuvant radiotherapy
Additional
New and
promising
Quality of life
Marital status
Published with kind permission of the editors and the UICC.129
cell poorly differentiated carcinoma) represent a risk
factor for presenting at a higher stage of disease. The
failure of screening to improve survival in a screened
population129 is in part due to so so-called overdiagnosis of indolent disease, proving that the term indolent
adenocarcinoma is not an oxymoron. Only performance
status equals stage in its impact on survival after all
treatment modalities. Others factors such as weight loss
and the presence of systemic symptoms are accepted as
important. Cell type, degree of differentiation, and vascular invasion may be significant, but reports vary depending upon stage and whether surgery was possible.130 Sex
is a prognostic indicator – females have better survival
independently of TNM stage and histology.131–133 Age
has an impact on treatment but is not an independent
variable. Certainly information on these factors should
be recorded and data presented in any report of results.
There is great interest in biologic markers in lung cancer,
and the hope that a panel of markers, including oncogenes and tumor suppresser genes, can provide an
independent, biologic method of anticipating outcome.
At present our knowledge of these markers is imperfect,
and there are still no markers that have translated into
the clinical setting because they do not discriminate in
a sufficiently robust way to allow therapeutic decisions
to be made.130 It is recommended that, where possible,
cryopreserved tissue from well-staged, surgical specimens should be stored for future studies.
On-going smoking is increasingly found to have an
effect on prognosis. All textbooks cite that the risk of
developing a second primary lung cancer following
successful management of NSCLC is 1% per patientyear, and this is doubled if the patient continues to
smoke. It is now starting to emerge that smoking can
interfere with the effectiveness of radiotherapy.134 Similarly, smoking can reduce the effectiveness of chemotherapy upregulation of the pathways targeted by
chemotherapy, thus inhibiting chemotherapy-induced
apoptosis.135 Smoking has a particularly strong inhibitory effect on tyrosine-kinase inhibitors (TKIs). The
BR.21 study on erlotinib in NSCLC showed that plasma
concentrations of the drug were around twice as high in
non-smokers and ex-smokers compared to current
smokers. This is attributed to a lack of induction of cytochrome P450 1 A isoforms by cigarette smoke as well as
a higher incidence of K-ras mutations in smokers resulting in faster plasma clearance of erlotinib in smokers.136
Genomics are starting to show promise in identifying
patients at high risk of recurrence.137 It remains to be
proven whether these patients will benefit from more
aggressive postoperative chemotherapy. Similarly,
ERCC1 is an enzyme that can repair the DNA damage
induced by cisplatin. When cisplatin-based adjuvant
chemotherapy was given to patients, those with tumors
that were ERCC1-negative had a significantly longer
survival than those with ERCC1-positive tumors.138
The SUV max also seems to indicate prognosis.139
When the SUV max is higher than 10, tumors tend to
be more likely to be poorly differentiated and to present
at a higher stage. For each stage, if the SUV max is
greater than the median value seen for that stage this
also tends to indicate a poorer prognosis – for example
Staging, classification, and prognosis 117
in stage IB NSCLC the four-year survival was 80% for a
SUV max lower than median, and only 66% when it
was higher than the median (p = 0.048). These values
were, respectively, 64% vs 32% (p = 0.028) for stage II
and 64% vs 16% (p = 0.012) for stage IIIA.
PROGNOSIS
The survival of patients with each stage of disease is
discussed in detail in the chapters on treatment in this
book, but a few comments are pertinent when considering staging. When reading the literature on the results
of treatment of lung cancer, especially surgical series,
the reader is reminded of two phenomena: what Shields
has termed ‘the diminishing denominator’,140 and the
impact of ‘stage migration’ or the Will Rogers effect.141
The diminishing denominator can give a false impression of the value of surgery in an advanced stage of lung
cancer by reporting only the results on patients found
to be within this stage at thoracotomy and surviving
complete resection. Other patients are ‘censored’ from
the analysis if found at thoracotomy not to fall into the
study population, if resection is not possible, if incomplete resection has been performed, and even if dying
after operation. The reported survival of patients in this
stage who survive complete resection gives little guidance to the clinician armed only with cTNM, and results
are further inflated by the use of actuarial survival statistics. Thus 300 patients with a presumptive advanced
stage (IIIA for example) may proceed to thoracotomy.
Eighty will be found to be in a lesser stage at thoracotomy, 60 will be technically irresectable (so-called open
and close thoracotomy), 95 will undergo an incomplete
resection (R1 or R2, as described in a previous section),
and 15 will die after surgery. The analysis is thus
restricted to the 50 patients who survived a complete
resection for the designated advanced stage. Therefore
the actuarial survival of the 10 who survive to five years
after complete resection is computed to be 20%. Whilst
this may impress the unwary, closer study reveals that
more patients (15) will die of such unwarranted surgery
than those in whom the prognosis is improved, at a cost
of 220 major operations and much morbidity.
Stage migration is an inevitable consequence of more
detailed staging. As one refines the group under study,
those eliminated usually cascade into the more advanced
stages, swelling their numbers, although a few will
prove to have less advanced stage disease. These new
recruits to the higher stages have a better prognosis
than the original patients do in that group, defined by
cruder staging techniques, and the prognosis of the
group is thus improved. The shifting populations are
evident in any study giving details of the results of
surgery based upon cTNM and pTNM. In one study,142
the number of patients who fell into the T1N0 category
fell from 349 to 264 when shifting from cTNM to pTNM
and, conversely, the number of patients with T3N0
disease rose from 109 to 147. This demonstrates the
improved staging achieved by thoracotomy. The fiveyear survival of patients based upon pTNM will always
be superior to that based upon cTNM, and this effect is
more pronounced in higher stage groups. In another
study,2 the five-year survival of T1N0 patients rose from
61% to 67%, a 10% improvement, when moving from
cTNM to pTNM, whilst survival of T3N0 patients rose
from 22% to 38%, an improvement of 87% in the survival of this group. These statistical realities are legitimate, but one must resist the temptation to attribute
the improved survival to the staging evaluation itself.
The prognosis of NSCLC is very variable in different
series. This is often a reflection of the rigor of both
the pre- and intra-operative staging of the cancer. If
pre-operative staging is not completely thorough there
will be 10–20% undetected N2 disease at thoracotomy,
provided that intra-operative staging has been done as
it should. However, there are still many centers that
do not routinely perform systematic nodal dissection
(which in itself is a term which is often abused). A telltale sign is the five-year survival of stage I NSCLC.
In properly staged patients this will be around 80%,
down to around 65% when staging is less rigorous.
Stage migration will then deploy its effects as stage
progresses.
When evaluating the benefits of any treatment for
lung cancer it is important to study each paper carefully, to determine the true denominator, and to note
all the tests used to define the population under study.
Thus the reader may be better able to place into context
the results reported in the following chapters.
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120. De Leyn P, Stroobants S, De Wever W et al. Prospective comparative study of integrated positron emission tomographycomputed tomography scan compared with remediastinoscopy
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122 Textbook of Lung Cancer
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FURTHER READING
Rami-Porta R, Ball D, Crowley J et al. on behalf of the International
Staging Committee. The IASLC Lung Cancer Staging Project:
proposals for the revision of the T Descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer.
J Thorac Oncol 2007; 2: 593–602.
Rusch VW, Crowley J, Giroux DJ et al. on behalf of the International
Staging Committee on Cancer Research and Biostatistics. The
IASLC Lung Cancer Staging Project: proposals for the revision
of the N Descriptors in the forthcoming (seventh) edition of the
TNM classification for lung cancer. J Thorac Oncol 2007; 2:
603–12.
Postmus PE, Brambilla E, Chansky K et al. on behalf of the International Staging Committee. The IASLC Lung Cancer Staging
Project: proposals for revision of the M Descriptors in the
forthcoming (seventh) edition of the TNM classification for
lung cancer. J Thorac Oncol 2007; 2: 686–93.
Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International
Staging Committee, Cancer Research and Biostatistics. The IASLC
Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M Descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification
of malignant tumors. J Thorac Oncol 2007; 2: 694–705.
Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International Staging Committee, Cancer Research and Biostatistics.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh)
edition of the TNM classification of malignant tumors. J Thorac
Oncol 2007; 2: 706–14.
10 Treatment of non-small cell lung cancer
10.1 Treatment of NSCLC: surgery
Robert J Korst
Contents Introduction • Historical summary • Stage I disease (T1–2N0) • Stage II disease (T1–2N1 and T3N0)
• Stage III disease • Stage IV disease • Special considerations • Palliative surgery • Summary
INTRODUCTION
Lung cancer is one of the leading causes of cancer death
worldwide. Approximately 80% of cases of newly diagnosed lung cancer are of the non-small cell type (NSCLC).
Unfortunately, a large percentage of these patients will
have inoperable disease on the basis of distant metastases (stage IV) or locally advanced disease (stage IIIB).
For the remaining patients with early stage disease (stage
I and II), as well as selected patients with locally advanced
disease (stage IIIA), complete surgical resection remains
the best hope for cure, provided that the operative risk
is tolerable.
Over the past four decades, several points regarding
the conduct of resection have become accepted as the
surgical management of NSCLC has evolved. First,
incomplete resections leaving either gross or microscopic disease behind will fail to cure the disease and
are rarely indicated in a palliative setting. Intraoperative
frozen section analysis should be employed frequently
to ensure negative margins. Second, general oncologic
principles should be followed, including the resection
of the tumor and surrounding normal lung (lobectomy
or pneumonectomy) with draining lymphatics and lymph
nodes. Third, the mediastinal lymph nodes should be
dissected to accurately stage the patient, and fourth, en
bloc resection of the tumor and surrounding structures
is desirable whenever technically possible.
Survival following surgical resection for NSCLC is
stage-dependent (Table 10.1.1). Despite the development of the principles mentioned above, less than 15%
of all patients can presently be expected to be cured of
their disease. This dismal figure underscores the need
for prevention as well as continued investigation into
better treatment options for patients with NSCLC.
HISTORICAL SUMMARY
Although non-anatomic pulmonary resection for lung
cancer had been reported in 1895, the first anatomic
lobectomy was performed by Davies in 1912. It was not
until the advent of an effective underwater drainage
system, however, that pulmonary resection could safely
be performed on more of a routine basis. Following a
report by Graham of the first pneumonectomy in 1933,
surgical resection became the treatment of choice for
lung cancer. Over the next several decades, various types
of anatomic lung resections continued to be described,
including segmentectomy, sleeve lobectomy, and pneumonectomy, as well as resection for superior sulcus
tumors.
Through the 1970s and 1980s, it became recognized
that despite radical resection with negative margins,
many patients with resected NSCLC ultimately died of
their disease, with the majority of recurrences being distant metastases. This fact was especially true for patients
found to have disease metastatic to the lymph nodes
(locally advanced disease) at the time of resection. As a
result of this observation, strategies which combine
treatment modalities (surgery, chemotherapy, and radiation) are becoming more popular and are the subject
of active investigation for nearly all stages of NSCLC. In
addition, recent breakthroughs in the use of adjuvant
chemotherapy following complete resection of NSCLC
are changing the postoperative management of patients
with this deadly disease.
STAGE I DISEASE (T1–2N0)
Patients with this early stage of NSCLC typically present
without symptoms and most are cured with primary
surgical excision. These tumors are usually peripheral in
location and are discovered on a routine chest radiograph.
These peripheral ‘coin lesions’ are mainly adenocarcinomas, or bronchioloalveolar carcinomas. Uncommonly,
a radiographically ‘occult’ tumor may be discovered.
Unlike the peripheral lesions, occult tumors are mainly
squamous in histology and patients may present with
hemoptysis. Not infrequently, occult tumors are detected
during screening bronchoscopy after a previous lung
124 Textbook of Lung Cancer
Table 10.1.1 Survival following resection for NSCLC by stage
(see text for references)
Stage
Stage I
Overall
T1N0M0
T2N0M0
Stage II
T1–2N1M0
T3N0M0
Chest wall invasion
Mediastinal invasion
Proximal bronchus
Stage III
N2
Clinically negative
mediastinum
Clinically positive
mediastinum
Five-year survival (%)
76
84
68
47
56
29
36
34
9
cancer resection,1 or in patients who have undergone
bronchoscopy as part of the work-up for another process, such as head and neck or esophageal cancer.
Complete surgical excision is the treatment of choice
for stage I NSCLC, provided the operative risk is acceptable. Patients should undergo preoperative pulmonary
function testing to assess lung reserve, as well as cardiac
evaluation if indicated from the patient’s history. The
operation of choice is anatomic lobectomy. Occasionally, a more extensive resection needs to be performed
when the location of the tumor is such that removal of
a single lobe is not adequate. When the tumor protrudes into the mainstem bronchus, sleeve lobectomy is
the procedure of choice to obtain negative bronchial
margins; however, a tumor involving the bronchus
intermedius usually requires a bilobectomy, while a
lesion more extensively involving the mainstem bronchus requires pneumonectomy. Pneumonectomy may
also be indicated in the rare circumstance when the
tumor is closely associated with the proximal, extrapericardial pulmonary artery. For upper lobe lesions that
invade the pulmonary artery to the lower lobe a vascular
sleeve resection can be performed, sparing the lower
lobe. Multiple series now suggest that sleeve resection for
central tumors produces results similar to that seen with
pneumonectomy from an oncologic standpoint.2,3
Although limited resections (wedge resection or segmentectomy) remain an option for patients with poor
pulmonary reserve, this practice should be avoided
whenever possible due to the higher rate of local recurrence and trend toward decreased long-term survival
when these lesser resections are performed, a standard
set by the results of The Lung Cancer Study Group
(LCSG) trial 821.4 In this study, patients with T1N0
NSCLC were randomized to undergo either lobectomy or
limited resection (wedge resection or segmentectomy).
Patients who underwent limited resection had a significantly higher rate of local recurrence than those in the
lobectomy group, with a survival difference approaching statistical significance. However, in the modern era
of lung cancer screening using computed tomography
(CT), many tumors are detected while still very small
(<1–2 cm). This observation, combined with the emergence of retrospective studies reporting excellent survival rates following limited resection for small, T1 lung
cancers,5,6 suggests that a trial similar to LCSG 821
should be initiated to reset the standard for these very
small, screen-detected tumors.
Most anatomic pulmonary resections for stage I NSCLC
have traditionally been performed using a posterolateral thoracotomy, during which a rib-spreading retractor is utilized. However, many surgeons now undertake
these resections using a complete, videothoracoscopic
(VATS) approach. The most commonly performed type
of VATS resection involves the creation of two thoracoscopy ports as well as a 6–8 cm ‘utility’ incision, the
latter used for dissection of the hilum as well as specimen
retrieval. Multiple published reports have suggested that
anatomic pulmonary resections can be performed safely,
and are oncologically sound when performed via VATS
for early-stage lung cancer.7,8 Additional benefits include
less postoperative discomfort as well as decreased length
of hospital stay with the VATS approach compared to
open thoracotomy. As a result, VATS lobectomy has
replaced its open counterpart for the management of
stage I lung cancer in many centers.
Although it has been suggested that mediastinal
lymph node dissection is unnecessary in patients with
very small T1 tumors, the vast majority of patients
undergoing resection for NSCLC should have this procedure routinely performed. Although this approach
has never definitively been shown to improve survival,
it is the only way to accurately stage a patient’s disease,
and adds very little time and morbidity to the operation.
In addition, approximately 16% of patients with peripheral T1N0 tumors where the primary tumor is less than
3 cm in size will have mediastinal node metastases.9
When resecting a right-sided tumor, the right paratracheal, pretracheal, subcarinal, and inferior pulmonary
Treatment of NSCLC: surgery 125
ligament nodes should be dissected. On the left, the
preaortic, aortopulmonary window, subcarinal and
inferior pulmonary ligament nodes are accessible. Given
the uncertain survival benefit of complete mediastinal
lymph node dissection for early-stage NSCLC, a randomized trial conducted by The American College of
Surgeons Oncology Group is currently underway to
investigate this question.
Operative mortality following pulmonary lobectomy
for all stages of disease should not surpass 2%, but should
be considerably less for patients with stage I disease.
Morbidity and mortality increase with higher stages of
disease and extended resections. Operative mortality
following pneumonectomy is near 6% in most series,
with some being even lower.10 The five-year survival for
patients with completely resected T1N0 lesions surpasses 80% in some reports, while this figure is reduced
to approximately 65% for T2N0 tumors. The overall
five-year survival for patients with completely resected
stage I NSCLC is approximately 75%.11 Recurrences
following complete resection for stage I NSCLC are
mainly in the form of distant metastases, as displayed
in Table 10.1.2.
No form of adjuvant therapy has traditionally been
recommended for patients undergoing resection of
stage I NSCLC. Recent randomized trials, however,
have suggested a small survival benefit for patients with
completely resected stage IB-III NSCLC. One of these,
the National Cancer Institute of Canada Clinical Trials
Group (NCIC) trial JBR.10, randomized 482 patients
with stage IB or II NSCLC to either surgery alone or
platinum-based adjuvant chemotherapy.13 Patients in
the adjuvant therapy arm enjoyed significantly longer
overall survival (69% vs 54% at five years) compared to
those who underwent surgery alone. Despite this, mature
results of the Cancer and Leukemia Group B (CALGB)
9633 trial, performed exclusively in stage IB patients, did
not support these findings. CALGB 9633 randomized
Table 10.1.2 Sites of first distant recurrence following
resection in 159 patients with stage I NSCLC lung cancer12
Site
Brain
Lung
Liver
Bone
Other
Disseminated
Number
51
20
14
11
8
5
344 patients with stage IB NSCLC to either surgery
alone or surgery followed by four cycles of paclitaxel/
carboplatin chemotherapy.14 No statistically significant
difference in survival was noted between groups. As a
result, the role of adjuvant chemotherapy in the management of patients with completely resected stage IB
NSCLC remains controversial. Many clinicians will recommend adjuvant chemotherapy to these patients if their
tumors appear to possess characteristics associated with
a poor prognosis (e.g. tumors greater than 5 centimeters,
vascular/lymphatic invasion). Adjuvant radiotherapy is
currently not recommended for patients with completely resected stage I NSCLC, in light of the results of
a meta-analysis showing that postoperative radiotherapy may increase mortality in these patients.15
Most clinicians would agree that patients require follow-up after resection for NSCLC; however, the nature
of the follow-up regimen remains controversial. Given
the poor prognosis associated with recurrent metastatic
disease in patients who have undergone resection of
NSCLC, follow-up regimens should probably be geared
toward the detection of second primary lung cancer
(SPLC), which occurs with an annual cumulative incidence of 2% per patient/year of follow-up.16 Recent published data suggest that serial computed tomography
(CT) of the chest has the ability to detect SPLC while still
in its early stages;17 however, the cost-effectiveness of
this approach has not yet been substantiated.
STAGE II DISEASE (T1–2N1 AND T3N0)
N1 disease
Patients with T1–2N1 NSCLC represent a small subset
in the spectrum of this disease, usually comprising less
than 10% of patients coming to surgery. As with stage
I, the majority of patients can be effectively treated with
lobectomy, although about a third will require pneumonectomy, mainly due to involved hilar lymph nodes
adherent to the pulmonary artery or major bronchi.
Similar to stage I disease, it is important to perform
a thorough mediastinal lymph node dissection in this
group of patients, especially since there is a higher incidence of occult N2 disease. Recurrence following complete resection for T1–2N1 NSCLC is common, with
five-year survival rates approaching only 45%.18 As
with stage I, the most common form of recurrence is
distant metastatic disease, especially if the tumor is an
adenocarcinoma. Patients enjoying a better prognosis
tend to be those with small primary tumors, squamous
histology, and only one involved lymph node.
126 Textbook of Lung Cancer
T3N0 disease
Chest wall involvement
T3 tumors invading the chest wall are readily amenable
to surgical resection. As a general guideline, one rib
above and one below the gross margin of the tumor
should be taken to ensure negative margins. Although
en bloc resection is desirable and should be achieved
whenever possible, discontinuous resection can be done
when absolutely necessary as long as meticulous attention is paid toward documenting margins. It currently
remains controversial whether a complete chest wall
resection, including ribs, is necessary for tumors invading only the parietal pleura. A parietal pleurectomy with
negative deep margins may be sufficient, but should be
used with extreme caution.
Following resection, the issue of chest wall reconstruction needs to be addressed. The first question regarding
this is whether the chest wall reconstruction is really
necessary, and this usually depends on the assessment
of chest wall stability. After resection of short segments
of one or two ribs, or up to three posterior segments
under the paraspinous muscles or scapula, reconstruction is not usually necessary. When reconstruction is
undertaken, the marlex/methylmethacrylate sandwich
technique readily restores stability and prevents the flail
chest phenomenon during breathing (Figure 10.1.1). A
Gore-Tex patch, stretched tightly, has also been used
with acceptable results. Mortality following chest wall
resection is low, but is related to the size and location
of the defect in the chest wall, the amount of lung
resected, and the technique of reconstruction.
Factors which affect long-term survival following resection of these tumors are the extent of chest wall involvement, the ability to completely resect the tumor, and
the presence or absence of lymph node involvement.
The overall five-year survival of patients with T3N0M0
tumors invading the chest wall undergoing complete en
bloc surgical resection is approximately 50–60%.19
Patients with a T3N0M0 tumor that involves only the
parietal pleura have a better prognosis than those where
the tumor invades into muscle and ribs.
Tumors invading the mediastinum
Tumors invading the mediastinal pleura, fat, nerves,
and pericardium, but not the major mediastinal vessels
or organs, represent another subset of the T3 classification. These patients have a notoriously poor five-year
survival following surgical resection alone. In part, this
poor survival is due to the high likelihood of mediastinal
node metastases and the low rate of complete resection
Figure 10.1.1
Stage IIB NSCLC (T3N0M0) invading the chest wall. (a) Chest CT
revealing a large lung mass invading the chest wall. Cervical
mediastinoscopy was negative, while transthoracic needle
aspiration revealed large cell carcinoma.(b) Chest radiograph
following right upper lobectomy, mediastinal lymph node
dissection, and resection of the involved chest wall. Stable
reconstruction was achieved using a marlex mesh and methylmethacrylate prosthesis.
attained when the mediastinum is invaded. Additionally, even when these tumors are completely resected and
the mediastinal nodes are negative, patients with T3
disease invading the mediastinum have a worse prognosis when compared to other types of T3 tumors.20
Due to the high frequency of N2 disease, patients
with evidence of mediastinal invasion on CT scan should
undergo cervical mediastinoscopy to rule out nodal
involvement or T4 disease. If N2 disease is detected,
induction (neo-adjuvant) therapy may offer these
patients a better chance at long-term survival, if surgical resection is being considered. If there is no N2, N3,
or T4 disease found at mediastinoscopy, these patients
can undergo primary surgical resection with five-year
survival rates of 30% if complete resection can be
performed.20
Treatment of NSCLC: surgery 127
Tumors in proximity to the carina
Tumors within 2 cm but not involving the main carina
comprise another subset of T3 tumors. As with the
other T3 tumors, patients with these proximal bronchial lesions are candidates for surgical resection. Technical considerations when resecting tumors involving
the main bronchi pertain to the extent of resection,
intraoperative airway management, and techniques of
sleeve resection. Small, solitary squamous cell lesions
confined to the left main bronchus with no invasion
through the bronchial wall can very occasionally be
handled with excision of the main bronchus alone, with
total lung preservation and primary anastomosis. However, frequently these lesions are multiple and are best
treated with endobronchial laser or radiation (brachytherapy). If resection is being considered for a solitary,
proximal lesion on the right, however, usually a pneumonectomy or right upper lobe sleeve resection is
required due to the close proximity of the right upper
lobe orifice to the main bronchus. Sleeve lobectomy (vs
pneumonectomy) is the preferred resection when possible for tumors extending into the orifice of the lobar
or mainstem bronchus.
When invasion into peribronchial tissues or N1 disease
is present, sleeve lobectomy can be attempted if the disease is limited, but pneumonectomy is usually required
for extranodal spread. If the tumor extends very close
to the carina, resection of the main bronchus flush with
the trachea may be required to encompass the tumor
with negative margins. In this case, stapling of the bronchial stump may not be possible and a hand-sewn closure
may be required. If not, tracheal sleeve pneumonectomy
is the procedure of choice.
Airway management and ventilation are of paramount
importance when the proximal bronchi are resected.
Standard double lumen endobronchial tubes or endobronchial blockers with single lung ventilation can be
utilized for sleeve resections of the main bronchi. Tracheal sleeve pneumonectomy requires ventilation of the
distal remaining lung. This problem can be handled in
several ways, including passage of a thin, single lumen
endotracheal tube past the anastomotic site, jet ventilation into the distal lung, or in-field ventilation through
the open bronchus using sterile ventilator tubing.
Factors which adversely affect long-term survival following resection include peribronchial extension of the
tumor and the presence of N2 nodal metastases. Overall five-year survival following complete resection for
tumors within 2 cm of the carina is currently reported
to be 36%;21 however, patients with tumor confined to
the main bronchi with no invasion of peribronchial tis-
sues or associated N2 disease have been reported to have
a five-year survival of 80% in one series.22 Patients with
T3 tumors approaching the carina associated with N2
nodal metastases separate from the primary tumor (‘true’
N2) have a negligible five-year survival. Patients with
N2 disease which is present by virtue of direct spread
from the primary tumor, however, remain surgical candidates. Therefore, it is mandatory to perform cervical
mediastinoscopy prior to an attempted resection to identify those patients with ‘true’ mediastinal nodal disease
who would receive no benefit from primary surgical
resection. If N2 nodes are identified at cervical mediastinoscopy, induction therapy may be of value, but this
awaits clinical trials.
The role of adjuvant therapy for stage II NSCLC has
evolved similar to that for stage I disease. The previously mentioned Canadian trial13 demonstrated a small,
but significant survival benefit of adjuvant, platinumbased chemotherapy for patients with stage II NSCLC
who have undergone complete surgical resection.
Although no clear survival benefit has been noted,
patients with incompletely resected tumors or those
with mediastinal nodal metastases should receive postoperative radiation therapy to decrease the incidence of
local recurrence.15 Intraoperative implantation of radioisotopes may potentially be of some benefit for those
patients who undergo an incomplete resection. The role
of induction chemoradiotherapy in poor prognostic T3
tumors (N2 disease, full thickness chest wall invasion)
is now being investigated.
STAGE III DISEASE
Stage IIIA (T3N1) disease
T3 tumors with associated ipsilateral bronchopulmonary or hilar lymph node involvement comprise the first
category of stage IIIA disease. The preferred treatment
is, again, complete resection via lobectomy with mediastinal lymph node dissection. The previously mentioned issues concerning N1 disease apply in this setting
as well.
Stage IIIA (N2) disease
The decision to perform primary surgical resection for
patients with N2 disease requires careful preoperative
selection, since the overall five-year survival for patients
with N2 disease undergoing surgical resection alone is
a mere 5–15%. Those with only single station, intracapsular nodal disease, T1 primary tumors, and ‘clinically’
negative mediastinums by mediastinoscopy or CT
128 Textbook of Lung Cancer
scanning are reported to enjoy a five-year survival of
approximately 30% following complete surgical resection, compared to less than 10% for those with ‘bulky’
N2 disease identified preoperatively and those with
associated T3 primary tumors.23 Patients with left upper
lobe tumors and N2 disease confined to level 5 or 6
have the best prognosis of all, with five-year survival
rates as high as 42% when completely resected.24 Unfortunately, patients with ‘minimal’ N2 involvement for
whom primary surgery is beneficial represent a small
fraction of all patients with N2 disease, and clearly further therapeutic advances need to be made for those
patients with bulky, ‘clinical’ N2 disease.
Although adjuvant radiotherapy provides no survival
benefit compared to surgery alone, a reduction in local
recurrence is seen.15 Unfortunately, 80% of patients
undergoing surgical resection for NSCLC with N2 nodal
disease recur at distant metastatic sites (especially brain),
suggesting that further systemic therapy is needed to
improve survival.
Postoperative, adjuvant chemotherapy has been used
in an attempt to improve survival for patients with
resected stage IIIA (N2) NSCLC. Until recently, however, this strategy has not been shown to be of significant benefit in the adjuvant setting. In this regard, a
meta-analysis of 52 previously conducted randomized
trials of adjuvant chemotherapy for completely resected
NSCLC suggested only a small advantage (5% at five
years) of cisplatin-based chemotherapeutic regimens
given in the adjuvant setting.25 As a result of the metaanalysis, the International Adjuvant Lung Cancer Trial
(IALT) randomized 1867 patients with completely
resected NSCLC to either observation or cisplatin-based
chemotherapy.26 Of these, nearly 40% had stage III disease. The overall survival rate across all stages was
significantly higher in the chemotherapy group (44.5%
at five years) versus the surgery alone group (40.4%),
representing a small, but significant advantage. Subgroup analysis, however, revealed that the patients
which received the most benefit were those with stage
III disease.
Data from Japan has suggested a significant survival
advantage for patients receiving oral tegafur plus uracil
(UFT) following complete surgical resection of NSCLC
compared with surgery alone. Although these results
have not been reproduced in all studies using this strategy, and no data exist outside of Japan, a recent metaanalysis including data from 2003 patients demonstrated
that adjuvant therapy with UFT does indeed provide a
survival advantage.27 However, this agent is not available for use in the USA.
Multimodality therapy
Induction chemotherapy emerged as an option for
patients with N2 disease after it became clear that only
a minority of these patients benefit from surgical resection alone and that preoperative radiation therapy has
no effect on survival. To date, many phase II trials of
induction chemotherapy or chemoradiation therapy
both with and without postoperative adjuvant therapy
have been reported. Preoperative chemotherapy, such
as the MVP regimen utilized at The Memorial Sloan
Kettering Cancer Center and The University of Toronto,
has shown survival benefit in this group of patients
when compared to historical controls.28,29 The majority
of reports, however, deal with preoperative chemoradiation and essentially mirror the results of the previously mentioned induction chemotherapy trials.
Although hundreds of patients have been enrolled in
such phase II studies, no real effect of the treatment can
be assessed for two reasons. First, the chemotherapy and
radiotherapy protocols have varied widely from one trial
to the next, as did the extent of preoperative staging,
making the results difficult to interpret. Second, patients
in these phase II trials are not randomized, and therefore no control groups exist other than historical data.
Three small phase III trials do exist comparing induction chemotherapy and surgical resection to surgical
resection alone in the treatment of patients with N2 disease (Table 10.1.3). Although different chemotherapy
protocols were utilized and the numbers were small,
the survival rates were significantly higher in two of
these studies30,31 in the chemotherapy groups compared
to the control arms, with the third showing a similar
trend.32 Surprisingly, in all three studies, the rate of
complete resection was no different in the treatment
arms compared to the control arms. These three small
phase III trials and the phase II trials that have been
matched to historical controls seem to suggest an improvement in survival for these patients, at least with induction chemotherapy, but the results of current, larger
phase III trials for N2 disease will be important, especially since a French trial suggested no benefit of induction chemotherapy for patients with N2 disease.33
Treatment-related mortality in the induction trials
has resulted from the chemotherapy, radiation therapy,
and surgery, or a combination of these modalities. Most
trials report a treatment-related death rate in the range
of 5–15%. Chemotherapy-related deaths are dependent
on the specific agent and dose, as well as the immunosuppressive effects of these drugs. Morbidity following
induction chemotherapy can be manifested in several
organ systems. Pulmonary function studies should be
Treatment of NSCLC: surgery 129
Table 10.1.3 Three phase III trials of induction chemotherapy for NSCLC with ipsilateral mediastinal lymph node metastases
Author
Number of patientsa
Chemotherapy agents
Percent resectablea
Median survivala,b
Pass32
13/14
85/86
29/16
Roth30
26/32
61/66
64/11
Rosell31
30/30
Cisplatin
Etoposide
Cisplatin
Etoposide
Cyclophosphamide
Mitomycin
Ifosfamide
Cisplatin
85/90
26/8
a
Induction chemotherapy followed by surgery group/surgery alone group.
Overall median survival in months.
b
repeated after induction chemotherapy to assess the
pulmonary effects of such drugs as mitomycin and cyclophosphamide, which appear to be toxic to both the pulmonary endothelium and epithelium, resulting in impaired
diffusion of gases. Cardiac toxicity of doxorubicin should
be assessed with a myocardial imaging study following
the administration of this drug, and creatinine clearance should be measured following treatment with cisplatin and the vinca alkaloids if the serum creatinine
level has become elevated. These chemotherapyspecific toxicities demand that the induction chemotherapy patient be monitored more closely in the
perioperative period to prevent failure of an already
compromised organ system.
Bronchial obstruction needs to be relieved prior to
the administration of cytotoxic drugs to avoid postobstructive pneumonia and death during leukopenic
events. This can be handled either with radiation therapy or endobronchial resection techniques/stents. Radiation therapy is also associated with toxicity that, when
given in combination with chemotherapy and surgery,
can result in the patient’s demise. Examples include the
enhanced pulmonary toxicity when radiation therapy is
used with mitomycin, the myocardial damage when
used with doxorubicin, and the higher incidence of
bronchopleural fistula in irradiated patients following
pulmonary resection.
Morbidity and mortality from the surgical procedure
itself can be minimized by careful anesthetic management,
close perioperative monitoring of cardiac, pulmonary,
and fluid status, as well as some specific interventions
to treat certain toxicities. For example, mitomycin pulmonary toxicity appears to be exacerbated by high inspired
oxygen fractions. Therefore, the lowest possible oxygen
concentration in the inspired gases should be used,
while maintaining adequate oxygenation of the blood.
Perioperative corticosteroids can effectively treat both
mitomycin and radiation-induced pulmonary toxicity
as well. Tight control over fluid administration should
be realized, thereby avoiding pulmonary edema as a
result of impaired cardiac and renal function, but still
maintaining enough volume for adequate end organ
perfusion.
Finally, the role of surgical resection itself for patients
with N2 disease was addressed by the results of the
North American Intergroup 0139 Trial.34 In this study,
patients who received induction chemoradiotherapy were
randomized to either surgical resection or continued
radiotherapy without an attempt at resection. Although
the initial survival analysis revealed no difference in
overall survival, progression-free survival was significantly prolonged in the patients undergoing resection.
This observation, combined with the higher treatmentrelated mortality in the surgical arm (mainly in pneumonectomy patients), suggests that if perioperative care
can be optimized, especially for patients undergoing
pneumonectomy, surgical resection may offer these
patients the best chance for long-term survival.
Stage IIIB (T4 or N3) disease
Patients with this stage of locally advanced NSCLC are
considered inoperable. Exceptions do exist, however,
and generally apply to selected patients with T4 disease. Tracheal sleeve pneumonectomy can be considered
for the occasional patient with endobronchial tumor
involving the main carina; however, involvement of
peribronchial tissue or lymph nodes should preclude
this procedure. The five-year survival for patients with
T4 (carina) N0 tumors undergoing tracheal sleeve
pneumonectomy has been reported to approach 20%;
however, the operative mortality from this procedure
can be as high as 15–30%.35,36
130 Textbook of Lung Cancer
It is presently debated whether subclavian artery
invasion represents T3 or T4 disease, but apical tumors
invading this vessel should be resected if a complete
resection can be performed. This vessel can be reconstructed either primarily or with a synthetic graft. Again,
for patients to benefit from such an extended resection,
node-negative status should be confirmed prior to
resection using cervical mediastinoscopy.
Sporadic reports exist concerning aortic resection for
T4 tumors with an occasional long-term survivor,37 but
no significant survival benefit has been demonstrated in
these patients. Similarly, although technically possible,
resection of tumors involving the vertebral body has
not been shown to provide a survival advantage.38 These
last two scenarios should be considered for clinical protocols involving induction chemo(radio)therapy, followed by reassessment. If a significant response is seen,
resection can be considered in the protocol setting.
If, at thoracotomy for presumed T3 disease, an incomplete resection is all that can be done due to involvement
of mediastinal organs or vessels (T4), partial resection
with implantation of radioisotopes combined with postoperative external beam radiation may provide some
benefit with up to a 10% salvage rate, but has never been
compared to primary (external) radiotherapy as an alternative approach.
Although technically considered to be T4 disease, patients
with multiple lesions in the same lobe (‘satellite’ lesions)
constitute a unique subgroup of stage IIIB NSCLC. Following anatomic resection, patients with T4 disease due
to the presence of satellite lesions enjoy appreciably
longer survival than other subgroups of stage IIIB lung
cancer.39 As a result, when satellite lesions are detected
preoperatively, patients should undergo lobectomy and
mediastinal lymph node dissection whenever possible.
STAGE IV DISEASE
Surgery for stage IV disease is limited to young, healthy
patients with a solitary site of metastatic disease, and an
easily resectable primary tumor contained within the
chest. An exhaustive search should be carried out prior
to consideration of resection of stage IV disease, looking
for other sites of metastatic disease not clearly evident
by history and physical examination. Positron emission
tomography (PET) may emerge as a useful test for this
purpose, and all suspicious lesions should be biopsied
to obtain a histologic diagnosis. Solitary bone, liver, and
skin metastases are rare, but the following sites warrant
mentioning due to their more frequent occurrence.
Brain metastases
Approximately one-third of patients with NSCLC and
brain metastases present initially with neurologic symptoms, with the lung cancer being found only after a
search for the primary tumor has been carried out. In
addition to the patients with stage IV disease at presentation, recurrences following resection of NSCLC are
most commonly distant metastases, and of these, nearly
30% are located in the brain. It is now accepted that
patients with solitary brain metastases from NSCLC are
best treated by resection of the brain lesion followed by
postoperative whole-brain radiation therapy. Using this
strategy, five-year survival in these patients should
approach 20%. Even if a cure is not obtained, survival
is prolonged and quality of life improved when compared to a non-surgical approach.40
When patients present with NSCLC and a single, synchronous brain metastasis, and both lesions are resectable, the brain tumor should be resected prior to the
primary tumor, provided that no urgent intrathoracic
process is occurring (i.e. massive hemoptysis). This strategy is based on the observation that recovery from
intracranial surgery is less intensive than that from thoracotomy. If the resectability of either lesion is in question
prior to surgery, one should approach the questionable
lesion first to ensure that both lesions can be completely
resected prior to undertaking a potentially unnecessary
operation. If a brain metastasis is found but a search for
the primary tumor is negative, one should proceed with
resection of the intracranial tumor.
Adrenal metastases
Solitary metastases to the adrenal glands are being diagnosed with greater frequency due to routine scanning of
the upper abdomen with newer generation, spiral CT
scanners. The utility of adrenalectomy for a solitary NSCLC
metastasis has been reported in small case series and individual reports. In a relatively large series of patients with
solitary adrenal metastases (23 patients), an overall survival of 23.3% was obtained after resection of the lung and
adrenal lesions.41 Patients with metachronous lesions and
a disease-free interval of more than six months received
the greatest benefit from this aggressive approach.
SPECIAL CONSIDERATIONS
Superior sulcus tumors
Superior sulcus tumors are apical lung cancers that are
at least T3 by definition, since they invade the chest
wall. In addition to chest wall invasion, these tumors
Treatment of NSCLC: surgery 131
also invade neighboring vital structures including the
brachial plexus, vertebral body, and subclavian vessels.42 Presenting symptoms almost always include pain
in the shoulder radiating down the upper, inner aspect
of the arm (T1 nerve root) as well as into the ulnar distribution in the hand (C8 nerve root). Patients may also
have Horner’s syndrome, resulting from invasion of the
stellate ganglion in the sympathetic chain, a condition
which implies advanced local invasion.
Treatment of these lesions is by surgical resection. Prior
to resection, mediastinal node metastases must be ruled
out using cervical medastinoscopy owing to the poor
prognosis of these patients after resection when N2 disease is present. Several different operative approaches
have been described, depending on whether the tumor
invades the anterior or posterior aspect of the first rib.
It is agreed that posterior lesions should be approached
through a posterolateral thoracotomy extending up to
the neck, as described by Shaw et al.42 This enables the
scapula to be lifted off the chest wall and access to the
apex of the hemithorax from outside the chest wall.
Tumors that appear to invade more anteriorly can be
approached through any number of anterior approaches,
the most common being an L-shaped transcervical incision43 and the hemiclamshell approach.44 The advantage of the hemiclamshell incision is easy access to the
pulmonary hilum for the performance of lobectomy
with mediastinal lymph node dissection. In addition to
lobectomy, the standard operation for superior sulcus
tumors includes the resection of at least the first rib, the
transverse processes of the vertebral bodies associated
with each resected rib, and the T1 nerve root.
Following complete resection, the five-year survival
of patients with superior sulcus tumors approximates
30%. Unfortunately, many patients do not have a complete resection due to invasion of the previously mentioned vital structures. To address this issue, the
Southwest Oncology Group Trial 9416 administered
induction chemoradiotherapy in a phase II design to
111 patients with superior sulcus tumors.45 Of the 83
patients who underwent subsequent thoracotomy, 92%
had a complete resection. The five-year survival was
44% for all patients and 54% for those who underwent
a complete resection. Given these encouraging results,
induction chemoradiotherapy followed by surgical
resection has become the standard for patients with
superior sulcus tumors in most centers.
Multiple primary tumors
It is not uncommon for patients to present with more than
one lung malignancy. Either these tumors represent
synchronous primaries or one lesion is a metastasis
from the other. When the tumors are of different histologies, the diagnosis of synchronous primary lung
cancers is made. If the lesions are of the same histology,
cervical mediastinoscopy should be routinely performed
because if positive mediastinal nodes are discovered,
the chance of one lesion being metastatic rises. Pathologic evidence of two separate primary tumors is the
presence of carcinoma in situ in both lesions; however,
this information is rarely present at the time of surgery.46 In many equivocal instances, the ‘benefit of the
doubt’ is given to the patient and the tumors are labeled
as synchronous primaries.
Optimal oncologic treatment for patients with synchronous primary NSCLC is two staged lobectomies for
contralateral tumors, and bilobectomy or pneumonectomy for ipsilateral tumors. In cases where the resectability of one lesion is questioned, the questionable tumor
should be resected first. If the patient’s lung function
permits only one lobectomy, a decision must be made
as to which lesion will be resected via lobectomy and
which will be approached with a limited resection.
Generally, the limited resection should be reserved for
the smaller, squamous cell cancers, since these are less
likely to spread via lymphatics than adenocarcinomas.
Limited resection should consist of segmentectomy
instead of wedge resection whenever possible. A third
option is to perform multiple segmentectomies in
patients with limited pulmonary reserve.
Bronchioloalveolar carcinoma
Bronchioloalveolar carcinoma represents a unique subtype of NSCLC which appears to be increasing in incidence. This increase may be real, or may represent
heightened recognition of this variant by pathologists.
This disease seems to occur mainly in elderly women
with a negligible smoking history. Three distinct clinical
scenarios seem to be able to arise with BAC.
First, and most common, patients may present with
a solitary pulmonary nodule. These lesions are usually
picked up by routine chest radiograph and are asymptomatic. Mediastinal lymph nodes are uncommonly
involved. Treatment is lobectomy and long-term survival seems to be excellent.
Second, some patients with BAC will present with
small lesions that resemble infiltrates, termed groundglass opacities (GGOs). These lesions are not visible on
standard chest radiography and are increasingly being
detected on screening, low-dose, computed tomography
(Figure 10.1.2). In addition, they tend to be multiple
and also recur frequently following resection, especially
132 Textbook of Lung Cancer
be used to confirm negative margins, and when positive, further tissue should be resected. A positive bronchial resection margin can be treated by reresection of
the bronchus and performance of a bronchoplastic procedure, or even pneumonectomy if necessary. Carcinoma
in situ remaining at the bronchial stump may not adversely
effect prognosis,49 but this has not conclusively been
proven and even this early disease should currently be
resected.
Figure 10.1.2
CT of the chest revealing a ground-glass opacity, a lesion not
visible on chest radiography. Biopsy revealed bronchioloalveolar
carcinoma.
in areas of lung distant from the primary tumor (multifocal BAC). This implies that this form of BAC may be
spread throughout the airway by means of aerosol.
Standard treatment is presently resection, but care must
be given to the conservation of lung, since these tumors
tend to recur with great frequency. Whether or not
these patients benefit from repeated attempts at resection as opposed to observation is currently unknown.
Third, a minority of patients will present with a lobar
infiltrate representing lobar replacement with BAC.
Radiologic studies give the appearance of dense consolidation that has arisen over a period of weeks to
months. This presentation of BAC carries a poor prognosis, with many patients recurring with widespread
infiltrative disease and respiratory failure following
resection. For this reason, it is unknown whether these
patients benefit at all from resection.
Prognosis in patients with BAC seems to correlate
most with the radiographic appearance of the lesion(s).47
Other factors that have been implicated as poor prognosticators in some studies, but not in others, are a
mucinous histology and the presence of vascular invasion. The effect of chemotherapy remains unknown in
patients with BAC. Isolated reports of successful double-lung transplantation for recurrent BAC with longterm survivors have been described, but this procedure
remains investigational in the treatment of BAC.48
Positive resection margins
Every attempt should be made intraoperatively to resect
with negative margins. Frozen section analysis should
Completion pneumonectomy
Patients with locally recurrent NSCLC or second primary tumors following resection should be evaluated in
a similar fashion to those who present with their first
cancer. If there is no evidence of distant disease and the
remaining pulmonary function is adequate, these patients
should be considered for completion pneumonectomy.
Completion pneumonectomy is a technically challenging operation, requiring that the surgeon review
the previous operative notes to learn about the anatomy
and potential hazards of the reoperation. Mobilization
of the lung should be performed intrapleurally whenever possible to avoid excessive bleeding and damage
to neighboring structures. Intrapericardial ligation of
the vessels also serves to reduce the chance of hemorrhage. Intraoperative use of topical hemostatic agents as
well as efficient coagulating devices is helpful.
Operative mortality following completion pneumonectomy is in the range of 10%, slightly higher than
that seen with standard pneumonectomy.50 Postoperative morbidity is in the 20% range, with a significant
proportion of complications related to bleeding. Longterm survival in patients with NSCLC who undergo this
operation is approximately 30%, indicating that completion pneumonectomy is a worthwhile procedure in
selected patients.50
PALLIATIVE SURGERY
Pleural disease
Patients with diffuse pleural disease (T4) typically present with dyspnea and a pleural effusion. The diagnosis
should be confirmed and is most easily obtained by placement of a chest tube and examining the fluid for malignant cells. Once the diagnosis of a malignant pleural
effusion is confirmed, pleurodesis with sterile talc or other
pleural irritant is warranted to prevent recurrence.
If a patient presents with obvious end-stage metastatic disease and a new pleural effusion, a simple thoracentesis may relieve some of the dyspnea and allow
Treatment of NSCLC: surgery 133
the patient to be discharged home to their family. This
strategy should be reserved for patients who are anticipated to expire within the next few weeks.
Thoracoscopic exploration is warranted in the following selected instances. First, if the fluid is negative
for malignant cells and a malignant diagnosis will affect
the treatment plan. Second, if the lung fails to re-expand after drainage of fluid, thoracoscopic intervention
may be necessary just for the strategic placement of
chest tubes to facilitate expansion, and third, after a
poor result from a bedside pleurodesis as manifested by
the rapid reaccumulation of fluid. The role of formal
decortication is very limited in these patients due to
their extremely short life expectancy.
Endobronchial disease
Unresectable endobronchial tumor is a not infrequent
occurrence in patients with NSCLC. Typically, these
patients may present with airway occlusion with distal
pulmonary collapse and pneumonia, dyspnea, and
hemoptysis. The endobronchial disease may be the
manifestation of either the primary tumor extending
proximally in the airway or of nodal disease eroding
into the proximal tracheobronchial tree. Many times
the patient has had a previous pulmonary resection and
has a recurrence at the bronchial stump.
Adequate palliation can be obtained using either laser
or stenting techniques. For bleeding lesions, laser therapy
with the Nd:YAG laser and electrocoagulation are the
preferred approaches. Obstructing lesions can be treated
using either approach. A combination of debridement
through a rigid bronchoscope and laser treatment to obtain
hemostasis is often an effective technique. Care must be
taken not to blindly laser tumor in the proximal segmental bronchi as perforation can occur. Recently, photodynamic therapy (PDT) has been used in cases of
endobronchial NSCLC. This technique needs further evaluation before it can be routinely used for this disease.
Endobronchial stents are typically of the silicone rubber or self-expanding wire variety. The type of disease
most amenable to stenting is that which is associated with
a patent airway both proximal and distal to the obstructing lesion. Silicone stents are deployed using a rigid
bronchoscope, while self-expanding wire stents are
typically deployed over a guidewire using fluoroscopy
as a guide. Silicone stents are removable, while wire stents
are not; however, the indications for stent removal in
patients with inoperable NSCLC are few. A recent development has been the introduction of an expandable,
silicone stent which is removable. However, its application for lung cancer patients remains undefined.
SUMMARY
Surgery for NSCLC has evolved considerably over the
past 50 years. Resection is currently indicated for patients
with early stage (I, II, selected IIIA) disease, while chemotherapy and radiation are used for more advanced
disease. The mainstay of surgical therapy remains anatomic lobectomy with complete mediastinal lymph node
dissection, provided the patient can physically tolerate
this procedure. Care must be taken to ensure a complete
resection since incomplete resections do not cure.
Recent developments in the care of resectable lung
cancer patients include the adoption of adjuvant chemotherapy for patients with completely resected stage
II–III disease, the importance of surgical resection in
the multimodal therapy regimen for stage IIIA NSCLC,
as well as the use of induction chemoradiotherapy for
superior sulcus tumors. With increasing use of lowdose, screening CT for individuals thought to be at high
risk for the development of lung cancer, the discovery
of much smaller tumors is increasing in frequency, and
further studies are necessary to establish the standard of
care for these lesions.
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Ginsberg RJ, Hill LD, Eagan RT et al. Modern 30-day operative
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Martini N, Bains MS, Burt ME et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995; 109: 120–9.
Winton TL, Livingston R, Johnson D et al. A prospective randomized trial of adjuvant vinorelbine and cisplatin in completely resected stage IB and II non small cell lung cancer.
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Strauss G, Maddaus MA, Herndon JE II et al, for the CALGB
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PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and metaanalysis of individual patient data from nine randomised
controlled trials. PORT Meta-analysis Trialists Group. Lancet
1998; 352: 257–63.
Rice D, Kim HW, Sabichi A et al. The risk of second primary
tumors after resection of stage I nonsmall cell lung cancer. Ann
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Korst RJ, Gold HT, Kent MS et al. Surveillance computed
tomography following complete resection for non-small cell
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Martini N, Burt ME, Bains MS et al. Survival after resection of
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Downey RJ, Martini N, Rusch VW et al. Extent of chest wall
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Martini N, Yellin A, Ginsberg RJ et al. Management of nonsmall cell lung cancer with direct mediastinal involvement. Ann
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Faber LP, Jensik RJ, Kittle CF. Results of sleeve lobectomy for
bronchogenic carcinoma in 101 patients. Ann Thorac Surg
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Nakahashi H, Yasumoto K, Ishida T et al. Results of surgical
treatment of patients with T3 non-small cell lung cancer. Ann
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Martini N, Flehinger BJ. The role of surgery in N2 lung cancer.
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data on individual patients from 52 randomized, clinical trials.
BMJ 1995; 311: 899–909.
Arriagata R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall cell lung cancer. N Engl J Med 2004; 350: 351–60.
27. Hamada C, Ohta M, Wada H et al. Survival benefit of oral UFT
for adjuvant chemotherapy after completely resected non-small
cell lung cancer. Proc Am Soc Clin Oncol 2004; abstract 7002.
28. Martini N, Kris MM, Flehinger BJ et al. Preoperative chemotherapy of stage IIIa (N2) non-small cell lung cancer: the
Memorial Sloan-Kettering experience with 136 patients. Ann
Thorac Surg 1993; 55: 1365–74.
29. Burkes RL, Ginsberg RJ, Shepherd FA et al. Induction chemotherapy with mitomycin, vindesine and cisplatin for stage III
unresectable non-small cell lung cancer: results of the Toronto
phase II trial. J Clin Oncol 1992; 10: 580–6.
30. Roth JA, Fossella F, Komaki M et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery
alone in resectable stage IIIA non-small cell lung cancer. J Natl
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31. Rosell R, Gomez-Codina J, Camps C et al. A randomized trial
comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl
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32. Pass HI, Pogrebniak HW, Steinberg SM et al. Randomized trial
of neoadjuvant therapy for lung cancer: interim analysis. Ann
Thorac Surg 1992; 53: 992–8.
33. Depierre A, Milleron B, Moro-Sibilot D et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II and IIIA non-small
cell lung cancer. J Clin Oncol 2002; 20: 247–53.
34. Albain KS, Scott CB, Rusch VW et al. Phase III comparison of
concurrent chemotherapy plus radiotherapy (CT/radiotherapy)
and CT/radiotherapy followed by surgical resection for stage
IIIA (pN2) non-small cell lung cancer (NSCLC): initial results
from Intergroup trial 0139 (RTOG 93-09). Proc Am Soc Clin
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35. Dartevelle PG, Khalife J, Chapelier A et al. Tracheal sleeve
pneumonectomy for bronchogenic carcinoma: a report of 55
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36. Tsuchiya R, Goya T, Naruke T, Suemasu K. Resection of tracheal carina for lung cancer. Procedure, complications and
mortality. J Thorac Cardiovasc Surg 1990; 99: 779–87.
37. Tsuchiya R, Asamura H, Kondo H et al. Extended resection of
the left atrium, great vessels, or both for lung cancer. Ann Thorac Surg 1994; 57: 960–5.
38. Grunenwald D, Mazel C, Girard P et al. Total vertebrectomy for
en bloc resection of lung cancer invading the spine. Ann Thorac
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39. Detterbeck FC, Jones DR, Kernstine KH, Naunheim KS. Lung
cancer. Special treatment issues. Chest 2003; 123 (1 Suppl):
244–58S.
40. Burt M, Wronski M, Arbit E et al. Resection of brain metastases
from non-small cell lung carcinoma. Results of therapy. J Thorac Cardiovasc Surg 1992; 103: 399–411.
41. Mercier O, Fadel E, de Perrot M et al. Surgical treatment of
solitary adrenal metastasis from non-small cell lung cancer.
J Thorac Cardiovasc Surg 2005; 130: 136–40.
42. Shaw RR, Paulson PL, Kee JL Jr. Treatment of the superior
sulcus tumor by irradiation followed by resection. Ann Surg
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43. Dartevelle P, Chapelier AR, Macchiarini P et al. Anterior transcervical-thoracic approach for radical resection of lung tumors
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105: 1025–34.
Treatment of NSCLC: surgery 135
44. Korst RJ, Burt ME. Cervicothoracic tumors: results of resection
by the ‘hemiclamshell’ approach. J Thorac Cardiovasc Surg
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45. Rusch VW, Giroux DJ, Kraut MJ et al. Induction chemoradiation and surgical resection for superior sulcus non-small cell
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Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;
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47. Ebright MI, Zakowski MF, Martin J et al. Clinical pattern and
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1640–6.
48. Etienne B, Bertocchi M, Gamondes J-P et al. Successful doublelung transplantation for bronchioloalveolar carcinoma. Chest
1997; 112: 1423–4.
49. Snijder RJ, de la Riviere AB, Elbers HJJ, van den Bosch JMM.
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the resection margin. Ann Thorac Surg 1998; 65: 212–16.
50. Gregoire J, Deslauriers J, Guojin L, Rouleau J. Indications, risks
and results of completion pneumonectomy. J Thorac Cardiovasc Surg 1993; 105: 91.
10.2 Treatment of NSCLC: radiotherapy
Merideth MM Wendland, William T Sause
Contents Introduction • Early disease • Locally advanced disease • Superior sulcus tumors
• Altered fractionation radiation therapy • Toxicity and patient selection • Prophylactic cranial irradiation
• Palliative therapy • Conclusion
INTRODUCTION
In the USA, lung cancer is the number one cause of
cancer-related death for both men and women.1 In
2005, an estimated 175 000 new cases of lung cancer
will be diagnosed and roughly 159 000 deaths from
lung cancer will occur. Approximately 80% of patients
with primary lung cancer are diagnosed with non-small
cell lung cancer (NSCLC).2
Radiation therapy remains a valuable therapeutic
modality in the treatment of NSCLC. In early stage disease, definitive radiation therapy may be employed for
patients who refuse or are medically unfit to undergo
surgical resection. Radiation therapy may also be used
as adjuvant therapy for patients with incomplete resection or node-positive disease. At initial presentation, many
patients who receive a diagnosis of NSCLC have locally
advanced disease. Historically, these patients were treated
with primary thoracic radiation therapy with poor longterm survival rates secondary to both progression of
local disease and development of distant metastases.
With the goal of improving clinical outcomes, multiple
permutations of combined-modality therapy for locally
advanced NSCLC have been investigated. The optimal
treatment for locally advanced NSCLC continues to
evolve, but combined-modality therapy has led to
improved survival rates versus treatment with radiation
alone, and is the standard of care.
EARLY DISEASE
In general, patients with stage I and II disease who are
medically fit undergo definitive surgical resection with
good results. Newer data have demonstrated that adjuvant chemotherapy after complete surgical resection
can improve overall survival.3–6 For patients who are
medically unfit for or refuse surgery, definitive radiation therapy is an alternative treatment modality that
still offers curative potential. Although outcomes with
radiation alone are inferior compared to those obtained
with complete surgical resection, five-year cause-specific
survival rates of approximately 30% in stage I and II
disease have been obtained with the use of modern radiation therapy planning and delivery techniques.7–9 Doses
considered to be ‘curative’ when using radiation therapy alone are considered to be approximately 65 to 70
Gray (Gy) with standard fractionation (1.8 to 2.0 Gy per
fraction, five fractions per week), or a radiobiologically
equivalent dose when altered fractionation is utilized.
Dose escalation with conventionally fractionated radiation therapy has demonstrated a dose–response relationship with respect to both local control and survival.10,11
Such dose escalation has not been associated with an
increase in acute toxicity when three-dimensional conformal radiation techniques are utilized.12,13 Stereotactic
body radiation therapy using hypofractionation has been
shown to produce excellent local control rates with
acceptable toxicity.14,15 A current phase II Radiation
Therapy Oncology Group (RTOG) protocol will evaluate the safety and efficacy of delivering 60 Gy in three
fractions using stereotactic techniques in patients with
early stage NSCLC.
When considering combined-modality therapy,
potential advantages of radiation therapy in the preoperative setting include possible improvement of the resectability of large tumors, prevention of dissemination of
tumor at the time of surgical resection, and the use of
lower doses of radiation. Disadvantages of this approach
include the inability to determine the precise surgical
stage and an increased risk of postoperative complications such as wound healing. Randomized data have
failed to demonstrate a statistically significant survival
benefit for the use of preoperative radiation therapy in
the treatment of early stage NSCLC.16
Postoperative radiation therapy (PORT) has also been
investigated in the context of randomized trials. The
Lung Cancer Study Group (LCSG) evaluated the role of
Treatment of NSCLC: radiotherapy 137
PORT consisting of 50 Gy in 25 fractions to the mediastinum following complete surgical resection in patients
with stage II and III squamous cell lung carcinoma.17
The rate of local failure as the site of first failure was
reduced from 20% to 1% (p <0.01) with the addition of
PORT for patients with node-positive disease. This did
not result in an overall survival benefit for stage II
patients, as approximately two-thirds of first failures
were distant. For patients with N2 disease, there was an
improvement in overall survival, although this difference was not significant.
In a randomized trial by the Medical Research Council
(MRC), patients with stage II and III disease were randomized to receive 40 Gy of PORT or no further therapy.18 In subgroup analysis, patients with N1 disease did
not have improved outcomes with the addition of PORT.
For patients with N2 disease, the addition of PORT
resulted in a one month improvement in median overall survival, delayed time to local recurrence, and a longer interval to the development of bone metastases.
A meta-analysis performed by the PORT Meta-analysis
Trialists Group confirmed that PORT does not confer a
survival benefit for patients with early stage NSCLC and
may actually decrease survival for patients with stage I and
II disease, with a reduction in two-year survival rate from
55% to 48% with the addition of PORT.19 Other studies
have supported the conclusion that PORT may result in
increased toxicity without survival benefit in stage I and II
disease, but it may be advantageous in stage III disease.20–24
LOCALLY ADVANCED DISEASE
Definition
It is estimated that 30% of patients with NSCLC have
locally advanced disease without distant metastases at
presentation, but few such patients present with disease
amenable to primary surgical resection with curative
intent.25 The term locally advanced as applied to NSCLC
generally implies stage III disease.26 Stage III disease is
subdivided into IIIA and IIIB. Generally speaking, patients
with stage IIIA disease (e.g. ipsilateral mediastinal nodal
involvement) have potentially resectable disease at presentation, while those with stage IIIB disease (e.g. mediastinal invasion, contralateral nodal involvement) do
not. Further, the volume of ipsilateral mediastinal nodal
disease has prognostic value.27 Thus, individuals with
stage III NSCLC comprise a heterogeneous group of
patients with a range of prognoses based upon disease
extent at diagnosis. As such, these patients present a
unique therapeutic challenge.
Single-modality therapy
While treatment with radiation therapy alone for patients
with locally advanced NSCLC is potentially curative,
long-term survival rates are disappointing and generally are less than 15%.28,29 Analyses of the patterns of
failure following treatment with radiation therapy alone
demonstrate that the poor survival rates are related not
only to the inability of local therapy to control the primary tumor, but also to the development of distant
metastases.29,30
The RTOG established prognostic groups determined
by recursive partitioning analysis (RPA) based on four
RTOG trials of patients with inoperable NSCLC treated
with definitive radiation therapy.31 Patterns of failure of
1547 patients with stage II, IIIA, or IIIB NSCLC treated
with radiation therapy alone were then determined
based on RPA prognostic group.32 The median survival
and the rates of primary and distant failures varied significantly based on RPA class, suggesting that specific
cohorts of patients may benefit from more aggressive
treatment directed at specific sites of failure.
Combined-modality therapy
When local control is defined by complete clinical,
radiographic, endoscopic, and histologic remission, the
local failure rate is as high as 92% at 5 years.30 Distant
failure rates after radiation therapy alone are approximately 80%.29 These findings have led to the exploration
of combined-modality therapy utilizing chemotherapy
in the treatment of such patients.
Many possible combinations of induction therapy
have been investigated in a multitude of trials evaluating the role of combined-modality therapy in the treatment of locally advanced NSCLC. Interpretation of the
data and comparisons of results between even well
designed trials are difficult for many reasons. There have
been several changes in the staging systems over time
and the terms ‘unresectable’, ‘marginally resectable’, and
‘locally advanced’ have been variably defined. Additionally, no standards exist regarding the extent of surgical
staging or resection, the dose of radiation therapy delivered, or the chemotherapeutic agents used and in what
combinations and doses. The optimal treatment of
locally advanced NSCLC continues to be defined, but
long-term survival rates have improved with combinedmodality therapy, which is now considered the standard
of care.33–35
There are two basic treatment protocols for administering combined chemotherapy and radiation. Sequential
treatment with chemotherapy followed by radiation therapy was the first widely utilized combination in locally
138 Textbook of Lung Cancer
advanced NSCLC. Concurrent chemoradiation has demonstrated promising results with respect to prolonging
survival, and is considered the current standard of care.
Sequential chemoradiation
When radiation therapy follows induction chemotherapy, the effects of chemotherapy decrease the local
tumor burden and may permit delivery of radiation to
a reduced tumor volume. Induction chemotherapy may
also eliminate or prevent the growth of subclinical systemic disease. Increased drug delivery with less overall
toxicity is also more likely compared to concurrent
administration. Potential drawbacks of sequential administration include a prolonged overall treatment time,
excessive toxicity due to chemotherapy preventing or
delaying the delivery of radiation, induction of accelerated repopulation, and chemotherapy-induced tumor
cell resistance resulting in reduced radiation efficacy.36–38
Many phase II trials have been designed to evaluate
whether or not survival is improved with the addition of
induction chemotherapy to radiation therapy in patients
with locally or regionally advanced NSCLC. Although
these trials have had conflicting results, several phase
III trials (Table 10.2.1) and three meta-analyses have
demonstrated a survival benefit, and recent updates have
provided relatively long-term data.
In North America, the Cancer and Leukemia Group
B (CALGB) 8433 trial is the landmark study of sequential chemoradiation versus radiation therapy alone for
the treatment of locally advanced NSCLC.39 A total of
155 eligible patients with clinical or surgical T3 or N2
NSCLC without evidence of distant metastases were
randomized to induction chemotherapy with cisplatin
and vinblastine followed by radiation therapy or radiation therapy alone. Radiation therapy to a total dose of
60 Gy in 30 fractions was the same in both arms and
began on day 50 in the combined-modality arm. All
patients had a good performance status and minimal
weight loss prior to study entry. The addition of chemotherapy did not impair the ability to deliver radiation
therapy, with 88% of patients in the combined-modality
arm and 87% of patients on the radiation therapy alone
arm completing radiation therapy per protocol. Longterm seven-year followup confirms that induction
chemotherapy improves median survival compared to
radiation therapy alone.40 Three other modern cisplatinbased trials have confirmed the CALGB experience.
A US Intergroup trial randomized 458 eligible patients
with good performance status, minimal weight loss, and
unresectable, localized NSCLC to receive once daily
radiation therapy to 60 Gy in 2 Gy fractions with or
without induction cisplatin and vinblastine.41 Patients
Table 10.2.1 Randomized trials of chemotherapy and radiation therapy versus radiation therapy alone
Trial
CT
RT dose (Gy)
Median survival (months)
p value
Three-year survival (%)
VP
60
60
13.7
9.6
VP
60
60
69.6 BID
13.8
11.4
12.3
VCPC
65
65
12.0
10.0
0.02
6b
3b
MIC
50c
50c
13.0
9.9
0.056
14
10
CALGB39,40
0.012
23
11
US Intergroup41,42
5b
8b
6b
a
0.03
French43,44
MRC45
CT: chemotherapy; RT: radiation therapy; CALGB: Cancer and Leukemia Group B; MRC: Medical Research Council; VP: vinblastine, cisplatin;
VCPC: vindesine, cyclophosphamide, cisplatin, lomustine; MIC: mitomycin, ifosfamide, cisplatin; BID: twice daily.
a
Versus the sequential arm.
b
Five-year rates.
c
Median RT dose.
Treatment of NSCLC: radiotherapy 139
randomized to a third arm received radiation therapy
alone twice daily to a total dose of 69.6 Gy. Median survival was statistically superior for the combined-modality
arm versus either the standard radiation therapy arm or
the twice-daily radiation therapy arm. Final results of this
study confirmed combined-modality therapy improves
median survival, but five-year survival rates remained
poor at less than 10%.42
In another phase III trial conducted in France, 353
patients with unresectable locally advanced squamous
cell or large cell lung carcinoma were randomized to
receive either radiation therapy alone (65 Gy in 2.5 Gy
fractions) or three monthly cycles of cisplatin-based
chemotherapy followed by the same radiation therapy
regimen.43 There was a significant decrease in distant
metastases for the combined-modality arm and the median
and two-year survival rates (21% vs 14%, p = 0.02,
overall).44 Re-analysis revealed that only 8% of patients
had continued local control at five years.30 Five-year
survival rates remained poor at 6% and 3%, likely secondary to the high rate of local failure on both arms.
The MRC randomized 447 eligible patients with good
performance status and localized, inoperable NSCLC to
receive radiation therapy alone or cisplatin-based induction chemotherapy followed by radiation therapy.45 On
both arms, the median radiation therapy dose was low
at 50 Gy. Median survival was improved with the addition of chemotherapy, although this difference was of
borderline significance.
As demonstrated by the above randomized trials, the
addition of platinum-based induction chemotherapy to
radiation therapy results in improved survival as compared to radiation therapy alone. This is particularly
true for short-term survival, but modest improvements
in long-term survival have been observed as well. Several smaller randomized trials have failed to confirm a
survival benefit for the addition of induction chemotherapy, but these trials may have lacked the power to
detect small differences in survival.46–49 Three large
meta-analyses have demonstrated a small but consistent
survival benefit in the order of 5–10% at one year for
the addition of induction chemotherapy to radiation
therapy for locally advanced NSCLC.50–52
Sequential versus concurrent chemoradiation
The benefit of combined-modality treatment with radiation therapy and chemotherapy was established by the
CALGB 8433 trial and confirmed by other randomized
phase III studies.40,42,44,45 These trials, however, did not
address the optimal sequencing of the two modalities.
Potential advantages of concurrent chemoradiation
include sensitization of tumor cells to radiation and
reduced overall treatment time.53 Potential disadvantages
of concurrent chemoradiation include increased morbidity requiring reductions in the dose intensity of chemotherapy and unplanned delays in the administration
of radiation therapy.37,38,54
An important early European Organization for Research
and Treatment of Cancer (EORTC) trial randomized 331
patients with unresectable stage I, II, or III NSCLC to
treatment with radiation therapy alone, radiation therapy with weekly cisplatin (30 mg/m2), or radiation therapy with daily cisplatin (6 mg/m2).55 On all three arms,
the same definitive split-course radiation therapy schedule consisting of 60 Gy in 20 fractions with a three-week
rest after the first 30 Gy was utilized. The administration of daily cisplatin was shown to significantly improve
overall survival (16% vs 2% at three years, p = 0.009
overall) and disease-free survival (31% vs 19% at two
years, p = 0.003 overall) compared to radiation therapy
alone. The weekly cisplatin arm also revealed a trend
towards improved survival compared to the radiation
alone arm. The survival benefit observed with the addition of low-dose daily cisplatin was likely due to radiation sensitization and improved local control.
While the EORTC trial above addressed the feasibility
of administering chemoradiation in a multicenter setting
and confirmed a survival benefit for combined-modality
therapy, it still did not address the optimal timing of
the two modalities. Several additional randomized trials
were designed to answer this question (Table 10.2.2).
The West Japan Lung Cancer Group (WJLCG) conducted a large phase III trial to directly compare survival for sequential versus concurrent cisplatin-based
chemoradiation.56 A total of 314 eligible patients with
unresectable stage III NSCLC were entered on the trial.
Both the response rate and the median survival were
significantly improved for patients who received concurrent chemoradiation as compared to sequential
treatment.
The RTOG also compared sequential versus concurrent
chemoradiation in a phase III randomized trial (RTOG
94-10).57,58 In this trial, patients with unresected stage
II–III NSCLC and good performance status were randomized to receive sequential chemoradiation, or concurrent chemoradiation with radiation delivered either
once or twice daily. With a median follow-up of 6.0 years,
the concurrent arm receiving once-daily radiation therapy had an improved median survival compared to the
sequential arm. The median survival of patients on the
concurrent twice-daily radiation therapy arm was not
statistically different from the sequential arm.
140 Textbook of Lung Cancer
Table 10.2.2 Randomized studies evaluating sequential versus concurrent administration of chemotherapy and radiation
therapy
Trial
Arm
WJLCG56
Sequential
Concurrent
Sequential
Concurrent, RT qd
Concurrent, RT BID
Sequential
Concurrent
Sequential
Concurrent
RTOG 94-10
Czech59
French
60
57
Response rate (%)
66.6
84.0
NR
NR
NR
47
80
NR
NR
p value
0.0002
NR
NR
0.001
NR
Median survival (months)
13.3
16.5
14.6
17.0
15.2
12.9
16.6
13.8
15.0
p value
0.04
0.046a
0.296a
0.023
0.41
WJLCG: West Japan Lung Cancer Group; RTOG: Radiation Therapy Oncology Group; qd: once daily; BID: twice daily; NR: not reported.
a
Versus the sequential arm.
Two additional randomized phase III trials, one conducted in the Czech Republic and another conducted
in France, both demonstrated a significant improvement with respect to median survival for concurrent
chemoradiation versus sequential treatment.59,60 Based
in part on the results of the above randomized trials, the
administration of chemotherapy and radiation therapy
concurrently, rather than sequentially, is considered
the standard of care for patients with locally advanced
NSCLC.
Induction chemoradiation
Once the efficacy and feasibility of concurrent chemoradiation for locally advanced NSCLC was established,
this approach replaced chemotherapy alone as the induction regimen prior to surgery in many trials. An important example is SWOG 8805, a phase II trial designed
to test the feasibility of concurrent chemoradiation followed by surgical resection in 126 patients with stage
IIIA and IIIB disease.61 Induction therapy consisted of
cisplatin and etoposide given concurrently with thoracic irradiation to 45 Gy. Patients with unresectable
disease, incomplete resection, or positive mediastinal
nodes received an additional two cycles of chemotherapy and radiation therapy to a total dose of 59.4 Gy.
Morbidity and mortality associated with this trial were
high. Mature results revealed no survival difference
between patients with stage IIIA and IIIB disease, with
a median survival of 13 months and 17 months, respectively.62 Absence of tumor in mediastinal nodes at surgery was the strongest predictor of long-term survival
after thoracotomy, with a median survival of 30 months
versus 10 months, and three-year survival of 44% vs
18% (p = 0.0005).
With the encouraging results of the above SWOG
phase II trial and others, an Intergroup phase III trial
conducted by the RTOG was initiated.63 In this trial, all
patients received induction chemoradiation and were
then randomized to surgical resection or further chemoradiation. Induction chemoradiation consisted of cisplatin and etoposide given concurrently with 45 Gy of
radiation therapy. Patients with responsive or stable
disease following induction therapy underwent surgical
resection followed by two postoperative cycles of chemotherapy, or continued radiation therapy to a total
dose of 61 Gy concurrent with two additional cycles of
chemotherapy. A total of 429 patients were entered on
the study, all with stage IIIA, N2 disease. These patients
were highly selected in that they had to be potential
candidates for pulmonary resection and eligibility criteria also required a Karnofsky Performance Status (KPS)
of 70 or greater. Of the 396 analyzable patients, 202
were randomized to undergo surgical resection following
induction chemoradiation and 194 received definitive
chemoradiation. The most recent results were reported
with a minimum of 2.5 years of follow-up per patient
(Table 10.2.3). There were 16 (7.9%) deaths on the
chemoradiation and surgery arm and 4 (2.1%) deaths on
the chemoradiation only arm. A higher rate of death was
observed following pneumonectomy versus lobectomy
(26% versus 1%, respectively). Although progression-free
survival was significantly improved with the addition of
surgery, median survival and five-year survival rates
were not significantly different between the two arms.
Treatment of NSCLC: radiotherapy 141
Table 10.2.3 Results of Intergroup trial 0139 (RTOG 9309), comparing induction chemoradiation followed by surgical resection
versus definitive chemoradiation63
Arm
Number of patients
ChemoRT
ChemoRT + S
p value
Progression-free survival
(months)
194
202
10.5
12.8
0.017
Median survival
(months)
Five-year
survival (%)
22.2
23.6
0.24
20.3
27.2
0.10
ChemoRT: chemoradiation; S: surgery; NR: not reported.
Pathologic N0 disease at the time of surgical resection
predicted for long-term survival. These results suggest
that, while surgical resection after induction chemoradiation increases progression-free survival compared to
definitive chemoradiation in patients with stage IIIA
NSCLC, the addition of surgery may also increase the
morbidity and mortality of treatment without improving overall survival. Surgical resection following induction chemoradiation may be considered in fit patients,
particularly if a lobectomy is to be performed.
The German Lung Cancer Cooperative Group (GLCCG)
conducted a phase III randomized study to investigate
the timing and fractionation of radiation therapy when
surgery is planned in patients with locally advanced
NSCLC.64 In this trial, 558 patients with stage IIIA and
IIIB disease received induction chemotherapy consisting of three cycles of cisplatin and etoposide. Patients
were then randomized to receive hyperfractionated
radiation therapy with concurrent carboplatin and vindesine followed by surgery, or surgery followed by
standard fractionated radiation therapy to 54 Gy without concurrent chemotherapy. There was no difference
between the two arms with respect to response rate
after induction, complete resection rate (45% in both
arms), treatment-related mortality, and three-year progression-free survival and overall survival.
SUPERIOR SULCUS TUMORS
Tumors of the superior sulcus, also known as Pancoast’s
tumors, are a distinct subset of locally advanced NSCLC.
Previously considered inoperable and fatal, the use of
single-modality radiation therapy has led to five-year
survival rates as high as 46%.65
The use of trimodality therapy is now considered standard of care for patients with tumors of the superior
sulcus. This is based primarily on a phase II (Intergroup
0160, SWOG 9416) study in which 110 eligible patients
with T3–4, N0–1 tumors of the superior sulcus received
induction therapy consisting of cisplatin and etoposide
given concurrently with thoracic irradiation to 45 Gy.66,67
This induction regimen was identical to that given in
SWOG 8805.61 A total of 95 (86.4%) patients had stable
disease or response to induction chemoradiation and
underwent surgical resection followed by an additional
two cycles of chemotherapy. Complete resection was
performed in 83 (94.3%) of the 88 patients who underwent thoracotomy. Pathologic complete response was
seen in 32 (36.4%) of the thoracotomy specimens and
an additional 26 (39.5%) revealed minimal microscopic
disease. The five-year and median survivals were 53% and
71 months, respectively, for patients who had a complete resection, and 41% and 33 months, respectively,
for all patients who were eligible for resection. This represented a significant improvement over historical data
for NSCLC of the superior sulcus.
ALTERED FRACTIONATION RADIATION THERAPY
Hyperfractionated and accelerated fractionation radiation
therapy have been investigated as potential approaches
to improve outcomes in patients with locally advanced
NSCLC. Delivering multiple fractions per day works to
counteract the effect of accelerated repopulation that
occurs during normal treatment breaks. An adequate
interval between fractions, generally six hours or longer,
allows for repair of sublethal damage in normal tissues,
thus minimizing any increase in acute side-effects. Late
effects are also decreased due to the lower dose per
fraction.53
A European multicenter trial randomized 563
patients with locally advanced NSCLC and good
performance status to either conventional radiation
therapy or continuous hyperfractionated accelerated
radiotherapy (CHART).68 The CHART regimen consisted of 36 fractions of 1.5 Gy each given three times
per day on 12 consecutive days. The use of CHART was
associated with a 9% improvement in overall survival at
142 Textbook of Lung Cancer
two years (29% vs 20%, p = 0.004). CHART was also
associated with an increase in severe dysphagia (19%
vs 3%), but this occurred primarily after the completion of radiation therapy and thus did not interfere with
radiation delivery. Subgroup analyses revealed the greatest benefit was for patients with squamous cell histology.
Jeremic and colleagues randomly assigned 131 patients
with stage III NSCLC to receive twice daily radiation
therapy to a total dose of 69.6 Gy with or without lowdose daily carboplatin and etoposide.69 The combinedmodality arm demonstrated an improved median
survival (22.0 vs 14.0 months) and an improved four-year
survival (23% vs 9%, p = 0.021). This represents an
approximately six-month improvement in median survival as compared to the concurrent chemoradiation arms
utilizing once daily radiation (Table 10.2.2).56,57,59,60
A randomized study by the Eastern Cooperative Oncology Group (ECOG 2597) compared once-daily radiation
therapy to hyperfractionated accelerated radiation therapy
(HART) following two cycles of induction chemotherapy
with carboplatin and paclitaxel.70 Once-daily radiation
therapy was delivered with 2.0 Gy fractions to a total dose
of 64 Gy. HART consisted of a total dose of 57.6 Gy using
1.5 Gy fractions delivered three times per day. The study
was closed early due to poor accrual. Based on the 141
patients who were enrolled, median survival was 20.3
months on the HART arm and 14.9 months on the daily
radiation therapy arm (p = 0.28). This also represents an
approximately 6-month improvement in median survival as compared to the concurrent chemoradiation
arms utilizing once-daily radiation (Table 10.2.2).56,57,59,60
While the initial results of altered fractionation radiation therapy in the treatment of locally advanced NSCLC
are promising, at this time there is no confirmed additional survival benefit for altered fractionation radiation
therapy alone over concurrent chemotherapy and radiation therapy. The hyperfractionated radiation therapy
arms of the United States Intergroup trial and RTOG
94-10 trial were unable to confirm a significant survival benefit when compared to conventional radiation
therapy, even with long-term follow-up.42,58 Combining chemotherapy with altered fractionation radiation
therapy has shown promise, but this approach has yet
to be optimally defined and continued investigation is
warranted.
TOXICITY AND PATIENT SELECTION
In locally advanced NSCLC, combined-modality therapy improves disease control at the cost of increased
toxicity. Without exception, patients enrolled on the
combined-modality or ‘more aggressive’ treatment arms
of clinical trials experience increased toxicity as compared to single-modality controls.39,41,55–57
Important factors that influence outcome in patients
with locally advanced NSCLC include age, performance
status, and degree of weight loss.71–73 Aggressive combinedmodality treatments require a ‘fit’ cohort of patients and
proper patient selection is critical, as highlighted by the
results of RTOG 90-15.74 This phase I/II trial utilized
cisplatin and vinblastine concurrent with twice-daily
radiation (1.2 Gy twice daily to 69.6 Gy) to treat patients
with unresected stage II, IIIA, or IIIB NSCLC. All patients
had a good performance status (KPS ≥70), but this trial
was initiated while RTOG 88-08 was still in progress
and, due to competition for enrollment, minimal weight
loss was not included in the eligibility criteria. Of the
42 eligible patients, 76% had greater than 5% weight
loss preceding study entry. Grade 4 or higher acute toxicity was observed in 45% of patients, with 7% of patients
dying of sepsis related to chemotherapy-induced leukopenia. Median survival was 12.2 months in all patients
and 17.5 months for the ten patients with less than 5%
weight loss.
Consideration must also be given to the timing of
surgical resection and the type of surgery that is planned
after induction therapy. In general, preoperative chemotherapy has not been shown to increase postoperative morbidity and mortality.75,76 Review of the Memorial
Sloan Kettering experience, however, has revealed that
right pneumonectomy following induction chemotherapy significantly increases the risk of surgical complications, with 24% of patients dying postoperatively.76 The
mechanism behind the increased mortality after right
pneumonectomy is not well understood and the role of
radiation therapy, if any, in increasing the risk of death
is not known.
PROPHYLACTIC CRANIAL IRRADIATION
The risk of central nervous system (CNS) failure is low
in patients with early stage disease who undergo surgical
resection. For patients with locally advanced disease,
15–30% will experience CNS failure as the site of first
relapse.62,77,78 The overall CNS failure rate increases with
increasing survival and is on the order of 20–50%.62,77–79
Prophylactic cranial irradiation (PCI) has been shown
in prospective randomized trials to delay and reduce
the incidence of failure within the brain, but it has not
been shown to improve survival.80,81 These studies have
Treatment of NSCLC: radiotherapy 143
been criticized for poor control of extracranial disease,
which was the cause of death in the majority of patients
and also likely contributed to reseeding of the brain
after whole brain radiation therapy was completed.
An ongoing North American Intergroup phase III
trial conducted by the RTOG randomizes patients with
stage III NSCLC who have been treated with definitive
combined-modality therapy and have responsive or
stable disease to receive 30 Gy in 15 fractions of whole
brain radiation therapy or no PCI. A study by the West
German Cancer Center will randomize patients with
locally advanced NSCLC to one of two fractionation
schemes of PCI (24 Gy in 12 fractions or 30 Gy in 15
fractions), or no PCI. These trials, which will collect data
on both survival and neuropsychologic sequelae of treatment, will hopefully clarify the role of PCI in patients
with locally advanced NSCLC.
PALLIATIVE THERAPY
Palliative endobronchial therapy can provide symptomatic improvement for bronchial symptoms such as
hemoptysis and obstructive pneumonia. Radiation can
be delivered with low-dose rate sources or, more commonly, with a high-dose-rate source using a remote afterloading device. Common treatment regimens include
21 Gy in three fractions delivered at 1.0 cm depth with
a high-dose-rate source and 30 Gy delivered at 1 Gy per
hour for low-dose-rate sources. No significant differences between the two techniques with respect to bronchoscopic response rate or complications have been
identified.82,83 Symptomatic improvement is usually
rapid and is generally seen in 50% of patients.84,85
Radiation therapy remains a useful palliative tool in
the treatment of patients with distant metastatic NSCLC.
Common sites of metastatic disease include brain and
bone. For patients with brain metastases, radiation therapy is generally employed, either as a sole modality or
in combination with surgical resection. The role of stereotactic radiosurgery, particularly in patients with controlled extracranial disease, continues to be defined.86
Between 20 and 40% of patients with NSCLC will
develop osseous metastases.87 Focal external beam radiation therapy is the most common method used to treat
symptomatic bone metastases. Several fractionation schemes
are commonly employed, but recent data in patients with
metastatic breast or prostate cancer suggest that 8 Gy in
a single fraction provides equivalent pain control to the
more protracted schedule of 30 Gy in 10 fractions,
although the retreatment rate is significantly higher.88
Superior vena cava (SVC) syndrome results from
compression of the SVC with compromised return of
venous blood flow to the heart. SVC syndrome occurs
in approximately 5% of all patients with lung cancer
and it is characterized by presentation with dyspnea,
facial and neck swelling, and distention of the veins of
the upper chest wall. Initial management may consist of
medical therapy such as diuretics and/or corticosteroids. Effective palliation is often quickly achieved by
the use of radiation therapy. Commonly, several large
fractions of 4 Gy are given for the first several days of
treatment.89,90 Palliation of the symptoms associated
with SVC syndrome is seen in approximately 90% of
patients within three weeks of initiation of therapy.91,92
CONCLUSION
Lung cancer is a very common disease and even relatively small advances in treatment have the potential to
impact the survival of thousands of patients. In the past
two decades, many trials of combined-modality therapy
have been conducted in an attempt to improve the survival of patients with NSCLC. The role of radiation
therapy is limited in patients with early stage disease
and is best suited to treat patients who are medically
unfit or refuse to undergo surgery. Radiation therapy
may also be used in this setting for patients who do not
undergo a complete surgical resection.
The best overall therapeutic regimen remains unclear
in patients with locally advanced disease, but the use of
combined-modality therapy in the treatment of such
patients has resulted in a modest but reproducible survival benefit compared to single-modality therapy.
Concurrent administration of chemotherapy and radiation therapy for patients with locally advanced NSCLC
has been shown to significantly improve survival as
compared to sequential therapy in randomized trials
and is the standard of care. The role of surgery in this
setting continues to be defined.
Based on patterns of failure, attention has focused on
improving local control and preventing progression of
distant disease. It is hoped that with continued advances
in all therapeutic modalities, the survival of patients
with NSCLC will continue to improve.
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brachytherapy for malignant endobronchial tumors: an update
on low-dose rate versus high-dose rate radiation therapy. Clin
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intraluminal brachytherapy in malignant airway obstruction of
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86. Chougule PB, Burton-Williams M, Saris S et al. Randomized
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10.3 Treatment of NSCLC: chemotherapy
Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias
Contents Introduction • Adjuvant chemotherapy after surgical resection • Preoperative (neoadjuvant)
chemotherapy • Chemotherapy for locally advanced unresectable (IIIA and IIIB) NSCLC • Chemotherapy
for patients with advanced NSCLC • Patients populations with special considerations • Second-line therapy
• Targeted therapies in advanced NSCLC
INTRODUCTION
The clinical development of chemotherapeutic agents
in non-small cell lung cancer (NSCLC) was initially
focused in the setting of stage IV disease. During the
1980s and early 1990s, six drugs, namely cisplatin,
ifosfamide, mitomycin C, etoposide, vindesine, and
vinblastine, were considered active against NSCLC,
with response rates reported in excess of 15%.1,2
Combination chemotherapy, most commonly cisplatin-based, was also investigated. Generally, higher
objective responses were achieved but still the benefit
for the patients was unclear by that time. Subsequent
randomized trials and meta-analyses established the
value of chemotherapy in the treatment of patients
with advanced NSCLC.3,4 The next steps were aimed
at the development of chemotherapy from a palliative
measure to a curative one, through its incorporation
into aggressive combined modality treatments for
locoregionally advanced disease, and/or its administration as adjuvant to radical surgery. More recently,
during the 1990s, a new generation of compounds
such as the taxanes (paclitaxel and docetaxel), the topoisomerase inhibitors (irinotecan, topotecan), active
analogs (gemcitabine), antimetabolites (pemetrexate),
and vinka alkaloids (vinorelbine) were integrated in
the treatment of NSCLC.5 These drugs administered
in patients with metastatic disease obtained singleagent activity in the range of 20–30%. When used in
combination with other active agents such as the platinums, significant response rates, often in excess of
40%, were reported in pilot phase II studies. The
newer agents have been also successfully used in chemotherapy regimens for the treatment of patients with
earlier stages of disease as well as in combined-modality treatment programs.
ADJUVANT CHEMOTHERAPY AFTER
SURGICAL RESECTION
Surgery remains the only curative treatment modality
for patients with NSCLC. However, even after complete
resection the overall survival remains disappointing,
with the five-year survival rates ranging from 67% for
patients with T1N0 disease to 23% for patients with N2
disease.6 Efforts to improve the survival of patients with
operable NSCLC have examined the addition of chemotherapy (CMT) and/or radiotherapy (RT) in the
postoperative setting. The rationale for the use of systemic therapy in completely resected NSCLC lies in the
detection of early micrometastatic disease at the time of
surgery and in the clinical observation that distant
recurrence is the predominant cause of relapse and
death after surgery.
From the first randomized trials to the 1995
meta-analysis
Early trials of postoperative chemotherapy started in
the 1960s failed to demonstrate any benefit on survival
by the incorporation of alkylating and immunotherapeutic agents.7 The vast majority of subsequent trials
employing cisplatin-based regimens8–11 did not show
any significant effect of chemotherapy on survival.
Common drawbacks in these studies were the overestimation of the potential benefit of adjuvant chemotherapy in the calculation of the sample size, the imbalance
in patient and treatment characteristics, the unfeasibility of reaching the planned accrual, and, finally, the low
compliance with most chemotherapy regimens used.
In 1995 a meta-analysis on the role of chemotherapy in
the treatment of NSCLC separately reviewed eight trials, assigning a combined total of 1394 patients to cisplatin-based adjuvant chemotherapy.12 A 13% reduction
148 Textbook of Lung Cancer
in the risk of death [hazard ratio (HR) 0.87 (95% CI:
0.74–1.02)] corresponding to an absolute survival benefit of 3% at two years (95% CI: 0.5% detriment to 7%
benefit) and 5% (95% CI: 1% detriment to 10% benefit)
at five years, in favor of chemotherapy, was reported.12
Despite the marginal statistical significance (p = 0.08),
these findings encouraged the initiation of several randomized trials investigating the role of platinum-based
regimens in patients with completely resected stage I,
II, and IIIA NSCLC (Table 10.3.1). These trials used
different types of chemotherapy and included different
proportions of stages I to IIIA NSCLC.
The North American Intergroup Trial INT0115 was
the only trial that compared the combination of chemotherapy plus thoracic radiotherapy versus radiotherapy
alone in patients with completely resected stage II or
IIIA NSCLC.13 INT0115 was negative, but yet, the trial
was underpowered to detect the small survival benefit
suggested by the meta-analysis and used thoracic radiotherapy as the comparator that is not considered as the
standard reference arm. The Big Lung Trial was also
clearly underpowered to look at differences in survival
in the range of 5%. With a median follow-up of only
2.9 years no significant benefit was shown by the addition of cisplatin-based chemotherapy pre- (4%) or postoperatively (96%).14
In the next sections the most important recent trials
of adjuvant chemotherapy are presented.
Adjuvant Lung Project Italy (ALPI trial)
The ALPI trial randomized 1209 patients with surgically staged I–IIIA NSCLC to receive MVP (mitomycin
8 mg/m2, day 1; vindesine 3 mg/m2, days 1 and 8; CDDP
100 mg/m2, day 1, every three weeks) for three cycles
(n = 606), or no treatment (n = 603).15 Stratification
factors included center, tumor size, lymph node involvement, and the intention to perform radiotherapy.
After a median follow-up of 64.5 months the study
failed to demonstrate any significant difference in terms
of overall survival [HR 0.96 (95% CI: 0.81–1.13); p =
0.589] and progression-free survival [HR 0.89 (95%
CI: 0.76–1.03); p = 0.128]. Median overall survival was
55 months in the chemotherapy arm and 48 months in
the surgery alone arm, while progression-free survival
was 37 and 29 months for the treatment and control
arms, respectively. No significant effect between treatment and stage of the disease emerged.
Treatment compliance data indicate that 69% of the
patients received the per protocol planned three cycles
of chemotherapy, although half of them required some
dose adjustment or omission. Chemotherapy was never
started in an additional 9%, mainly due to consent
withdrawal. Radiotherapy was completed in 65% of the
patients initially planned in the MVP arm and in 83%
of the control group.
International Adjuvant Lung Cancer trial (IALT trial)
The IALT trial randomly allocated patients with surgically resected stage I, II, or III NSCLC to receive cisplatin-based chemotherapy or observation.16 The primary
endpoint was overall survival and secondary endpoints
were disease-free survival (DFS), second-primary cancers, and adverse events. A total of 3300 patients was
required for the trial to have 83% power with a twosided test to detect an absolute improvement of 5%,
and 90% power to detect a 5.6% difference in overall
survival at five years. However, the trial was terminated
prematurely after the enrollment of 1867 patients out
of the 3300 initially planned because of a slow down in
patient recruitment rate.
Each participating center had to determine the pathologic stage of the disease to include, the dose of cisplatin
(80, 100, 120 mg/m2 per cycle for 3–4 cycles), the drug
to be combined with cisplatin (etoposide, vinorelbine,
vindesine, or vinblastine) and the administration of
sequential chest radiotherapy.
Finally, 932 patients were enrolled in the chemotherapy arm and 935 in the control group. Approximately
37% had disease stage I, 24% stage II, and 39% stage
III. Twenty-seven percent of patients received postoperative radiotherapy, while cisplatin plus etoposide was
the most frequently utilized regimen.
After a median follow-up period of 56 months, the
DFS rate at five years was 39.4% for the chemotherapy
arm vs 34.3% for the observation arm [HR 0.83 (95%
CI: 0.74–0.94; p <0.003)]. Furthermore, overall survival favored the chemotherapy arm [44.5 vs 40.4% at
five years; HR 0.86; (95% CI: 0.76–0.98); p <0.03].
Compliance with chemotherapy was relatively poor, with
74% of the patients in the chemotherapy arm receiving
at least three treatment courses. Moreover, 70% of the
patients treated with chemotherapy and assigned to
chest radiotherapy completed their course, compared
with 84% of these who did not receive chemotherapy.
Seven (0.8%) patients died of chemotherapy-related
toxicity.
The results observed in the IALT trial are in the same
range as those reported in the 1995 meta-analysis.7 The
large number of patients in the IALT analysis may explain
the significance of the results compared with the smaller
number of analyzed patients in the ALPI trial. Moreover, the use of a three-drug regimen and the higher
No of
488
1209
1867
381
119
ALPI trial15
IALT trial16
Big Lung
Trial14
JCOG 9304
trial28
patients
INT011513
Trial
IIIA (N2)
I–IIIA
I–IIIA
I–IIIA
II–IIIA
Disease
stages
included
VP-16 (120 mg/m2,
d 1–3); CDDP
(60 mg/m2, d 1)/
radiotherapy only
(both arms received
a total of 50.4 Gy
radiotherapy)
Mit 8 mg/m2, d 1;
VND 3 mg/m2,
d 1 & 8; CDDP
100 mg/m2, d 1,
q3w, for three
cycles/observation
CDDP + vinka
alkaloids or
VP-16/observation
CDDP/VND,
CDDP/mit/If,
CDDP/mit/
vinblastine or
CDDP/VNB/
observation
CDDP 80 mg/m2,
d 1; VND 3 mg/m2,
d 1 & 8: ×3 cycles/
observation
CT regimen/
control arm
Table 10.3.1 Reported phase III trials of adjuvant chemotherapy in NSCLC
58
64
74
69
69
Compliance
to CT (%)
Median
NR
34.6
56
64.5
44
follow-up
(months)
Hazard
0.86
1.02
—
−2b
−7.9c
0.96
0.93
ratio of
death
4.1
1
−6a
Five-year
absolute
survival
benefit (%)
(Contiuned)
0.89
0.90
<0.03
0.589
0.56
p
149
840
ANITA trial24
IB–IIIA
IB
65
CDDP (50 mg/m2,
d 1 & 8 q 4w);
VNB (25 mg/m2)/
observation
PCL 200 mg/m2/
carboplatin AUC
6/observation
CDDP 100 mg/m2/
VNB 30 mg/m2/
observation
56d
85
74
(at 12 mo)
61
(at 24 mo)
80
Compliance
to CT (%)
UFT
(250 mg/m2/day)
for 2 years/
observation
UFT/observation
CT regimen/
control arm
>70
48
6.44
(years)
60
72
Median
follow-up
(months)
8.6
3
15
4.6
3
Five-year
absolute
survival
benefit (%)
0.79
0.80
0.69
0.77
—
Hazard
ratio of
death
0.013
0.32
0.011
0.011
0.047
p
b
Estimated 5-year survival rates were 39% for the RT only group and 33% for the CT-RT group.
Estimated 2-year survival rates were 60% for the observation group and 58% for the CT group.
c
5-year survival rates were 28.2% in the chemotherapy arm and 36.1% in the control group.
d
Dose density of vinorelbine.
CT: chemotherapy; RT: radiotherapy; q3W: every three weeks; VP-16: etoposide; UFT: oral uracil-tegafur; CDDP: cisplatin; Mit: mitomycin; VND: vindesine; If: Ifosfamide; VNB: vinorelbine; PCL: paclitaxel;
carboplatin AUC 6: carboplatin Area Under Curve 6.
a
344
IB–II
482
CALGB 9633
trial22,23
I–III
2003
UFT metaanalysis18
NCIC-JBR10
trial19
I
Disease
stages
included
999
No of
patients
UFT trial17
Trial
Table 10.3.1 Continued
150
Treatment of NSCLC: chemotherapy 151
frequency of postoperative radiotherapy in the ALPI
trial might also have led to the negativity of this trial.
UFT adjuvant trials
Uracil-tegafur (UFT) is a combination of uracil, an
inhibitor of dihydropyrimidine dehydrogenase (DPD),
and tegafur, a prodrug of 5-fluorouracil, that has been
extensively studied in Japanese patients with NSCLC.
UFT has been studied either as single-agent therapy following surgery or following one or more cycles of cisplatin-based chemotherapy. In all those trials, UFT was
administered as a single daily oral dose over a prolonged period of time.
The largest trial on postoperative UFT therapy randomly assigned 999 patients with completely resected
pathologic stage I adenocarcinoma to receive either oral
uracil-tegafur (250 mg/m2/day) for two years (498
patients) or no treatment (501 patients).17 Stratification
factors were tumor stage (T1 vs T2), sex, and age. The
median follow-up period was 72 months in the UFT
group and 73 months in the control group. The fiveyear overall survival rate was 88% (95% CI: 85–91) for
the UFT group and 85% (95% CI: 82–89) for the control group. Survival benefit was significant in patients
with T2 tumors (85% vs 74% for the UFT and observation groups, respectively; HR 0.48; 95% CI: 0.29–0.81;
p = 0.005), while for patients with T1 disease no significant difference was observed. Although toxicity was
minimal, compliance was only 74% at 12 months and
61% at 24 months.
Recently, a meta-analysis examining the effectiveness
of UFT as postoperative treatment of NSCLC was published.18 This meta-analysis included 2003 eligible
patients; most (98.8%) had squamous cell carcinoma
or adenocarcinoma, and stage I disease; the tumor classification was T1 in 1308 (65.3%), T2 in 674 (33.6%), and
the nodal status was N0 in 1923 (96.0%). The median
duration of follow-up was 6.44 years. The survival rates
at 5 and 7 years were significantly higher in the surgery
plus UFT group (81.5% and 76.5%, respectively) than in
the surgery alone group (77.2% and 69.5%, respectively;
p = 0.011 and 0.001, respectively). The overall pooled
hazard ratio was 0.74 (95% CI: 0.61–0.88; p = 0.001).
National Cancer Institute of Canada (NCIC)
JBR10 trial
This trial randomly assigned 482 patients with completely resected, pathologic stage IB and II (patients with
T3N0 disease were excluded) to receive either postoperative adjuvant chemotherapy with cisplatin (50 mg/m2,
days 1 and 8 every 4 weeks for four cycles) and vinore-
lbine (25 mg/m2, reduced from 30 mg/m2 for unacceptable toxicity, weekly for 16 weeks) or no chemotherapy.19
The study endpoints were overall survival, recurrencefree survival, quality of life, and toxicity.
At five years of follow-up, the five-year survival rates
were 69% for the chemotherapy arm and 54% for the
control arm [HR 0.69 (95% CI: 0.52–0.92); p = 0.011],
with an absolute survival benefit of 15% for patients
receiving chemotherapy. Subgroup analyses according
to stratification factors did not demonstrate significant
improvement in survival for patients with disease stage
IB receiving chemotherapy compared to the observation
group (p = 0.79). In the planned stratified Cox regression analysis, significant factors associated with improved
survival included chemotherapy as compared with observation (HR for the difference in survival, 0.67; 95% CI:
0.51–0.89; p = 0.006) and squamous histology as compared with adenocarcinomas (p = 0.005). Despite the
positive results, compliance with chemotherapy was
relatively low, with only 65% of the patients receiving
three or four cycles. Moreover, 77% had at least one
dose reduction or omission and 55% required one or
more dose delays. Nineteen percent of the patients who
received at least one dose required hospitalization for
medical problems related to toxicity. There were two
chemotherapy-related deaths. Furthermore, treatment
was associated with a significant negative impact on
quality of life.20
A retrospective analysis evaluated the influence of age
on survival, chemotherapy delivery, and toxicity in the
BR.10 trial.21 Overall survival for patients older than
65 years was better with chemotherapy versus observation [HR 0.61 (CI: 0.38–0.98); p = 0.04) despite the fact
that older patients received significantly fewer doses of
cisplatin and vinorelbine. Fewer elderly patients completed treatment and more refused treatment compared
to the young (p = 0.03). The authors concluded that
patients older than 75 years require further study.
Cancer and Leukemia Group B (CALGB) 9633 trial
This trial randomly assigned 344 patients with completely resected stage IB (T2N0) NSCLC to four cycles
of paclitaxel/carboplatin chemotherapy (paclitaxel 200
mg/m2/carboplatin AUC 6) versus surgery alone. Like
the NCIC CTG study, there was no planned thoracic
radiotherapy. In this trial compliance with chemotherapy was high, with 85% of the patients receiving three
or four treatment cycles. In the first report of the trial,22
after a median follow-up time of 34 months, 71% of
patients who had received chemotherapy were alive
compared with 59% of those who had surgery alone
152 Textbook of Lung Cancer
[HR 0.62 (95% CI: 0.41–0.95); p = 0.028]. Overall survival at four years and failure-free survival also favored
the chemotherapy group. However, an updated analysis after 54 months of median follow-up showed a nonsignificant trend towards improvement of overall
survival by the addition of chemotherapy [HR 0.80
(90% CI: 0.60–1.07); p = 0.1]. A significant prolongation in DFS favoring adjuvant chemotherapy was still
present [HR 0.74 (90% two-sided CI: 0.57–0.96); p =
0.027].23 It should be noted though that the trial does
not have adequate power to detect small differences in
overall survival that may be clinically significant.
Adjuvant Navelbine International Trialists
Association (ANITA) trial
Patients participating in the ANITA trial were required
to have completely resected, stage IB–IIIA NSCLC. This
trial randomized 840 patients to postoperative chemotherapy (four cycles of cisplatin 100 mg/m2 every
4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly)
or observation only.24 The five-year survival rates favored
the chemotherapy arm; 51.2% vs 42.6% of the patients
were alive in the chemotherapy and the control group,
respectively [HR 0.79 (95% CI: 0.66–0.95); p = 0.013]. In
a subset analysis, chemotherapy significantly improved
survival in stages II and IIIA, but not in stage IB.
ANITA confirmed the results of the NCIC and CALGB
trials in a less selected population (disease stage IB–IIIA)
observed for a longer follow-up period (>70 months).
However, in this trial significant chemotherapy-related
toxicity was also reported, with 84.6% and 12.5% of
the patients experiencing grade 3–4 neutropenia and
febrile neutropenia, respectively. The median percentage of chemotherapy dose delivered was only 56% and
76% for vinorelbine and cisplatin, respectively.
Recent meta-analyses
Eleven randomized controlled trials including a total of
5716 patients reported after the 1995 meta-analysis were
reviewed in an abstracted-data-based meta-analysis.25
In this analysis, hazard ratio estimates suggested that
adjuvant chemotherapy yielded a significant survival
advantage over surgery alone [HR 0.872 (95% CI: 0.805–
0.944); p = 0.001]. In a subgroup analysis, cisplatinbased chemotherapy regimens (3786 patients) showed
consistent results, with the HR estimates in most trials
favoring adjuvant chemotherapy (HR 0.891 (95% CI:
0.815–0.975); p = 0.012). In addition, single-agent UFT
therapy (1751 patients) resulted in a significant survival
benefit, with an HR of 0.799 (95% CI: 0.668–0.957;
p = 0.015).
A second meta-analysis based on abstracted data from
19 randomized adjuvant trials that enrolled 7200 patients
was reported by Sedrakyan et al.26 This meta-analysis
added summary data from seven trials and approximately 5000 patients to information provided by the
1995 meta-analysis.12 An 11% reduction in the mortality was reported for cisplatin-based regimens and 17%
for UFT treatment, as compared to surgery alone. It
should be noted that neither meta-analysis included the
newer trials that reported substantial benefits associated with adjuvant chemotherapy.19,22,24
A third meta-analysis pooled individual patient data
from the five largest trials (ALPI, ANITA, BLT, IALT, and
JBR10) of cisplatin-based chemotherapy in completely
resected patients conducted after the 1995 meta-analysis.27 With a median follow-up of 5.1 years the overall
HR of death was 0.89 (95% CI: 0.82–0.96; p <0.005),
corresponding to a five-year absolute benefit of 4.2% by
the addition of chemotherapy. The benefit varied with
stage, with the HR for stage IA 1.41 (95% CI: 0.96–2.09),
stage IB 0.93 (95% CI: 0.78–1.10), stage II 0.83 (95%
CI: 0.73–0.95), and stage III 0.83 (95% CI: 0.73–0.95).
The recent data from randomized adjuvant trials
have changed the standard of care for patients with
completely resected NSCLC. Consistent reductions in
the risk of death have been observed with cisplatinbased adjuvant chemotherapy. Subset analysis of the
large randomized trials,16,19,24 as well as the recent metaanalysis,27 suggests that the benefit is greatest in patients
with stages II and III. The role of chemotherapy in earlier disease stages and the optimal drug to combine
with cisplatin remain to be determined. Advantages in
disease-free survival and three-year survival might support the consideration of adjuvant paclitaxel/carboplatin in stage IB NSCLC. Up to now there are no
confirmatory data on the efficacy of UFT in the adjuvant treatment of NSCLC outside of Japan.
Considering the significant chemotherapy-associated
toxicity, one might suggest that this treatment should
be restricted to those patients with good performance
status, rapid recovery from surgery, and no significant
comorbidity. No prospective data are available on the
postsurgical management of elderly patients with
resected disease.
PREOPERATIVE (NEOADJUVANT) CHEMOTHERAPY
Induction chemotherapy before surgery
Preoperative chemotherapy presents several theoretic
advantages, including reduction of tumor volume that
Treatment of NSCLC: chemotherapy 153
could enhance local control, evaluation of response to
chemotherapy, early eradication of micrometastatic disease, and higher patient compliance compared to postoperative chemotherapy.
Phase II studies evaluating the role of preoperative
chemotherapy in patients with stage IIIA disease demonstrated an average response rate of 60%, with 55% of
patients undergoing thoracotomy and 49% having
complete resections; median survival time was approximately 16 months, and five-year survival rate was 30%
in chemoresponsive patients, with 50% of patients
achieving a pathologic complete response.5 Phase III
trails of neoadjuvant therapy in NSCLC, are presented
in Table 10.3.2. In a randomized trial by Rosell et al,
patients with stage IIIA NSCLC were randomly assigned
to undergo either immediate surgery, or surgery preceded by three cycles of chemotherapy with mitomycin
(6 mg/m2), ifosfamide (3 g/m2), and cisplatin (50 mg/m2).29
In another trial, patients with stage IIIA NSCLC
were randomly allocated to three cycles of preoperative
chemotherapy with cyclophosphamide (500 mg/m2,
day 1), etoposide (100 mg/m2, days 1 to 3), and cisplatin (100 mg/m2, day 1) or to upfront surgery alone.30 In
both studies, radiotherapy was administered in over
half of the patients. An interim analysis revealed a statistically significant difference in favor of the induction
chemotherapy arm in both studies, resulting in a termination of the accrual after only 60 patients (out of the
120 initially planned) had been enrolled. The observed
survival differences also remained highly significant in
subsequent analyses after almost seven years of followup.31,32 It should be noted that the small number of
patients included in these studies weakens the power of
their observations. Furthermore, the trial by Rosell et
al29 has been criticised because of the poor survival outcomes of the control arm.
One study randomly assigned patients with stage
IIIA (T0–3) or T3 (N0–1), or locally treatable stage IIIB
(T4, N3), NSCLC to receive neoadjuvant docetaxel
(100 mg/m2 every three weeks) (n = 134) or no chemotherapy (n = 140) before surgery or curative-intention
radiotherapy.33 Median survival was 14.8 months in the
docetaxel group and 12.6 months in the control group
(p = non-significant). Median times to disease progression were 9.0 months (docetaxel arm) and 7.6 months
(control arm).
Preoperative chemotherapy might also have a role in
earlier disease stages. In a multicenter phase III study
conducted by the French Thoracic Cooperative Group,
355 patients with clinical IB–IIIA disease were randomly
assigned to receive two cycles of induction mitomycin
(6 mg/m2, day 1), ifosfamide (1.5 g/m2, days 1 to 3), and
cisplatin (30 mg/m2, days 1 to 3) followed by surgery
and two postoperative cycles or surgery alone.34 Patients
with pT3 or pN2 received postoperative radiation. The
overall response to induction chemotherapy was 64%.
Although median survival favored the chemotherapy
arm, the difference failed to reach statistical significance
(37 months for the chemotherapy arm vs 26 months
for the surgery alone arm, p = 0.15). Subgroup analysis
Table 10.3.2 Phase III trials of neoadjuvant chemotherapy in NSCLC
Trial
No of patients
Disease stages
included
CT regimen/
control arm
Median survival
(months)
p
CEP ×3→surgery→
CEP ×3 vs surgery
PIM→surgery→RT
vs surgery→RT
PE ×2→surgery→
PE ×4 vs surgery
MIP ×2 → surgery →
MIP ×2 vs surgery
64 vs 11
0.008
26 vs 8
<0.001
28.7 vs 15.6
NS
37 vs 26
NS
14.8 vs 12.6
NS
42 vs 37
NS
MD Anderson30
60
IIIA (N2), some IIIB
Spain29
60
IIIA (N2)
NCI36
27
IIIA (N2) biopsy
French Thoracic
Cooperative
Group34
Mattson et al33
355
IB–IIIA
274
III
Pisters et al35
354
IIA–IIIA
T×3→surgery vs
surgery
Ta/Carbo ×3→
surgery vs surgery
C: cyclophosphamide; E: etoposide; P: cisplatin; I: ifosphamide; M: mitomycin; T: docetaxel; Ta: paclitaxel; Carbo: carboplatin, NS: non-significant.
154 Textbook of Lung Cancer
revealed a significant benefit in patients with N0–1 disease
[relative risk (RR) 0.68 (95% CI: 0.49–0.96); p = 0.027],
but not for the group with N2 disease [RR 1.04 (95%
CI: 0.68–1.60); p = 0.85].
Finally, a recently reported phase III study evaluated
neoadjuvant chemotherapy in patients with clinical
stage T2N0, T1–2N1, and T3N0–1 (excluding superior
sulcus tumors). Patients were stratified by clinical stage
(IB/IIA vs IIB/IIIA) and were randomized to receive
either paclitaxel and carboplatin (every three weeks for
three cycles) plus surgery or surgery alone.35 The primary endpoint was a 33% increase in overall survival
over the expected 2.7 years median for surgery alone.
After a median follow-up of 28 months during which
354 patients had been enrolled, the trial was prematurely terminated due to the positive data coming from
the adjuvant chemotherapy trials. Median progressionfree survival was 29 months for the neoadjuvant group
and 20 months for the surgery only group [HR 0.85
(CI: 0.63–1.14); p = 0.26]. Median overall survival was
42 months and 37 months, for the preoperative and surgery only arms, respectively [HR 0.88 (CI: 0.63–1.23);
p = 0.47].
In general, preoperative chemotherapy induces a high
rate of objective responses. Further investigation is
required to select the ideal regimen in terms of efficacy
and safety and to identify subgroups of patients and/
or predictive factors associated with greater benefit.
Randomized trials evaluating the comparative efficacy
of adjuvant and neoadjuvant chemotherapy are also
warranted.
Induction chemoradiotherapy before surgery
The concurrent administration of chemotherapy with
radiotherapy has been used before surgery in patients
with stage III disease in an effort to improve survival
outcomes. Although surgery might be associated with
higher morbidity and mortality after preoperative treatment, the feasibility of this approach has been demonstrated in several phase II studies.
In the North American Intergroup trial 0139 (INT
0139), 429 patients with T1–3 pN2 disease deemed
resectable at presentation were randomized either to
induction concurrent chemoradiotherapy with 45 Gy
and cisplatin (50 mg/m2 on days 1, 8, 29, and 35) and
etoposide (50 mg/m2 days 1 to 5 and 29 to 33) followed
by surgery (for non-progressors) or to definitive chemoradiation (with cispaltin and etoposide) to 61 Gy.37 Both
groups received consolidation chemotherapy with two
cycles of cisplatin and etoposide. Although progressionfree survival was significantly prolonged in the surgery
arm (14.0 vs 11.7 months; p = 0.02), overall survival was
not different (22 months) between arms. There were
more early non-cancer deaths on the surgical arm, but
overall survival curves crossed so that, by year 3, the
overall survival favored the surgery arm (38% vs 33%).
Long-term follow-up of the INT 0139 confirmed the
superior progression-free survival and showed a trend
for superior five-year overall survival for the trimodality
therapy.38 In a subgroup analysis, patients who achieved
pathologic N0 disease had a favorable long-term survival. Moreover, patients who underwent lobectomy
had superior survival over patients receiving definitive
chemoradiotherapy (p = 0.002).
The German Lung Cancer Cooperative Group randomly assigned 558 patients with selected pathologic
stages IIIA and IIIB NSCLC subsets to chemotherapy
with cisplatin/etoposide for three cycles followed by
hyperfractionated radiotherapy to 45 Gy concurrently
with carboplatin/vindesine and then surgery or chemotherapy with cisplatin/etoposide for three cycles followed
by surgery and then radiotherapy to 54 Gy.39 Both
groups received additional radiotherapy if a complete
resection was not achieved. Of note, both arms received
radiotherapy but the timing and fractionation, as well
as the chemotherapy drugs, differed. No significant differences were observed regarding the three-year progression-free survival (18% vs 20%, p = non-significant)
and the three-year survival (26% vs 25%, p = non-significant). This study has been criticized because of the
low resection rates, and the inclusion of radiotherapy in
both arms.
The role of aggressive induction therapies in the
management of resectable stage III disease remains to
be determined. It seems that in N2 disease, patients
who achieve significant downstaging experience prolonged survival. However, the optimal management of
these patients with surgery versus definitive chemoradiation needs further clarification. The role of chemoradiation before surgery in earlier disease stages needs
to be identified.
CHEMOTHERAPY FOR LOCALLY ADVANCED
UNRESECTABLE (IIIA AND IIIB) NSCLC
Up to one-third of patients with NSCLC present with
disease that remains localized to the thorax, but is
considered too extensive for surgical treatment (stages
IIIA and IIIB). Historically, radiotherapy (RT) represented the standard of care for these patients.40 However, results were disappointing with five-year survival
Treatment of NSCLC: chemotherapy 155
rates of less than 5%, due to the high incidence of
both locoregional relapses and distant metastases. This
observation led to efforts for the development of more
active, multimodality therapies that incorporate
chemotherapy.
Chemotherapy followed by radiotherapy
Several randomized phase III studies compared RT with
the bimodality therapy of induction chemotherapy, followed by RT. Generally, studies with larger sample size
incorporating more intensive chemotherapeutic regimens demonstrated a significant survival benefit in
favor of the combined modality treatment (Table 10.3.3).
It was also suggested that the main impact of systemic
chemotherapy was a reduction in the rate of distant
relapses.41 The positive results of these randomized trials have been confirmed by two meta-analyses.12,42
Concurrent chemoradiotherapy
The simultaneous administration of chemotherapy and
RT provides the advantages of early administration of
systemic treatment as well as the additional theoretic
benefit of increasing locoregional control. Furthermore,
concurrent chemoradiotherapy offers a reduction in the
treatment time compared to the sequential approach.
In the clinical setting, concomitant chemoradiotherapy is associated with significant toxicities including
esophagitis, risk of radiation pneumonitis, and increased
myelosuppression.
The results of several phase II studies provided preliminary evidence supporting the feasibility of the addition of chemotherapy to RT.45 Subsequent randomized
trials, employing either the concurrent or the sequential
mode, compared the combined therapy with RT alone
(Table 10.3.4). Several trials demonstrated a significant
Table 10.3.3 Selected phase III trials comparing sequential chemo-RT vs RT only, in patients with advanced NSCLC
Trial
n
Stage
Regimen
Survival (median)
CALGB 843343
155
III
PV→RT (60 Gy) vs RT (60 Gy)
RTOG, ECOG,
and SWOG44
452
III
PV→RT (60 Gy) vs RT (60 Gy)
vs HFx-RT (69.6 Gy)
CMT + RT 13.8 months; RT 9.7
months (p = 0.0066)
3-year survival: CMT + RT 23%;
RT 10% (p = 0.012)
7-year survival: CMT + RT 13%;
RT 6% (p = 0.012)
Median survival: CMT + RT 13.2
months (p = 0.04 vs RT); RT 11.4
months; HFx-RT 12 months (NS)
3-year survival; CMT+RT 17%; RT
11%; HFx-RT 14%
5-year survival: CMT+RT 8%
(p = 0.04 vs RT); RT 5%; HFx-RT
6% (NS)
P: cisplatin; V: vindesine; HFx-RT: hyperfractionated RT; CMT: chemotherapy.
Table 10.3.4 Randomized phase III trials comparing combined chemoradiotherapy versus radiotherapy alone
Trial
n
Regimen
Survival (median)
Le Chevalier46
Schaake-Koning47
354
331
Soresi48
Morton49
Blanke50
95
121
215
PLVC + RT (65 Gy) vs RT (65 Gy)
P (weekly) + RT vs P
(daily) + RT vs RT
P + RT (50 Gy) vs RT (50 Gy)
MACCu + RT vs RT
P + RT ×3 cycles vs RT
2-year survival: 21% vs 14% (p = 0.02)
2-year survival: 19% vs 26% vs 13%
(p = 0.009; daily P + RT vs RT)
16 months vs 11 months; p = NS
2-year survival: 21% vs 16%; p = NS
43 weeks vs 46 weeks; p = 0.394
P: cisplatin; V: vindesine; L: lomustine; C: cyclophosphamide; M: methotrexate; A: doxorubicin; Cu: CCNU; NS: non-significant.
156 Textbook of Lung Cancer
survival benefit in favor of the combined modality
treatment,46,47 whereas others did not.48–50 Two large
meta-analyses suggested a small, but statistically significant improvement in survival with the combinedmodality regimens. In the meta-analysis by Pritchard
and Anthony, a significant decrease in the relative risk
of death with combined therapy was shown at both
one and three years in patients with unresectable stage
III disease.51 Similarly, Marino et al reported a 24%
reduction in the risk of death at one year and a 30%
reduction at two years for combined cisplatin-based
chemotherapy and radiotherapy.42
Definitive testing of concurrent chemoradiotherapy
versus the sequential approach in the phase III setting
has been also performed (Table 10.3.5). The concurrent administration of platinum-based chemotherapy
with radiotherapy demonstrated a modest although statistically significant survival benefit compared with the
sequential administration. Median survival was 15–17
months in the concurrent arm versus 12.9–14.6 months
in the sequential arms.52–55 It is interesting that the two
largest randomized trials have demonstrated remarkably similar results.52,54
The West Japan Lung Cancer Group randomly assigned
320 patients to a combination of cisplatin (80 mg/m2,
days 1 and 29), vindesine (3 mg/m2, days 1, 8, 29, and
36), and mitomycin (8 mg/m2, days 1 and 29) given
concurrently with 56 Gy of radiotherapy, split into two
28 Gy courses separated by 10 days, versus the same
chemotherapy given as induction followed by 56 Gy of
continuous radiotherapy.52 The concurrent approach
was significantly superior (p = 0.03998), with a median
survival of 16.6 versus 13.3 months and five-year survival rates of 15.8% versus 8.9%, respectively.
RTOG 9410 evaluated the use of cisplatin (100 mg/m2,
days 1 and 29) and vinblastine (5 mg/m2 weekly for five
Table 10.3.5 Phase III trials comparing sequential versus concurrent chemoradiotherapy
Trial
n
Regimen
Survival (median)
p
West Japan52
320
P/Vin/M + RT
(56 Gy; split course) vs
P/Vin/M → RT (56 Gy;
continuous)
Concurrent 16.6 months;
sequential 13.3 months
0.03998
Two-year survival: concurrent
34.6%; sequential 27.4%
Five-year survival: concurrent
15.8%; sequential 8.9%
Concurrent 15 months;
sequential 13.8 months
Two-year survival: concurrent
35%; sequential 23%
Sequential 17 months;
concurrent (daily RT)
14.6 months; concurrent
(HFx-RT) 15.6 months
Four-year survival: sequential
12%; concurrent (daily RT)
21%; concurrent (HFx-RT)
17%
Concurrent 16.6 months;
sequential 12.9 months
Three-year survival:
concurrent 18.6%;
sequential 9.5%
NR
GLOT-GFPC57
RTOG 94–1054
Czech Republic55
212
610
102
PE + RT (66 Gy) → PV
vs PV → RT (66 Gy)
PVi → RT (60 Gy) vs
PVi + RT (60 Gy) vs
PE + HFx-RT (69.6 Gy)
PV + RT (60 Gy) vs
PV → RT (60 Gy)
P: cisplatin; Vin: vindesine; M: mitomycin; E: etoposide; V: vinorelbine; Vi: vinblastine; HFx-RT: hyperfractionated RT; NS: non-significant;
NR: not reported.
NR
NS
NS
0.046
0.046
0.023
NR
Treatment of NSCLC: chemotherapy 157
doses) followed by once-daily radiotherapy (60 Gy) versus cisplatin and vinblastine at the same doses given concurrently with the same radiotherapy, or cisplatin (50
mg/m2, days 1, 8, 29, and 36) and oral etoposide (50 mg
twice daily for 10 doses on weeks 1, 2, 5, and 6) given
concurrently with hyperfractionated radiotherapy (69.6
Gy given in 1.2 Gy fractions twice daily). In this trial 610
patients with unresectable NSCLC were randomly
assigned to one of three arms. Both the median survival
and the four-year survival were significantly better in the
concurrent daily radiotherapy arm when compared with
the sequential arm (17 vs 14.6 months; p = 0.038) and
(21% vs 12%), respectively. The hyperfractionated radiotherapy arm showed a median survival of 15.6 months,
that did not reach statistical significance compared with
the sequential treatment.54 Movsas et al reported on the
quality adjusted time without symptoms of toxicity analysis of RTOG 9410.56 Although reversible non-hematologic toxicity was higher in the sequential arm, the
overall mean toxicity was highest in the sequential arm,
further supporting the use of concurrent chemoradiation
in locally advanced unresectable disease.
Multiple efforts in the phase I/II setting focused on
the incorporation of the newer chemotherapeutic agents
such as paclitaxel, gemcitabine, vinorelbine, and topoisomerase I inhibitors into chemoradiotherapy treatment. In general, acceptable toxicity and high response
rates have been demonstrated. In a randomized phase
III trial by Fournel et al, a trend towards better survival
was observed in favor of the concurrent approach.57
However, chemotherapy was different between the two
arms. In the sequential arm, cisplatin (120 mg/m2 days
1, 29, and 57) and vinorelbine (30 mg/m2 weekly for
12 doses) was followed by thoracic irradiation (66 Gy in
33 fractions). In the concurrent arm, cisplatin and etoposide for two cycles were given with the same radiation
dose. Patients received consolidation chemotherapy
with cisplatin (80 mg/m2 on days 78 and 106), plus
vinorelbine (30 mg/m2 weekly for eight cycles). The
median survival was 13.8 months for the sequential and
15 months for the concurrent arm (p = non-significant).
The two-year survival showed a trend in favor of concurrent chemoradiotherapy (35% vs 23% for sequential),
with updated results awaited.
Induction chemotherapy followed by concurrent
chemoradiotherapy
The potential advantage of using both induction and
concurrent modality treatments lies in the enhancement
of both the exposure to systemically active doses of chemotherapy and locoregional control of the disease.
Two hundred and eighty-three patients with inoperable stage III NSCLC were entered into a randomized trial
by the Cancer and Leukemia Group B (CALGB) and the
Eastern Cooperative Oncology Group.58 All received
induction chemotherapy with vinblastine and cisplatin
for five weeks followed by radiation therapy or radiotherapy concomitantly with weekly carboplatin. There
was no difference with respect to overall survival (13%
with carboplatin and 10% with radiotherapy alone) at
four years.
CALGB also conducted a trial which randomly
assigned 303 patients with stage IIIA/B disease to receive
induction paclitaxel (200 mg/m2) and carboplatin (AUC
6) for two cycles, followed by either radiotherapy alone
(60 Gy) or the same radiotherapy concurrently with
weekly paclitaxel (60 mg/m2). Median survival was
19.2 months versus 14.6 months in favor of the concurrent chemoradiotherapy arm, but the difference did not
reach statistical significance.59
Another CALGB trial randomly assigned 366 patients
to either induction paclitaxel (200 mg/m2) and carboplatin (AUC 6) followed by chemoradiotherapy [66 Gy
concurrently with weekly carboplatin (AUC 2) and
paclitaxel (50 mg/m2)] versus immediate chemoradiotherapy alone. Both median and one-year survival were
similar between the two arms (14.0 months, 48% versus
11.4 months, 58%; p = 0.154).60
The role of consolidation therapy after concurrent
chemoradiation has also been investigated. Southwest
Oncology Group (SWOG) reported on a phase II study
of concurrent chemoradiation with full doses of cisplatin (50 mg/m2, days 1, 8, 29, and 36) and etoposide
(50 mg/m2, days 1 through 5, and days 29 through 33)
followed by three cycles of docetaxel single agent (75 to
100 mg/m2). In this group of patients with pathologically documented stage IIIB disease, a promising median
survival of 27 months was achieved.61 However, only
59% of the 83 relevant patients received all three cycles
of docetaxel, illustrating the difficulties of consolidation
chemotherapy after definitive chemoradiation.
In a randomized phase II non-comparative study by
Belani et al, patients with unresected stage IIIA and IIIB
disease received two cycles of induction paclitaxel and
carboplatin followed by sequential RT (n = 91), or two
cycles of induction paclitaxel and carboplatin followed
by weekly paclitaxel and carboplatin with concurrent
RT (n = 74), or weekly paclitaxel and carboplatin plus
concurrent RT followed by two cycles of paclitaxel and
carboplatin (n = 92).62 The three arms were to be compared with a historical control using the sequential chemoradiotherapy arm of the RTOG 8808 trial, for which the
158 Textbook of Lung Cancer
available reported median survival time was 13.7 months.63
Median survival times for the sequential and concurrent arms were 13 and 12.7 months, respectively. The
concurrent/consolidation arm was associated with the
best outcome (median overall survival 16.3 months,
p = 0.34) and greater toxicity rates.
Currently, concomitant chemoradiotherapy is considered the standard therapy of unresectable stage III
NSCLC. However, it applies only to patients with good
performance status. For the present, there is no value of
adding induction chemotherapy with currently established agents. The role of consolidation chemotherapy
remains to be confirmed in randomized trials.
CHEMOTHERAPY FOR PATIENTS WITH
ADVANCED NSCLC
Patients with advanced NSCLC (stage IIIB with pleural
or pericardial effusion or stage IV), treated with best
supportive care (BSC) alone, have a median survival of
4–5 months and a one-year survival of approximately
10%.64 Throughout the 1970s and 1980s, combination
chemotherapy (usually cisplatin-based) resulted in objective responses rates in 20 to 30% of lung cancer patients,
but median survival was only six to eight months, and
few patients survived longer than one year. The most
frequently used regimens were the combinations of cisplatin with etoposide, vindesine, or vinblastine. Several
randomized trials, addressing the question of whether
the benefit of chemotherapy outweighed the cost of
toxicity over best supportive care alone, demonstrated
a small, but statistically significant survival benefit for
patients receiving chemotherapy.5 Due to limitations in
most of these studies, meta-analyses were performed to
address the same question.42,65,66 In the largest of these
meta-analyses, alkylating agents were associated with a
detrimental effect on survival, while cisplatin-based
chemotherapy conferred a 27% reduction in the risk of
death, and a 10% absolute increase in one-year survival
rates.12 Thus systemic cisplatin-based chemotherapy
has since been considered as standard care in most
patients with advanced NSCLC.67
First-line therapy
Platinum-based chemotherapy
Between 1981 and 1991, several randomized trials,
with more than 1900 patients enrolled, evaluated a wide
range of first-generation cisplatin-based chemotherapy
regimens.68–71 No significant differences emerged between
regimens, or between studies.
Le Chevalier et al were the first to compare the combination of a second-generation over a first-generation
cisplatin-based doublet.72 In this trial, patients treated
with cisplatin/vinorelbine had significantly longer median
survival compared to those treated with cisplatin/
vindesine (40 weeks vs 32 weeks; p = 0.04). Moreover,
this study demonstrated that cisplatin was necessary
since a cisplatin/vinorelbine combination was superior
to vinorelbine alone (40 weeks vs 31 weeks; p = 0.01)
(see Table 10.3.6.). Further randomized trials addressing
the same question demonstrated that second-generation
regimens are generally associated with improved efficacy,
toxicity, quality of life, or a combination of these endpoints, although statistically significant survival gain was
not uniformly found.
More recently, second-generation cisplatin-based
regimens have been more widely used. Direct comparison of these regimens in randomized phase III trials
failed to demonstrate a particular combination to be
clearly superior for NSCLC. The results of appropriately
sized trials comparing second-generation platinumbased doublets are presented in Table 10.3.7.
ECOG 1594, one of the largest randomized trials,
assigned a total of 1207 patients with advanced NSCLC
to a reference regimen of cisplatin and paclitaxel or to
one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and
paclitaxel. Patients were stratified according to ECOG
performance status (0 or 1 vs 2), weight loss in the previous six months (<5% vs ≥5%), the stage of disease (IIIB
vs IV or recurrent disease), and the presence or absence
of brain metastases. In this study no difference was
observed in terms of response rate or overall survival
between the different chemotherapy regimens; response
rates ranged from 17 to 22% and median survival from
7.4 to 8.1 months. The cisplatin/gemcitabine arm showed
significantly longer time to tumor progression when
compared with the reference arm (4.2 vs 3.4 months,
p = 0.001). Differences in the toxicity profiles of each
regimen were identified, with cisplatin/gemcitabine causing more thrombocytopenia, cisplatin/docetaxel causing more neutropenia, and the carboplatin/paclitaxel
arm causing the lowest rate of potentially life-threatening
adverse events.81
TAX 326 was another large trial that randomized
1218 patients to one of three treatment groups: docetaxel/
cisplatin (DC regimen), docetaxel/carboplatin (DCb
regimen), or the control arm of vinorelbine/cisplatin (VC
regimen). Patients treated with DC had a median survival of 11.3 versus 10.1 months for VC-treated patients
(p = 0.044). The two-year survival rate was 21% and
Treatment of NSCLC: chemotherapy 159
Table 10.3.6 Randomized trials of cisplatin plus a new agent versus cisplatin plus an old agent
Trial
Therapy
Le Chevalier72 V/P
Vi/P
Bonomi73
Ta (low)/Pa
Ta (high)/P
E/P
Giaccone74
Ta/P
Ten/P
Cardenal75
G/P
E/P
Niho76
CPT/P
Vi/P
Negoro77
CPT/P
Vi/P
Kubota78
T/P
Vi/P
No of patients
206
200
198
201
200
166
166
68
67
100
103
129
122
151
151
Odds ratio (%)
Median survival (weeks)
30
19
25.3
27.7
12.4
28
41
41
22
29
22
44
32
37
21
40
32
41.2
43.3
32.9
42.9
42.0
37.7
30.3
45
50
50
46
49.3
41.9
One-year survival (%)
40
32
37.4
40.3
32
41
43
26
32
43
48
46
38
48
43
p
0.04
0.048b
NS
NS
NS
NSc
NS
a
Paclitaxel (low): 135 mg/m2 intravenously over 24 hours; paclitaxel (high): 175 mg/m2 intravenously over 24 hours plus granulocyte colony-stimulating
factor.
b
Comparing the two paclitaxel groups combined with the etoposide/cisplatin group; other comparisons were not significant.
c
Survival differences were significant in the stage IV subset.
P: cisplatin; Vin: vindesine; E: etoposide; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; Ten: Teniposide; G: gemcitabine; T: docetaxel; Vi: vindesine;
CPT: irinotecan; NS: non-significant; NR: not reported.
Table 10.3.7 Selected phase III trials comparing second-generation platinum-based doublets
Trial
n
Regimen
Median survival (months)
p
SWOG 950979
ILCSG80
ECOG 159481
TAX 32682
408
607
1207
1218
P/V vs Carbo/Ta
Carbo/Ta vs P/V vs P/G
P/Ta vs P/G vs P/T vs Carbo/Ta
P/V vs P/T vs Carbo/T
8.0 vs 8.0
9.9 vs 9.5 vs 9.8
7.8 vs 8.1 vs 7.4 vs 8.1
10.1 vs 11.3 vs 9.4
NS
NS
NS
0.04a
NSb
a
P/V vs P/T, p = 0.04 in favor of P/T.
P/V vs Carbo/T, p = NS.
P: cisplatin; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; G: gemcitabine; T: docetaxel; Vi: vindesine; CPT: irinotecan; NS: non-significant;
NR: not reported.
b
14% for DC and VC, respectively. Overall response rate
was 31.6% for DC and 24.5% for VC (p = 0.029).
Median survival (9.4 vs 9.9 months, p = 0.657) and
objective response rate (23.9% vs 24.5%) were similar
for patients treated with DCb and VC, respectively. The
incidence of neutropenia, thrombocytopenia, infection,
and febrile neutropenia was similar with all three regimens. Patients treated with either docetaxel regimen
had a consistently improved quality of life compared to
those treated with VC.82
Non-cisplatin-containing chemotherapy
Cisplatin-based chemotherapy is associated with considerable cisplatin-related toxicity.83 Thus, nausea and
emesis are often severe and delayed, whereas neurotoxicity, renal toxicity, and ototoxicity are dose-related
and difficult to handle. Cisplatin administration requires
additional hydration that is intolerable to a significant
proportion of NSCLC patients due to old age and/or
concomitant cardiac or cardiopulmonary diseases.
Additionally, a prolonged hospital stay is mandatory,
160 Textbook of Lung Cancer
critical from the convenience as well as the economic
aspects.84,85
Cisplatin versus carboplatin
The substitution of cisplatin for carboplatin has been
employed as a means to overcome cisplatin-related incovenience. Several randomized trials have compared cisplatin with carboplatin doublets.82,86,87 In a trial by Rosell
et al, 618 patients were randomized to receive paclitaxel in combination with either cisplatin or carboplatin.
The study was designed to demonstrate a non-inferior
response rate with carboplatin.This was the only trial to
demonstrate a statistically significant improvement
in overall survival in favor of the cisplatin arm (9.8 vs
9.2 months, p = 0.019).86
TAX 326, although not designed to directly compare
the 814 patients randomized to docetaxel/cisplatin and
docetaxel/carboplatin arms, demonstrated a statistically
significant improvement in survival for docetaxel/cisplatin compared to the control arm of cisplatin/vinorelbine. Cisplatin/vinorelbine itself resulted in numerically
superior survival outcomes compared to the carboplatin/docetaxel combination.82
Finally, a meta-analysis using abstracted data identified eight trials including 2948 patients that evaluated
the substitution of cisplatin for carboplatin. Cisplatinbased chemotherapy resulted in higher response rates
without any difference in overall survival [HR 1.050
(95% CI: 0.907–1.216); p = 0.515). Based on the above
data it is reasonable to conclude that cisplatin might be
slightly superior to carboplatin. Although this difference is slim, it might have an impact for earlier disease
stages. The choice of the compound to be used should
be made on a case to case basis and should be tailored
to the patient’s needs.88
Platinum versus non-platinum doublets
The development of the newer agents led to novel, effective non-platinum-containing chemotherapy regimens
and to the initiation of several randomized trials designed
to determine whether these regimens are comparable to
platinum-based combinations in terms of efficacy.89–95
In general, these trials did not demonstrate a statistically significant survival benefit in favor of patients
treated with platinum-based doublets (see Table 10.3.8).
In three trials, a trend towards better overall survival
was observed in patients treated with platinum-based
combinations.91,92,95 On the other hand, another study
demonstrated that the combination of vinorelbine and
gemcitabine was superior to vinorelbine plus carboplatin
Table 10.3.8 Platinum- versus non-platinum-based doublets
Author
Regimen
Georgoulias89
T/P
T/G
Ta/C
Ta/G
G/V
G/P
P/V
G/P
Ta/P
Ta/G
G/P
G/P/V
G/V → V/If
GVP
GV
V/P
T/G
Kosmidis90
Gridelli91
Smit92
Alberola93
Laack94
Georgoulias95
No of
patients
441
248
254
501
490
557
287
117
134
Response
rate (%)
Median TTP
(months)
32
31
28
35
25
}30
9.5
8
6.3
6.1
17 weeks
22 weeks
22 weeks
5.6
4.4
3.9
6.3
10
9.5
10.4
9.8
32 weeks
38 weeks
38 weeks
8.9
8.1
6.7
9.3
5.7
19.3
22.3
8.5
8
8.1
32.4 weeks
35.9 weeks
9.7
9
37
32
28
42
41
27
28.3
13
39.2
30
Median OS
(months)
p
One-year
survival (%)
NR
NS
0.32
0.08
NS
41.7
41.4
NR
32.6
35.5
26.5
38
NS
NS
0.96
5
P: cisplatin; V: vinorelbine; G: gemcitabine; T: docetaxel; If: Ifosfamide; Ta: paclitaxel; C: carboplatin; Epi: epirubicin; NR: not reported;
NS: non-significant; TTP: time to tumor progression; OS: overall survival.
34
27.5
33.6
34.3
40.8
Treatment of NSCLC: chemotherapy 161
in terms of response rate, progression-free survival,
overall survival, and clinical benefit.96
In most trials, non-platinum doublets were associated
with a more favorable toxicity profile.89,91,93–95 However,
in two of them no significant differences in terms of
toxicity were reported.90,92 Two trials evaluating the issue
of cost-effectiveness reported contradictory results,
with one study demonstrating superiority of platinumbased doublets,92 whereas in the other no difference
between the two arms was reported.90
It should be noted here that none of the above mentioned trials was adequately sized to test equivalence,
precluding safe conclusions regarding the comparative
activity of platinum versus non-platinum doublets.
A recently published meta-analysis reviewed 37 randomized phase II and III studies comparing a platinumbased regimen with the same regimen either without
cisplatin or with cisplatin replaced by a non-platinum
compound, in patients with advanced NSCLC.97 This
meta-analysis included a total of 7633 patients and
reported on the response rates, activity, and survival of
platinum- versus non-platinum-based chemotherapy.
A 62% increase in the odds ratio (OR) for response was
attributable to platinum-based therapy (p <0.0001).
When the analysis was restricted in trials that had combinations of the newer agents as the comparator, the
benefit was 17% in favor of platinum (14 trials including
3204 patients; p = 0.042).
Overall, the one-year survival rate was 34% and 29%
for the platinum- and non-platinum-containing regimens,
respectively (p = 0.0003). However, when platinumbased therapies were compared to combinations of the
newer agents, no statistically significant increase in oneyear survival was found (36% vs 35%, p = 0.17). When
the toxicity of platinum-based regimens was compared
with newer, non-platinum combinations, significantly
higher hematologic toxicity, nausea and vomiting, and
toxic death rate were observed, but no significant increase
in febrile neutropenia rate, neurotoxicity, or nephrotoxicity was reported.97
Accordingly, the current American Society of Clinical
Oncology (ASCO) guidelines make no distinction between
platinum-based and non-platinum doublets as the preferred first-line treatment in patients with advanced
NSCLC.98
Two drugs versus one drug
A third way to deal with the chemotherapy toxicity in
patients with advanced NSCLC is to use a single-agent
chemotherapy rather than combination treatments.
Several trials have compared a doublet versus a singleagent therapy (Table 10.3.9).
Most studies evaluated a platinum-based doublet
versus the corresponding non-platinum monotherapy,102–104,106,107 some tested a new drug versus a
platinum older drug combination,99,101 and others compared cisplatin monotherapy versus a platinum new
drug combination.84,85,105,108
In general, new single agents were shown to be
equally effective and less toxic than the old cisplatinbased doublets.99,101 However, most of the studies evaluating the newer agents over a platinum new drug
combination have clearly demonstrated a superiority
for the combination therapy.85,102,104,105 Similarly, most
of the studies comparing platinum agents to newer
platinum-based doublets demonstrated a superiority
for the combination therapy.105,108
Based on the above data, ASCO guidelines98 suggest
that two-drug combination chemotherapy remains the
standard first-line treatment of patients with advanced
NSCLC.
Triplets for the treatment of advanced NSCLC
Several randomized trials evaluated the potential role of
three-drug combinations as a means of improving survival outcomes in NSCLC. The most recent studies are
presented in Table 10.3.10. Although three drug combinations led to significantly higher response rates, they
failed to demonstrate any benefit in terms of time to
tumor progression and overall survival, while they were
associated with significantly higher toxicity.
Duration and timing of first-line therapy
The optimal duration of treatment in patients with
advanced NSCLC has also been evaluated in randomized trials. In a trial by Smith et al, 308 patients were
randomized to receive three or six cycles of mitomycinvinblastine and cisplatin.112 No survival difference was
observed between the two arms, while patients receiving six treatment cycles experienced significantly higher
toxicity. In a randomized trial by Socinski et al, 230
patients received the paclitaxel/cisplatin doublet for
either four cycles, or until disease progression.113 Upon
progression, all patients were treated with weekly paclitaxel. The median survival did not differ significantly
between the two arms (8.5 months for the ‘until progression’ group vs 6.7 for the ‘four cycles’ group, p = 0.63).
It is interesting to note that in the treat ‘until progression’ arm the median number of cycles administered was
four. Toxicity was higher in this arm due to the cumulative neuropathy. Accordingly, ASCO guidelines support the administration of no more than six cycles of
first-line chemotherapy. In non-responding patients
treatment should be stopped at four cycles.98
162 Textbook of Lung Cancer
Table 10.3.9 Randomized studies comparing single-agent versus combination therapy
Author
Regimen
Manegold99
G
P/E
P/Vin
P/CPT-11
CPT-11
G
P/Vin
P/Vin
P/V
V
G/C
G
Ta/P
Ta
P/G
P
P/Tir
P
T/P
T
Negoro100
Vansteenkiste101
Le Chevalier102
Sederholm103
Lilenbaum104
Sandler105
von Pawel85
Georgoulias106
No of patients
156
ORR (%)
17.2
7
31.7
43.7
20.5
20.2
20
19
30
14
30
12
30
16
30.4
11.1
27.5
13.7
36.5
21.7
398
169
612
229
586
522
446
319
Median TTP
(months)
4.2
3.7
NR
Median OS
(months)
p
NR
45.6 weeks
46 weeks
50 weeks
9.2
6.7
13.7
5.5
NR
8.0
9.2
7.2
6
11
4
9
8.5
NR
6.5
5.6
9.1
3.7
7.6
12.9 weeks 34.6 weeks
11.6 weeks 27.7 weeks
4.0
10.5
2.5
8
One-year
survival (%)
NR
NR
NS
38.3
41.8
0.13
0.01a
NS
0.023
0.004
0.0078
NS
22
19.3
NR
NR
36
31
39
28
33.9
22.5
44
43
a
P/V vs V.
G: gemcitabine; P: cisplatin; E: etoposide; Vin: vindesine; V: vinorelbine; C: carboplatin; T: docetaxel; Ta: paclitaxel; Tir: tirapazamine; NR: not reported;
NS: non-significant; ORR: overall response rate; TTP: time to tumor progression; OS: overall survival.
Table 10.3.10 Randomized trials comparing triplets versus doublets for the treatment of advanced NSCLC
Author
Regimen
Alberola93
P/G
P/G/V
G/V
G/V/P
P/G
M/I/P
Ca/G
M/I/P
M/Vin/P
P/V
P/G
P/G/V
Laack94
Crino109
Danson110
Comella111
No of patients
370
287
307
372
180
ORR (%)
Median survival (months)
42
41
13
28
38
26
30
33
9.3
8.2
8.3
7.5
8.6
9.6
8.5
8.7
25
30
47
8.1
9.7
11.8
p
NS
NS
NS
NS
NS
P: cisplatin; G: gemcitabine; V: vinorelbine; M: mitomycin; I: ifosfamide; Ca: carboplatin; Vin: vinblastine.
The optimal time for the patients to be started on
chemotherapy has not been studied in randomized trials. However, since chemotherapy clearly prolongs survival and patients with impaired performance status
(PS) demonstrate poor tolerance to chemotherapy, the
current recommendations suggest the initiation of treatment as soon as possible, prior to any deterioration of
patients’ PS.98
Treatment of NSCLC: chemotherapy 163
PATIENT POPULATIONS WITH SPECIAL
CONSIDERATIONS
Elderly populations
About 40% of patients diagnosed with NSCLC are aged
70 years or older. It is estimated that only 25% of elderly
patients finally receive chemotherapy.114 Elderly patients
were frequently excluded from large co-operative group
trials due to considerations for increased toxicity. However, in an analysis of the Statistics, Epidemiology, and
End Results (SEER) database, the efficacy of chemotherapy in the elderly is equivalent to that in younger
patients.115 Moreover, age has not been established as
an independent prognostic factor for survival.
The Elderly Lung Vinorelbine Italian Study (ELVIS)
was one of the first large prospective randomized trials to
evaluate the role of chemotherapy in elderly patients.116
A total of 161 patients 70 years of age or older were
randomized to receive vinorelbine (30mg/m2, days 1
and 8, every three weeks) or BSC. Overall survival was
significantly better in the vinorelbine arm (28 weeks
versus 21 weeks, p = 0.03) and quality of life was significantly improved with chemotherapy. The same group
of investigators subsequently conducted the Multicenter
Italian Lung Cancer in the Elderly Study (MILES),
designed to test whether the combination of vinorelbine and gemcitabine was superior to either single agent
alone.117 This trial, which enrolled 698 patients, failed
to demonstrate any difference in terms of response rate
or overall survival between arms. However, a smaller trial
(n = 120) that compared vinorelbine monotherapy to
the vinorelbine-gemcitabine combination reported a survival benefit in favor of the combination arm (median
overall survival 6.7 months vs 4.2 months, p <0.01).118
Currently, ASCO guidelines recommend single-agent
therapy for the treatment of elderly patients with
NSCLC.98
Patients with poor performance status
PS has been consistently identified as one of the most
important prognostic factors in patients with advanced
NSCLC.5 It has also been established that patients with
ECOG PS of 0–1 derive significant benefit from systemic chemotherapy, while patients with ECOG PS 3–4
should be offered palliative care.5 However, it is less
clear which is the optimal treatment of patients with PS 2.
Generally, these patients have short survival and are
anticipated to experience high toxicity rates when combination chemotherapy is considered.81,119,120 For the
present, most of the data regarding the management of
this particular patient population are mainly derived
from subgroup analysis of larger trials. It should be
noted though that PS 2 patients constitute only a small
proportion of patients enrolled in first-line treatment
trials, despite the fact that they account for 30–40% of
the total NSCLC population.
In an interim analyis of ECOG 1594 trial, PS 2 patients
experienced high rates of severe toxicity in all three
cisplatin-based doublets.81 However, patients treated in
the carboplatin/paclitaxel arm had acceptable toxicity
rates, suggesting that this regimen could be suitable for
further evaluation in this patient population.81 Subgroup analysis of PS 2 patients from a CALGB trial that
randomized patients to receive paclitaxel monotherapy
or a combination of carboplatin and paclitaxel demonstrated significantly superior survival and tolerable toxicity for patients treated with the combination.104
Until definitive data derived from trials focusing on
this particular group of patients emerge, single-agent
chemotherapy with the newer agents should be the preferred option for PS 2 patients.121 Carboplatin- or lowdose cisplatin-based chemotherapy might also be used.121
In any case, patient preferences, the existing co-morbidities, and the anticipated chemotherapy-related toxicity should be considered prior to the final decision.
SECOND-LINE THERAPY
The availability of new active regimens in the first-line
setting has prompted several investigators to consider
second-line therapy for patients with advanced NSCLC,
since a substantial percentage of patients maintain a
good PS upon recurrence. Initial studies employing the
newer agents either alone122,123 or in combination124,125
showed significant activity in pretreated patients with
advanced NSCLC. However, most of these studies were
small, and many did not report details on prior treatment or patient characteristics; in addition, although all
the studies reported response rates, very few provided
median survival times or one-year survival rates, thus
precluding safe conclusions for the value of second-line
chemotherapy.
Docetaxel was the first agent to be tested as secondline therapy in randomized phase III trials. In a study
by Fossella et al, 373 patients pretreated with platinumcontaining regimens were randomized either to two
dose levels of docetaxel (75 mg/m2, or 100 mg/m2) or to
a single agent (ifosfamide or vinorelbine) control arm.126
Although no statistically significant difference was
observed in terms of overall survival between the three
arms, docetaxel 75 mg/m2 resulted in a longer time to
164 Textbook of Lung Cancer
progression and higher one-year survival rates compared
to the control arm (32% vs 19%, p = 0.025). Furthermore, about 30% of patients in the control group eventually received docetaxel, a fact that may have diminished
observable differences between the two arms. In a trial
by Shepherd et al, 204 patients with platinum refractory disease were randomized to receive docetaxel 100
mg/m2 or best supportive care alone.127 An interim
analysis that identified significant toxicity in the docetaxel arm led to the reduction of docetaxel dose to 75
mg/m2. The final analysis showed that, although the
response rate was only 7%, patients treated with docetaxel achieved a higher time to tumor progression (2.5
vs 1.6 months, p <0.001) and overall survival (7 vs
5 months, p = 0.047) compared to the control group. The
study by Shepherd et al established docetaxel as the standard comparator arm for subsequent randomized trials.
Based on the results of these studies, the FDA approved
docetaxel as second-line therapy in NSCLC.
A non-inferiority phase III study compared docetaxel
with pemetrexed, a multitargeted antifolate, as secondline therapy in NSCLC.128 Five hundred and seventy-one
patients were randomized to receive docetaxel (75 mg/m2)
or pemetrexed (500 mg/m2) plus vitamin supplementation. No significant difference was observed in overall
(pemetrexed 8.3 months vs docetaxel 7.9 months) or
one-year survival (29.7% for both drugs). Furthermore,
neutropenia and febrile neutropenia were significantly
lower with pemetrexed. This trial led to the approval of
pemetrexed in the second-line treatment of NSCLC.
A weekly schedule of docetaxel was compared with
the classic every three weeks schedule in two randomized phase III trials.129,130 In the trial by Gridelli et al,129
comparable overall survival rates were reported (6.7 vs
5.8 months for the weekly arm) but the weekly schedule
was associated with better safety and quality of life profiles. In contrast, in the trial by Schuette et al,130 a trend
towards better survival was observed for patients in the
weekly arm (>8 months versus 5.8 months, p = 0.08).
Additional investigations in the field of second-line
therapy focused on the introduction of two-drug combinations in the second-line setting that generally resulted
in high toxicity rates without any survival benefit over
monotherapy.131
TARGETED THERAPIES IN ADVANCED NSCLC
Although chemotherapy has resulted in some progress
in the overall management of patients with lung cancer
in recent years, with increasing use of neoadjuvant and
adjuvant strategies and second-line chemotherapy, treatment outcomes for NSCLC continue to be disappointing.
Fortunately, the picture is changing with the introduction of targeting therapies. Inhibition of the epidermal
growth factor receptor (EGFR) family is at the forefront,
led by the tyrosine kinase inhibitors gefitinib (Iressa®)
and erlotinib (OSI-774 Tarceva®), but angiogenesis
inhibition with bevacizumab (Avastine®) has also produced interesting data from recent trials. The basis for
the development of this mode of therapy is described
elsewhere in this book.
Erlotinib has been approved by health authorities in
many countries for the treatment of patients with locally
advanced or metastatic NSCLC after failure of at least
one prior chemotherapy regimen. The study by the
Canadian Clinical Trials Group delivered the backbone
of the data for this decision. The study included a total
of 731 patients randomized using a 2:1 randomization
scheme: 488 in the erlotinib arm and 243 in the placebo arm. EGFR status was determined for 238 of the
731 study patients for whom tissue samples were available prior to the study. A positive EGFR expression status was defined as having at least 10% of cells staining
for EGFR. Survival of erlotinib-treated patients was
superior to that of placebo-treated patients and median
survival duration of erlotinib-treated patients was 6.7
months, compared with 4.7 months for placebo-treated
patients. Exploratory univariate analysis showed a larger
survival prolongation in two subsets of patients: those
who never smoked and those with EGFR-positive
tumors. Erlotinib was also superior to placebo in terms
of progression-free survival, and had a response rate of
8.9 versus 0.9%. Severe rash occurred in 8% and severe
diarrhea occurred in 6% of erlotinib-treated patients.132
Similar results have been obtained in phase II trials
with erlotinib. The clinical and biologic features associated with EGFR have been analyzed in studies performed in the US, Europe, South Korea, Taiwan, China,
and Japan, and considerable efforts have been made to
identify predictive factors for response to elucidate the
molecular mechanisms involved. The most important
advance has been the identifiation of somatic mutations
in the 90% or so of patients with objective responses to
gefitinib or erlotonib. In addition to non-smoker females
and adenocarcinoma, Asian descent has turned up as
an important predictive prognostic factor associated
with the response and survival benefit of both gefitinib
and erlotinib.
In addition to the phase III trials with the two tyrosine
kinase inhibitors, several articles have been published
based on experience with a compassionate-use program
Treatment of NSCLC: chemotherapy 165
in patients with advanced NSCLC who have failed prior
chemotherapy or were unfit for chemotherapy. Some of
the studies have specifically analyzed the efficacy and
tolerability of gefitinib in patients with poor performance status or in elderly patients. All studies have
shown that gefitinib has clinical antitumor activity and
also good tolerability, with higher response rates in the
Asian studies than in European or European-heritage
Americans.133
With respect to bevacizumab, a monoclonal antibody
directed against the vascular endothelial growth factor
(VEGF), the results of a randomized trial in 444 patients
with metastatic NSCLC were presented at the ASCO
meeting in 2005. Bevacizumab was added to paclitaxel
and carboplatin (PCB) and compared with chemotherapy alone (PC). The response rate (27% versus 10%,
p <0.0001), progression-free survival (6.4 months
versus 4.5 months, p <0.0001), and median survival
(10.2 months versus 12.5 months, p = 0.0075) were
higher in the bevacizumab arm. Both regimens were well
tolerated, but hemorrhage was more frequent in the
PCB arm (4.1% versus 1.0%). There were 11 treatmentrelated deaths (9 in the PCB arm and 2 in the PC arm),
of which 5 were due to hemoptysis, all in the PCB arm.
It is noteworthy that the trial excluded patients with
squamous cell carcinoma, and thus mainly included
patients with adecarcinoma.134,135
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11
Treatment of small cell lung cancer
11.1 Treatment of SCLC: surgery
Hisao Asamura, Riken Kawachi
Contents Introduction • Primary surgery • Induction chemotherapy plus adjuvant surgery
• Salvage surgery
INTRODUCTION
The role of surgery in the management of small cell
lung cancer (SCLC) remains a controversial and as yet
undecided issue despite re-examination of this role over
the past 30 years. The British Medical Research Council
performed two large, randomized, prospective trials of
surgery versus radiotherapy in the 1960s and 1970s,
which reported the failure of surgery alone to control
this disease when compared to radiotherapy.1,2 Although
the results of this trial set the standards for non-surgical
treatment for SCLC thereafter, this study must be criticized
from the present view point for the following issues:
•
•
•
•
SCLC located in the peripheral lung was excluded
from the study since only tumors diagnosed by rigid
bronchoscopy prior to the treatment were enrolled.
Complete resection of the tumor could be achieved
in only 48% of the patients assigned to the ‘surgery’ arm.
No intraoperative staging was done.
Modern clinical staging techniques (CT scan and
mediastinoscopy) were not used. As a result, these
studies included very few patients with very early
stage disease (T1–2N0M0) who are thought to
benefit from surgery most.
In the late 1960s and mid-1970s, surgery for early
stage SCLC was championed by other reports, where
survival was significant for tumors located in the periphery of the lung confined to the lung, with N0 status,
and treated by lobectomy.3,4 Reports in the late 1970s
and early 1980s further demonstrated that surgical
therapy alone could provide curative treatment in up to
25% of such patients.5,6 A report by the Veterans
Administration Surgical Oncology Group showed a
23% five-year survival rate for 132 patients resected,
and concluded that resection was definitely indicated in
patients with T1N0 lesions, and probably indicated in
those with T1N1 or T2N0 lesions.6
Since these earlier studies, the arrival of new diagnostic tools, such as the higher resolution CT scan and
positron emission tomography, has enabled identification of very limited disease with a higher potential for
cure. In addition, platinum-based combination chemotherapeutic regimens have become available since the
early 1980s, with an objective response rate as high as
80%. With the addition of postoperative chemotherapy,
even better long-term survival in this very early stage of
disease has been reported. In stage I disease, up to 70% of
patients will be cured. In more advanced disease (stages
II and IIIA), when the tumor is totally excised at surgery
and treated with postoperative chemotherapy, five-year
survivals in the range of 20–30% can be expected.7,8
However, as for non-small cell lung cancer (NSCLC),
the prognosis of patients with N2 disease is quite poor,
and the chance of surgical intervention is least.9,10
The role of surgery in multimodality therapy to improve
control of the primary site has been investigated by utilizing induction chemotherapy prior to surgical
resection.11–13 These programs have also included consolidation chemotherapy as well as mediastinal radiotherapy with or without prophylactic cranial irradiation.
The final role that has been suggested for surgery in the
treatment of SCLC is that of ‘salvage’ treatment when
primary chemo-irradiation fails to control the local disease or when recurrence occurs and only the primary
site is affected.14 In these instances, surgical treatment
after reinduction chemotherapy has been utilized as a
‘salvage’ procedure.
In summary, the present-day role of surgery in the
management of SCLC can be categorized into four
groups:
•
•
•
•
primary surgery (surgery alone);
primary surgery followed by systemic adjuvant
chemotherapy;
induction (neoadjuvant) chemotherapy/chemoradiotherapy followed by surgery; and
salvage surgery after definitive chemoradiotherapy.
Treatment of SCLC: surgery
Upfront surgery without any following additional treatment is becoming less common since the higher activity
in extensive disease (ED) SCLC has been established
and become well known. Another reason for upfront
surgery is preoperatively undiagnosed tumors, especially clinical T1 and T2N0 diseases in peripheral locations, which continue to be resected by surgeons and
are found to be SCLC postoperatively.
PRIMARY SURGERY (SURGERY ALONE AND SURGERY
WITH POSTOPERATIVE CHEMOTHERAPY)
Complete resection of SCLC, often without prior knowledge of the cell type, will result in significant five-year
survival. Several reports have suggested that early stage
SCLC can be cured by surgical resection alone
(Table 11.1.1).10,12,15–29 For instance, Shah et al15 retrospectively analyzed the prognosis of 28 patients who
received surgery alone for SCLC; and reported a fiveyear survival of 43.3%. They have stated that the prospects of cure by operation are similar to those with
NSCLC. However, the most recent series reporting their
data suggest that postoperative chemotherapy is a necessary part of treatment (Table 11.1.1).23 In most centers, following surgical resection, a minimum of four to
six courses of adequate two- or three-drug regimen chemotherapy is advised. In a co-operative international
lung cancer multimodality treatment trial, 112 patients
with SCLC underwent initial surgical resection and
were then randomized to receive one of two intensive
postoperative chemotherapy regimens.30 The projected
36-month survival rate for 43 patients with N0 disease
was 65%; for 43 with N1 disease, 52%; and for 26 with
N2 disease, 29%. If hilar and mediastinal lymph node
disease is found at the time of surgery, postoperative
mediastinal irradiation is also advised, although its role
is not certain. The role of prophylactic cranial irradiation has yet to be decided as well.
More recently, Brock and co-workers emphasized that
highly selected patients with SCLC might benefit from
surgery and adjuvant chemotherapy, particularly if the
chemotherapy was platinum-based.23 In the retrospective study, the five-year survival for patients with stage
I disease who received adjuvant chemotherapy was 63%,
and among them, the five-year survival for patients
receiving platinum chemotherapy was 86%. In the Japan
Clinical Oncology Lung Cancer Study Group trial
(JCOG9101), the study also reported better survival for
early stage SCLC patients.22 Sixty-one patients with
completely resected SCLC received chemotherapy.
Ninety percent of the patients received two to four
171
courses of chemotherapy consisting of cisplatin and
etoposide. Three-year survival was 61%, 68% in clinical
stage I disease.
Badzio and co-workers, in their retrospective analysis,
demonstrated a beneficial effect for surgical resection.21
They used matched case–control methodology to minimize
selection bias. A group of 134 patients were selected for
comparative analysis; 67 were treated with surgical resection followed by chemotherapy and 67 were managed
with chemoradiotherapy. They demonstrated a significant
difference in survival between operated and non-operated
patients. Five-year survival in patients treated with and
without surgery was 27% and 4%, respectively. The relative hazard ratio of death in patients treated with surgery was 0.42 (95% confidence interval 0.28–0.61). In
their study, survival advantage was observed in patients
with N0/N1 except for N2 disease, and they suggested
that surgery added to chemotherapy might benefit in
limited SCLC.
However, it is still difficult to compare this multimodality surgical approach to chemoradiation alone, since
medical oncologists on the whole do not classify these
‘very limited’ tumors as a separate entity.31 Despite this,
some retrospective analyses have been performed. Osterlind and co-workers, in their retrospective analysis,
failed to demonstrate any beneficial effect for surgical
resection.32 While they demonstrated a significantly
better prognosis for 79 patients who met criteria for surgical resectability prior to treatment than for 696 patients
who did not, there was no significant difference in survival between 33 operated and 46 non-operated patients.
Again in this study, however, only 33% of the operated
patients underwent complete resection, which suggested
that the criteria for resectability were not predictive
enough, and the authors’ unfavorable statement regarding
the benefit of surgery was not conclusive. On the other
hand, Shepherd and co-workers have suggested a twofold improvement in survival utilizing surgery as part of
the treatment, by improving control of the primary site.12
It must be emphasized that the description of stage of
patients in such a study, by not only limited disease
(LD)–ED but also the tumor, node, metastasis (TNM)
system is crucial to make the comparison possible
between primary surgery and chemoradiation alone.
INDUCTION CHEMOTHERAPY PLUS ADJUVANT
SURGERY
The role of surgery in more proximal tumors with clinical N1 or minimal N2 disease (but still resectable by
172 Textbook of Lung Cancer
Table 11.1.1 The clinical outcome of patients who underwent primary surgery with or without postoperative adjuvant
chemotherapy for SCLC
Author
No of patients
Median survival (months)
(a) Surgery + chemotherapy
ISC-LCSG16
183
Coolen17
15
Davis18
37
Muller19
45
18
Toronto Group12
Salzer10
Cataldo20
79
25
60
21
Badzio21
67
JCOG22
61
Brock23
45
(b) Surgery ± chemotherapy
Lucchi24
127
Miyazawa25
Merkle26
Maassen27
12
25
170
124
(c) Surgery alone
Coolen17
15
Shah15
28
Sorensen28
Shore29
76
40
a
30-month survival.
3-year survival.
b
18
Five-year survival rate (%)
63a (TN0M0)
37b (TN2M0)
27
60 (stage I)
50 (stage I)
35 (stage II)
21 (T3N2)
36
57 (stage I)
28 (stage II)
34 (stage IIIA)
40
25 (N2 disease)
40 (stage I)
36 (stage II)
15 (stage III)
27
59 (stage I)
31 (stage II)
4 (stage III)
57
76 (stage I)
38 (stage II)
39 (stage III)
63 (stage I)
25 (stage II/III)
22.6
47.2 (stage I)
14.8 (stage II)
14.4 (stage III)
50 (latter period)
8 (former period)
18
20
13
12 (stage I)
43.3
57.1 (stage I)
55.5 (stage II)
12
27
Treatment of SCLC: surgery
173
Table 11.1.2 The clinical outcome of patients who underwent induction (neoadjuvant) chemotherapy followed by surgery
for SCLC
Author
No of patients
Median survival (months)
17
Salzer37
Holoye38
Johnson39
Lad40
Wada41
11
37
25
38
11
13
14
14
26
24
70
17
Fujimori43
21
61.9
Eberhardt42
Veronesi44
46
23
36
24
Prager33
Baker34
Williams35
Shepherd36
33
21
Not reached (stage I)
16 (stage II)
12 (stage III)
Five-year survival rate (%)
65a
48
36
47
25
19
15.4
30.70
80 (c-stage I/II)
50.3 (p-stage I/II)
66.7a
73.3a (c-stage I/II)
46
25a
91a (stage I)
14a (stage II/III)
a
3-year survival.
NSCLC criteria) is less apparent. The results of ever
published studies are summarized in Table 11.1.2.33–44
Among these, the experience of the Toronto Group12
and the Innsbruck Group10 suggested that with this
combined modality treatment, utilizing surgery as an
adjuvant, five-year survival rates in the range of 40%
can be obtained (Table 11.1.3). Those tumors with
good responses to chemotherapy, having been downstaged by the time of surgery to an N0 level, have a
five-year survival rate as high as 60–70%. Persisting
nodal disease yields a less satisfactory 20–30% five-year
survival rate. An interesting side-light of such therapy
is the fact that many of the resected tumors contain no
remaining SCLC, but do contain persisting elements of
NSCLC.
The North American Lung Cancer Study Group
reported the results of a randomized trial comparing
the non-surgical to the adjuvant surgical approach in
limited disease (Figure 11.1.1).40 Although most of the
146 patients randomized following induction chemo-
Table 11.1.3 Induction chemotherapy followed by surgery
for SCLC (the Toronto Group results)
Stage
Overall
N0
N1
N2
No of patients
Median
survival
(years)
Estimated
five-year
survival rate (%)
38
11
13
14
1.8
Not reached
1.3
1
38
45
30
40
therapy were initially staged as ‘limited’ (versus ‘very
limited’), the results of this randomized trial showed no
difference in survival of either arm. In 70 patients in the
surgery group, complete resection was possible in 77%,
and the pathologic complete response rate after induction chemotherapy was 19% compared with the clinical complete response rate of 40%. This study also
174 Textbook of Lung Cancer
Registration
Induction chemotherapy (CAV) × 5
Objective response
therapy followed by surgery, the comparative, randomized study between standard chemoradiotherapy and
multimodality treatment including surgery is not realistic. The future directions of the study should be, therefore, the well-prepared phase II trial with novel regimens
as an induction treatment after the most updated preoperative staging, including PET scanning.
Randomize
Thoracotomy
No surgery
Thoracic and brain radiation
Figure 11.1.1
Diagram of study design of Lung Cancer Study Group Study 832.
failed a subset analysis that attempted to isolate the
‘very limited’ group, although very few patients were
included in this subset.
Eberhardt and co-workers reported an excellent local
control and remarkable long-term survival in LD-SCLC
patients undergoing aggressive trimodality treatment.42
Of 46 patients with LD-SCLC undergoing induction
therapy (chemotherapy for stage I/II, chemoradiotherapy including hyperfractionated accelerated radiotherapy for stage IIIA/IIIB), 32 patients underwent surgical
resection with a complete resection rate of 72%. The
authors reported that the median survival and five-year
survival rate of all 46 patients were 36 months and
46%, respectively. Especially for 32 completely resected
patients, 68 months and 63% were reported, as well as
a 100% local control rate. This kind of aggressive multimodality approach using intensive local therapy such
as surgery and hyperfractionated accelerated radiotherapy might be promising in the treatment of LD-SCLC,
and may be one of the future directions for trials in
these patients.
Looking at the results of the ever published studies,
the five-year survival rates of patients who underwent
induction (neoadjuvant) chemotherapy and subsequent
surgery ranged from 25 to 65%, and many were at
around 40%. These data clearly indicated that such a
multimodality approach to LD-SCLC is feasible, and
promising in terms of prognosis. However, the role of
surgery in the multimodality treatment has not been
clearly defined by the small to medium sized one-arm
study. On the other hand, considering the limited number of patients who might be candidates for induction
SALVAGE SURGERY
The Toronto Group has promulgated the concept of
‘salvage’ surgery for SCLC, in which two situations are
clearly defined.14 Tumor recurrence might happen at
exactly the same place as the primary site, even after a
complete response (CR) has been achieved by definitive
chemoradiotherapy (Figure 11.1.2a). Alternatively the
persistent primary tumor might grow after definitive
chemoradiotherapy is over (Figure 11.1.2b). Salvage
surgery is generally indicated in these two special cases
with a curative intent. Patients with mixed SCLC/
NSCLC at diagnosis and persistent NSCLC after induction chemotherapy are also prime candidates for this
type of surgery, since the non-small cell component of
the primary tumor might remain because of the difference in the response to the systemic chemotherapy. For
this category of surgery for SCLC, it is important to differentiate the concept of salvage surgery from that of
planned induction chemoradiotherapy followed by surgery. In the latter setting, the surgery is planned upfront
as a part of treatment plan, usually for resectable, histologically proven SCLC, where the schedule and dose
are determined on the premises of the following surgery. In salvage surgery, the chemoradiotherapy is
planned definitively for itself, and the indication for
surgery arises only when the clinical situation after
definitive chemoradiotherapy fits the criterion for it.
For this purpose, mediastinoscopy is utilized to eliminate patients with unresectable disease. In the Toronto
study, 28 patients with limited SCLC who did not have
a complete remission with standard treatment, or who
had only local recurrence after treatment and appeared
to be completely resectable, underwent surgery. Pathologic examination showed only SCLC in 18 patients,
mixed SCLC and NSCLC in 4, and only NSCLC in 6.
A median survival of 74 weeks and a five-year survival
rate of 23% were reported. This study suggests the existence of occasional SCLC patients who will benefit from
salvage surgery after relapse or failure to respond to
chemotherapy and radiotherapy.
Treatment of SCLC: surgery
175
Salvage
surgery
(a)
PR
Cx-Rx
Salvage
surgery
(b)
CR
Cx-Rx
Recurrence
Figure 11.1.2
Indication of ‘salvage’ operations in the treatment of SCLC. Surgical resection is considered when the recurrent tumor shows up at exactly
the same site as the primary tumor after a complete response (CR) has been achieved by definitive chemoradiotherapy (a), or when the
persisting primary tumor grows after the definitive chemoradiotherapy is over (b).
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11.2 Treatment of SCLC: radiotherapy
Christopher M Lee, William T Sause
Contents Introduction • Where are we now? • Current recommendations
• Radiotherapy for palliation • Future directions
INTRODUCTION
Small cell carcinoma of the lung (SCLC) comprises
approximately 20% of newly diagnosed bronchogenic
malignancies.1 Multiple studies have revealed SCLC to
be a highly aggressive carcinoma that is clinically and
biologically very different from non-small cell carcinoma of the lung (NSCLC). Due to significant chemosensitivity and the known high propensity of spread beyond
the chest, chemotherapy was utilized as the primary
treatment of this disease several decades ago.2–4 Despite
the extreme chemosensitivity and remarkable initial
response rates in patients with limited stage disease, the
use of chemotherapy alone led to intrathoracic failures
in up to 80% of patients and mean survivals of only
10–14 months.2 After it was revealed that radiotherapy
could decrease locoregional failures, it became increasingly utilized in the 1970s and 1980s. It was only after
two separate meta-analyses reported improved survival
outcomes with the use of radiation therapy in combined
modality treatment that thoracic irradiation (TI) was
accepted as a necessary part of the standard of care.
Both meta-analyses reported a 5–7% improvement in
two- and three-year survival and an approximate 25%
improvement in local control rates with the addition of
radiotherapy treatment.5,6
Concurrent thoracic irradiation with platinum-based
chemotherapy is now considered the standard treatment in limited stage SCLC. The use of a concurrent
cisplatin/etoposide regimen has significantly decreased
the toxicity observed from prior regimens containing
cyclophosphamide, doxorubicin, and vincristine, leading to significant improvement in patient tolerability to
combined modality therapy.2–4,7–9 A survival benefit
with the use of prophylactic cranial irradiation (PCI) in
patients with limited stage disease who have experienced a complete response to initial concurrent therapy
with TI and systemic chemotherapy was also confirmed
in a meta-analysis.10
Despite recent advances in treatment, the optimal
treatment strategies for individual patients with newly
diagnosed SCLC remain elusive. A number of questions
require further study in this disease, such as optimization of both chemotherapy (schedule, choice of agents,
timing, dosing) and radiation therapy (dose, fractionation, timing, volume treated) regimens. In addition,
statistical analysis cannot replace clinical judgment
when considering the individual patient, tumor characteristics, and the potential risks and benefits of specific
therapies. Hopefully with further information gained
from ongoing and future research endeavors, appropriate therapy will be utilized to decrease the death rate
from this thoracic malignancy. Future work is also
needed to continue to delineate clinical and biologic factors which can guide treatment and account for disparities in outcome between varied subsets of patients.
As will be further addressed in this chapter, the optimal
timing, dose, and fractionation schedules for PCI continue to be under study.
WHERE ARE WE NOW?
Thoracic irradiation
Many practical issues, such as radiation dose, volume,
fractionation, and optimal integration with chemotherapy, remain unresolved. Trying to ‘fine-tune’ combinedmodality treatment for SCLC is a formidable challenge.
It must be accepted that the individual benefits attributable to the different parts of this puzzle are likely to be
numerically small, and manipulation of one aspect may
produce a cascade of events with conflicting effects on
overall outcome. These methodologic problems have
resulted in substantial difficulty in designing appropriate randomized trials to address these questions.
No large randomized trials have been performed
looking at radiation dose as the only variable. Previous
retrospective analyses of thoracic radiation used after
cyclophosphamide- and doxorubicin-containing chemotherapy regimens have suggested that radiation doses as
high as 50–60 Gy are necessary for durable local control (standard fractionation). Even in the current era of
178 Textbook of Lung Cancer
concurrent thoracic radiation therapy and chemotherapy, a major site of recurrence continues to be within
the previously irradiated field (30% in-field alone recurrence and 20% in-field recurrence combined with systemic recurrence).11,12 Choi et al reported improved local
control for doses of 40–50 Gy compared with doses of
<40 Gy.11 An additional study by Papac et al reported
local control of 97% after use of 60 Gy.13 Choi and coworkers from the Cancer and Leukemia Group B
(CALGB) identified 70 Gy to be the maximum tolerated
dose of radiation using standard fractionation for treatment in combination with chemotherapy.12 In addition,
the CALGB reported results from a phase II trial of 70
Gy thoracic irradiation in combination with three cycles
of concurrent carboplatin and etoposide, following an
induction with two cycles of paclitaxel and topotecan.
Their reported median failure-free survival was 12.9
months and median overall survival was 19.8 months,
with a one-year survival of 70%.14 Miller et al have also
reported supporting evidence that higher radiation
doses are tolerable.15 They retrospectively evaluated
outcomes of 65 patients treated with 58–66 Gy (standard fractionation), with either concurrent or sequential chemotherapy, and found that the treatment was
extremely tolerable. Komaki et al reported on the Radiation Therapy Oncology Group (RTOG) 9712 study,
which was a phase I dose-escalation study, of thoracic
radiation therapy with concurrent cisplatin/etoposide
in limited stage SCLC. Thoracic radiation was given in
1.8 Gy daily fractions to a total dose of 36 Gy, followed
by smaller boost fields encompassing only the gross
disease delivered with escalations of 1.8 Gy bid during
the final days to establish the maximum tolerated dose
(MTD). The MTD was found to be 61.2 Gy in 34 fractions of 1.8 Gy when given with two cycles of cisplatin/
etoposide (concurrently) and followed by two additional cycles of cisplatin/etoposide.16
A further practical question concerns the optimal target volume for thoracic irradiation. This issue is increasingly debated now that the standard of care has changed
from sequential to concurrent thoracic radiation with
chemotherapy. The tradition of irradiating large volumes
covering all ‘prechemotherapy tumor involvement’ with
generous margins or prophylactic irradiation of distant
lymphatic drainage sites may no longer be necessary,
and more modest radiation treatment volumes will lead
to lower rates of serious pulmonary toxicity. There
remains no consensus at this point as to whether prechemotherapy or postchemotherapy visible volumes
should be treated.17–20 The optimal safety margin around
the visible tumor and necessary elective nodal radiation
also remain sources of study and debate. A common
treatment policy constructs treatment fields to encompass
the original tumor with 1.5–2.0 cm margins. One prospective trial by Kies et al revealed no difference between
large-field thoracic radiation therapy and limited-field
therapy, although conflicting results are apparent in the
literature.15–18,20,21 A balance must be made with each
individual patient which evaluates potential toxicity of
enlarging radiation fields versus the risk of local recurrence of disease. New imaging modalities such as positron emission tomography (PET) are also expected to
help answer key questions regarding optimal treatment
volumes.
With recent increased interest in altered fractionation
schedules for radiation therapy, accelerated hyperfractionation appears to be a logical choice for SCLC due to
the high sensitivity of cancer cells, the normal-tissuesparing effect of twice-daily fractionation (with a greater
than six-hour interval between fractions), and the ability to defeat rapid proliferation of tumor cells. Several
phase II studies of radiation given in multiple daily
fractions, either concurrently with cisplatin and etoposide or in an interdigitated sequence, have been followed by a large intergroup randomized trial.22,23 In
this study, 417 patients were treated with concurrent TI
starting with the first cycle of etoposide and cisplatin
(PE) chemotherapy and randomized between a standard schedule (1.8 Gy in 25 daily fractions over five
weeks to a total dose of 45 Gy) or a hyperfractionated
schedule (45 Gy in 1.5 Gy fractions twice daily over three
weeks). With mature follow-up, the five-year survival
rate was significantly improved in the twice-daily arm
(26 vs 19%). However, the hyperfractionated arm had
higher rates of acute toxicity, as would be expected.23
An additional trial studying this issue was a North Central Cancer Treatment Group (NCCTG) study, which
compared concurrent cisplatin/etoposide (two cycles)
and either twice-daily, split-course TI to 48 Gy in
5.5 weeks or once-daily TI to 50.4 Gy in daily fractions
of 1.8 Gy, both given after three cycles of cisplatin/
etoposide. They found no difference in three-year overall survival and locoregional control between the splitcourse/twice-daily fractionation and daily fractionation
treatment schemas.24 Schild et al reported the median
and five-year survival rates to be 20.4 months and 22%
for twice-daily versus 20.5 months and 21% for oncedaily thoracic radiation, respectively (p = 0.7).25 In analyzing these studies side-by-side, it appears that one
possible explanation is that the split-course regimen is
an inferior regimen due to an extension of overall
treatment time allowing for tumor cell regeneration.
Treatment of SCLC: radiotherapy 179
The issue of radiotherapy timing is also not resolved.
An early three-arm randomized CALGB trial suggested
that the best survival/toxicity ratio can be obtained by
delaying radiation until the fourth cycle of chemotherapy.26 This may be in part due to a marked reduction in
the chemotherapy dose when thoracic radiation was
applied early and also due to high rates of treatmentrelated fatalities in schedules using concurrent radiation
with cyclophosphamide, methotrexate, lomustine, and
doxorubicin. More recent trials which utilize cisplatin/
etoposide or cisplatin/etoposide alternating with
cyclophosphamide/doxorubicin/vincristine show clear
superiority for early (cycle one or two of chemotherapy)
utilization of TI.27–29 These randomized trials testing
the timing of thoracic irradiation are illustrated in
Table 11.2.1.20,26–29 Fried et al performed a meta-analysis which evaluated the timing of TI in combined
modality therapy for limited-stage SCLC.30 This analysis of 1524 patients revealed a significantly higher twoyear survival in the early group, and there was a
suggestion of a similar trend at three and five years. This
advantage was also thought to be due to the significantly improved outcomes found in trials employing
platinum-based chemotherapy and hyperfractionated
radiation therapy regimens. Once-daily regimens and
doxorubicin-based chemotherapy were found not to
provide any statistically significant improvements in
overall survival.
Brain metastases and prophylactic
cranial irradiation
Brain metastases are common sites of failure in SCLC
and multiple reports have confirmed that prophylactic
cranial irradation (PCI) has a role in the therapeutic
strategy among patients with limited stage disease who
are complete responders to systemic chemotherapy and
thoracic irradiation.5,10 At diagnosis, 20% of patients
have evidence of spread into the brain, which rises to
50% at two years and to more than 80% postmortem.31–34
The concept of PCI, taken from settings such as acute
lymphoblastic leukemia, demonstrated 20 years ago
that moderate radiation doses can significantly reduce
the rate of brain metastases. In multiple small historical
trials, no evidence of survival benefit was seen and the
short overall survival underestimated the degree of the
observed risk. In addition, initial reports of CNS morbidity subsequent to cranial irradiation tempered the
enthusiasm for PCI in the past.35–39 Nevertheless, the
problem of CNS disease and its control have continued
to evolve in clinical practice. The modest effectiveness
of radiotherapy or chemotherapy for patients with
established brain metastases as well as the subsequent
functional consequences and negative impact that brain
metastases have on quality of life has lead to re-evaluation
of PCI in a series of second-generation trials. These were
designed to address issues of effectiveness as well as
morbidity of treatment.
Table 11.2.1 Trials evaluating the timing of thoracic irradiation
Author
RT timing
RT dose
Five-year survival rate (%)
p
Cycle 1
Cycle 4
50 Gy/24 fx
7
13
0.08
Week 3
Week 15
40 Gy/15 fx
20
11
0.008
Week 1
Week 18
40–45 Gy/22 fx
11
12
0.4
Week 1
Week 6
54 Gy/36 fx
30
15
0.052
Cycle 1
Cycle 4
45 Gy/30 fx
24
18
0.097
Perry26
Murray28
Work20
Jeremic27
Takada29
RT timing: radiation therapy timing with respect to chemotherapy; RT dose: radiation therapy prescribed dose; fx: number of fractions.
180 Textbook of Lung Cancer
Oncologists have found through multiple recent
studies that the use of PCI alone with lower dose-fractionation schedules (<3 Gy), and without concomitant
chemotherapy, does not lead to significant long-term
neurotoxicity.33,40 It should be emphasized that these
recent trials have included patients who have experienced
complete remission following systemic chemotherapy
and thoracic irradiation for limited stage disease. This
has been confirmed by multiple recent prospective trials which have included neurologic assessments (before
and after therapy) in their study requirements. These
have revealed that, on initial pretreatment neuropsychologic assessments (prior to PCI administration), 40–60%
of patients had documented abnormalities, and initial
results have not shown any significant differences in
neurocognitive function when comparing those patients
who received PCI with those who did not.10,33,40–42 The
only prospective trial which documented a significant
decrease in cognitive function in a PCI group was a
CALGB trial which utilized concurrent chemotherapy
with brain irradiation. All patients in this trial had PCI
administered with chemotherapy and there was a noted
significant change in neurocognitive function during
the course of treatment, which suggests that the combination of chemotherapy and PCI has a negative impact
on cognitive functioning.43 These studies concluded that
PCI should be administered without concomitant chemotherapy and lower fractionation schedules (<3 Gy)
should be considered for all patients who experience a
complete response after initial treatment with systemic
chemotherapy and thoracic irradiation.
CURRENT RECOMMENDATIONS
Radiotherapy plays an important role in the treatment
of SCLC patients. Its optimal utilization requires close
collaboration between all the specialists involved in the
care of these patients, and thoracic radiation oncologists should be an intrinsic part of the multidisciplinary
team. Only in this way can safe and efficient progress
be made in this regard. Limited stage patients with
SCLC should be managed by specialists using a formal
multimodality protocol of treatment, and preferably in
the context of a clinical trial. The accepted standard
practice in many centers is to use concurrent chemotherapy with radiation delivered early in the course of
chemotherapy treatment to a dose equivalent of 50 Gy
with standard fractionation (approximately 10 Gy/
week). Concurrent chemoradiotherapy with drugs
other than cisplatin and etoposide may necessitate dose
modifications and reductions on the grounds of toxicity.
Having selected the patients who are likely to go on to
TI and possibly PCI, it is important to obtain a prechemotherapy radiologic series that will inform subsequent radiotherapy planning. This preferably would
include a computed tomography (CT) scan of the thorax and upper abdomen. These must be available,
together with a contemporary and comparable series of
radiologic investigation, to the radiation oncologist at
the time of treatment planning (Figure 11.2.1). The
decision on what radiotherapy treatment volume to use
will depend on the extent of original tumor involvement, the degree of response to and the choice of chemotherapy, the patient’s lung function and performance
status, and the dose, fractionation, and timing of the
radiotherapy course.
In practice, most radiation oncologists would irradiate areas of prechemotherapy involvement with a margin consistent with safety. This is a minimum of 1 cm
on the transverse and 2 cm in the sagittal plane of
involvement. Prophylactic irradiation of nodal sites
remote from the initial sites of involvement, such as
routine irradiation of the supraclavicular fossa in
patients with upper lobe tumors, is probably not necessary and adds considerably to toxicity. Because SCLC
often presents in the vast majority of cases with a bulky
central tumor and extensive mediastinal involvement,
these treatment volumes are large. In addition, irradiation of large intrathoracic tumor volumes to a high and
homogeneous dose represents a technical challenge.
The main trade-offs are between the radiation dose
delivered to surrounding normal lung, esophagus, and
heart, and the radiation tolerance of the spinal cord. A
safe approach requires composite and sophisticated
planning techniques (Figures 11.2.2 and 11.2.3), similar
Figure 11.2.1
Prechemotherapy axial CT image illustrating a newly diagnosed
small cell carcinoma of the left lower lung lobe.
Treatment of SCLC: radiotherapy 181
to those used in the treatment of NSCLC, often using
phased or ‘shrinking’ field techniques.
The choice of volume for PCI is simple. The entire
cranial cavity and contents need to be irradiated, usually using opposing lateral portals (Figure 11.2.4). The
areas needing particular attention are the meningeal
reflections of the cribriform fossa and middle cranial
fossa. TI and PCI administered using conventional
doses and fractionation after chemotherapy lead in
most cases only to trivial acute side-effects. Tiredness,
esophagitis, and lymphopenia are the most common.
They are self-limiting, and in the vast majority of cases
do not require further treatment beyond simple symptomatic measures. Administration of concurrent chemotherapy and hyperfractionated accelerated TI regimens
is much more toxic, with esophagitis and hematologic
toxicity often being dose-limiting. These may be slow
to recover from, and may compromise further treatment tolerance. The most significant side-effects are
late pulmonary toxicity, late CNS toxicity of PCI: spinal
cord damage, and cardiac failure due to irradiation of
large areas of the heart and to anthracyclines.
RADIOTHERAPY FOR PALLIATION
The exquisite radioresponsiveness of SCLC makes
radiotherapy a useful agent for palliative treatment of
metastatic, symptomatic, or recurrent disease in patients
resistant to or unsuitable for systemic chemotherapy.
The approach will best be individualized and similar to
that used in NSCLC. In general, short and undemanding courses of irradiation including single-fraction
treatments can be used, aimed at symptom control
through tumor shrinkage and associated with little or
no additional toxicity. Commonly used regimens
include 37.5 Gy in 15 fractions, 30 Gy in 10 fractions,
20 Gy in five fractions, or single treatments of 8–10 Gy.
FUTURE DIRECTIONS
Figure 11.2.2
Anterior-posterior digitally reconstructed radiograph (DRR)
illustrating a typical radiation portal which includes the primary
tumor mass and adjacent hilar/mediastinal lymph nodes.
(See color plate section, page xv)
Future clinical trials are necessary to evaluate optimal
treatment schedules for patients newly diagnosed with
SCLC. The current vogue for accelerated hyperfractionated regimens, with their associated increased survival
rates and increased levels of acute toxicity, also needs
continual future critical evaluation. The optimization of
scheduling of thoracic irradiation and chemotherapy is
another area where further work is needed. The current
Figure 11.2.3
Conformal radiotherapy planning techniques allow
escalated radiation doses to be delivered safely
with simultaneous sparing of surrounding critical
structures. In this example, a combination of
anterior-posterior and oblique fields (four fields in
total) are utilized to decrease radiation dose to the
nearby spinal cord. (See color plate section, page xvi)
182 Textbook of Lung Cancer
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Right lateral digitally reconstructed radiograph (DRR) illustrating
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11.3 Treatment of SCLC: chemotherapy
Heine H Hansen, Morten Sørensen
Contents Introduction • Second-line chemotherapy • Treatment of elderly and poor-prognosis patients
• Targeted therapies
INTRODUCTION
In the last decade much attention has been directed
towards the treatment of non-small cell lung cancer
(NSCLC), resulting in considerable progress in its management, which is in contrast to small cell lung cancer
(SCLC). The treatment of SCLC has, unfortunately,
been at a standstill in recent years, with relatively few
large clinical randomized trials, which may reflect the
lack of innovative treatment options but also a declining proportion of lung cancer patients presenting with
SCLC, which now in many countries constitutes less
than 20% of all newly diagnosed lung cancers. Thus, in
the US the proportion of SCLC among all lung cancer
histologic types decreased from 17.26% in 1986 to
12.95% in 2002. Noteworthy, in the same study, the
proportion of women with SCLC increased from 28%
in 1973 to 50% in 2002.1 Still, the treatment of SCLC
continues to represent a major challenge. Despite a high
rate of initial response, most patients will eventually
relapse and long-term survival remains a disappointing
10–15%. The disseminated nature of SCLC, displaying
a high frequency of metastases at the time of diagnosis
combined with a high sensitivity to cytostatic agents,
has led to the use of chemotherapy as the primary treatment of choice in all its stages. In the overview provided in this chapter, the current standard chemotherapy
in the management of SCLC will be discussed.
The most effective agents are listed in Table 11.3.1.
The most commonly used combinations include a platinum compound together with the podophyllotoxins,
usually etoposide. Combinations including vincristine,
cyclophosphamides/ifosfamides, doxorubicin, or taxanes are also highly active. Examples of frequently used
treatment schedules are listed in Table 11.3.2.2,3 In a
trial by Sundstrøm et al,4 including 436 eligible patients
with limited (n = 214) and extensive disease (n = 222),
a combination of etoposide and cisplatin was shown to
be superior to a three-drug combination of cyclophosphamide, epirubicin, and vincristine. For all patients
the two- and five-year survival rates in the EP (etoposide and platinum) arm (14% and 5%) were significantly higher compared with the three-drug arm (6%
and 2%, p = 0.0004). Patients with limited disease
received thoracic radiotherapy concurrently with chemotherapy cycle three, and those achieving complete
remission during the treatment period also received
cranial irradiation.
Among the new agents, much attention has been
given to the incorporation of the new topoisomerase
inhibitors in combination with either cisplatin or carboplatin (Table 11.3.3).
In a Japanese study5 that included only patients with
extensive disease, survival rates with a combination of
irinotecan plus cisplatin were superior to those with
etoposide and cisplatin, with one-year survival being
58.4% versus 37.9%, and median survival 12.8 months
versus 9.4 months; also response rates of 84% versus
68% were in favor of irinotecan and cisplatin. Grade 3
and 4 diarrhea occurred in 16% in the irinotecan combination compared with none in the etoposide arm.
The study was prematurely stopped after the enrollment of 152 patients out of the planned 230 patients,
as recommended by a preplanned interim analysis. A
confirmatory randomized study was initiated in the US
by Hanna et al,6 with randomization of 331 patients to
either irinotecan or etoposide, both in combination
with cisplatin. An unequally balanced randomization
was performed, allocating one-third of patients to
etoposide and two-thirds to the irinotecan arm. In both
arms, four cycles were delivered every three weeks. After
the enrollment of 30 patients, inclusion was restricted
to patients in performance status 0 and 1 due to an
excessive toxic death rate among patients with performance status 2. As in the Japanese study, myelotoxicity
and febrile neutropenia were more frequent in the
etoposide arm, whereas gastrointestinal toxicity was
more common in the irinotecan arm, including 21%
of patients suffering from grade 3–4 diarrhea. Unfortunately, this study could not confirm the encouraging
Treatment of SCLC: chemotherapy 185
Table 11.3.1 Agents used in SCLC: most frequently chosen
agents for inclusion in combination regimens
Alkylating agents
Cisplatin
Carboplatin
Ifosfamide
Cyclophosphamide
Antimitotic agents
Vincristine
Paclitaxel
Topoisomerase inhibitors
Etoposide
Irinotecan
Topotecan
Doxorubicin
Table 11.3.2 Commonly used regimens in SCLC
Regimen
PE
Cisplatin
Etoposide
CE
Carboplatin
Etoposide
ICE
Ifosfamide
Carboplatin
Etoposide
– with or
without
midcycle
vincristine
Dosage and schedule
25 mg/m2 iv on days 1–3 or 60–80
100 mg/m2 iv on days 1–3 or
115 mg/m2 iv days 3–5 q 3 wks
AUC 6 day 1 iv
100–120 mg/m2 iv days
1–3 q 3 wks
5000 mg/m2 iv day 1 +
300–400 mg/m2 iv day 1
100–200 mg/m2 iv days
1–3 + mesna 500 mg/m2 day 1
and 3000 mg day 2
1.0 mg/m2 day 14
Japanese data and no significant differences were seen
in the overall survival, time to progression, or response
rate. Median survival times were 9.3 versus 10.2 months
in the irinotecan/cisplatin and etoposide/cisplatin arms,
respectively.
The differences observed between the American and
the Japanese studies might be related to differences in
the scheduling of both cisplatin and irinotecan. Also
other factors, such as pharmacogenetic variations in the
two study populations might contribute to the different
results. Polymorphisms exist between Asians and
Caucasians with regard to the gene responsible for the
glucuronidation of SN-38, the active metabolite of
irinotecan. Preliminary data from a German study on
59 evaluable patients have also been published and the
study will proceed as a phase III trial comparing, again,
irinotecan versus etoposide, but in this study combined
with carboplatin rather than cisplatin.7 It is conceivable
that the data from the latter trial combined with existing data may determine whether etoposide or irinotecan is the superior drug in combination with platinum
compounds in SCLC.
In one of the largest randomized trials ever conducted
in patients with extensive SCLC, topotecan given orally
together with cisplatin was compared with iv etoposide
plus cisplatin in 784 patients with extensive SCLC. Overall survival was equal, 9.1 vs 9.3 months.8
With respect to some of the other newer agents, paclitaxel has been tested in several trials combined with
standard etoposide and platinum-based chemotherapy.
Used as single agent, paclitaxel has shown response rates
of 29–41% in both previously treated and untreated
SCLC patients. Based on survival data, none of three
randomized trials published increased median survival
in patients with extensive disease, but add to the risk of
toxic death in frail patients with extensive disease.9
Results from other trials trying to incorporate epirubicin or gemcitabine have also been rather disappointing,
with no differences in response rates or progression-free
or overall survival compared to standard regimens.9
With respect to scheduling of drugs, it has been demonstrated that etoposide is more effective when given as
a five-day course than when the same dose is given over
24 hours. Prolonged periods of three to four weeks of
continuous treatment of etoposide are being explored
at present. In that regard, it is noteworthy that oral
etoposide has been shown to be inferior to combination
chemotherapy administered iv.10
For both limited and stage I–III and extensive stage IV
disease, the overall response rates achieved are >70%,
whereas complete response with no clinical or histopathologic evidence of malignancies is initially obtained
in 30–40% of patients with limited disease and 15–20%
of patients with extensive disease. The median survival
for patients with limited disease is about 14–18 months,
and usually 8–10 months for extensive disease, whereas
long-term survival (beyond five years) is 10–15% and
3–5%, respectively, for the two stages. One should be
aware that survival results vary according to selection criteria and more representative results from national studies may be less encouraging. With respect to the duration
186 Textbook of Lung Cancer
Table 11.3.3 Major randomized trials evaluating topoisomerase I inhibitors in combination with platinum in extensive SCLC
No of patients
Etoposide + CDDP
Irinotecan + CDDP
Etoposide + CDDP
Irinotecan + CDDP
Etoposide + carboplatin
Irinotecan + carboplatin
Etoposide + CDDP
Topotecan (oral) + CDDP
Response rate (%)
154
331
59
784
68
84
44
48
50
71
69
63
Median survival (months)
9.4
12.8
10.2
9.3
12
10
9.3
9.1
Author
Sundstrøm4
Noda5
Hanna6
Schmittel7
CDDP: cisplatin.
of treatment needed to produce optimal results, a period
of 4–6 months, usually corresponding to 4–6 cycles of
chemotherapy, is currently an acceptable standard.
A meta-analysis of published, randomized controlled
trials suggests, however, that maintenance or consolidation therapy improves survival. New randomized clinical trials are therefore needed to further refine the place
of this approach in the treatment of SCLC.11
In recent years, new approaches to chemotherapy
have been undertaken to improve the treatment results,
including dose-dense chemotherapy, which has the theoretic potential to augment tumor cell kill. The role of
dose-dense therapy remains controversial in SCLC due
to conflicting results in various randomized studies
conducted over the years.12
Intensity of chemotherapy can be increased, particularly as a consolidation treatment by the use of autologous
bone-marrow infusion, and more recently by peripheral blood stem cells. One of the most recent trials to
evaluate this treatment concept has been performed by
British investigators, who randomly assigned 318 ‘better-prognosis patients’ to standard combination chemotherapy with ifosfamide, carboplatin, and etoposide (ICE)
delivered at four-week intervals or to dose-dense ICE in
similar doses, but given at two-week intervals supported
by granulocyte colony-stimulating factor (GCSF) (filgrastim) and autologous blood transfusions.13 Chest
radiotherapy was performed according to local guidelines, which for all patients consisted of sequential
radiotherapy. Approximately 10% of all patients had
extensive disease. The median relative dose intensities
were 99% and 182% in the standard and dose-dense
arms, respectively. Response rates, median survival times,
and two-year survival rates were 80% versus 88%, 13.9
versus 14.4 months, and 22% versus 19% in the standard
and dose-dense arms, respectively. The authors
concluded that the dose-dense strategy has reached a
plateau and further attempts to pursue this strategy in
SCLC do not seem justified.13
In a French study, more intensive treatment with four
instead of two drugs resulted in an improved one-year
survival (40% versus 27%), but with more severe hematologic toxicity.14
Other treatment approaches include scheduling of
drugs based on cell-kinetic observations15 or the use of
anticoagulants such as warfarin, but the results are
inconclusive. Noteworthy in that regard are the data by
Altinbas et al,16 who randomized 84 limited and extensive disease patients to combination chemotherapy with
or without the addition of low molecular weight heparin (LMWH) (dalteparin, 5000 U daily). Treatment was
safe, with no treatment-related deaths and only a few
manageable bleeding episodes. Overall survival increased
significantly in the LMWH arm to 13 months, compared
with 8 months in the chemotherapy-alone arm. The study
represents a very small sample size and the hypothesis
needs to be evaluated in a properly sized randomized
phase III study.
Another attempt to improve chemotherapy is alternating combination chemotherapy using different noncross-resistant combinations, because resistant clones
of SCLC cells, which are present either at the time of diagnosis or develop during chemotherapy, are thought to be
the reason for treatment failure in most patients. Again,
the impact on survival is modest. The use of biologic
response modifiers, such as interferon as maintenance
therapy or adjuvant vaccination with Bec2/bacille
Calmette-Guerin, has also been tested, but again with
disappointing results.17,18 GCSF and granulocyte macrophages CSF, given to counter the hematologic effects
of combination chemotherapy, lessen the severity of
neutropenic episodes, but they do not appear to influence survival significantly, in spite of the increased doses
of chemotherapy.19 Nor did the addition of GCSF to
Treatment of SCLC: chemotherapy 187
primary antibiotic prophylaxis result in cost savings in
the study by Timmer-Bonte et al.20
SECOND-LINE CHEMOTHERAPY
Because of its high relapse rate, the management of relapsed
SCLC is a very common clinical problem. Good-quality
studies to guide the decision-making process are very
scarce, even though new evidence has emerged from
recent studies. Using non-cross-resistant regimens at
multifocal relapse, a response rate of 20–25% is obtained,
with a median duration of survival of 3–4 months. If
there is a longer chemotherapy-free interval before
relapse, the same drug combination that initially produced a response may be repeated, with response rates
up to 50%, but again the effect is rather shortlasting.
Until recently it was not known whether second-line
therapy influences survival as no randomized trials had
compared chemotherapy against best supportive care
(BSC). To answer this important question, 141 relapsed
patients were randomly allocated to oral topotecan
2.3 mg/m2 on days 1–5 every three weeks or to best supportive care.21 Prognostic and predictive factors for
response were equally balanced. Approximately twothirds of the patients had performance status 0 or 1.
Topotecan resulted in a modest response rate of 7% and
44% of patients achieved stable disease. Median survival
time with BSC was 13.9 weeks (95% confidence interval
(CI) 11–18.6 weeks), and with topotecan 25.9 weeks
(95% CI 18.3–31.6 weeks), and the overall six-month
survival rate was 49% compared with 26% on the best
supportive care arm (p = 0.01). The largest numerical
survival benefit was seen in patients with the longest
treatment-free interval. Dyspnea and pain were reduced
in the topotecan arm compared with best supportive care
(3% versus 9% and 3% versus 6%, respectively), indicating better symptom control in the topotecan arm.21
It is still an open question which type of second-line
therapy is superior. Randomized trials have found that
intravenous topotecan resulted in equal response rates
and survival compared with a combination of cyclophosphamide, doxorubicin, and vincristine (CAV).22 Furthermore, iv and oral topotecan showed similar responses in
a randomized trial.23 It is also noteworthy that amribucin, a totally synthetic 9-aminoanthracycline, has shown
significant activity with an overall response rate of 50%
(CL25–75%) in a phase II study including 60 Japanese
patients with refractory or relapsed SCLC.24 If the patient
has a local relapse and has not received irradiation previously, palliative radiotherapy is often the treatment of
choice as second-line treatment.
TREATMENT OF ELDERLY AND POOR-PROGNOSIS
PATIENTS
Knowledge of the optimal treatment of the elderly is
limited, as most large randomized trials tend to exclude
elderly patients. This occurs despite the fact that more
than one-third of patients with SCLC are >70 years old
and the proportion of elderly in the population is continuously increasing, as the average expected lifetime
increases in the general population.25
In patients >70 years old, Ardizzoni et al26 evaluated
two regimens of cisplatin and etoposide – full dose (FD)
and reduced dose (RD) – in a two-stage, randomized,
non-comparative phase II design. The primary endpoint
was the rate of treatment success defined as the proportion of patients receiving at least three courses of the
planned dose of full dose chemotherapy on time and
achieving an objective response without grade 3 and 4
toxicity or any chemotherapy-related complications.
The median number of adminstered cycles was four in
both arms and approximately the same percentage of
patients completed the treatment per protocol in both
arms (75 vs 22%). Median survival times and one-year
survival rates were 31 versus 41 weeks and 18% versus
39% on the RD and FD arms, respectively. RD chemotherapy thus offers no advantage over FD chemotherapy,
which is in accordance with previously randomized trials, indicating that presumably less toxic treatment
regimens can compromise the goal of palliation, symptom control, and survival. In another study with an
elderly population in which more than 90% of the 220
patients were >70 years old and 25% of patients had
performance status 2 or 3, split-dose cisplatin was compared with carboplatin in combination with etoposide.
Response rates, palliation score, and progression-free
and overall survival were equal, indicating that carboplatin can substitute for cisplatin in a palliative setting
without compromising clinical outcome.27
TARGETED THERAPIES
The use of therapies based on mechanisms that target
critical molecular pathways of tumors has also been
tested in SCLC, but to a lesser degree than in NSCLC.
Phase II trials have explored the use of maintenance
therapy with the antiangiogenic drug thalidomide, and
the drug has also been evaluated in a phase III trial with
119 patients, which was stopped prematurely because
of low accrual rate.28,29 The data from the study of 92
randomized patients are inconclusive, but noteworthy is
the longer median survival on the thalidomide arm
188 Textbook of Lung Cancer
compared with the placebo-treated arm (11.7 months
versus 8.7 months). Other interesting phase II trials
have used temsirolimus, which targets the mTOR
kinase,30 and also bortezomib, which is a proteasome
inhibitor,31 while other agents tested include G3139, an
antisense oligonucleotide directed at the BCL2 gene.32
In addition the EGFR tyrosine kinase inhibitors gefitinib and imatinib, a KIT receptor tyrosine kinase, and
the farnesyltransferase inhibitor R115777 have been
evaluated in patients with relapsed SCLC,33–35 but the
studies are too small to justify firm conclusions.
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2. Laurie SA, Logan D, Markman BR et al. Practice guideline for the
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3. Thatcher N, Qian W, Clark PI et al. Ifosfamide, carboplatin,
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5. Noda K, Nistriwaki Y, Kawahara M et al. Irinotecan plus cisplatin compared with eposide plus cisplatin for extensive small
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6. Hanna NH, Bunn PA, Langer C et al. Randomized, phase III
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7. Schmittel A, Fischer von Weikersthal L, Sebastian H et al. Irinotecan plus carboplatin versus etoposide plus carboplatin in
extensive disease small cell lung cancer: a randomized phase II
trial. Proc Am Soc Clin Oncol 2005; 24: 632 (abstract 7046).
8. Eckardt JR, von Pawel J, Papai Z et al. Open-label, multicenter,
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14. Pujol JL, Daurés JP, Riviére A et al. Etoposide plus cisplatin with
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15. Hirsch FR, Hansen HH, Hansen M et al. The superiority of
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cell cycle analysis in the treatment of extensive small-cell lung
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16. Altinbas M, Coskun HS, Er O et al. A randomized clinical trial
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2004; 2: 1266–71.
17. Ruotsalainen TM, Halme M, Tamminen K et al. Concomitant
chemotherapy and IFN-α for small cell lung cancer: a randomized multicenter phase III study. J Interferon Cytokine Res
1999; 19: 253–9.
18. Giaccone G, Debruyne C, Felip E et al. Phase III study of adjuvant vaccination with Bec2/Bacille Calmette-Guerin in responding
patients with limited-disease small-cell lung cancer (European
Organisation for Research and Treatment of Cancer 0897108971B; Silva study). J Clin Oncol 2005; 23: 6854–64.
19. Timmer-Bonte JN, de Boo TM, Smit HJ et al. Prevention of
chemotherapy-induced febrile neutropenia by prophylactic
antibiotics plus or minus granulocyte colony-stimulating factor
in small-cell lung cancer: a Dutch randomized phase III study.
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20. Timmer-Bonte JNH, Adang EMM, Smit HJM et al. Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer.
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21. O’Brien MER, Ciuleanu T-E, Tsekov H et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin
Oncol 2006; 24: 5441–7.
22. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus
cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;
17: 658–67.
23. von Pawel J, Gatzemeier U, Pujol JL et al. Phase II comparator
study of oral versus intravenous topotecan in patients with
chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19:
1743–9.
24. Onda S, Masuda N, Seto T et al. Phase II trial of amrubicin for
treatment of refractory or relapsed small-cell lung cancer: Thoracic Oncology Research Group Study 0301. J Clin Oncol
1996; 24: 5448–53.
25. Rossi A, Maione P, Colantuoni G et al. Treatment of small cell
lung cancer in the elderly. Oncologist 2005; 10: 399–411.
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26. Ardizzoni A, Favaretto A, Boni L et al. Platinum-etoposide chemotherapy in elderly patients with small-cell lung cancer:
results of a randomized multicenter phase II study assessing
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Forza Operativa Nazionale Italiana Carcinoma Polmonare and
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study. J Clin Oncol 2005; 23: 569–75.
27. Kunitoh H, Okamoto H, Watanabe K et al. Randomized phase
III trial of carboplatin (Cb) or cisplatin (P) in combination with
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small cell lung cancer (ES-SCLC) in remission. Proc Am Soc
Clin Oncol 2005; 24: 661 (abstract 7166).
29. Pujol J, Breton J, Gervais R et al. A prospective randomized
phase III, double-blind, placebo-controlled study of thalidomide in extended-disease (ED) SCLC patients after response
to chemotherapy (CT). Lung Cancer 2005; 49: S54 (abstract
O-159).
30. Pandya K, Levy D, Hidalgo M et al. A randomized phase II ECOG
trial of two dose levels of temsirolimus (CCI-779) in patients with
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(abstract 7168).
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1187–93.
12 Malignant mesothelioma
Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney
Contents Introduction • Epidemiology • Pathogenesis • Pathobiology • Global transcriptional
profiling in MM • Immunobiology • Animal models • Clinical presentation and course • Diagnosis
• Management • Future directions
INTRODUCTION
Malignant mesothelioma (MM) is an aggressive malignant tumor of serosal surfaces. It most commonly affects
the pleura, but also involves peritoneal and occasionally other serosal surfaces. It was considered a rare disease before about 1960, but has increased dramatically
in incidence since that time, almost certainly owing to the
widespread use of asbestos fibers in the postwar industrial boom.
Our aim in this chapter is to summarize the main
features of the disease and provide an update of recent
developments. The latter should be of substantial interest to the reader, since there have been a number of
recent publications in mesothelioma research that not
only have begun to unravel the mysteries of the disease,
but have also provided a new palliative standard of
care, and the prospect of further new approaches to
therapy for this otherwise treatment-resistant problem.
Advances have been in the area of pathogenesis and
mechanisms, particularly the identification of the growth
factors involved in the disease, the potential role of nonasbestos agents such as the SV40 virus, and the identification of tumor suppressor gene lesions in this disease.
Advances have also been made in the immunobiology
and immunotherapy of the disease, in the development
of new chemotherapy trials, and in the areas of epidemiology and medicolegality.
In this chapter, we shall begin by reviewing the epidemiology and biology of MM, particularly with regard
to its pathogenesis and immunobiology. We shall then
summarize the clinical aspects of the disease, and finish
the chapter with a discussion of possible future directions based upon these recent advances.
EPIDEMIOLOGY
In 1960 Wagner et al1 reported an association between
asbestos and both pleural and peritoneal MM in a case
series of the North Western Cape Province of South
Africa, where blue asbestos (crocidolite) was mined. Since
then, many reports supporting the relationship between
occupational or environmental exposure to asbestos
and the subsequent development of MM have been
published from all parts of the world.2,3 The relationship
is clearly one of cause and effect. This has been shown
in case series and cohort studies.
Wagner’s initial study identified the difference in risk
from direct occupational exposure and brief or indirect
exposure to asbestos. The risk of development of MM is
directly related to the duration and intensity of exposure to asbestos. Therefore, if asbestos exposure
occurred at a young age then the lifetime risk of development of MM is higher than in someone whose exposure occurred at a later age. Asbestos workers had direct
occupational exposure to asbestos, and their families
received brief or indirect exposure via clothes and hair
brought home from the work-place.4 Other employees
working in the same area as asbestos workers were also
subject to greater risk.
Epidemiologic studies have shown that 50–80% of
individuals with MM have an identifiable exposure to
asbestos.5 Therefore in 20–50% of cases there is no
obvious exposure to asbestos, and examination of the
lung mineral fiber content shows that in many of these
subjects there is a lower lung fiber burden than seen in
subjects with asbestosis.6 This supports the evidence
that MM may occur after brief and indirect exposure to
asbestos. As a group, however, patients with MM have
markedly increased lung fiber burdens when compared
with a reference population.
Asbestos fiber dimensions and type play an important role in the development of MM, with longer and
thinner asbestos fibers causing more damage than
shorter and wider fibers because they can deposit within
and penetrate the lungs (see below). The critical fiber
dimensions appear to be less than 0.25 mm in diameter
and greater than 5 mm in length to produce MM, and,
Malignant mesothelioma 191
while the risk of developing MM from exposure to
chrysotile fibers is lower than that from amphibole
fibers, large amounts of chrysotile can cause MM, possibly because of contaminating tremolite fibers.7 A potential role for SV40 is also described.
PATHOGENESIS
Mesothelial tissues
Mesothelial tissues include all those that line the cavities that were derived from the embryonic mesodermal
celomic cavity. The tissue develops as a continuous epithelial layer, which covers the pleura, the pericardium,
and the peritoneal cavity. In the pleura, it exists as a
single layer of mesothelial cells, resting on a basement
membrane. The cells are variable in shape, from flat to
cuboidal to columnar. Their rate of division is generally
slow, but it is increased in response to inflammatory
damage. Mesothelial cells are actively phagocytic in culture, and they can take up asbestos fibers.8 This may be
important in their susceptibility to transformation, since
they are not normally exposed to chronic insults.
Etiologic agents
Asbestos
Asbestos is a collective name for a group of fibrous minerals composed of hydrated magnesium silicate. They
divide into serpentines, which are short and curved,
such as chrysotile, and amphiboles, which are long and
needle-like, such as crocidolite. Not all of the different
forms have had widespread commercial use – in fact,
90% of industrial asbestos is chrysotile. The mining
and use of asbestos were maximal in 1973, and are now
in decline because it has become clear that exposure to
asbestos can cause a number of pulmonary conditions.
These include pleural plaques, diffuse pleural thickening, rounded atelectasis, and asbestos-related pleural
effusions. As mentioned above, there is an association
between asbestos and MM, and it now seems reasonably clear that the duration and dose of exposure to
asbestos correlate with the risk of developing MM.9
The physical characteristics of the asbestos fibers are
important in the development of MM. It is generally
thought that the amphiboles, particularly crocidolite,
are more carcinogenic for mesothelial tissues.5 Some
cases of MM occur following exposure to chrysotile,
although this apparent association may be due to contamination of this form with amphiboles. However, in
experimental situations, the two groups of asbestos
fibers are equally mutagenic to mesothelial cells. In
these studies, the chrysotile was introduced intrapleurally, and it may be that the shape of these fibers makes
it less likely that they would penetrate the intact lung
after inhalation. Consistent with this hypothesis, the
most carcinogenic fibers in animal studies have been
shown to have a diameter of less than 1.5 µm and a
length of greater than 8 µm, i.e. a high length-to-width
ratio.10 The disease progresses through the formation of
granulomatous lesions that have a surface layer of mesothelium, with subsequent neoplastic transformation.
Mesothelial cells have been shown to be 10 times more
sensitive than bronchial epithelial cells to the direct
cytotoxic effects of asbestos fibers,11 but, after intraperitoneal injection of asbestos, the initial response is from
macrophages, with resultant inflammation and cytokine
production.12 The fibers cause iron-catalyzed generation
of reactive oxygen metabolites, which have a direct
toxic effect, causing DNA point mutations and strand
and chromosomal breaks.13 These events usually lead
to cellular apoptosis, but particular mutations, combined with the direct mitotic damage of cells by asbestos
fibers14 and the increased proliferation induced by
inflammation, may increase the risk that these cells survive despite their genetic changes. The end result is
malignant transformation.
SV40
The double-stranded DNA virus SV40 has been suggested as a possible etiologic agent in the development
of MM. In 1994, Carbone and co-workers found SV40like sequences in 60% of frozen MM specimens by
polymerase chain reaction (PCR). The majority of these
patients also had a history of asbestos exposure, raising
the possibility of SV40 acting as a co-carcinogen. SV40
is a papovavirus whose normal host is the monkey. As
a small virus, it is dependent on its host for the enzymes
of replication except for the large T antigen (TAG).
When the virus infects a cell, the TAG is transcribed
from the viral genome. TAG binds to the specific SV40
origin of replication, pulling apart the DNA strand,
allowing viral DNA synthesis. In this way, the virus is
able to bypass the normal cellular controls on replication, and will even do so in quiescent cells. This process
is facilitated by TAG binding to both p53 and the retinoblastoma protein (pRb), with inactivation of these cell
cycle checkpoints.
It is presumed, but not proven, that SV40 was introduced into humans as a result of the Salk polio vaccines
used in the 1950s. It has been estimated that up to 30%
of vaccines used were contaminated by SV40 as a result
of culturing the poliovirus in rhesus monkey kidney
192 Textbook of Lung Cancer
cells. SV40 had long been known to be tumorigenic in
rodents, but in 1992 Bergsagel et al15 found evidence of
TAG sequences in childhood tumors. This discovery
was followed by evidence obtained by Carbone’s group,16
suggesting an oncogenic role of SV40 in causing MM in
hamsters. They found that 100% of hamsters that were
injected with intrapleural SV40 developed MM, and
this led to the sequencing of SV40 in human MM by
this group.17
Since then, a number of other studies have confirmed
Carbone’s findings, with the proportion of cases ranging from 44 to 86% of MMs tested. One dissenting
group has been that of Strickler,18 who examined MM
tissue from 50 patients with two separate primer sets
and did not detect any SV40 sequences. This group also
undertook a retrospective cohort study comparing
those people who were likely to have received contaminated polio virus against those who did not, and found
no increase in the incidence of a number of cancers,
including mesothelioma.19 As Strickler’s group concedes, the cohort studied has not yet reached the age of
peak incidence for MM.
In two separate studies, Carbone’s group have gone
on to study possible mechanisms by which SV40 may
contribute to the pathogenesis of MM. They have found
that the SV40 sequences present in MM tissue samples
retain the ability to inactivate both p5320 and pRb.21
The potential to overcome these checkpoints in cellular
proliferation could be crucial in enabling a tumor to
survive and progress. While such speculation is inviting, reservations remain about the place of SV40 in cancer. Clearly SV40 is not essential for the development
of MM, since many cases do not express TAG sequences.
Are such tumors different in their behavior – and what
of those that do not express TAG? There may be as yet
undiscovered co-factors that are more important for
tumorigenesis. If we are to accept the polio vaccine
contamination hypothesis then why is TAG expressed
in tumors of children who were too young to be immunized in this setting? Artefactual presence would call
into question all of the above research, but there must
otherwise be previously undescribed vertical transmission of the virus or some other means of human infection. Further investigations and more accurate
molecular and proteomic reagents are required to determine more clearly how SV40 fits into the pathogenesis
of MM.
Other agents
One-quarter of people who develop MM have had no
known exposure to asbestos. While some of these cases
may arise from occult exposure, a number of other possible agents have been proposed to cause the disease.
These include thoracic radiotherapy, intrapleural thorium dioxide, and other silicates, including erionite and
zeolite. The numbers of cases attributed to radiation
exposure are very small. A genetic predisposition has
also been suggested by occasional reports of clusters of
disease within a family, but again numbers are small
and co-exposure is difficult to exclude. Although asbestos exposure and smoking have been shown to be synergistic in terms of the likelihood of development of
bronchogenic carcinoma, there is no known association
between smoking and MM.22
Pathogenesis
The molecular evolution of most tumors is currently
believed to follow that of the classic model described for
the development of colon cancer by Volgelstein et al.23
In this model, a single cell develops a genetic mutation
that enables it to proliferate despite absent or even negative growth-stimulatory signals from normal tissue.
Such mutations can occur in response to a carcinogen
such as asbestos in MM, as discussed above. The multistep accumulation of further mutations to cells in this
clone leads to the development of the hallmarks of a
frank malignancy, namely autocrine growth, invasion,
and the ability to metastasize. This whole process may
occur over a period of many years. Alterations enabling
this malignant pattern of growth to occur may include
oncogene activation or mutation, loss of tumor suppressor genes, and autocrine or paracrine secretion of
growth factors. Determining which changes a cell
undergoes to develop this malignant phenotype has the
potential to provide insights into new methods of treatment for a tumor. In MM, considerable progress has
been made over the last ten years in elucidating candidate factors, but no clear single pathogenic pathway has
yet been found.
Chromosomal abnormalities
Asbestos is known to induce chromosomal mutations
directly. This may occur by the production of reactive
metabolites as mentioned above, by interference with
the mitotic spindle at division, or by direct chromosomal adherence resulting in fragmentation. The majority of cases of MM subjected to cytogenetic study have
shown karyotypic changes,24 and a wide range of complex and heterogeneous chromosomal abnormalities
have been described. Chromosomal gains have been
found to be as frequent as losses, and some of these are
relatively common, such as loss of 4, 22, 9p, and 3p,
Malignant mesothelioma 193
and gain of 7, 5, and 20.25 Significant correlation between
certain losses (1 and 4) and a high content of asbestos
fibers in lung tissue has been shown. The mean chromosomal number has also been shown to correlate with
survival in patients with MM. Those patients with a normal chromosome number and no clonal abnormalities
had the longest average survival.26
Of the many abnormalities described, there are some
alterations that are of particular interest in terms of
pathogenesis. Monosomy 22 is the most common
numerical cytogenetic change, and has been correlated
with mutations in the neurofibromatosis type 2 (NF2)
gene.27 The loss of at least one locus in 1p (nearly all in
1p22) was found in 74% of examined specimens,28 and
42–62.5% of cases of MM have been found to have loss
of heterozygosity of one or more loci on chromosome
3p.29 These changes are of interest in that there is a gene
for cellular senescence on chromosome 1 and a tumor
suppressor gene located on chromosome 3.13 Polysomy
of chromosome 7 is common, and the number of copies
of the short arm of this chromosome has been found to
be an adverse prognostic feature.24 The loci for the epidermal growth factor receptor (EGFR) and the plateletderived growth factor A chain (PDGF-A) are both
present on this chromosome (see below). In one study,
83% of cell lines had deletions of 9p,30 which is the
location of the gene for p16INK4 (see below). Sixty-one
percent of MM specimens were also found to have allelic
losses in 6q in four discrete locations, most of which
had losses in more than one of these regions.31 As was
postulated by Bell et al,31 the consistent losses seen in
certain areas may imply that these regions are the sites
of tumor suppressor genes, the loss of which is central
to the development of the tumor.
Oncogenes
Specific oncogenes have been found to be central to the
progression of many malignancies, but as yet this has
not been particularly well studied in MM. Of interest,
however, are the findings that the v-src gene has been
shown to cause MM in chickens32 and that the EJ-ras
gene causes tumorigenic transformation of mesothelial
cells when transfected.33 There is no evidence that these
oncogenes play a role in human MM. The most promising candidates have been c-fos and c-jun, which have
been implicated in animal models. The levels of both
c-fos and c-jun mRNA have been shown to be upregulated when rat pleural mesothelial cells are exposed to
asbestos.34 This pathway has been further investigated
by showing that these changes are prevented by the use
of N-acetylcysteine35 and by calphostin C, a protein
kinase C inhibitor.36 Such findings could implicate
these proto-oncogenes in the pathogenesis of MM, but
the levels of c-Fos protein were found to be similar in
MM and non-neoplastic mesothelial tissue.37 Wild-type
K-Ras was found in all 20 MM cell lines examined by
Metcalf et al.38 c-Myc immunocytochemical expression
is common,39 but c-myc was not found to be amplified
in murine MM cell lines.40
Tumor suppressor genes
In order for a tumor to continue to proliferate in the
face of genomic damage, it is necessary that it avoid the
normal cellular processes for the detection of such damage. Tumor suppressor genes enable the cell either to
arrest the cell cycle with the possibility of repair or to
undertake programmed cell death (apoptosis). Mutation
or loss of a tumor suppressor gene enables an altered
cell to continue through the cell cycle unchecked, and
allows further proliferation. The most well-described of
the tumor suppressors is TP53, which is known to be
mutated in a majority of human cancers.41 Alterations
in TP53 have been found in 75% of murine MM cell
lines,42 but wild-type p53 was normally expressed in
most human MM cell lines38 and demonstrated by
immunohistochemistry in primary tumors.43
The retinoblastoma protein pRb prevents progression of a damaged cell into S phase when it is hypophosphorylated. Its level of expression in human MM
cell lines has been shown to be normal.44 Mouse double-minute 2 (MDM2), a protein that can inhibit the
function of both p53 and pRb, is not overexpressed in
human MM,45 although a proportion has been shown
to have positive staining for MDM2.46 The possibility of
expressed pRb being abnormal in this tumor has been
raised by the finding that a monoclonal antibody specific for the epitopes between exons 21 and 27 showed
no immunoreactivity by immunohistochemistry, whereas
a polyclonal antiserum showed staining in all MMs
examined.47
In keeping with the frequent loss of chromosome 9,
the product of the CDKN2 gene, p16INK4, was found to
be abnormally expressed in 12 of 12 primary MMs and
15 of 15 MM cell lines.48 p16INK4 normally inhibits
phosphorylation of pRb, and thus its loss would allow
uncontrolled progress through this stage of the cell cycle.
Deletions of the portion of chromosome 9 containing
CDKN2A, but not CDKN2B, were also found in MM cell
lines,49 whereas p16 has previously been found to be
deleted in 85% of MM cell lines but only 22% of primary tumors.50 Seventy-two percent of primary MMs
have also been found to have co-deletions of p15 and
194 Textbook of Lung Cancer
p16.51 p16/CDKNA2 was homozygously deleted in 59
out of 80 human tumors52 and patients with intact p16
had a significant survival advantage.53
The third tumor suppressor of particular interest in
MM is the NF2 gene. This was found to be mutated in
41% of MM cell lines examined by Sekido et al54 and
53% of cell lines examined by Bianchi et al.55 This latter
group also found that three-quarters of these mutations
were confirmed to be present in the primary tumor.
This finding for MM in humans does not correlate with
the disease in rats, where mutations were not found.56
The Wilms’ tumor gene (WT1) is expressed in normal mesothelium during embryogenesis. It is potentially interesting in view of the fact that one of the
actions of the WT1 protein is to control the transcription of genes such as those for PDGF-A,57 insulin-like
growth factor (IGF)-II,58 transforming growth factor
(TGF-β),59 and the IGF-I receptor (IGF-IR).60 All of
these have been described as potential autocrine growth
factors in MM, and the deletion of WT1 could allow
excessive production. Expression of WT1 mRNA has
been found in most human MM cell lines examined and
in most primary tumors.61,62 The level of expression has
been found to be variable, but there was no inverse correlation found between expression of WT1 and IGF-II
or PDGF-A.63 A further study using mutational screening found no significant changes to WT1, and also
found no correlation between WT1 immunostaining
and EGFR or IGF-IR levels.64
PATHOBIOLOGY
The diagnosis of MM is usually made on the basis of
histologic analysis, from which the tumor can be classified as follows:
1.
2.
3.
4.
Epithelial: the tumor mass consists of papillary,
tubular, acinar-like, or solid tissue in which cuboidal tumor cells form a pavement-like appearance.
The amount of stroma within the tumor is variable.
Sarcomatous: the tumor mass consists of spindleshaped cells forming organized bundles, though
whirls, ‘herring bone’, or irregular patterns of
tumor cells also occur.
Desmoplastic: the tumor mass consists of a sizable
connective tissue component with variable cellularity and pleomorphism. Epithelium-like structures are not present in this form.
Biphasic: the tumor mass consists of a mix of the
epithelial and sarcomatous forms. This is the most
common type.
Differential diagnosis of MM from reactive mesothelium or adenocarcinoma is an important aspect of analysis of biopsy samples. Cytologic diagnosis is based first
on the malignant nature of the samples by generally
applicable criteria (nuclear polymorphism, irregularity
of nuclear membrane, chromatin distribution), followed
by confirmation of the mesothelial characteristics. These
characteristics include a characteristic cytoplasmic
appearance, a brushlike border and multinucleation.
Further confirmation can be obtained by ultrastructural
analysis, showing long microvilli and numerous intermediate filaments.65 The differential diagnosis of MM
from metastatic adenocarcinoma has been facilitated by
the availability of extensive immunohistochemical panels, including mesothelial markers such as calretinin,
mesothelin, podoplanin, and thrombomodulin, and
glandular markers such as CEA, LeuM1, and B72.3. In
addition more specific markers of lung adenocarcinoma
such as TTF-1 are now available.66 However, distinguishing MM from benign mesothelial cells remains a
challenging area in cytologic diagnosis. Strong membrane staining for EMA on the majority of mesothelial
cells is considered indicative of malignancy.67
GLOBAL TRANSCRIPTIONAL PROFILING IN MM
Using various global transcription profiling ‘microarray’
strategies, several studies have been performed in MM
with various aims: to understand the genetics and biology
of MM, to identify genes that may be useful for early
diagnosis, for determining prognosis, and to identify
potential targets for the development of new therapies.
Experimental models examining asbestos-induced
transformation of mesothelial cells68 as well as studies
using human MM patient samples have shown activation of pathways common to the development of many
cancer types. Such functions relate to growth and proliferation, cell-cycle progression, apoptosis, invasion,
and metastasis. Pathways including the insulin-like
growth factor-1, p38 MAPK, Wnt/β-catenin, and integrin signaling have been found to be important for MM
development.69,70
Diagnostic strategies for distinguishing MM from
lung adenocarcinoma have been suggested based upon
gene expression profiling.71,72 As well, specific markers
such as osteopontin were shown in gene expression
studies to be upregulated in MM, and may be of possible value as a serum marker for MM.73
Some studies have concentrated on finding gene
‘signatures’ that can be used as to predict prognostic
Malignant mesothelioma 195
indicators for MM.74–77 However, it appears that clinical
prognostication based on gene expression profiling is
not significantly superior to that achieved using classic
clinical parameters such as age, sex, epithelial histology, lymph node status, and tumor stage.77 Global
microarray profiling, however, has revealed potential
new clinical targets such as the aurora kinases.77
IMMUNOBIOLOGY
The human disease
In contrast to many other tumors, there is little evidence in MM that specific immune responses are initiated against the tumor during the course of the disease.
Some descriptions of leukocytic infiltrations have been
reported in the literature, but these examples are rather
non-systematic and use very broad characterizations.
What is evident is that the extent of infiltration depends
on the individual tumor.78,79 One unusual form of MM
is termed lymphohistiocytoid MM – so called because
there is evidence of lymphocytes infiltrating the tumor
mass.80 Although suggestive of specific immune recognition of the tumor, there is no direct evidence that
supports this hypothesis, and these cells may simply
reflect a non-specific inflammatory response. In fact,
early attempts to isolate MM-reactive killer cells from
patients proved unsuccessful.81 Overall, the lack of
tumor-infiltrating lymphocytes (TILs), as with many
other tumors, has been attributed either to a lack of
tumor antigen expression or to other factors, such as
the secretion of immunosuppressive cytokines, that
diminish the overall immunogenicity of the tumor.
However, more recent work has suggested that an
immune response is generated in a significant proportion (28%) of MM patients.82 In these studies, patient
sera reacted with a panel of human MM cell lines as
determined by Western blot analysis. When sequential
sera were analyzed, it was found that the titer increased
with the progression of the disease. Importantly, the
MM-reactive antibodies within the sera were of the IgG
class, indicative of immunoglobulin class switching,
and hence the involvement of the cellular arm of the
immune response, which is obligatory for this process.
These are important data, which will lead to identification of a number of potential tumor-associated antigens
(TAAs), the characterization of which will be invaluable
in the context of potential vaccination strategies or
immunotherapeutic treatments.
In addition, clinical studies have suggested that, even
if an immune response is not a normal event in the
disease process, this malignancy may be susceptible to
immunotherapy. In a small trial using intralesional therapy with granulocyte–macrophage colony-stimulating
factor (GM-CSF), while there was no direct evidence of
a tumor-specific immune response, the one patient who
showed a partial response also had an intense lymphocytic infiltration in biopsy samples.83 Apart from using
this direct administration of a cytokine, efforts have
been made to utilize gene therapy techniques in treatment. In particular, the use of genes encoding cytokines
has been the most prevalent, in the hope that they will
boost or enhance any ongoing antitumor response.
Although gene therapy has provided some encouraging
results in animal models, the difficulty with this technique in solid tumors, such as MM, is the inability to
transduce all tumor cells with the gene of interest.
Therefore some emphasis has been placed on trials in
which cytokine genes are transferred via viral vectors
such as vaccinia.
The growth of tumors is often considered to be
immunosuppressive, and MMs have been shown to
secrete a number of cytokines or factors that are known
to modulate immune responses, including PDGF,
TGF-β, and interleukin-6 (IL-6). As is quite often the
case with such products, they are responsible for coordinating or mediating a number of processes, and
PDGF and TGF-β have also been shown to be growth
factors for MMs. The role of these molecules in influencing the immune response to MM has not been investigated deeply, and what we know has been elucidated
in animal models (see below).
Another potential mechanism whereby MMs might
evade immune recognition is by the downregulation of
HLA class I molecules, such as has been reported for
melanoma. However, a survey of a panel of human and
murine lines has shown that these tumors all express
class I molecules, and therefore they can still be targets
for the immune response.
ANIMAL MODELS
A number of different models of MM have been established in animals to understand the pathogenesis of the
disease and to test potential therapeutic agents. Spontaneous mesotheliomas have not been described in mice
or hamsters and occur very rarely in rats. However,
natural and synthetic fibers, chemicals, and metals have
been shown to induce pleural and peritoneal mesotheliomas in rodents.84 Additionally, intrapleural inoculation of hamsters with SV40 virus causes pleural
196 Textbook of Lung Cancer
100
% Survival
mesotheliomas in 100% of cases.85 The injection of
asbestos fibers into pleural and peritoneal cavities produces malignant mesotheliomas in 20–30% of mice.86,87
These mouse mesotheliomas are comparable to the
human disease with respect to latency, superficial
growth of tumor on the serosal surface, and the accumulation of ascites.88 Although this is not a viable working model for the testing of therapies due to the long
latency period and low incidence of disease development, it has led to the generation of many asbestosinduced mesothelioma cell lines.86 Subcutaneous
inoculation of these mesothelioma cell lines into syngeneic mice induces solid tumors which grow rapidly and
are easily accessible for monitoring efficacy of drug
treatments. As these tumors exhibit the diagnostic characteristics of the human tumor, despite their anatomic
dislocation, they have been used extensively to study
the immunobiology of MM89 and to evaluate efficacy of
chemotherapies, immunotherapies, and combination
therapies.90–92
More recently, genetically modified transgenic mouse
mesothelioma models, with features of asbestos-induced mesothelioma, have been devised and it is hoped
that these new models will enable further testing of
drug therapies and study of the disease. Although loss
or mutation of p53 is not considered a trait of mesothelioma, the first transgenic model used was a p53 knockout mouse, originally created to study a range of cancers.
Although a proportion of homozygous p53−/− knockout mice developed disease soon after asbestos inoculation, these mice have a short lifespan of only 22 weeks
and the rest died of other causes, rendering them unsuitable for modeling this disease.93 More promisingly, the
heterozygous p53+/− knockout mice have a longer
lifespan and 76% of these mice had developed asbestos-induced mesothelioma compared to 32% wild-type
mice, at 44 weeks after initial asbestos exposure. These
p53+/− heterozygous mice have been used in further studies investigating loss of heterozygocity in asbestos-induced tumors.94
Human malignant mesotheliomas frequently accumulate genetic alterations affecting the Nf2 and
CDK2A/Arf tumor suppressor gene loci. When Nf2+/−
knockout mice are exposed to asbestos, they develop
mesothelioma more rapidly and at a higher incidence
than wild-type littermates.95,96 Analysis of the tumors
showed that they recapitulated the most common
molecular features of human malignant mesothelioma.
They had frequent deletions in the Arf/CDK2A locus,
inactivation of p53, and activation of the AKT signaling
pathway.97
80
line 299h
line 304i
60
line 266s
wild type
40
20
0
0
10 20 30 40 50 60 70 80 90 100
Weeks after asbestos exposure
Figure 12.1
Mice expressing SV40 are more susceptible to asbestos-induced
MM. Mice bearing the SV40 Large T gene driven by the mesothelin
promoter showed increased sensitivity to asbestos-induced MM.
Shown is the survival of these mice (‘MexTAg transgenic mice’)
after two injections of 3 mg asbestos were given in the peritoneum, 4 weeks apart. Mouse lines 299h, 304i, 266s, and wt
(wild-type) contain 100, 30, 1, and 0 copies of TAg, respectively.
The number of animals in each group is noted. Median survival
times were line 299h, 24 weeks; line 304i, 36 weeks; line 266s,
55 weeks, and wt, 56 weeks. Log rank tests showed survival was
significantly different between all mouse lines, with the exception
of 266s and wt. p Values were 0.005 or less.98
The injection of asbestos fibers into the peritoneum
of mice induces mesotheliomas in less than a third of
mice, between 7 months and 2 years after the first asbestos exposure. Although this method has provided the
mouse mesothelioma cell lines that are useful tools in
the subcutaneous model, the model itself is impractical
for further studies of the disease, such as assessment of
drug efficacy. We have constructed a novel transgenic
mouse model, MexTAg, which directs SV40 TAg
expression to the mesothelial compartment using the
mesothelin promoter. When MexTAg mice, containing
100 copies of the TAg transgene (299h mice), are
injected with asbestos, not only do all of the animals
develop MM but disease occurs much more rapidly
than in wild-type mice (Figure 12.1).98 At 38 weeks all
299h mice had developed MM, whereas 87% of wildtype mice remained healthy. Furthermore, at the end of
the experiment, only 25% of wild-type mice had developed MM. Thus, this model is suitable to examine the
efficacy of preventative and therapeutic drugs and also
to investigate the molecular events occurring at the
early stages of MM development. While MexTAg mice
unexposed to asbestos did not develop MM, in another
transgenic mouse model, which expresses SV40 TAg
under the control of the cytokeratin 19 gene, MM and
other tumor types developed; however it was unfortunate that these mice were unable to breed.99
Malignant mesothelioma 197
Applications to therapy
As mentioned above, immunomodulatory molecules
such as TGF-β are produced by MM cells as obligate
growth factors. One could therefore hypothesize that
interventions that target such factors may be very effective from two aspects: first, by interfering with the
growth cycle of the tumor cells, and, second, by allowing an immune response to be generated. In experiments in which TGF-β production was reduced by
inhibiting translation of these proteins using antisense
DNA technology, tumor growth could be inhibited but
not eradicated.100 Inhibition of tumor growth was concomitant with treatment – the effects were lost on cessation of treatment. No evidence of an improved antitumor
response was noted in these experiments. This result
may have several explanations, including that the amount
of TGF-β required for tumor cell growth is significantly
greater than that required for immunosuppression.
Such approaches are worthy of further investigation –
possibly in combination with other treatments. See the
section below on ‘Future directions’.
CLINICAL PRESENTATION AND COURSE
MM usually develops in males with a history of occupational exposure to asbestos. The latency period
between asbestos exposure and the development of
MM is at least 20 years.1,101 Therefore patients are usually over 50 years of age.102 However, non-occupational
exposure does occur, and in some of these cases the
exposure occurred in childhood. Patients with pleural
MM usually present with symptoms of chest pain or
discomfort, dyspnea, and cough. In fact, the presence
of chest wall pain in any at-risk patient is a strong clue
to the possible presence of MM. Early in the course of
the disease, dyspnea is the commonest symptom, and
is due to the presence of an effusion. The majority of
patients with pleural MM will have a malignant pleural
effusion, which is usually bloodstained, often loculated,
and of large volume. As the tumor progresses, chest discomfort or tightness may occur. The dyspnea may improve
because of fusion of the pleural surfaces and resolution
of the effusion, or therapeutic talc pleuradesis. Unremitting chest pain may occur as the tumor locally invades
the intercostal nerves. Eventually, the lung becomes
encased by tumor, leading to worsening of dyspnea and
chest tightness. The tumor commonly spreads by direct
extension to involve the chest wall, the mediastinum,
other pleura or the diaphragmatic surface, the pericardium, and the liver. Invasion of the pericardium leads
to a pericardial effusion, which worsens the dyspnea.
Spread to local lymph nodes occurs in 40% of cases,
but hematogenous spread is less common and rarely
clinically significant. Weight loss occurs in the late
stages of the disease.
Examination findings in the early stages of the disease usually reflect the presence of a pleural effusion,
with dullness to percussion and reduced breath sounds.
As the tumor progresses and encases the entire hemithorax, the hemithorax may contract, chest expansion
becomes noticeably restricted, and dullness to percussion and reduced breath sounds are found over the
affected area. Breathing sounds can be ‘harsh’ rather
than reduced, and sometimes are frankly ‘bronchial’ in
nature. Protrusion of tumor through the intercostal spaces
tends to occur at sites of previous thoracocentesis, chest
tube insertion, or thoracotomy incision. Supraclavicular lymphadenopathy and ascites may be present if the
tumor has spread to these areas. Paraneoplastic syndromes are rare, but can include hypercalcemia, autoimmune hemolytic anemia, and inappropriate secretion
of antidiuretic hormone (SIADH).103 Thrombocytosis
with a platelet count of greater than 400 000/µl occurs
in approximately 30% of cases,102 but does not commonly lead to increased thrombotic events. Those with
peritoneal disease experience abdominal pain and distension, weight loss, anorexia, and bloating. Peritoneal
MM rarely invades superiorly through the diaphragm.
DIAGNOSIS
Radiology
The most common chest X-ray abnormality in early
stage disease is the presence of a pleural effusion. Pleural thickening or small focal pleural masses may be seen
on computed tomography (CT) of the chest, and CT is
useful in differentiating pleural fluid from pleural
thickening,104 although ultrasound is often required. CT
scanning also provides information on the state of the
pulmonary parenchyma, the mediastinum, and invasion of the chest wall.105,106 As the disease progresses
there is diffuse involvement of the pleura and larger,
pleurally-based masses may become obvious. The pleural
effusion often becomes loculated. Eventually, the lung
becomes encased in a thick pleural rind of tumor that
compresses the underlying lung. Magnetic resonance
imaging (MRI) is useful for delineation of chest wall
invasion. MM is also FDG-PET avid; however the role
of PET scanning in staging, prognosis, and treatment
planning is still under investigation.107,108
198 Textbook of Lung Cancer
•
Cytology
Most patients with MM present with a pleural effusion,
and therefore thoracocentesis is often the first diagnostic procedure. Large amounts of pleural fluid should be
obtained and sent for cytologic examination; this will
be diagnostic in 30–50% of cases.103 The fluid should
be examined using light microscopy and immunochemical stains for cytokeratins and vimentin and
immunohistochemical stains (especially CEA and EMA)
to differentiate adenocarcinoma from MM (see above).
The accuracy of EMA in cytologic studies depends upon
the clone of antibody used in the analysis. The combination of cytologic assessment of pleural fluid and histopathology on closed pleural biopsy specimens can
increase diagnostic accuracy for pleural malignancy,
including MM.112
Biomarkers
Measurement of tumor markers in effusions may provide a complementary tool to aid in effusion diagnosis.
Differential levels of CEA, cancer antigen (CA)15.3,
CA72.4, CA19.9, CA549, neuron-specific enolase, or
cytokine fragment 19 (CYFRA 21-1) differentiate malignant from benign effusions.113,114 However, there are
fewer data available for the differential diagnosis of MM
from other cancers. Low levels of CEA in effusions of
MM patients provide a strong negative predictive value
for this disease.115–117 However, there are few studies
reporting markers with a positive predictive value for
MM. Elevated CA15-3 levels have been reported in
MM,114–116 and in one study as being able to differentiate
MANAGEMENT
MM is an almost uniformly fatal disease that is not usually
curable with surgery, chemotherapy, or radiotherapy.
1.5
1.0
0.5
0.0
Asb-Exposed
•
lack of useful pleural tissue;
difficulty in interpretation of small biopsy
samples;111
the need to distinguish MM from reactive mesothelial inflammation and metastatic pleural tumors;
difficulty in differentiating histologic subtype on a
small specimen.
MM
•
•
between MM and bronchial cancer.116 Higher levels of
hyaluronic acid have been reported in effusions from MM
patients compared to those with other malignant diseases;
however the difference was too small for diagnostic
purposes,117 whereas there is discrepancy in the literature on the ability of CYFRA 21-1 levels to differentiate
between MM and other pleural malignancies.116,117
Recently, we showed that mesothelin levels in effusions
above 20 nM are highly suggestive of malignancy, particularly of MM; at this cut-off value the assay had a sensitivity of 77% for non-sarcomatoid MM, and a specificity
of 98% relative to non-malignant effusions and 86%
relative to non-MM malignancies (Figure 12.2).118
Mesothelin levels have also been shown to be useful in
monitoring disease progress/regression.118
Elevated mesothelin levels were observed in some
effusions before a definitive cytologic and/or histologic
diagnosis could be made. One patient, an 87-year-old
male, who presented with recurrent blood-stained exudative effusions which were negative for malignancy by
cytologic examination, had elevated mesothelin levels
in his effusion. In this case a definitive diagnosis
of MM was made 10 months after the initial mesothelin-positive effusion sample.
SMRP(OD 420 nm)
Histopathology
Accurate diagnosis of MM can be time-consuming, and
may require more than one diagnostic procedure because
of the difficulty in obtaining malignant tissue for histopathologic assessment. Pleural biopsies, obtained via
closed or open (thoracoscopy/thoracotomy) procedures,
improve the diagnostic yield. Pleural biopsy samples
should be assessed by immunohistochemistry and electron microscopy, since these are the important studies
to assist in making a definitive diagnosis.109,110 The major
problems associated with closed pleural biopsies are:
Figure 12.2
Serum mesothelin in MM patients versus asbestos-exposed
controls. Individual patient data are plotted as the mean
absorbance measurement at 420 nm of duplicate serum samples
diluted 1 in 100. Dashed line represents the normal range.
(Adapted from Robinson et al,119 with permission.)
Malignant mesothelioma 199
The potential treatment options are the same as for other
malignancies, namely surgery, radiotherapy, chemotherapy, immunotherapy, gene therapy, supportive care, or
combination therapy utilizing some or all of the above
treatments. However, there are major differences from
other cancers, because in MM it is often difficult to objectively quantify the location and extent of disease, and
the patients are older and often have underlying illness
that makes them unfit for aggressive, rigorous treatment
plans. The relative rarity of the condition means that few
large prospective clinical trials have been published,
and clinicians must rely on retrospective clinical trials
with small numbers of patients. Here, we concentrate
on the palliative management of patients with advanced
disease, the most common presentation. However, surgery with the aim of cure will also be discussed.
Chemotherapy
Until 2003, there were no randomized clinical trials
demonstrating an improvement in survival, quality of
life, or lung function for any palliative chemotherapy
regimen in MM. In 2003, a landmark clinical trial was
published by Vogelzang et al, comparing overall survival, response rates, toxicity, and quality of life in 226
patients with advanced MM randomized to cisplatin
plus pemetrexed, and 222 to single-agent cisplatin.120
Patients receiving cisplatin and pemetrexed had a significantly longer median survival than those on cisplatin alone (12.1 months versus 9.3 months, p = 0.02).
Forty-one percent of patients on the combination arm
had objective tumor responses, compared with 17% in
the single-agent arm (p <0.0001). The combination
arm experienced greater toxicity; however this was
rarely clinically significant and was in part ameliorated
by supplementation with folate and vitamin B12. This
trial also demonstrated small but statistically significant
benefits for combination chemotherapy in global quality of life and symptom distress measures, and larger
benefits for pain, dyspnea, and cough after 18 weeks of
treatment.121 Similar results have been obtained for
another combination chemotherapy using cisplatin and
raltitrexed, significantly improving overall survival as
compared with cisplatin alone.122 Single-arm studies
also suggest good response rates for cisplatin and
gemcitabine,123,124 but this combination has not been
tested in phase III clinical trials. Overall, these studies
have shown that combination chemotherapy, in appropriate patients, can give palliative benefits by decreasing tumor bulk, increasing survival, improving lung
function, and improving quality of life. The timing of
chemotherapy (on diagnosis versus when symptomatic)
and duration of chemotherapy (four versus six versus
more cycles of treatment) are questions for further study.
There are currently no predictive markers of response
to chemotherapy, although patients with ECOG performance status of 2 or worse may be less likely to
benefit.121,124
Radiotherapy
Hemithoracic radiotherapy has a limited role in the palliative management of MM due to the difficulty in delivering adequate doses to a large treatment field. However,
low-dose palliative radiotherapy to limited fields can
very effectively relieve pain from enlarging chest wall
masses.125 Radiotherapy also has an important prophylactic role in preventing chest wall infiltration and
development of masses at the sites of previous invasive
instrumentation such as chest drains or pleural biopsies.126 All patients at risk of local chest wall infiltration
should be considered for this simple procedure.
Immunotherapy and gene therapy
These are relatively new treatment options, and their
role alone or in combination with surgery or radio- or
chemotherapy has not yet been adequately evaluated. It
is known that systemic interferon-α (IFN-α),127,128
IL-2,129 and GM-CSF83 have some activity in selected
cases of MMs, but none has achieved a response rate
sufficient to warrant their recommendation in all
patients. Combining IFN-α with chemotherapy has
also produced no added benefit.130
Surgery
Four types of operation have been performed as treatment for mesothelioma: extra pleural pneumonectomy
(EPP), pleurectomy/decortication, limited pleurectomy,
and thoracoscopy with talc pleurodesis. EPP involves
an en bloc resection of the pleura, lung, ipsilateral
hemidiaphragm, and pericardium. Butchart et al131
reported that this procedure carried an operative mortality rate of 30%, but since then there have been a few
studies reporting a reduction in operative mortality rate
to 6–9%.132–135 This was most likely due to improved
patient selection, experience, and better postoperative
care. Median survival in these studies ranged from 8 to
16 months. Pleurectomy/decortication involves attempting to remove all obvious pleural disease without
removing the underlying lung. The operative mortality
rate is 1.8%;136 however, long-term survival is not significantly increased in most patients. Limited pleurectomy
is a palliative procedure designed to resect part of the
parietal pleura to control a pleural effusion. Thoracoscopy
200 Textbook of Lung Cancer
with talc pleurodesis is an effective palliative procedure for
control of effusion.
Overall, in most cases, surgical procedures alone will
not lead to any significant improvement in survival.
However, Sugarbaker et al137 showed that trimodality
therapy (resection of tumor, chemotherapy, and radiotherapy) in highly selected patients can lead to a small
proportion of patients with long-term survival. In this
study, operative morbidity rate was measured at 17%,
mortality rate was 6%, and overall survival was 16
months. There are no completed randomized clinical
trials to support this practice; however the MARS trial,
run out of the United Kingdom, is currently randomizing patients to surgery as part of trimodality therapy,
or palliative management (including chemotherapy)
alone. Patient selection for ‘curative’ surgery is not standardized; however an aggressive approach to staging
and preoperative investigation that may include PET
scanning, mediastinoscopy, contralateral thoracoscopy
with blind biopsies, and laparoscopy has been advocated.138 Optimal surgical technique is also debated.139,140
Referral to a thoracic surgeon with experience in EPP
should be considered in fit patients with early stage,
potentially resectable disease.
Chemotherapy and radiotherapy
Chemotherapy and radiotherapy are components of socalled ‘trimodality’ therapy; however the optimum timing (pre- or postoperative), regimen, and duration of
chemotherapy are unclear. Clinical trial results are not
yet available to inform these decisions. In clinical practice, a common approach is to use cisplatin and pemetrexed due to the demonstrated activity of this
combination in advanced disease.120 However, it is still
unclear whether chemotherapy is best used preoperatively or postoperatively. Neoadjuvant chemotherapy
may avoid a morbid operation in patients with rapidly
advancing and treatment-resistant disease, and patients
are fitter preoperatively. However, some surgeons consider EPP to be more technically challenging postchemotherapy, and would prefer an adjuvant approach. A
disadvantage of adjuvant chemotherapy is that not all
patients will be fit enough for treatment after surgery.
There are several approaches to integrating postoperative radiotherapy into the trimodality program. The
lowest locoregional recurrence rates post-EPP are in
those series using high-dose postoperative hemithorax
irradiation.141 Recent guidelines for three-dimensional
conformal radiotherapy suggest a dose of 54 Gy in 30
fractions five days per week to the ipsilateral thoracic
cavity, chest wall incisions, and drains, with attention
to normal tissue tolerance for the contralateral lung,
spinal cord, heart, esophagus, and other vital structures.142 Intensity-modulated radiotherapy (IMRT) is a
promising newer technology that may deliver better
local control results;143 however it is not widely available, and there have been reports of subsequent fatal
pneumonitis which suggest caution in implementing
this technology.144 Nevertheless, only patient series
using an aggressive multimodality approach achieve
clinically meaningful five-year survival rates.145
FUTURE DIRECTIONS
In this section, we shall highlight directions in which
MM research is heading, focusing on aspects that could
prove to be clinically useful.
Diagnosis
There has recently been an upsurgance of interest in the
use of tumor biomarkers for the clinical management of
MM. Soluble mesothelin-related proteins in particular
are being intensively investigated. Mesothelin is a differentiation marker of mesothelial cells. Through various post-transcriptionally and post-transcriptionally
processed soluble forms of mesothelin can be detected
in the serum and in the pleural fluid of patients with
MM. Approximately 50% of MM patients have elevated
levels at the time of diagnosis, and up to 84% with
advanced disease.118,146
There is considerable interest in screening asbestosexposed individuals for the early detection of MM. Given
that mesothelin levels have been observed to be elevated
in some individuals up to five years before clinical presentation, mesothelin represents a strong candidate for
a screening program.146 However, the sensitivity of the
screening program will be limited, given that at diagnosis not all individuals have detectable mesothelin proteins in their sera. Currently, methods of combining
different biomarkers and a program that measures
changes in biomarker values, rather than absolute values, are being evaluated. The principle reason for developing a screening strategy for MM would be to commence
treatment on early stage tumors which would hopefully
prove more effective than treatment in more advanced
disease. However, prospective studies and randomized
trials would be required to test such an hypothesis.
Therapy
Future therapies in MM will have two aims. The first is to
alleviate symptoms. Patients with MM often experience
Malignant mesothelioma 201
profound weight loss, fevers, hypoalbuminemia, and
pain. Recent studies have identified cytokines that are
likely to contribute to this, particularly IL-6. In animal
studies, blockade of IL-6 has had a profound effect on
animals’ clinical status, although the actual antitumor
effect was modest, and possibly related to the improvement in the host’s well-being. If a simple method of
inhibiting IL-6 activity in vivo can be established, it is
likely that this could be given to patients with MM to
alleviate their systemic symptoms. Such therapy might
involve receptor blockade or IL-6-signaling blockade
(e.g. via the SOCS molecules).147
The second area in which new developments in therapy might occur is in the generation of antitumor
effects.
Development of new agents
Anti-angiogenic agents
VEGF is an autocrine growth factor in MM,148 and
VEGF expression in MM is correlated with microvessel
density,149 a poor prognostic feature in this disease.150
Bevacizumab is a recombinant humanized anti-VEGF
monoclonal antibody which acts by blocking VEGF
binding to the VEGF receptor. A clinical trial of bevacizumab in combination with chemotherapy is completed
but as yet unreported. Other anti-angiogenic agents
including thalidomide are currently in clinical trials in
mesothelioma.
Immunotherapy
Trials have begun of immunotherapy in its various
forms in MM, and it is likely that in the future the limited but clear success of this approach will be augmented, probably in combination with other therapies.
While established agents such as recombinant IFN-α
have had limited but surprising effects,127 combining
this approach with chemotherapy has not proved more
efficacious.130 This may be partly because of the toxicity
of chemotherapeutic approaches. It is therefore likely that
future immunotherapeutic approaches to MM will
involve other strategies, particularly the local administration of immunomodulatory agents The continuous
infusion of GM-CSF into MM produced some tumor
shrinkage and mononuclear cell infiltrates, but proved
technically demanding.83 Less technically demanding
means to improve delivery of these agents to the tumor
are likely to be developed. There are three possibilities:
improved continuous-infusion technology, depot release
preparations, and gene therapy. The last is the most
advanced. Initial studies using immunologic gene therapy in MM have involved the administration of virus–
cytokine constructs. In one pilot study, this approach
was shown to be feasible to produce a T-cell infiltrate
in the tumor and to be free of side-effects in the patient
and in contacts.151 These are very early days for the
immunologic gene therapy of MM, and there is no
doubt that in the future we shall see further developments in this area. Other gene therapy strategies that
have been utilized have included herpes simplex TK
‘suicide gene’ therapy, which has produced some
responses, and which may be working by a combination of tumor shrinkage and necrosis generating antitumor immune effects. Other gene therapy approaches
that have been utilized preclinically include the use of
antisense oligonucleotides to block MM growth factors
such as PDGF and TGF-β. This approach has proved
most efficacious in vivo, and has caused a profound
reduction in tumor growth in animal models.100 It is
likely that future treatment of MM will involve such
gene therapy approaches, provided that the concentration of antisense oligonucleotides can be increased
within tumors to a level sufficient to cause the required
biologic effects.
Recently, the autolgous MM tumor has been used in
vaccine studies, with local GM-CSF used as the adjuvant. This approach clearly induced anti-MM immune
responses, although substantial tumor regressions were
not seen.152
Combination therapies
It seems likely that the most effective treatment of MM
will require combination therapy. Combinations include
some of those described above, for example molecular
approaches to increase the sensitivity of tumor cells to
chemotherapeutic agents combined with systemic
administration of such agents, or a combination of suicide gene therapy with immunotherapy. In addition, it
is possible that chemotherapy can be strategically combined with immunotherapy in a way that augments the
efficacy of each; for example, it is possible that cycles of
drug therapy may alter the antigenic profile of tumor cells
so that they provide new targets for immunotherapy.
The future development of effective therapies in MM
is likely to rely on two fundamental principles. First, it
will be essential to understand the basic biology and
immunology of the disease before optimal therapies can
be developed. MM is a disease that has remained mysterious for many years, yet over the past five years or so the
underlying pathogenic mechanisms and immunobiology
have begun to be elucidated. Second, it is likely that
combined therapy will be necessary, and that each component will need to have independently proven efficacy,
202 Textbook of Lung Cancer
i.e. it will be important to build on treatments that
already have a track record of clear success at reducing
tumor bulk.
Tumor biology and epidemiology
In terms of epidemiology, it would be interesting to see
whether, in the future, other agents besides asbestos are
either sole etiologic agents in MM or act as co-factors
with asbestos. The recent identification of the SV40
virus as a potential factor in the development of MM is
of interest,20 and it will also be interesting to see if other
infectious agents that have known oncogenic effects are
identified. A number of viruses are at least partially
trophic to the pleural mesothelium (e.g. causing the
clinical syndrome of viralpleurisy), and a potential role
for such viruses in the generation of MM may be identified in the future. Similarly, there are a large number of
cases of MM in whom the level of asbestos exposure is
no higher than that of the background population. It
has been assumed that these cases represent the unfortunate small proportion of patients who develop a tumor
with low levels of carcinogen (similar to the small proportion of sun-exposed individuals who develop UVinduced skin cancers). Nevertheless, it remains possible
that other agents may be identified as etiological agents
in MM. For example, many patients with MM are farmers,
and, while it has always been assumed that this is because
they have been exposed to asbestos in their farming
activities, it would be interesting to determine whether
or not inhalation of potentially carcinogenic pesticides
may contribute to the development of the disease.
Finally, the future may see the development of preventive measures in MM. There are some populations
that are at extremely high risk of developing MM, for
example, those exposed to crocidolite as children. A
number of studies have been undertaken in an attempt
to reduce their risk, such as the use of prophylactic
vitamin A. This has shown some efficacy, but many
of these individuals still develop MM.153 The abovementioned identification of MM antigens raises the possibility that a tumor vaccine may be developed for MM.
Such at-risk groups would welcome such a vaccine.
However, there are two major hurdles to overcome.
First, these vaccines are difficult to test because they
need to be given to large numbers of patients and
followed for a long period of time before any valid efficacy can be determined: for example something like
5000–10 000 patients, followed over a period of five
years or so. Second, as most tumor antigens are selfantigens, the risk of autoimmune disease in vaccinated
patients would be substantial. This may cause pleurisy,
peritonitis, or pericarditis. It is thus possible that the
development of an MM vaccine may be limited by the
almost inevitable occurrence of such side-effects in a
significant proportion of those vaccinated. If these sideeffects are minimal then the benefit may outweigh the
risk, but the logistics of determining this are substantial. Most tumor vaccines are used in an adjuvant setting, i.e. they are used in patients once the disease is
already diagnosed.
In many ways, the future directions in MM research
and treatment will parallel those for other tumors, and
yet, in other ways, in view of the rather unusual clinical
and biologic behavior of MM, they will be unique to
that disease. Certainly MM is a very aggressive disease
that has been largely resistant to all therapeutic attempts
tried. In view of the increasing incidence of this disease
and the poor success rate with current therapies, it is
hoped that in the future the application of modern
molecular and biologic techniques to the problem, in
association with the commitment of managing clinicians to utilize novel therapeutic approaches, combined
with the courage of the afflicted population, will lead to
the development of improved methods of diagnosis,
therapy, and prevention of MM.
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pleural effusions: analysis of 116 cases and review of the literature. Oncologist 2005; 10: 501–7.
Villena V, Lopez-Encuentra A, Echave-Sustaeta J et al. Diagnostic value of CA 549 in pleural fluid. Comparison with
CEA, CA 15.3 and CA 72.4. Lung Cancer 2003; 40: 289–94.
Miedouge M, Rouzaud P, Salama G et al. Evaluation of seven
tumour markers in pleural fluid for the diagnosis of malignant
effusions. Br J Cancer 1999; 81: 1059–65.
Alatas F, Alatas O, Metintas M et al. Diagnostic value of CEA,
CA 15-3, CA 19-9, CYFRA 21-1, NSE and TSA assay in
pleural effusions. Lung Cancer 2001; 31: 9–16.
Fuhrman C, Duche JC, Chouaid C et al. Use of tumor markers
for differential diagnosis of mesothelioma and secondary
pleural malignancies. Clin Biochem 2000; 33: 405–10.
Creaney J, Yeoman D, Naumoff L et al. Soluble mesothelin in
effusions – a useful tool for the diagnosis of malignant
mesothelioma. Thorax 2007; 62: 569–76.
Robinson BW, Creaney J, Lake R et al. Mesothelin-family
proteins and diagnosis of mesothelioma. Lancet 2003; 362:
1612–16.
206 Textbook of Lung Cancer
120. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study
of pemetrexed in combination with cisplatin versus cisplatin
alone in patients with malignant pleural mesothelioma. J Clin
Oncol 2003; 21: 2636–44.
121. Gralla RJ, Hollen PJ, Liepa AM et al. Improving quality of life
in patients with malignant pleural mesothelioma: results of the
randomized pemetrexed + cisplatin vs. cisplatin trial using the
LCSS-meso instrument. Proc Am Soc Clin Oncol 2003; 22: 621
(abstract 2496).
122. van Meerbeeck JP, Gaafar R, Manegold C et al. European Organisation for Research and Treatment of Cancer Lung Cancer
group and the National Cancer Institute of Canada. Randomized phase III study of cisplatin with or without raltitrexed in
patients with malignant pleural mesothelioma: an intergroup
study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer
Institute of Canada. J Clin Oncol 2005; 23: 6881–9.
123. Byrne MJ, Davidson JA, Musk AW et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study.
J Clin Oncol 1999; 17: 25–30.
124. Nowak AK, Byrne MJ, Williamson R et al. A multicentre phase
II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87: 491–6.
125. Davis SR, Tan L, Ball DL. Radiotherapy in the treatment of
malignant mesothelioma of the pleura, with special reference
to its use in palliation. Australas Radiol 1994; 38: 212–14.
126. Boutin C, Rey F, Viallat JR. Prevention of malignant seeding
after invasive diagnostic procedures in patients with pleural
mesothelioma. A randomized trial of local radiotherapy. Chest
1995; 108: 754–8.
127. Christman TI, Manning LS, Garlepp MJ et al. Effect of interferon-alpha 2a on malignant mesothelioma. J Interferon Res
1993; 13: 9–12.
128. Morene de la Santa P, Butchart EG. Therapeutic options in
malignant mesothelioma. Curr Opin Oncol 1995; 7: 134–7.
129. Astoul P, Picat-Joossen D, Viallat JR, Boutin C. Intrapleural
administration of interleukin-2 for the treatment of patients
with malignant pleural malignant mesothelioma: a phase II
study. Cancer 1998; 83: 2099–104.
130. Upham JW, Musk AW, van Hazel G et al. Interferon alpha
and doxorubicin in malignant mesothelioma: a phase II study.
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131. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in the management of diffuse malignant
mesothelioma of the pleura. Experience with 29 patients.
Thorax 1976; 31: 15–24.
132. Sugarbaker DJ, Heher EC, Lee TH et al. Extrapleural pneumonectomy, chemotherapy, and radiotherapy in the treatment of
diffuse malignant pleural malignant mesothelioma. J Thorac Cardiovasc Surg 1991; 102: 10–15.
133. DeLaria GA Jr, Faber LP, Kittle CF. Surgical management
of malignant mesothelioma. Ann Thorac Surg 1978; 26:
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134. DeValle MJ, Faber LP, Kittle CF, Jensik RJ. Extrapleural
pneumonectomy for diffuse, malignant mesothelioma. Ann
Thorac Surg 1986; 42: 612–18.
135. Pass H, Kranda K, Temeck BK et al. Surgically debulked
malignant pleural malignant mesothelioma: results and prognostic factors. Ann Surg Oncol 1997; 4: 215–22.
136. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural
pneumonectomy in malignant pleural malignant mesothelioma. J Thorac Cardiovasc Surg 1991; 102: 1–9.
137. Sugarbaker DJ, Strauss GM, Lynch TJ et al. Node status has
prognostic significance in the multimodality therapy of diffuse,
malignant mesothelioma. J Clin Oncol 1993; 11: 1172–8.
138. Alvarez JM, Ha T, Musk W et al. Importance of mediastinoscopy, bilateral thoracoscopy, and laparoscopy in correct
staging of malignant mesothelioma before extrapleural pneumonectomy. J Thorac Cardiovasc Surg 2005; 130: 905–6.
139. British Thoracic Society Standards of Care, Statement on malignant mesothelioma in the United Kingdom. Thorax 2001; 56:
250–65.
140. Butchart EG. Contemporary management of malignant pleural
mesothelioma. Oncologist 1999; 4: 488–500.
141. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural
pneumonectomy in malignant pleural mesothelioma. A Lung
Cancer Study Group trial [see comment]. J Thorac Cardiovasc
Surg 1991; 102: 1–9.
142. Senan S, van de Pol M. Considerations for post-operative
radiotherapy to the hemithorax following extrapleural pneumonectomy in malignant pleural mesothelioma. Lung Cancer
2004; 45: S93–6.
143. Ahamad A, Stevens CW, Smythe WR et al. Promising early
local control of malignant pleural mesothelioma following
postoperative intensity modulated radiotherapy (IMRT) to the
chest. Cancer J 2003; 9: 476–84.
144. Allen AM, Czerminska M, Janne PA et al. Fatal pneumonitis
associated with intensity-modulated radiation therapy for
mesothelioma. Int J Radiat Oncol Biol Phys 2006; 65: 640–5.
145. Sugarbaker DJ, Flores RM, Jaklitsch MT et al. Resection margins,
extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant
pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999; 117: 54–63; discussion 63–5.
146. Robinson BW, Creaney J, Lake R et al. Mesothelin-family proteins
and diagnosis of mesothelioma. Lancet 2003; 362: 1612–6.
147. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of
negative regulators of signal transduction. J Leukoc Biol 1998;
63: 665–8.
148. Strzzi L, Catalano A, Vianale G et al. Vascular endothelial
growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 2001; 193: 468–75.
149. Ohta Y, Shridhar V, Bright RK et al. VEGF, VEGF type C, and
their receptors play an important role in angiogenesis and
lymphangiogensis in human malignant mesothelioma tumors.
Br J Cancer 1999; 81: 54–61.
150. Kumar-Singh S, Vermeulen PB, Weyler J et al. Evaluation of
tumor angiogenesis as a prognostic marker in malignant
mesothelioma. J Pathol 1997; 182: 211–16.
151. Robinson BW, Mukherjee SA, Davidson A et al. Cytokine gene
therapy or infusion as treatment for solid human cancer.
J Immunother 1998; 21: 211–17.
152. Powell A, Creaney J, Broomfield S et al. Recombinant GMCSF plus autologous tumor cells as a vaccine for patients with
mesothelioma. Lung Cancer 2006; 52: 189–97.
153. de Klerk NH, Musk AW, Ambrosini GL et al. Vitamin A and
cancer prevention II: comparison of the effects of retinol and
beta-carotene. Int J Cancer 1998; 75: 362–7.
13 Summary of treatment
Heine H Hansen
Contents Introduction • Small cell lung cancer • Non-small cell lung cancer • Mesothelioma
INTRODUCTION
A short summary of the management of small cell lung
cancer (SCLC), non-small cell lung cancer (NSCLC),
and mesothelioma is given in this chapter based on the
evidence from randomized trials, even though it should
be realized that patients included in clinical trials are not
representative of the patient population as a whole.
Additional information on the management of lung cancer can be found in recent review articles.1–8
SMALL CELL LUNG CANCER
Limited disease
Surgical resection, followed by postoperative chemotherapy, is the treatment of choice for the rare patient who
presents with stage I or II disease. The results for SCLC
are equivalent to the treatment of stage I and II NSCLC.
For the more typical SCLC patient who presents with
bulky limited disease, combination chemotherapy is
the mainstay of treatment, in conjunction with radiotherapy. For chemotherapy, the combination of etoposide and cisplatin (EP) has become the most commonly
recommended regimen. The combination of carboplatin
and etoposide produces similar results to cisplatin and
etoposide, and has a more favorable toxicity profile.
Maintenance chemotherapy does not result in any substantial improvement in survival.
Based on meta-analyses, chest irradiation has shown
superior survival results in patients receiving combination chemotherapy and radiotherapy compared with
those receiving chemotherapy alone. The optimal timing and dosing of chest irradiation are still uncertain,
but there is a tendency to initiate radiotherapy early
during the first two courses, at total doses of at least 50
Gy. Hyperfractionated radiotherapy given twice a day
has yielded superior survival data in one randomized
trial compared with conventional radiotherapy when
combined with cisplatin and etoposide.
Prophylactic cranial irradiation (PCI) has also been
demonstrated to have a statistically significant impact
on survival in patients with limited disease who achieve
a complete remission, and it also reduces the lifetime
risk of cerebral metastases. The optimal dose and timing of radiotherapy are again uncertain; most frequently,
the total dose should not exceed 30 Gy given in fractions of 2.5 Gy daily.
Extensive disease
A combination of etoposide and cisplatin is the preferred standard treatment. The replacement of etoposide with irinotecan given together with cisplatin has
resulted in significantly better median and one-year
survival in one randomized trial, whereas no difference
was observed in a subsequent trial. Again, carboplatin
can be substituted for cisplatin because of similar activity and fewer side-effects, even though myelosuppression is greater. Recent results have indicated that a
four-drug combination of etoposide, cisplatin, epirubicin, and cyclophosphamide may be superior to etoposide and cisplatin alone.
With regard to maintenance therapy, the hypothesis
has been tested of adding either oral etoposide or topotecan to the treatment regimen in patients demonstrating a response to initial therapy. The results showed a
slight improvement with etoposide in terms of median
progression-free survival, whereas topotecan did not
show any significant difference. The impact of dose
intensification remains uncertain.
None of the phase III trials incorporating new agents
have shown superior results compared with classic combinations such as cisplatin/carboplatin and etoposide.
With respect to PCI, very recent data has also demonstrated benefit as measured by improvement in median
survival in patients presenting with extensive SCLC.
In patients presenting with poor prognostic factors,
such as performance status 3–4, involvement of the liver
and bone marrow, or severe co-morbid diseases, the initial dose of chemotherapy should be reduced, and careful monitoring is recommended over the first weeks.
Elderly patients with poor performance status and
widespread disease have a substantially higher risk of
208 Textbook of Lung Cancer
incurring treatment-related complications, and generally
have a poor outcome. Supportive measures alone are
often the best option for some of these patients.
Recurrent disease
The treatment options depend on the anatomic site of
relapse, symptomatology, and previous treatment. Local
relapse in patients without prior chest irradition is best
treated with palliative radiotherapy. Late relapse in
patients who initially responded to a platinum-containing regimen should be treated with the same regimen
again. Otherwise, single-agent chemotherapy with topotecan or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine is the treatment of
choice. Newer agents are being tested in this group of
patients, either as single agents or in combinations, but
usually yield response rates of < 20%.
NON-SMALL CELL LUNG CANCER
Stages I, II, and resectable IIIA
Stage IA
The standard therapy for stage I NSCLC continues to be
complete surgical resection when possible. This should
include lobectomy plus sampling of all mediastinal
nodal stations or complete lymph node dissection.
However, the surgical technique to perform a lobectomy
or pneumonectomy and mediastinal exploration may
change as experience with minimally invasive surgery
grows. Recent data have revealed encouraging results
with video-assisted thoracic surgery (VATS) lobectomy
and mediastinal sampling or dissection. With minimally
invasive surgery becoming more popular, the efficacy of
minimal resections such as segmentectomy and wedge
resection is also being readdressed as smaller tumors
(<1–2 cm) are being identified with spiral computed
tomography (CT) scans. Another critical question is the
relationship of tumor size to nodal metastasis. Data
have been presented suggesting that histology and size
may be beneficial in determining nodal risk.
For patients who are medically inoperable, advances
in radiotherapy such as three-dimensional (3D) conformal and stereotactic radiosurgery are producing more
durable results with decreased toxicity, and five-year
survival rates up to 40%.
Stage IB–IIIA
The results of several large randomized trials of postoperative chemotherapy have been published, but these
results differ and are therefore difficult to interpret.
It appears that the weight of evidence indicates that
postoperative cisplatin-based chemotherapy improves
survival after surgery in patients with stage IB to IIIA
NSCLC, resulting in an absolute survival advantage at
five years. Similar results have been obtained by Japanese investigators using an oral drug combination
of uracil and tegafur (UFT), both in individual trials
and when meta-analyses of the results were performed.
The results were most impressive in patients with
adenocarcinomas.
Alternatively, neoadjuvant therapies are increasingly
being used. Although large randomized trials investigating this important topic continue to enroll patients,
recent experience has indicated that neoadjuvant chemotherapy does not significantly increase surgical morbidity or mortality.
For patients with operable stage III (N2) disease, the
number of lymph nodes involved and the ability to eradicate tumor from the lymph nodes with neoadjuvant
therapy have been found to be important prognostic
factors. The pivotal question about the role of surgery
in the treatment of stage IIIA (N2) disease is still open and
awaits the results from several ongoing trials. As multimodality therapy leads to improved survival for patients
with operable NSCLC, an increased frequency of isolated
brain metastases has been observed, and the potential
value of PCI is being tested in selected subgroups.
Inoperable stage III
Concurrent chemotherapy/radiotherapy is the standard
of care for patients with inoperable stage III NSCLC.
However, numerous questions remain regarding the
optimal means to combine these two modalities and
whether there is a benefit of additional therapy before
or after chemotherapy/radiotherapy. Randomized phase
II trials with newer cytotoxic agents given with concurrent radiation or trials incorporating an induction or
consolidation chemotherapy approach have failed to
show median survivals beyond the standard 16–18
months in most instances. Trials evaluating altered
radiotherapy fractions have also not improved survival.
Important areas of future research include the roles of
3D conformal radiotherapy, intensity-modulated radiotherapy (IMRT), hyperfractionated radiotherapy, and
the addition of targeted agents, with several of the latter
demonstrating radiosensitization capabilities.
Stage IV (and IIIB with pleural effusion)
Doublet chemotherapy for stage IIIB with pleural effusion and stage IV NSCLC patients with adequate performance status has been shown in multiple randomized
Summary of treatment 209
studies to improve survival and quality of life, and
remains the standard of care. Numerous randomized trials have been performed during the last decade in order
to identify the best platinum-based regimen; no major
differences have been observed with respect to efficacy
– only with regard to toxicity and cost. Current trials
have continued to support this finding. Furthermore,
randomized trials that included a non-platinum regimen have shown such regimens to be equivalent in efficacy to platinum regimens, but with a more favorable
toxicity profile. Controversy continues over the number
of cycles of chemotherapy to be administered in the
first-line setting. Several guidelines suggest a maximum
of six cycles, but there is an accumulation of data indicating that three or four cycles are sufficient. Although
numerous phase II cytotoxic regimens have been evaluated, none has produced amazing results. The major
focus has therefore switched to targeted therapies.
A variety of targeted agents are currently being evaluated. At the forefront of the promising agents are the
epidermal growth factor receptor (EGFR) inhibitors,
gefitinib (Iressa), erlotinib (Tarceva), and a monoclonal
antibody against the vascular endothelial growth factor
receptor (VEGFR), bevacizumab (Avastin). Among
these, gefitinib and erlotinib have been approved by
health authorities in various countries as second- or
third-line treatment for NSCLC patients resistant to conventional combination chemotherapy.
A host of targeted agents are in earlier stages of clinical evaluation, such as cyclooxygenase-2 (COX-2)
inhibitors, the preapototic inhibitor exisulind, proteasome inhibitors, bexarotene (Targretin), and vaccines.
Improving upon the efficacy of second-line docetaxel,
investigators have focused on the addition of a second
cytotoxic agent or on giving taxanes in a weekly schedule. Among the targeted agents, erlotinib has resulted
in improved survival and quality of life in a large randomized trial comparing erlotinib with placebo. When
added to platinum containing chemotherapy, bevacizumab has also yielded higher response rates, progression-free survival, and median survival in advanced
NSCLC, with the majority of patients having adenocarcinoma, and it has recently been approved in the US
and in Europe for this group of patients.
Several small studies showed a favorable survival
improvement for doublet therapy, but further investigation is needed. Pemetrexed (Alimta), a novel multitargeted antifolate, has in a randomized trial resulted in
similar reponse rates, median survival, and overall
survival to docetaxel, but toxicity favored the pemetrexed arm, with significantly less neutropenia.
For the elderly population or patient with poor performance status, two-drug cytotoxic combinations,
single-agent chemotherapy with vinorelbine or gemcitabine, and targeted therapy with gefitinib or erlotinib
have proved to be of therapeutic value.
MESOTHELIOMA
Surgery should be considered when mesothelioma
remains localized, usually as extrapleural pneumonectomy, with excision of the diaphragm and the pericardium en bloc. Palliative local procedures include partial
pleurectomy, decortication, or pleurodesis. Chemotherapy and/or radiotherapy have not yet proved to be effective in preventing local recurrence, nor has the use of
photodynamic therapy or intracavitary chemotherapy.
With respect to chemotherapy, quantitative and qualitative overviews of the literature have suggested that cisplatin may play an important role in combination therapy.
It is also emerging that response rates of 30–40% can be
obtained when combining cisplatin with other agents,
e.g. raltitrexel and pemetrexed. A combination of cisplatin and pemetrexed has in one randomized trial been
superior to cisplatin alone, resulting in superior response
rate, duration of response, and quality of life.
REFERENCES
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Laskin JJ, Sandler AB. State of the art in therapy for non-small
cell lung cancer. Cancer Invest 2005; 23: 427–42.
Grunenwald DH. The role of surgery in non-small-cell lung
cancer. Ann Oncol 2005; 16 (Suppl 2): ii220–2.
Buter J, Giaccone G. Medical treatment of non-small-cell lung
cancer. Ann Oncol 2005; 16 (Suppl 2): ii229–32.
Giaccone G. Twenty-five years of treating advanced NSCLC: what
have we achieved? Ann Oncol 2004; 15 (Suppl 4): iv81–3.
Movsas B. Will future progress in non-small-cell lung cancer be
step by step … or by leaps and bounds? J Clin Oncol 2005; 23:
5859–61.
Ceresoli GL, Gridelli C, Santoro A. Multidisciplinary treatment
of malignant pleural mesothelioma. The Oncologist 2007; 12:
850–63.
Stahel R (ed). Acheving survival improvement in thoracic
tumors: from therapeutic strategy management to pharmacogenomics. Lung Cancer 2007; 57: Suppl 2.
Lally BE, Urbanic JJ, Blackstock AW et al. Small-cell lung cancer: have we made any progress over the last 25 years? The
Oncologist 2007; 12: 1096–1104.
14 Therapeutic bronchoscopy for palliation
of lung tumors
Peter WA Kunst, Pieter E Postmus, Thomas G Sutedja
Contents Introduction • Indications • Techniques to remove endobronchial tumors • Bronchoscopic
treatment of extraluminal tumors • General remarks, economic aspects, and recommendations
INTRODUCTION
Lung cancer, although rare at the beginning of the
20th century, is currently known to be the most
lethal cancer in Western society, and its incidence is
rising very fast in the developing countries. All societies with an increase in tobacco consumption will
face increasing morbidity and mortality due to their
smoking habits, including a steep increase in lung
cancer incidence and mortality.
The overall progress in therapeutic outcome during the last three to four decades has been small. The
large majority of lung cancer patients are still doomed
to die of their disease. For the patients with metastatic disease with or without locoregional tumor
progression, optimal palliation to improve quality of
life (QoL) is the main aim of treatment. This includes
relief of symptoms such as shortness of breath,
hemoptysis, pain, weight loss, and depression. Several approaches are available to establish temporary
relief of symptoms including optimal pain medication, radiotherapy, chemotherapy, bronchodilation,
and, in rare cases, even surgical resection.
INDICATIONS
The clinical tumor classification (TNM) and the
patient’s general condition are important factors in
the treatment strategy. Improving symptoms in central airway tumors is only meaningful if:
•
•
•
the larger airways obstructed by tumor are accessible to bronchoscopic instruments;
airway collapse due to loss of integrity of the
tracheobronchial wall can be prevented, for
instance by stenting the airway;
additional information on extraluminal disease
and/or vascular involvement can be obtained
by computed tomography (CT) or endobronchial ultrasonography (EBUS) to get additional
information;
•
•
information about the regions with low gas
exchange (i.e. after radiation or due to significant
peribronchial disease) is taken into account, as
these regions will improve little after treatment;
a potential interference of immediate action, i.e.
stenting and debulking, with additional treatment can be prevented. Such anticipation
requires a conscious decision to apply a tailored
strategy.1–7
For the majority of patients, relief of dyspnea, hemoptysis, severe cough, or obstructive pneumonia is the
major goal. Improvement in gas exchange is the aim
of airway reopening. Any bronchoscopic treatment
may only enhance the dead-space ventilation if local
perfusion is hampered by tumor growth. A disproportionate loss of regional perfusion together with CT
findings of extensive peribronchial disease are good
indicators for gross extraluminal involvement.8–14
TECHNIQUES TO REMOVE ENDOBRONCHIAL
TUMORS
Mechanical obstruction removal
After the introduction of the most simple example
of the rigid bronchoscope by Killian late in the
19th century, new therapies became available. The rigid
bronchoscope could be used to core out tumor mechanically to obtain airway patency and immediately
improve quality of life. Even after the introduction of
the fiberoptic bronchoscopes and videobronchoscopes, the advantages of the rigid bronchoscope for
the purpose of obstruction removal are clear. The
larger working channel of the rigid scope provides
better access, facilitating safer manipulation and the
passage of larger instruments such as forceps and
large-bore suction tubes to aspirate secretions and
blood.9,10 This is a considerably more attractive option
to using the fiberoptic scope, in which bleeding is
expected and large amounts of tissue or secretions
Therapeutic bronchoscopy for palliation of lung tumors 211
need to be evacuated.9,15 The rigid method safeguards
better ventilation during the procedure of recanalization and allows additional stenting in the case of
extraluminal obstruction to be carried out more
easily. The disadvantage of the rigid technique –
requirements for expertise, adequate sedation, or
general anesthesia – may pose some hurdles. It is
therefore important to consider whether interventional pulmonologists should limit their expertise to
proficiency with the fiberoptic procedures alone
when dealing with imminent suffocation in the worst
possible scenario, while the majority of patients are
at highest risk from locally advanced cancers that
have failed previous conventional treatment modalities.
Laser resection
Laser is an acronym for light amplification by stimulated emission of radiation. Lasers produce a beam of
monochromatic, coherent light that can induce vaporization, coagulation, hemostasis, and necrosis. Several
types of lasers [argon, KTP, carbon dioxide (CO2),
neodymium:yttrium–aluminium–garnet (Nd: YAG)
can be used, depending on the considerations of
physics and laser–tissue interaction. The most commonly used lasers are the CO2 laser, which is mainly
used for superficial treatment in water-containing tissue, and the Nd: YAG laser, which has a much deeper
scattering effect for treating bulky tumor in many
oncologic disciplines. The latter has been the main
choice to obtain a much greater penetration due to
the deep scattering of 1064 nm wavelength light by
tissue containing hemoglobin, hence its superior coagulative properties. The enormous heat-sink effect leads
to obtaining late necrosis at a depth which cannot be
determined, hence the use of a red pilot light and
forward firing.
In 1976 the first report on endobronchial use of a
laser to vaporize the obstructing tumor was published by Laforet et al.16 Afterwards the use of lasers
became popular, especially in the USA, because of an
excellent promotion campaign by equipment manufacturers.17 Cavaliere and co-workers showed the
benefits of the procedure in more than 2000 patients
with over 90% immediate recanalization after treating obstruction in the main bronchi or trachea.
The overall mortality is lower than 0.5%.18,19 Serious
complications, which occur in less than 3% of
all patients, are hemorrhage, pneumothorax, and
cardiorespiratory failure over time. These are due
to the profound heat transfer into tissue from the
laser beam, which causes necrosis deep beyond
the surface of impact. Awareness of the anatomic
relationship within the mediastinal organs is therefore necessary.
The uncontrolled application of high power can lead
to disastrous effects, such as perforation of the bronchial wall and too-extensive necrosis, because the
depth effect of the Nd: Yag laser is not always immediately apparent. Therefore it is necessary to know
the extent of the endobronchial mass to define the
treatment area. Bronchography has been used prior
to treatment to assess the length of the bronchial
obstruction.20,21 Nowadays, CT scanning or EBUS
might be useful for defining the extent of the endobronchial and peribronchial mass.22,23 A large observational study of the value of EBUS in therapeutic
bronchoscopy showed that EBUS guided or changed
therapy significantly in 43% of cases. Changes included
adjustment of stent dimensions, termination of tumor
debridement when nearing vessels, and referral for surgical interventions rather than endoscopic treatment.23
Electrocautery and argon plasma coagulation
Electrocautery (EC) and argon plasma coagulation
(APC) are the use of local heat application with probes
that conduct electrons toward the target tissue (tissue
welding). An alternating electrical current conduit is
used to prevent neural and muscular responses. Many
cheap, reusable applicators are available. Electrocautery and APC are other ‘hot’ alternatives to Nd:YAG.24
Although the costs of the EC and APC technique are
far lower than for Nd:YAG, it has not become very
popular in the USA, apparently without any obvious
reason since the results are more or less comparable
to the Nd:YAG laser and APC is superior in obtaining
hemostasis of large mucosal hemorrhagic surfaces.25
The technique is simply based on the use of electrons to produce heat in the target tissue while the
equipment is a standard facility in every operating
theatre. An applicator or probe is needed which can
be passed through the working channels of the rigid
or flexible bronchoscope. This technique has a lower
risk of airway perforation due to the superficial effects
of electrons as they dissipate easily in tissue.
APC uses ionized argon gas for the non-contact
mode of tissue spraying conduit, which can superficially coagulate large hemorrhagic surfaces in a matter
of seconds. Electrons always seek the pathway
of least resistance; coagulation can be limited to a depth
of only a few millimeters by choosing an appropriate
energy setting. This self-limiting effect is especially
exploited in APC, as the ionized argon gas
deviates electrons towards the area of least resistance,
212 Textbook of Lung Cancer
i.e. hemorrhagic wet surfaces, and away from crusted,
already treated, tissue.
APC has been used in surgery for more than 20 years,
particularly for the hemostasis of superficial bleeding.
Although APC has become well established in gastrointestinal endoscopy since its introduction in 1991,
very few reports of its use in bronchoscopy exist.
Reichle et al showed that recanalization of malignant
airway stenoses had good results in 67% of patients.
Despite less penetration compared with the Nd:YAG
laser, extensive bronchial tumors were treatable, and
coagulated tumor fractions were removed either with
forceps or the rigid bronchoscope tip.25 The second
indication was bleeding in the central airways; good
hemostasis was achieved in over 98% of patients.25 No
head to head comparison of Nd:YAG laser and EC or
APC has been done; from several phase II type studies
the results seem to be more or less comparable. The
estimated incidence of clinically significant bleeding
in patients treated with EC is 2.5%.26 The most
important advantage is the fact that, with EC and
APC, the immediate coagulative effect is clearly visible and matches the histologic depth of necrosis – the
principle of ‘you immediately see what you get’. Too
much heat, however, can lead to extensive scarring.
Cryotherapy
Cryotherapy is repetitive rapid cooling (Jules Thompson
effect) and spontaneous thawing of the target tissue,
using liquid gas and specially designed flexible applicators to crystallize the cellular contents of the target
tissue, causing late necrosis.27–31 The ultimate effect is
caused by delayed disintegration of water-containing
tissue. Thawing restores circulation, hence this
technique is not suitable for quick palliation of
a hemorrhagic mass, despite sparing cryoresistant
cartilage and fibrous tissue. The simple equipment,
reusable applicator, and easy principles are clear
advantages. In a report by Forest et al,28 necrosis was
found near the cryoprobe impact site and was maximal two hours after treatment; a second peak was
observed after four days. Around this central necrotic
area, apoptotic cells were found. Apoptosis was maximal after eight hours. Thus a second bronchoscopy
is necessary to remove slough. No large series on
local treatment with cryotherapy for early stage lung
cancer are available in the literature; only a few reports
have shown good results (complete response) when
used for palliation.29,30 In a study in which patients
with an obstructive tumor were treated with cryotherapy followed by irradiation, no sign of residual
tumor was found in 17 of 26 patients.30
Endobronchial brachytherapy
Brachytherapy comprises intraluminal irradiation of
a tumor area within the tracheobronchial tree by
means of a catheter. The catheter is connected to an
afterloading device that transports the tiny radioactive source, iridium-192, to preprogrammed positions
during the session, in a step wise fashion, according
to precalculated volume dosimetry. Accurate sausagelike dosimetry with rapid fall-off towards the periphery is theoretically attractive. However, a tumor is not
perfectly oval in shape, with the irregular extensions
to smaller bronchi, while delivery of an accurate dose
to the target volume is hampered by the patient’s
breathing and cough, which may lead to movement
of the catheter, despite the short (10–15 minutes)
duration. Irradiation damages all tissue. Data from
good randomized trials are available.32–35 Fractionated
external radiotherapy is preferred over brachytherapy
as an initial treatment in better performing patients
because it provides better overall and more sustained
palliation, with fewer retreatments and a modest gain
in survival time.32 However, when both techniques
are combined it increases local control,33 especially
in the cohort of squamous cell cancer, in alleviating
symptoms caused by local tumor recurrence,34 and
provides higher rates of re-expansion of collapsed
lung, resulting in (transient) lower levels of dyspnea.
However, this beneficial effect was only observed
among patients with obstructing tumors in the central
airways.35 Elusive accuracy in dosimetry, expensive
equipment, need for repeated doses and non-selective
damage causing radiation stenosis, fibrosis, and
late fatal hemorrhages or bronchial fistula are
disadvantages.36,37
Photodynamic therapy
Photodynamic therapy (PDT) is bronchoscopic illumination of tissue containing photosensitizers to
initiate a photochemical cascade reaction due to the
formation of oxygen radicals.12,38 Although photosensitizer molecules are selectively retained in the target
tissue after injection, in vivo and histologic studies
do not show selective tumor damage which may lead
to deep eschar formation and extensive fibrosis.
The degree of intra- and extraluminal tumor mass
and tumor location may limit the efficacy of PDT,
since optimal or homogeneous illumination is difficult to achieve.39,40 Cautious interpretation of apparent complete response by bronchoscopy is advocated
since residual tumor might be present by microscopic
evaluation. A cure cannot be expected in patients
with tumor infiltration of the cartilage and bronchial
Mechanical
crushing
Iatrogenic
foreign body
Efer–Dumon
set + various
stents
Hemostasis
Equipment
Disadvantages
Lifesaving!
Outward
displacement
High expertise
Outward
displacement
Teams’ expertise
for emergency
Extraluminal
only alternative!
Result
Performance
Tissue damage
Mechanism
Indication
Logistics
Stent
Electrocautery and
argon plasma
coagulation
Cryotherapy
Photodynamic therapy
Brachytherapy
Special laser
Standard facility and Liquid coolant
Special laser and
Special radiation
requirements
applicators
with applicators
requirements
facility
Intraluminal only, with different depth necrosis depending on each mechanism and technical application with
or without dosimetric calculations; deep dosimetry in non-selective technique causes damage to the normal
tissue surroundings of the central airways including the tracheobronchial wall!
Extreme heat
Shallow heat
Rapid cooling
Formation of
Ionizing radiation
transfer
transfer
slow thawing
oxygen radicals
High expertise
Easy
Easy
Complex process
Complex process
Profound
Superficial
Crystallization
Thrombosis and
Structural damage
carbonization
coagulation
of watery tissue
secondary hypoxic
necrosis
Immediate,
Immediately
Hours–days +
Hours–days +
Days to weeks;
invisible depth
visible depth
secondary
secondary necrosis
non-selective
necrosis
Profound
Superficial
Vascular
Primary vascular
Systemic vascular
coagulation
coagulation
disruption!
thrombosis
disruption
Burn, explosion,
Superficial
Delayed effect
Prolonged skin
Fibrosis, stenosis,
and perforation
scarring
photosensitivity
and hemorrhage
Expensive
Standard
Liquid
Special laser + special
Expensive
laser + laser
facility + cheap
coolant + applicators
fibers + sensitizers!
radiation facility
fiber
probes
Laser (Nd:YAG)
Table 14.1 Advantages and disadvantages of each technique for palliative treatment of tumor blockage in the central airways
213
214 Textbook of Lung Cancer
Table 14.2 Results of large series regarding palliative bronchoscopic treatment
Technique
Results
Complications
Remarks
Stent (Dumon4)
1574 prostheses
(1058 patients)
Tracheal 54%;
LMB 21%;
RMB 18%
Migration 9.5%;
granuloma 7.9%;
obstruction 3.6%
Nd:YAG
(Cavaliere19)
2610 resections
(1838 patients)
93% good
results
60 cases (0.3%);
mortality 0.4%
Elecrocautery
(Sutedja24)
56
39/56 (70%)
complete
1 bleeding 3.7%
Argon plasma
(Reichle25)
Cryotherapy
(Maiwand30)
PDT (review
Moghissi38)
HDR
Brachytherapy
(Speiser60)
364 (482 sessions)
67% good result
153
Dyspnea 64%;
hemostasis 93%
CR >70%
11 patients (7.2%)
Average time
stent will be
in place minimum
4 months
maximum
4.7 years
Mortality due
to cardiovascular
and respiratory
problems
Non-responders;
extraluminal
disease
Excellent
hemostasis
No mortality
295
80%
recanalization
Fatal bleeding
7%; stenosis 11%
ERT 60 Gy vs
+ HDR 2 × 4.8 Gy
(Huber33)
Randomized
42 vs 56
Med. survival
similar 28 vs
27 weeks!
Fatal bleeding
14.2%!
636
muscular layer.41–43 Secondary necrosis, due to tumor
hypoxia, and fibrin plug formation make it necessary
to perform a ‘clean-up’ bronchoscopy to prevent
respiratory failure. Due to skin photosensitivity, which
may occur in 20–40% of patients, although not leading to irreversible skin damage,44 new photosensitizers are sought.45 Fatal bleeding after PDT has been
reported.44,46 As the PDT effect is known to be mainly
vascular, caution is necessary in treating tumors close
to large vessels.
Cell culture studies and animal studies indicate a
possible synergistic effect of combining PDT with ionizing radiation. One randomized study in a limited
number of patients reported the benefit of PDT additional to external radiotherapy, with regard to quality
of life and physiologic scores. PDT plus external
radiotherapy provided a better and more durable local
control compared to external radiotherapy alone.47
Various: non-fatal
Up to 28% skin
photosensitivity
No different
effect of dose
fractions,
ND:YAG
precanalizing
procedures
Squamous cell
cohort 7 weeks
longer median
survival
Another study assessed the safety and effectiveness of
combined brachytherapy and PDT in patients with
bulky endobronchial lung cancer. Thirty-two patients
were treated; tumors were extensive, with lengths
ranging from 10 to 60 mm along the bronchus and
estimated volumes ranging from 40 to 3500 mm3. At
a mean follow-up of 24 months, 26 patients were
free of residual tumor and local recurrence.48
BRONCHOSCOPIC TREATMENT OF
EXTRALUMINAL TUMORS
Stenting
Stenting is the insertion of tailored endoprostheses to
recanalize large airways and restore airway patency.
It is the only possible solution for obstruction caused
by extraluminal tumor compression. Since 1965,
Therapeutic bronchoscopy for palliation of lung tumors 215
with the introduction of the Montgomery tube, many
different kinds of stents have been developed.49 However, despite many improvements the optimal stent
is still being sought. Nowadays there are rigid and
flexible stents, made of different materials. The main
point of consideration is the anatomic size of the airways and the cause of the limited airway patency. In
benign disease a silicone stent is definitely preferred
over a metallic one, whereas in malignant disease no
stent is in favor.50–54 Depending on the position of
the compression, either a Y-shaped stent or a normal
one can be inserted.
The second goal of stenting could be considered to
be the sealing of fistulas between the respiratory tract
and the digestive tract.55,56 The best way to introduce
a stent is still by the rigid bronchoscope, although
some stents can be inserted by the flexible scope. The
literature has shown that stenting improves QoL and
has a good acceptance and tolerance.57,58
Stent insertion can be simple; however dealing with
the complications such as migration, perforation,
granuloma, and infection can be a great challenge, and
requires a certain level of expertise of the team.
GENERAL REMARKS, ECONOMIC ASPECTS, AND
RECOMMENDATIONS
Current bronchoscopic techniques provide the bronchoscopist with alternatives for local palliation. Each
technique has its own merits and limitations. Treatment choice is based upon the following: clinical
presentation, the experience and skill of the bronchoscopist, the availability of additional techniques,
anesthetic care, intensive care for the post-treatment
period, and technical support in the hospital. Economic aspects may further influence the choice.
When the indications have been properly assessed,
any of the treatments can be equally successful in dealing with an emergency situation, when a technique is
chosen to immediately relieve the symptoms
(Tables 14.1 and 14.2). as long as the bronchoscopist
is aware of the limitations and dangers of each approach
and is confident about the benefit of treatment. The
frequent occurrence of emergency situations in patients
with a poor prognosis makes it impossible, and maybe
even unethical, to perform a randomized study to look
for the best palliative technique. The population at
risk is not homogeneous and the follow-up period
might be expected to be relatively short. Many patients
will die due to disease progression outside the treatment area. So the question about the best palliative
technique is and remains academic. However, what
technique to use depends first on the availability in the
center, second on the expertise with the technique,
and third, on the oncology principle (curative vs palliative). Although some techniques might appear simple, it might be wise to concentrate a particular
procedure in a limited number of centers, in order to
minimize the complications, improve treatment of the
complications, and to have a better local control or
cancer-specific survival. The latter has never been
proven for endobronchial therapy, but from other
studies we know that the outcomes that measure
tumour control relate to the surgeon’s expertise.59
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15 Complications of lung cancer
Vincenzo Minotti, Michele Montedoro, Maurizio Tonato
Contents Introduction • Infections • Major hemoptysis • Chest pain • Pleural effusion
• Superior vena cava syndrome • Cardiac tamponade • Extrathoracic complications
• Paraneoplastic syndromes
INTRODUCTION
The majority of patients with lung cancer will have troublesome symptoms at some time during the course of
their disease due to the disease itself or its complications.
Complications in lung cancer patients depend on the
location of the tumor, its locoregional spread, and the
presence of metastatic growth. Moreover, lung cancer,
especially small cell lung cancer (SCLC), is associated
with paraneoplastic syndromes more frequently than
any other type of cancer is.
Clinicians must keep in mind the most frequent
complications of lung cancer, since a timely diagnosis
and adequate treatment are essential in order to ameliorate symptoms.
Although a multitude of signs and symptoms may be
manifested by patients with lung cancer, the focus of
this chapter will be on the more frequent and severe
complications due to intrathoracic growth of tumor
and to remote effects that are not related to direct invasion or metastasis (Table 15.1).
INFECTIONS
Pulmonary infections frequently complicate the course
of patients with lung cancer, and are often the direct
cause of death. Infections can be present at the time of
cancer diagnosis, complicate the treatment course, and
result in death. Causes of infection include bronchial
obstruction, aspiration, immunosuppression from radiation and/or chemotherapy, disruption of local host
defenses due to tumor invasion, and necrosis of both
normal and tumor tissue. To determine the causes of
infection, Nagata and colleagues1 reviewed the case
records and autopsy data of 304 patients who died of
lung cancer. They showed that the local and systemic
effects of the lung cancer itself were probably more
important than either antineoplastic agents or cortico-
steroids in predisposing the patient to bacterial infections. Perlin and colleagues2 reviewed retrospectively a
cohort of 121 lung cancer patients in an attempt to
identify the frequency of infection and to determine its
impact on the survival of those patients. Infections were
documented in 85 patients (70%); the most common
organisms were streptococci, Staphylococcus aureus,
Klebsiella pneumoniae, Enterobacter aerogenes, and
Pseudomonas aeruginosa. The median survival of all
infected patients was 4.2 months, which was significantly shorter than that of uninfected patients, who had
a median survival of 12.9 months. In the only prospective study done to date, involving 96 consecutive lung
cancer patients at diagnosis, Putinati and colleagues3
reported an incidence of secondary respiratory infections in 33 patients (34%). Major pathogens responsible for infection were Haemophilus spp., S. aureus, and
P. aeruginosa.
In a review, Berghmans et al4 reported 435 episodes
of fever and/or infection occurring in 275 patients with
lung cancer. The majority of infections involved the
upper and lower respiratory tract (56%).
Pulmonary infections depend on the particular pattern of growth of the lung cancer. Centrally located
tumors produce airway obstruction, which may cause
an obstructive pneumonitis, while peripheral large tumor
masses occasionally cavitate and present as malignant
abscesses. Such patients suffer from typical symptoms
of pneumonia, including fever, chills, and a productive
cough with streaky hemoptysis. Non-small cell lung
cancer (NSCLC), particularly squamous cell carcinoma,
may present with a shaggy cavitary opacity, indistinguishable from a conventional anaerobic lung abscess on
chest radiograph. Extensive central necrosis is responsible for the cavitary appearance. Several clinical clues may
suggest the presence of cancer, including persistent
hemoptysis, relative absence of fever and leukocytosis,
and radiographic location in a region of the lung
with minimal surrounding pneumonitis. A rare and
Complications of lung cancer 219
Table 15.1 Most frequent and severe complications of lung
cancer
•
•
•
•
•
•
•
•
Infections
Major hemoptysis
Chest pain
Pleural effusion
Superior vena cava syndrome
Cardiac tamponade
Paraneoplastic syndromes
Extrathoracic complications (brain metastases,
spinal cord compression)
severe complication of lung cancer is the formation of
a tracheo- or broncho-esophageal fistula, which can
manifest by paroxysmal violent cough after meals and
recurrent aspiration pneumonia.
Bronchoscopy is useful to establish a microbiologic
diagnosis5 and to search for an underlying lung cancer
in patients with atypical resolution of pneumonia by
chest radiography. For example, in a study of 115 cases
with a clinical profile of chronic bacterial pneumonia,
bronchoscopy disclosed newly diagnosed NSCLC in
14% of cases.6 Identification of a definitive etiologic
agent is of great importance for rational antimicrobial
treatment of pulmonary infections. Because infecting
flora can include aerobic Gram − and Gram + species as
well as anaerobes, broad-spectrum antimicrobial therapy is warranted, as for postobstructive and aspiration
pneumonias, but the duration is typically prolonged
(weeks to months).7 Endobronchial obstruction with
distal uncontrolled pneumonia or a lung abscess can be
treated by endoscopic removal of tumor with laser or,
in the case of an abscess, by percutaneous or bronchoscopic drainage of the abscess.
MAJOR HEMOPTYSIS
Hemoptysis is the presenting symptom in 7 to 10% of
patients with lung cancer. Approximately 20% will
have hemoptysis some time during their clinical course.
However, massive hemoptysis is a rare event, with 3%
having terminal massive hemoptysis. Most patients
experience blood-streaked sputum. Santiago and colleagues8 reviewed the records of 264 patients who
underwent bronchoscopy for unexplained hemoptysis
in order to determine its causes. Bronchogenic carcinoma was the most common cause, accounting for 29%
of the cases. The diagnosis of bronchogenic carcinoma
was established endoscopicalIy in 65 (82%) of 78 patients.
Four patients with carcinoma had normal chest radiographs. These four patients had centrally located lesions
that were diagnosed endoscopicalIy. Massive hemoptysis is arbitrarily defined as expectoration of at least 100
to 600 ml of blood in a 24-hour period, or intrabronchial bleeding at such a rate as to present a threat to
life.9 Massive hemoptysis due to lung cancer has a much
poorer prognosis than hemoptysis of other etiologies.
The mortality of massive hemoptysis may be as high as
59 to 100% in patients with bronchogenic carcinoma.10
Death from hemoptysis is usually attributed to asphyxia
rather than to exsanguination. This horrific complication is associated more frequently with central squamous
cell carcinoma. These tumors tend to be large and
angioinvasive, and to undergo spontaneous necrosis
and cavitation. Hemoptysis results from necrosis and
destruction of lung parenchymal support for vessels, as
well as from neovascularization of the tumor. The initial priority of therapy is to maintain the airway to optimize oxygenation and to stabilize the hemodynamic
status.11
Clinically stable patients should be positioned with
the bleeding side in a dependent position, to reduce aspiration of blood into the contralateral lung. Supplemental oxygen, sedatives, bed rest, mild cough suppression,
and avoidance of excessive thoracic manipulation are
helpful. Traditionally, a rigid rather than a flexible
bronchoscope is generally preferred with massive bleeding, when the need to remove large clots is anticipated.
Because of its larger diameter, a rigid bronchoscope is
particularly effective in suctioning, oxygen administration, and airway control. Usually the airway can be protected from blood aspiration by inflating a Fogarty
balloon catheter proximal to the bleeding site. The balloon can be left in place while the patient is stabilized
and considered for additional therapy.
Another approach to protect functional airways
involves placing a special endotracheal tube with inflatable distal cuff into the non-bleeding right or left main
stem bronchus. The use of a double-lumen tube permits adequate suctioning of blood. However, placement
of the tube requires experienced personnel. Urgent surgical intervention should be considered when bleeding
is associated with persistent hemodynamic and respiratory failure.
In patients who are not candidates for surgery because
of severe prognosis, extensive disease, co-morbid
conditions, prior pulmonary resection or inadequate
pulmonary reserve (predicted postoperative FEV1 less
220 Textbook of Lung Cancer
than 0.8–1l), several non-operative techniques have
been reported to control massive hemoptysis. Prolonged
tamponade with a Fogarty balloon catheter, ice-saline
lavage, and arteriography with therapeutic embolization of bronchial arteries have been reported to be successful in controlling bleeding. However, no prospective
comparative trials have been conducted on the efficacy
of these various techniques, and it is well known that
conservative non-surgical management of massive
hemoptysis carries a high mortality rate.
Radiation therapy (endobronchial or external beam)
and laser therapy may be useful in controlling bleeding
lung tumors. Palliative management should also be aimed
at reducing awareness and fear. A combination of a
parenterally administered strong opioid and a benzodiazepine is usually required.
CHEST PAIN
Pain is a significant problem in cancer patients in general and lung cancer patients in particular. Chest pain
is reported at presentation in one-quarter to one-half of
patients with lung cancer,12 and usually arises via direct
invasion or metastatic involvement of pain-sensitive
intrathoracic structures (mediastinum, pleura, or chest
wall). Marino and colleagues13 reported early thoracic
pain in 40% of 164 patients with lung cancer without
extrathoracic or distant metastasis. Pain was present on
the side of the neoplasm in 80% of the patients.13
Peripheral tumor invading the costal parietal pleura
and chest wall gives rise to sharp, intermittent, pleuritic
pain. This type of pain may also be caused by obstructive pneumonitis or associated pulmonary embolus.
Brachial plexus
(arm and
shoulder pain)
Sympathetic trunk]
(Horner’s
syndrome)
Subclavian
artery
and vein
Other patients suffer from a poorly localized, vague,
persistent discomfort, sometimes associated with central tumors with mediastinal extension and possible
involvement of perivascular and peribronchial nerves.
It is important to distinguish the chest pain that accompanies direct contiguous chest wall extension from rib
metastases.
A characteristic pain syndrome is caused by local
extension of an apical lung tumor at the superior thoracic inlet. Such a tumor is called a superior pulmonary
sulcus tumor, and the associated pain is known as Pancoast’s syndrome (Figure 15.1). The most common initial symptom is shoulder pain, produced by neoplastic
involvement of the brachial plexus, parietal pleura,
endothoracic fascia, vertebral bodies, and first, second
and third ribs.14 The pain is often severe and unrelenting; while initially confined to the shoulder and scapula, it later radiates down the arm, following an ulnar
distribution, reflecting involvement of the C8 and T1
nerve roots. Pulmonary symptoms and signs are conspicuously absent, while arm weakness signifies
advanced brachial plexus invasion. With further extension through the intervertebral foramina in 5% of
patients initially, but in as many as 25% later in the
course of the disease, compression of the spinal cord
and paraplegia may result.15 The majority of cases of
Pancoast’s syndrome are caused by NSCLC, most commonly squamous, followed by adenocarcinoma and
large cell carcinoma. SCLC is only rarely associated
with this syndrome.
Although in the past a histologic diagnosis was not
considered necessary before therapy, the wide variety of
diseases that can result in Pancoast’s syndrome (other
primary thoracic neoplasms, metastatic and hematologic
Vertebral body
Vagus nerve
Recurrent nerve
(vocal cord
paralysis)
T4
A tumor of any size with
invasion of the mediastinum, or
involving heart, great vessels,
trachea, (a) esophagus, (b)
vertebral body or carina or
presence of malignant pleural
effusion
Figure 15.1
Schematic of International Staging System definitions
for superior sulcus tumors, including Pancoast’s
syndrome. (Reproduced with permission from
Mountain CF. A new international staging system for
lung cancer. Chest 1986; 89: 225S).
Complications of lung cancer 221
neoplasms, infectious processes, neurogenic thoracic
outlet syndrome) now mandates a conclusive diagnosis
before definitive treatment is started. The chest radiograph may show an obvious apical mass, but frequently
only a subtle increase in density is visible at the apex,
and is often missed. Magnetic resonance imaging (MRI)
has become the diagnostic modality of choice, because
of its superiority to CT in delineating tumor extension
to vascular and neural structures, vertebrae, and the
spinal canal.
Therapeutic modalities for superior sulcus tumors
involve combinations of preoperative, intraoperative,
and postoperative radiotherapy, and either surgery or
radiotherapy alone. Surgical resection after preoperative
radiotherapy has been the most common treatment of
superior sulcus tumors. However, there is no conclusive
scientific evidence to recommend the standard use of
preoperative radiotherapy for such tumors. Proponents
of these treatment modalities based their recommendations on retrospective data. Standard resection is usually
performed by en bloc resection of the tumor, generally
by lobectomy, including chest wall, and may also be
accompanied by resection of the involved paravertebral
sympathetic chain, stellate ganglion, lower trunks of
the brachial plexus, and, in some cases, the subclavian
artery and portions of the thoracic vertebrae.
Contraindications to surgical treatment include extensive involvement of the brachial plexus and paraspinal
region, especially the intervertebral foramina, bodies,
and laminae of the vertebrae. Radiotherapy at doses
of at least 60 Gy (dose range 20–70 Gy) can be used
alone as a primary treatment, especially for inoperable
superior sulcus tumors, palliating pain in up to 90% of
patients.16
The role of intraoperative and postoperative radiotherapy is unclear at present, and they should be used
mainly in patients who are found to have unresectable
tumors after a surgical attempt.17 Recently, induction
chemoradiotherapy has been reported to enhance complete resection rates and improve survival compared with
historical controls and is likely to become the new standard treatment for localized superior sulcus tumors.18
Clinical factors associated with improved survival
include good performance status, a weight loss of less
than 5% of total body weight, and achievement of local
control and pain relief after treatment.19 Standard pain
management techniques, including stepwise analgesics
and radiation therapy, are usually effective in controlling pain initially in many patients. Some patients may
require additional measures, including nerve blocks,
spinal analgesia, or even palliative surgery.
PLEURAL EFFUSION
Approximately 25% of patients with lung carcinoma
develop a malignant effusion during the course of their
disease. Impaired drainage from the pleural space is the
predominant mechanism for the accumulation of fluid
associated with malignancy. Tumor cells either seed the
mesothelial surface or invade the subserous layer. When
the mesothelial surface is involved, tumor cells are
abundant in pleural fluid; with subserous involvement,
only a few malignant cells are exfoliated into the pleural
space. Peripheral tumors, most commonly adenocarcinomas, may directly seed the pleural space.
Patients usually present symptoms that compromise
their quality of life, including progressive dyspnea, cough,
and/or chest pain.20 Symptoms appear to be closely
related to the rate of pleural fluid accumulation rather
than to the total volume. Accompanying fever is usually
a sign of atelectasis and infection. About one-quarter of
patients with malignant pleural effusions are asymptomatic. The fluid itself may be serous, serosanguineous, or grossly bloody, and typically it is ipsilateral to
the main tumor and of moderate to large volume. The
finding of malignant cells in the fluid confirms stage
IIIB disease and a relatively poor prognosis. However,
not all pleural effusions associated with lung cancer are
due to pleural metastasis. Occasionally, fluid formation
is only indirectly related to the tumor. Patients are at
increased risk for pleural effusions from postobstructive
pneumonia, atelectasis, pulmonary emboli, and drug or
radiation reactions. In one series, 4 of 73 NSCLC patients
with pleural effusion had surgically resectable tumors
and survived for intervals ranging from 3 to 14 years.21
The diagnosis should be made on physical examination and confirmed by chest radiograph. The latter may
be the only clue to the presence of pleural effusion.
Approximately 300 ml of fluid is required for detection
of a pleural effusion on a standard posteroanterior chest
film. The lateral decubitus chest film is extremely useful
in cases of subpulmonic effusion, detecting significantly
smaller quantities of pleural fluid. Loculated effusions
can be localized with ultrasonography or CT scan. The
most definitive and simplest method of identifying a
malignant pleural effusion is by cytologic examination.
A sample of 250–1000 ml of fresh pleural fluid should
be sent to the cytology laboratory for examination. The
diagnostic efficacy increases on repeated aspirations, from
approximately 50% positivity on initial thoracentesis to
65% on the second sample and to 70% on the third.22
The management of malignant pleural effusions depends
on the treatment options of the primary malignancy.
222 Textbook of Lung Cancer
Systemic treatment may control pleural effusion due to
SCLC, although therapeutic thoracentesis may still be
required to control symptoms. Patients with SCLC who
present ipsilateral effusions as their only manifestation
of metastatic spread beyond the primary tumor and
regional lymph nodes may have an overall response
rate, complete response rate, and survival equivalent to
patients staged as having limited disease.23
If effective systemic treatment is not available, treatment is often palliative, usually consisting of sequential
thoracentesis or tube thoracostomy with or without
sclerotherapy. Therapeutic thoracentesis may improve
patient comfort and relieve dyspnea. The subjective
response to drainage and the rate of fluid reaccumulation should be monitored. Repeated thoracenteses are
reasonable if they achieve symptomatic relief, if fluid
reaccumulation is slow, and if the patient’s expected
lifespan is very short. Used alone it is not an effective
means for preventing recurrence. The mean time to fluid
reaccumulation in one series was as short as 4 days, with
a 98% recurrence rate at 39 days.24
If life expectancy is reasonable, obliteration of the
pleural space, either by parietal pleurectomy or by
instillation of sclerosants that cause inflammation and
subsequent pleural symphysis, can prevent recurrent
accumulation of fluid. The efficacy of chemical pleurodesis depends upon complete evacuation of pleural
fluid by tube thoracotomy followed by introduction of
an effective sclerosing agent into the pleural space and
retention of the agent in the chest for sufficient time to
induce an inflammatory fibrosis.25
Several agents have been used for pleurodesis, including talc, tetracycline, doxycycline, bleomycin, and others, with variable efficacy rates.25 In two meta-analyses
of trials of adults who underwent pleurodesis for malignant pleural effusion, talc was the most effective sclerosant.26 Talc may be delivered as a slurry by way of a
chest tube after drainage or at the time of thoracoscopy,
using insufflation. The efficacy of these two approaches
was compared in a prospective randomized trial.27 Survival rates and success of the pleurodesis were similar
in both arms, but quality of life scores were higher in
the group that was treated thoracoscopically. Traditionally, large bore (20–28 Fr) chest tubes have been used
for drainage before pleurodesis. In recent years several
studies have indicated that small-bore (8–14 Fr) catheter
drainage and sclerosis may be comparable in efficacy.28
Another approach involves placement of an indwelling pleural catheter through which the patient can
drain pleural fluid in the ambulatory setting. Advantages include the ease of insertion, rapid drainage of
recurrent symptomatic effusion, and minimal hospitalization required for catheter insertion and care.29 A
phase III trial compared the efficacy of an indwelling
pleural catheter with chest tube and doxycycline sclerotherapy for recurrent symptomatic malignant pleural
effusion in 144 patients. The pleural catheter had similar efficacy to doxycycline pleurodesis in relieving
symptoms that were secondary to pleural effusion.
Patients who were treated with the pleural catheter had
a shorter hospital stay.30
SUPERIOR VENA CAVA SYNDROME
The principal vascular syndrome associated with extension of lung cancer into the mediastinum is superior
vena cava syndrome (SVCS), most commonly caused
from compression by a large primary tumor or its mediastinal lymph node metastases, but also from intraluminal thrombosis. Patients characteristically complain
of headache, swelling of the face, neck, and upper
extremities, or a host of thoracic symptoms, such as
dyspnea, cough, chest pain, and dysphagia. Physical
examination may show facial edema, neck vein distension, and striking collateral engorgement over the anterior chest wall and upper abdomen. The degree of
collateral vein formation reflects the time over which
superior vena cava obstruction has developed and the
relative anatomic site of the blockade, since obstruction
above the azygos vein is better tolerated. Signs of airway obstruction (e.g. stridor) or intracranial pressure
(stupor or convulsion) should prompt rapid evaluation
and treatment. When typical signs are present, complete SVC obstruction is easily diagnosed. The CT scan
is likely to show tumor masses, and can also reveal the
presence of thrombi and collateral vessels.
Lung cancer accounts for 65–90% of patients with
SVCS, with approximately 85% of primary lung tumors
occurring on the right, primarily in the right upper lobe
or right mainstem bronchus. Among 2000 patients presenting lung cancer, 4% had SVCS.31 By cell type, SCLC
predominates as the cause of SVCS, followed by
squamous cell carcinoma. In addition to lung cancer,
lymphoma, and other malignancies, benign causes of
obstruction of the SVC include fibrosing mediastinitis,
thrombosis, inflammatory adenopathy, postirradiation
fibrosis, and aneurysms.
Contrary to prior clinical wisdom, it has been convincingly demonstrated that the SVCS does not constitute a true medical emergency requiring urgent treatment
without a tissue diagnosis.32 The immediate causes of
Complications of lung cancer 223
death directly related to SVC obstruction are airway
obstruction and intracerebral hemorrhage. In the
absence of significant airway obstruction and signs of
severely elevated intracranial pressure, definite diagnosis can be obtained before therapy. An accurate diagnosis is also especially important in view of the diverse
etiologic considerations mentioned above. Bronchoscopy and, depending on the clinical circumstances,
node biopsy, mediastinoscopy or even thoracotomy can
be employed safely and effectively to diagnose lung
cancer in this setting.
Most patients with SVCS secondary to lung cancer
have resolution of symptoms after initiation of radiation or chemotherapy.33 Before instituting radiotherapy
in SVCS, general medical maneuvers, including oxygen
support, bed rest with elevation of the head of the bed,
and corticosteroids, may be used as temporizing measures.
Chemotherapy is particularly useful when SVC
obstruction is secondary to SCLC, although radiotherapy has been used in selected series. There is no difference in outcome or in time to resolution between the
two,34 but chemotherapy offers the advantage of simultaneous management of systemic disease and avoidance
of large-field irradiation to the heart and lung. Resolution of the syndrome is prompt (7–10 days), and is
achieved in 43–100% of cases.35 If the chemotherapy
drugs include vesicants, these should not be injected
into the dilated, high-pressure, upper-extremity veins.
The right upper extremity should be avoided for any
drug administration, since the rate of blood flow is
markedly decreased, and thrombosis, phlebitis, and
erratic drug distribution are likely.
Radiation is generally indicated in the management
of the patient with SVCS secondary to NSCLC. Initial
treatment with two to four fractions of 300–400 cGy,
followed by conventional fractionation to a total dose of
3000–5000 cGy, has been advocated on the basis of
limited evidence suggesting a prompter response with
this schedule. One study evaluated the efficacy of treating patients with SVCS with a short course of hypofractionated irradiation.36 The study compared a regimen of
8 Gy fractions once a week (to a total dose of 24 Gy)
within two weeks, versus a program of delivering
only two fractions of 8 Gy (to a totaI dose of 16 Gy)
within a week. In both regimens, a good palliative result
was established; however, the results of the 24 Gy regimen were superior. Using the 24 Gy regimen, partial
responses were obtained in 96% of patients, and 56%
achieved complete response. The 16 Gy regimen yielded
a complete response in only 28% of patients. Median
overall survival was longer with the higher-dose regimen
(nine months), compared with the low-dose regimen
(three months). Anticoagulation with heparin may be
of benefit in SVCS resulting from intraluminal thrombosis of the SVC. Rapid onset obstruction that causes
respiratory compromise must be treated emergently;
percutaneous stenting may be the treatment of choice.37
Analysis of 23 retrospective trials that assessed the efficacy of superior vena cava stenting showed that 151 of
159 patients (95%) had relief of SVC obstruction after
stenting.38
CARDIAC TAMPONADE
Neoplastic cardiac tamponade is one of the true emergencies of clinical oncology. It may appear abruptly and
cause death in a patient who otherwise has good shortterm life expectancy. Carcinoma of the lung is associated with the highest frequency of malignant pericardiac
effusion, accounting for 37% of reported cases.39 Haskell
and French40 reported on 23 patients in whom cardiac
tamponade was the initial presentation in malignancy:
7 of these patients had lung cancer. Pericardial involvement arises either from direct extension of the tumor or
because of retrograde spread through mediastinal and
epicardial lymphatics. Cardiac tamponade may also be
caused by postirradiation pericarditis with fibrosis or
by encasement of the heart by tumor. The amount of
fluid necessary to cause tamponade may be small (less
than 200 ml) when the effusion accumulates rapidly or
when the pericardium is non-compliant owing to fibrosis. When the pericardial effusion is chronic, over 1 liter
may accumulate before causing tamponade.
The symptoms of cardiac tamponade are non-specific.
The most frequent complaints are apprehension, chest
pain, and dyspnea. Occasionally, cough, hoarseness,
hiccups, nausea, and abdominal pain are prominent
complaints. Elevated jugular venous pressure, tachycardia, and narrow arterial pulse pressure are almost always
seen. Pulsus paradoxus, an abnormally large drop in arterial systolic pressure during inspiration (>10 mmHg), is
a hallmark of cardiac tamponade. The chest radiograph
may show a large globular (‘water bottle’) heart, but
cardiac silhouette may appear normal when the effusion has accumulated rapidly or is less than 250 ml.
Sinus tachycardia and low voltage (QRS complex < 5 mV)
are usually present on a 12-lead electrocardiogram.
QRS complex electrical alternans, pathognomonic of
cardiac tamponade, is infrequently seen. A pericardial
effusion may be quickly and accurately diagnosed by
224 Textbook of Lung Cancer
echocardiogram. Two-dimensional echocardiography
is more sensitive than M-mode, because it displays virtually the entire circumference of the heart. Certain
two-dimensional echocardiographic findings help to
determine the functional significance of a pericardial
effusion. Diastolic right atrial and right ventricular collapse occur early during the development of cardiac
tamponade. However, physical examination and noninvasive tests may not elucidate the functional significance of pericardial effusion, particularly in patients
with associated cardiopulmonary disease. In such cases,
right heart catheterization or diagnostic pericardiocentesis is indicated.
Definitive treatment of cardiac tamponade requires
decompression of the heart either surgically or by pericardiocentesis. Supportive therapy, including intravenous fluids, pressor agents, and oxygen, is of limited
benefit. Acute pericardial tamponade with hemodynamic instability is life threatening, and must be alleviated
by prompt fluid removal – most rapidly by pericardiocentesis. If the patient develops cyanosis, dyspnea,
shock, or impaired consciousness, a pulsus paradoxus
greater than 50% of pulse pressure, or a decrease of
more than 20 mmHg in pulse pressure, emergency
pericardiocentesis must be performed. If the patient is
hemodynamically stable, a more definitive procedure
should be performed. Zwischenberger and Bradford41
recommend echocardiography or CT-guided percutaneous tube pericardiotomy to accomplish both diagnosis and therapy at the initial intervention. Once the
pericardium has been drained, these authors use doxycyclin or bleomycin for sclerotherapy. If sclerotherapy
does not control the effusion, they proceed with subxiphoid pericardiotomy for evacuation of the effusion.
A subxiphoid pericardial window can be performed under
local anesthesia, and is reported to control the effusion
in almost all patients. The high control rate and low
incidence of complications with subxiphoid pericardiotomy have also led other investigators to conclude
that this procedure can be used instead of pericardiocentesis for initial treatment of cardiac tamponade.42
EXTRATHORACIC COMPLICATIONS
Lung cancer frequently metastasizes to distant organs.
More than 60% of patients with SCLC, and approximately
30–40% of those with NSCLC, have stage IV metastatic
disease. The usual sites of distant metastatic disease
include the adrenals, brain, liver, lung and bone, although
virtually any organ can be affected. Metastases may
present at the same time as the primary tumor or may
occur much later, and they may be single or multiple,
clinically silent or requiring urgent diagnosis and treatment. Manifestations resulting from distant metastases
depend on the specific organ involved and are similar
to those for other kinds of cancer.
Brain metastases
The most frequent metastatic neurologic complications
of lung cancer are metastases to the brain. Clinically
diagnosed brain metastases are present at initial presentation in 4–19% of SCLC patients,43 and the incidence
rises to 50% in patients not receiving prophylactic cranial irradiation.44 Patients with NSCLC, especially those
with adenocarcinoma, often develop brain metastases
during the course of their disease.45
Brain metastases may be detected before the primary
tumor is found or at the same time (synchronous presentation), but more commonly (80%) the diagnosis of
the lung cancer antedates the development of the brain
metastases (metachronous presentation). Focal neurologic abnormalities and global deficit of higher mental
function are the commonest findings, with headaches
being the most frequent symptom at presentation. Headaches occur in approximately 50% of patients with brain
metastases, more commonly in those with multiple
metastases and with metastases in the posterior fossa.
Headeache may be associated with other symptoms
characteristic of increased intracranial pressure, such as
vomiting, visual blurring and confusion. Focal weakness is the presenting symptom in 20–40% of patients.
Deficits of higher mental function (memory problems
and mood or personality changes) are reported by onethird of patients, whereas cognitive dysfunction as
detected by standard tests of mental status may be present in as many as 75%. Seizures occur in approximately
10% of patients as the first sign of metastases. CT and
MRI are the primary radiographic means of evaluating
patients suspected of having brain metastases. MRI is
more sensitive in detecting multiple lesions, and allows
improved visualization of the brainstem.
The prognosis for patients with brain metastases is
very poor, and depends on their functional and neurologic status, evidence of systemic tumor involvement,
and whether the brain metastasis is truly solitary. Twothirds of patients will have improvement in their neurologic signs and symptoms with the use of steroids,
but only for a short time (maximum one month). Dexamethasone is the most commonly used glucocorticoid,
because it has minimal mineralcorticoid activity as
compared with other steroids.
Complications of lung cancer 225
Conventional dosing with dexamethasone for brain
edema is 16 mg/day. Currently there are three treatment options available for patients with a known NSCLC
and a solitary intracranial metastasis: surgical resection,
whole brain radiation therapy (WBRT), and stereotactic
radiosurgery (SRS). Most often, some combination of
these methods of treatment is preferable. Surgical resection plus postoperative WBRT is currently the treatment
of choice for patients with surgically accessible single
brain metastases.
The data supporting surgery for single brain metastases come from many retrospective studies46 and two
randomized prospective trials,47,48 the results of which
show that surgical resection is of benefit in selected
patients. In the first randomized trial, by Patchell et al,47
patients with known systemic cancer were treated either
with biopsy of the suspected brain metastases plus
WBRT or with complete surgical resection of the metastases plus WBRT. A statistically significant increase in
survival time was found in the surgical group (40 weeks
versus 15 weeks). In addition, patients receiving surgery also had a significant decrease in recurrence at this
surgical site and an improved quality of life. A second
randomized study48 evaluated 63 patients randomized
either to complete surgical resection plus WBRT or to
WBRT alone. Survival was significantly longer in the
surgical group (10 months versus 6 months), and a
non-significant trend towards longer duration of functional independence was seen in the surgically treated
patients. On the basis of these data, surgery and radiotherapy are usually recommended for good performance status patients with a solitary cerebral metastasis.
However, over 50% of isolated brain lesions are not
amenable to surgery. SRS is an alternative method able
to deliver a highly focused, single dose of radiation to a
well-defined, small intracranial target, thus minimizing
exposure to the normal surrounding brain. No randomized prospective trials have compared SRS to surgery.
Many studies of SRS for patients with intracranial
metastases have reported similar median survival times
to surgery.49
A retrospective study has demonstrated equal local
tumor control rates and equal neurologic death rates
between surgery and SRS.50 A prospective but nonrandomized study of patients with lung cancer (both
SCLC and NSCLC) demonstrated significantly longer
median survival for SRS with or without WBRT over
WBRT alone (10.6 months and 9.3 months vs 5.7
months, p <0.0001).51 A randomized study of WBRT
alone versus WBRT plus SRS in patients with two to
four intracranial metastases showed significantly
improved local control, with a trend toward increased
survival for WBRT plus SRS.52 Based on the available
data, the appropriate SRS dose following WBRT is 20
Gy in tumors less than 2 cm in size, 18 Gy in tumors
2 to 3 cm in size, and 15 Gy in tumors more than 3
cm. The majority of patients with brain metastases
present with multiple lesions, and are not candidates
for aggressive local therapy. The mainstay of treatment
is palliative WBRT.53 Many studies have compared different radiation schedules and doses. Final results
from the Royal College of Radiologists’ trial54 suggest
that a hypofractionated course of WBRT could palliate
symptoms with minimal toxicity. Patients with NSCLC
who are elderly or have a poor performance status
could benefit from a short course of treatment. Some
studies indicate that chemotherapeutic agents may
cross the blood–brain barrier in patients with brain
metastases.55 The observed response rate to chemotherapeutic agents was reported to be similar in the brain
(16–35%) to other organs.56,57 Two studies on concomitant radiotherapy and chemotherapy for brain metastases in NSCLC reported higher objective response
rates (58–76%).58,59 Moreover, both studies demonstrated a neurologic improvement in more than 50%
of patients. Whether there is a definitive role for chemotherapy or combined chemoradiotherapy in the
treatment of brain metastases in patients with NSCLC
will have to be determined by prospective studies,
taking into account survival and quality of life as their
main endpoints. Patients with SCLC and brain metastases at presentation should be treated with primary
chemotherapy. Whether consolidating cranial radiotherapy should be given after a few courses of initial
chemotherapy is unclear. In patients who are unfit for
chemotherapy or who have brain relapses during or
immediately after chemotherapy, some palliative effect
can be obtained with a short course of WBRT. As with
NSCLC, combined chemoradiotherapy should be considered only in the context of a clinical trial.
Spinal cord compression
After brain metastases, spinal cord compression (SCC)
is the most frequent neurologic complication of lung
cancer. Five percent of patients with lung cancer
develop SCC, more frequently at an interval after the
diagnosis, usually six months.60 In a retrospective
study on metastatic SCC secondary to lung cancer,
Bach et al61 observed some variations between the
different types of lung cancer. In SCLC, 75% of the
cases of SCC were diagnosed during the first month
after the primary malignant diagnosis was established,
226 Textbook of Lung Cancer
which contrasts with 12 months for adenocarcinoma
and 21 months for squamous subtypes. Lung cancer
has a predeliction to metastasize to the spine. The
most common mode of SCC is that due to expansion
or collapse of the vertebral body (85%) or neural
arch. Paraspinal lung cancer may also directly invade
the extradural space through the intervertebral
foramen, producing SCC without vertebral body
involvement.
Malignant SCC is a medical emergency, and the key
to successful management is early diagnosis and prompt
treatment. All too often, the diagnosis is made too late
for useful treatment. Those patients who present paraparesis, sensory symptoms, and sphincteric dysfunction usually pose no difficulty in diagnosis. Patients
with more subtle presentations must be identified, and
an appreciation of the earliest clinical manifestation is
therefore essential. Isolated back pain is the initial
symptom in 70–95% of patients, and it always antedates diagnosis of SCC by several days to many months.
Pain can be local or radicular. Symptoms other than
pain suggest compromise of neural structures. Weakness is present in approximately 80% of patients, and
may be most evident when it affects proximal muscles
of the lower extremity, creating difficulty when climbing stairs or rising from chairs. Non-painful sensory
symptoms include paraesthesias, which in SCC usually
begin in the feet and gradually ascend, ultimately stopping at a specific level that the patient may indicate.
Loss of proprioception, producing ataxia, and sphincteric dysfunction are often late manifestations. Careful
neurologic examination usually identifies the neurologic level and establishes the diagnosis.The evaluation
of the patient with SCC must be speedy and resolutive.
Although 80% of patients show abnormalities on plain
spinal radiography, normal spine films do not exclude
epidural metastases. MRI is being recognized as the
diagnostic method of choice in SCC.
Patients diagnosed with epidural cord compression
should be treated urgently. Loss of ambulation or
sphincter function before treatment is associated with a
poor response to treatment and an adverse prognosis.
About 80% of patients with little or no ambulatory dysfunction retain the ability to walk. Patients who are
paraparetic recover ambulation in 20–60% of cases.
Paraplegia improves in response to treatment in no
more than 16% of cases.62,63 When the diagnosis of epidural compression has been made, dexamethasone
should be administered. There is good evidence that
the administration of high-dose steroids (dexamethasone 96 mg intravenous bolus, then 24 mg orally four
times a day for three days, then taper over ten days)
improves the postradiation ambulatory rate compared
with those who do not receive any steroids.64 However,
the utility of moderate-dose steroids (dexamethasone
10 mg intravenous bolus, then 4 mg intravenously,
with a taper over two weeks) remains unclear. There
is fair evidence that dexamethasone does not need to
be given to asymptomatic ambulatory patients with
radiographic cord compression who are receiving radiotherapy.65 The decision to proceed with surgery or radiotherapy is based on the individual patient’s specific
circumstances.
Although based on inconclusive evidence, some general treatment recommendations can be suggested.66,67
Patients who present spinal instability or bony compression of their spinal cord, with no histologic diagnosis, with redevelopment of epidural compression in a
previously radiated site, and with neurologic deterioration during radiotherapy, should be considered for surgical resection. Postsurgically ambulatory patients may
benefit from postoperative radiotherapy. Other patients
can be treated effectively with radiotherapy alone, specifically those with a life expectancy of three months or
less, more than one level of simultaneous SCC, paraplegia of greater than 12–24 hours’ duration, and co-morbid conditions that preclude surgery.
PARANEOPLASTIC SYNDROMES
Complications of lung cancer that are not related to
direct invasion, obstruction, or metastatic effects of the
tumor are generally termed paraneoplastic. Paraneoplastic syndromes comprise a group of disorders mediated
by the production of circulating factors by, or in response
to, lung cancer. These syndromes are numerous and
occur in 10–20% of lung cancer patients, and include
endocrine, neurologic, cardiovascular, skeletal, and
cutaneous manifestations (Table 15.2). In this review,
we focus only on the most common syndromes.
Paraneoplastic endocrine syndromes
Syndrome of inappropriate antidiuretic hormone
Syndrome of inappropriate antidiuretic hormone
(SIADH) results from inadequate secretion of antidiuretic hormone (ADH, vasopressin), which is almost
exclusively associated with small cell histology. Up to
50% of SCLCs have elevated levels of ADH, but fewer
than 10% have clinically apparent disease. SCLC is estimated to account for 75% of tumor-associated SIADH.
Complications of lung cancer 227
Table 15.2 Paraneoplastic syndromes of lung cancer
Syndrome
Clinical frequency (%)
Isotype
Endocrine
Inappropriate ADH
Ectopic ACTH
Humoral hypercalcemia
5–10
3–7
10
SCLC
SCLC
Most frequently with
squamous cell types
Neurological
Lambert–Eaton
Peripheral neuropathy
Encephalopathy
Myelopathy
Cutaneous and musculoskeletal
Clubbing/hypertrophic pulmonary
osteoarthropathy
Dermatomyositis
Acanthosis nigricans
Vascular and hematologic
Hypercoagulable state
Thrombophlebitis
Non-bacterial thrombotic endocarditis
6
Rare
Rare
Rare
}
SCLC
10
}
More with adenocarcinoma
}
More with adenocarcinma
Rare
Rare
10–15
Uncommon
Uncommon
The main features of SIADH are water intoxication and
hyponatremia. Diagnostic criteria include:
•
•
•
•
hypo-osmotic hyponatremia;
inappropriately concentrated urine (urine osmolarity >100 mosmol/kg);
euvolemia;
normal renal, adrenal, and thyroid function.
The clinical features are related to osmotic water shift
that leads to increased intracellular fluid (ICF) volume,
specifically brain cell swelling. More often, hyponatremia develops insidiously, and adaptive mechanisms
tend to minimize the increase in the ICF volume and its
symptoms. Most patients experience minimal symptoms, and are discovered on routine laboratory evaluation when they have hyponatremia. Symptoms most
frequently associated with hyponatremia include
anorexia, nausea, vomiting, headache, and mildly altered
mental status. In severe or rapid-onset hyponatremia,
patients may experience symptoms related to cerebral
edema, resulting in confusion, irritability, seizures, coma,
and, ultimately, respiratory arrest.
In evaluating a patient with hyponatremia, the physician must carefully exclude other causes and non-malignant conditions associated with SIADH. The first
step in the diagnostic process is to assess volume status.
As SIADH is one of the so-called euvolemic hyponatremic states, the physician must recognize all diseases
associated with volume overload, such as congestive
heart failure, nephrotic syndrome, and severe liver disease. On the other hand, it is also important to exclude
causes of hypovolemic hyponatremia that develops as a
consequence of electrolyte-free water retention.
Once the patient has been determined to be euvolemic, other causes of hyponatremia associated with a
normal extracellular fluid volume must be ruled out,
including glucocorticoid deficiency, hypothyroidism,
and renal disease. Finally, other causes of SlADH must
be excluded before the disorder is accepted as a paraneoplastic syndrome. Well-known non-malignant conditions associated with SIADH include pulmonary
infections, central nervous system disorders (e.g. head
trauma, space-occupying lesions, and cerebrovascular
accidents) and drugs (most commonly chlorpropamide,
carbamazepine, tricyclic antidepressants, thiazide
diuretics, morphine, cyclophosphamide, and vincristine). List and colleagues68 reviewed 350 cases of SCLC
and noted that 40 (11%) met a strict definition of
SIADH similar to that outlined above, and 33 of them
had the syndrome at initial presentation. Chemotherapy of the associated SCLC is generally associated with
228 Textbook of Lung Cancer
improvement in the syndrome. SIADH has not been
shown to be a negative prognostic factor in terms of
response to chemotherapy. In 80% of patients, the
serum sodium returns to normal within three weeks of
the start of chemotherapy, and this may predate other
indices of response. Additional management of the
hyponatremia may be necessary while waiting a response
to chemotherapy, or when the tumor is resistant to
therapy.
Supportive measures such as fluid restriction and pharmacologic therapy can be undertaken to treat SIADH.
For patients with sodium levels below 130 mmol/l,
placement on free-water restriction (500 ml/day) is
generally recommended, in addition to treatment of the
primary malignancy. In the event that this measure does
not bring the serum sodium level above 130 mmol/l,
the tetracycline antibiotic demeclocycline (150–300 mg,
6–8 hourly) can be used, which induces nephrogenic
diabetes insipidus such that the distal tubule becomes
refractory to the effect of arginine vasopressin. In
patients with more severe or life-threatening symptoms
related to hyponatremia (serum sodium less than
115 mmol/l), treatment consists of intravenous fluids
with 0.9% saline (rarely, hypertonic saline) and diuresis
with a loop diuretic such as intravenous frusemide
(furosemide). The rate of correction of hyponatraemia
depends on the absence or presence of neurologic
dysfunction. This is, in turn, related to the rapidity of
onset and magnitude of the fall of the serum sodium.
The rate of correction of the sodium is best limited to
1–2 mmol/l/h, or a maximum of 20 mmol/l/day until a
Ievel of 120–130 mmol/l is reached. More rapid correction has been associated with the development of central pontine myelinolysis, which is characterized by
flaccid paralysis, dysarthria, and dysphagia.
Ectopic adrenocorticotropic hormone syndrome
Cushing’s syndrome is due to the chronic effects of an
excess of glucocorticoid hormone, most often iatrogenic
resulting from therapy with glucocorticoid drugs. Adrenocorticotropic hormone (ACTH)-secreting pituitary
microadenomas (Cushing’s disease) account for some
80% of cases of endogenous Cushing’s syndrome. About
15–20% of cases of Cushing’s syndrome are due to
ectopic ACTH or corticotropin-releasing hormone
(CRH) production. SCLC and bronchial carcinoid
tumors account for most of these cases.69 The classic
signs and symptoms include truncal obesity, cutaneous
striae, moon face, buffalo hump, proximal myopathy
and weakness, osteoporosis, diabetes mellitus, hypertension, and personality changes. However, lung cancer
patients with Cushing’s syndrome often do not have the
classic clinical finding. The commonest physical findings are edema (83%) and proximal myopathy (61%).70
Myopathy with weakness and muscle wasting is much
more common in ectopic ACTH production. Moreover,
hyperpigmentation is found in ectopic ACTH production, but not in Cushing’s disease. Most patients will
have a hypokalemic alkalosis, and about half will be
hyperglycemic. This difference in presentation may be
due to the rapid growth of the malignancy, relatively
high levels of ACTH, and the fact that patients may not
live long enough to develop the more classic features of
the syndrome.
Cushing’s syndrome occurs in approximately 5% of
cases of SCLC, although raised concentrations of immunoreactive corticotropin can be detected in as many as
50%. In a review of more than 500 patients with SCLC,
23 cases (4.5%) of Cushing’s syndrome were identified.70 Thirteen patients had the syndrome at initial
diagnosis, and ten developed it at the time of relapse of
their disease after therapy. All of these patients had a
shorter survival compared with patients without the
syndrome. This may be due in part to the observed
complications (infections and gastrointestinal ulceration) related to prolonged exposure to high levels of
corticosteroids secondary to ectopic ACTH production.
The diagnosis of Cushing’s syndrome is best established
by 24 hour urine-free cortisol measurements or lowdose dexamethasone suppression testing (0.5 mg every
six hours for eight doses).71 The primary therapy of
ectopic Cushing’s syndrome secondary to lung cancer
is treatment of the underlying tumor. If patients experience significant clinical effects from the hypercortisolism, cortisol production blockers (steroid synthesis
inhibitors), such as aminoglutethimide, mitotane,
metyrapone, and ketoconazole, are said to be beneficial. Because of its rapid onset of action and favorable
toxicity profile, ketoconazole (300–400 mg twice a day)
has become the therapy of choice for ectopic ACTH.72
Suppressors of ACTH production, such as the somatostatin analog octreotide,73 have shown some efficacy.
Humoral hypercalcemia
Hypercalcemia is probably the most common metabolic
complication of cancer and, since determination of the
serum calcium level became routine, the recognition of
patients with hypercalcemia associated with cancer has
increased. Hypercalcemia may be related to direct bone
destruction or to secretion of a parathyroid hormone
(PTH)-related protein or other bone-resorbing substances
(cytokines) secreted by the tumor. A PTH-related
Complications of lung cancer 229
protein that shares an N-terminal sequence with PTH,
but has a unique C-terminal portion, has been shown
to be responsible for most cases of hypercalcemia of
malignancy. Elevated levels of PTH-related protein by
radioimmunoassay were found in 30 of 42 patients
(71%) with hypercalcemia of malignancy, but only in 3
of 23 patients with cancer (13%) but with normal calcium levels.74 In a study of 200 consecutive patients
with untreated bronchogenic carcinoma, the overall
frequency of hypercalcemia was 12.5%.75 Of these 25
patients, 14 did not have evidence of bony metastases.
Humoral hypercalcemia was most commonly observed
in those with squamous cell histology, and was uncommonly observed with adenocarcinoma and SCLC.
The symptoms associated with hypercalcemia generally correlate with the magnitude and rapidity of the
rise in serum calcium. Mild hypercalcemia is generally
asymptomatic. More severe hypercalcemia is frequently
associated with neurologic, gastrointestinal and renal
symptoms. The neurologic manifestations range from
mild drowsiness, progressing to weakness, depression,
lethargy, stupor, and coma. Gastrointestinal symptoms
may include constipation, nausea, vomiting, anorexia,
and peptic ulcer disease. Hypercalcemia-induced nephrogenic diabetes insipidus often results in polyuria,
leading to extracellular fluid (ECF) volume depletion
and a reduction in the glomerular filtration rate (GFR),
which may lead to a further increase in calcium concentration. Cardiovascular effects include shortened QT
interval, broadened T wave, heart block, ventricular
arrhythmia, and asystole. Individual patients may manifest any combination of these signs and symptoms to
varying degrees.
Hypercalcemia may be completely reversible with
effective treatment of the underlying cancer; it is important to recognize that hypercalcemia per se does not
rule out the possibility of curative therapy, including
surgery, if indicated. The prognosis for patients with
hypercalcemia and no further treatment of the underlying malignancy is extremely poor, with median survivals of 30–45 days.76 The symptoms and the magnitude
of the hypercalcemia are key considerations in determining the need for aggressive therapy. If the serum
calcium concentration is greater than 14 mg/dl, immediate treatment is indicated, even if symptoms are
absent. In the case of mild calcium elevation (<12 mg/dl)
in patients with widely metastatic and incurable malignancy, it may be most appropriate to give supportive
care only, without specific therapy for the hypercalcemia. Otherwise, most patients with serum calcium values of 12–14 mg/dl should be treated. The approaches
to the management of hypercalcemia can be divided
into four specific areas:
•
•
•
•
treating the underlying tumor;
correcting dehydration;
enhancing renal excretion of calcium;
inhibiting accelerated bone resorption.
The intravenous administration of isotonic saline is
an important component, and is the first step in the
management of severe hypercalcemia with associated
symptoms. A widely used regimen is to administer 3 l
of isotonic saline daily, recognizing that the rate of fluid
administration may need to be varied if symptoms and
signs of fluid overload appear. The next step is to add a
loop diuretic, such as frusemide, that will increase calcium excretion.
This initial treatment usually has little effect on calcium
levels, effecting a median decrease of only 1.0 mg/dl.
Specific therapy to inhibit accelerated bone resorption
is often necessary. Bisphosphonates are potent inhibitors of bone resorption that have dramatically changed
the therapeutic approach to hypercalcemia. These compounds have poor gastrointestinal absorption, and are
best used intravenously. Pamidronate and zoledronate
are the most useful of the commercially available compounds. Normalization of serum calcium is obtained
after three days (range 1–11 days), and normocalcemia
is maintained for a variable length of time (median of
one to two weeks). Bisphosphonates are well tolerated;
the only clinically detectable side-effect is transient fever
in about 20% of the cases.
Other inhibitors of osteoclast activity include calcitonin, plicamycin, and gallium nitrate. Calcitonin inhibits bone resorption, increases renal calcium excretion,
and has a rapid onset of action. The hypercalcemia effect
begins within hours, with a nadir in serum calcium within
12–24 hours, but the effect on calcium concentrations
is modest and transient, and calcitonin alone has no
place in the treatment of severe hypercalcemia. However,
in very severe cases, it is an excellent addition to the lateracting bisphosphonates or plicamycin. Plicamycin (mithramycin) inhibits osteoclastic RNA synthesis. It lowers
the serum calcium more quickly than bisphosphonates
do, but significant side-effects (raised transaminases,
nephrotoxicity with proteinuria, thrombocytopenia, nausea, and local inflammation or cellulitis at sites of extravasation) decrease enthusiasm for this agent unless the
calcium concentration needs to be lowered very rapidly.
Gallium nitrate also inhibits bone resorption. As with
bisphosphonates, it takes several days before a nadir in
230 Textbook of Lung Cancer
serum calcium is reached, and this lasts about a week.
Side-effects are frequent and severe, and include nephrotoxicity, hypophosphatemia, and anemia. The need
to treat patients for five days with a continuous infusion
and its toxicity limit the use of this compound in the
treatment of hypercalcemia.
Paraneoplastic neurologic syndromes
Paraneoplastic neurologic syndromes have long been
recognized, and these disorders are now thought to
result from the cross-reaction of antitumor antibodies
with antigen also present in neural tissue.77
One such antigen is the nuclear-associated HuD protein, which has been cloned by use of high-titer antibodies from the serum of patients with paraneoplastic
syndromes.78 In health, the antigen is expressed only in
neural tissue, but is expressed by all SCLCs, perhaps
reflecting the apparent neuroendocrine origin of this
tumor. Why high titers of anti-HuD antibodies develop
in some patients with SCLC is unknown.
Neurologic paraneoplastic syndromes include sensory,
sensorimotor, and autonomic neuropathies and encephalomyelitis. Neurologic symptoms of encephalomyelitis
include dementia (limbic encephalitis), cerebellar degeneration, brain-stem encephalitis, and myelitis. Sensory
neuropathy and encephalomyelitis often occur together,
and are associated primarily with SCLC.
Symptoms may precede the diagnosis of lung cancer
by many months, or they may be the first sign of tumor
recurrence. Direct metastatic effects as well as metabolic
or infectious processes must be excluded as contributors to the neurologic findings. The severity of neurologic symptoms is not related to tumor bulk; in fact, a
primary malignant lesion may be undetected before
death, despite disabling symptoms. In a patient with the
appropriate neurologic findings, positive anti-Hu antibody, and significant smoking history, a diligent diagnostic evaluation should be undertaken. The most helpful
diagnostic test is probably CT of the chest, with careful
attention to mediastinal or hilar nodes.
Fluorodeoxyglucose (FDG)-PET scanning has also
been used with some success.79
Lambert–Eaton myasthenic syndrome
The neurologic syndrome most commonly recognized
is the Lambert–Eaton myasthenic syndrome, reported
to occur in up to 6% of cases of SCLC. Clinically, this
syndrome is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction due to impaired
release of acetylcholine from the cholinergic nerve terminals. Symptoms are most pronounced in the pelvic
girdle and thigh muscles, making it difficult for patients
to climb stairs or get out of a bathtub. Other symptoms,
such as dysarthria, dysphagia, diplopia, and ptosis, may
occur. It is distinguished from myasthenia gravis by the
absence or minor involvement of bulbar or extraocular
muscles. Standard electromyography characteristically
demonstrates a reduced amplitude of the compound
muscle action potential, which increases immediately
after 10–15 seconds of maximal voluntary contraction,
or during high-frequency nerve stimulation, while there
is a steady decrease in classic myasthenia. The manifestations of the disease may occur as long as two to four
years before the diagnosis of SCLC.
The syndrome is thought to result from autoantibodymediated impairment of presynaptic neuronal calcium
channel activity, which impairs the nerve stimulusinduced release of acetylcholine.80 Treatment-induced
remission of the SCLC may cause attenuation or remission of the syndrome in some patients. The use of
acetylcholinesterase inhibitors is of limited benefit. 3,4Diaminopyridine enhances the release of acetylcholine,
and has been shown to be effective in treating both the
motor and the autonomic deficits of the syndrome.81
Immunosuppressive treatment may provide benefit, but
its effects are usually delayed and incomplete. Many
patients become severely debilitated from their motor
dysfunction, regardless of the status of their lung cancer.
Paraneoplastic cerebellar degeneration
Paraneoplastic cerebellar degeneration (PCD) is a disorder that is charaterized by ataxia, nystagmus, diplopia,
dysarthria, and dysphagia. It is most often associated
with SCLC, and 44% of patients have elevated anti-Hu
antibodies. Individuals with anti-Hu antibodies are more
likely to be women, have extracerebellar manifestations
(encephalomyelopathy or sensory neuropathy), have
severe disability, and have localized or undetected tumor
at the time of death. Less that one half of patients with
PCD have abnormal neuroradiologic studies. Pathology
reveals inflammatory infiltrates, perivascular lymphocytic cuffing, and loss of Purkinje cells. Neither treatment
of the tumor, nor the immune modulating therapy alters
the course of PCD. Those with PCD and small cell carcinoma have a shorter survival than those without PCD.82
Progression of neurologic disease is the cause of death in
most patients with PCD who have positive anti-Hu antibodies and in a few who are anti-Hu negative.82
Peripheral neuropathy
Patients with cancer who suffer from a peripheral
neuropathy usually do so from causes other than
Complications of lung cancer 231
paraneoplastic syndromes (e.g. neoplastic invasion, chemotherapeutic agents, and nutritional and metabolic
disorders). Therefore a careful evaluation for other
causes of peripheral neuropathy should be made before
the disorder is accepted as a paraneoplastic syndrome.
One exception is the subacute sensory neuropathy
occurring in patients who have the anti-Hu antibody,
where the presence of the antibody establishes the diagnosis as a paraneoplastic syndrome and the cancer as
highly likely to be SCLC. In about 20% of all patients
with a subacutely developing pure sensory neuropathy,
cancer is the underlying cause. Subacute sensory neuropathy is usually a rapidly developing severe disorder
in which patients lose all modalities of sensation, usually in all four extremities. The disorder is clinically distinguishable from cisplatin sensory neuropathy, because
cisplatin neuropathy causes loss of proprioception and
spares pain and temperature sensation. Although the
disorder may begin in the face or trunk, it commonly
begins distally in the extremities and extends proximally. The sensory loss is so severe that patients may be
unable to walk, use their hands, or co-ordinate movements. The neurologic symptoms may precede the
diagnosis of SCLC by several months.83 Electrodiagnostic tests show absent sensory potentials. Motor nerve
conduction and F waves may be entirely normal. The
neuropathologic findings include drop-out of neurons
in the dorsal root ganglia, inflammatory infiltrates
mainly composed of T cells, and anti-Hu antibody on
the surface and in the nuclei of the remaining sensory
neurons.
Other neurologic syndromes
Among the other SCLC-associated neurologic syndromes
are limbic encephalopathy, necrotizing myelopathy, intestinal dysmotility syndrome, opsoclonus-myoclonus, and
cancer-associated retinopathy (CARS).
Anti-Hu antibody has been noted in patients with
SCLC presenting these rare neurologic paraneoplastic
syndromes.84 Limbic encephalopathy is characterized
by memory loss and behavioral changes, including
dementia, which often antedate the diagnosis of cancer.
Necrotizing myelopathy is an unusual neurologic paraneoplastic syndrome, and is characterized by a relatively acute, rapidly ascending paraplegia that culminates
in rapid deterioration and death.
Intestinal pseudo-obstruction of the bowel is the
most well-defined isolated autonomic symptom. Patients
may suffer weight loss, refractory constipation, and
abdominal distension. Neurologic studies show loss of
neurons in the myenteric plexus with inflammatory
infiltrates. Serum antibodies to myenteric and submucosal neural plexus of the jejunum and stomach have been
found in patients with SCLC.85 Opsoclonus-myoclonus
is another paraneoplastic syndrome commonly associated with SCLC. Neurologic manifestations involve
myoclonus, truncal ataxia, and progressive involuntary
rapid eye movements. The cerebrospinal fluid reveals
increased protein with mild pleocytosis. Imaging studies are often interpreted as normal. Treatment of the
SCLC can lead to partial or even complete recovery.
CARS is a rare paraneoplastic syndrome and it is
most commonly associated with SCLC. CARS is suspected to be caused by autoimmune degeneration of
the retinal photoreceptors. The triad of photosensitvity,
scotomes, and attenuated retinal arteriole caliber suggests the diagnosis of CARS. The use of steroids has
been reported to result in some improvement of visual
symptoms.86 Most cases progress to blindness, even
with treatment of the cancer.
Paraneoplastic cutaneous and musculoskeletal
syndromes
Digital clubbing and hypertrophic pulmonary osteoarthropathy are the other major paraneoplastic syndromes
that are associated with lung cancer, almost exclusively
with NSCLC.87 Digital clubbing is characterized by subungual soft tissue thickening, most commonly involving
the fingernails, which are often bulbous in appearance
(Figure 15.2). Clubbing of the digits is one of the most
commonly discussed findings on pulmonary medicine
clinical rounds. Etiologic factors include hereditary and
both non-pulmonary and pulmonary diseases, including bronchogenic carcinoma.
Hypertrophic pulmonary osteoarthropathy (HPO)
is less common than digital clubbing, and is usually
associated with intrathoracic malignancy, especially
lung cancer, and often resembles rheumatoid arthritis
(Figure 15.3). It is characterized by painful symmetric
polyarthritis that generally involves the ankles, wrists,
and knees. HPO is due to proliferative periostitis of the
long bones, often with little or no evidence of clubbing.
The onset of HPO is often acute, may precede the diagnosis of cancer by months, and usually, but not invariably, is associated with inoperability. The cause of HPO
is not known, but may be due to a humoral agent.
Patients with HPO frequently have consulted a rheumatologist or orthopedic specialist before the ultimate
diagnosis of lung cancer is suspected and a chest radiograph is obtained. In patients who smoke and present
arthralgia, HPO must be included in the differential
diagnosis. Radionuclide bone scans typically show
232 Textbook of Lung Cancer
nary disease. Weakness usually moves gradually and
progressively. Although they do not occur in all patients,
muscle tenderness and aches may be very striking. The
inflammation characteristically causes elevations of serum
levels of aldolase and creatinine kinase, and alternation
of liver function tests. Although most patients respond
initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness
develops.
Figure 15.2
Digital clubbing.
Figure 15.3
Hypertrophic pulmonary osteoarthropathy.
increased uptake at the distal ends of the affected long
bones, and this may be confirmed by evidence of new
bone formation on plain-film radiographs. The spine
is spared. The syndrome may resolve with response of
the cancer; however, no effective form of treatment is
recognized, including aspirin and non-steroidal antiinflammatory agents.
Other cutaneous paraneoplastic syndromes include
dermatomyositis, acanthosis nigricans, and hyperkeratosis of the palm and soles. These conditions are rarely
seen in patients with lung cancer. Dermatomyositis is a
rare but very disabling complication of lung cancer.
The patient presents weakness and a characteristic rash.
Sometimes the disease presents as a cardiac or pulmo-
Paraneoplastic vascular and hematologic
syndromes
The association between cancer and venous thromboembolism is well known. Over a hundred years ago,
Trousseau reported cases of episodic migratory thrombophlebitis in patients with cancer. The pathogenic
mechanisms for the association include hypercoagulability due to activation of clotting by tumor cells, vessel
wall injury, and stasis. Occasionally, the thromboembolic event occurs before the diagnosis of cancer, and it
has been suggested that deep venous thrombosis may
be a predictor of the subsequent diagnosis of cancer.
Two studies have noted a significant association between
primary venous thrombosis and the subsequent development of cancer.88,89 This link seems particularly
strong in patients with recurrent deep venous thrombosis. Lung cancer and other malignancies, especially
those of the gastrointestinal tract (e.g. the pancreas),
are commonly associated with Trousseau’ s syndrome.
Pulmonary embolism has been observed at autopsy in
20% of patients with lung cancer, and may precede the
diagnosis of cancer;90 25% of adult patients with acute
pulmonary embolism may develop cancer within five
years.91 There appears to be a general activation of the
clotting system in patients with lung cancer, the clinical
consequence much more often being thrombosis rather
than bleeding.
Disseminated intravascular coagulation (DIC) is another
state of hemostatic disarray, characterized by the inappropriate co-existence of enhanced fibrin production
and fibrinolysis. DIC has been reported as a complication of many neoplastic disorders, but is most likely to
occur in carcinoma of the lung, prostate, breast, and
gastrointestinal tract, in melanoma, and in leukemia.
In its grossest form, DIC is readily recognized by prolongation of the thrombin time, prothrombin time, and
partial thromboplastin time, by a decrease in the concentration of plasma fibrinogen and other clotting
factors, by thrombocytopenia and by the presence
in serum of antigens reacting with antiserum to fibrinogen or its derivatives. However, apparent DIC, with
Complications of lung cancer 233
consumption of platelets and clotting factors and bleeding, is rare and is most commonly associated with acute
promyelocytic leukemia and adenocarcinoma.
Non-bacterial thrombotic endocarditis (NBTE), also
known as marantic endocarditis, probably relates to
this hypercoagulable state, and is generally defined as
vegetations on the heart valves or wall that contain
fibrin and platelets, but without evidence of infection.
It is particularly associated with bronchoalveolar carcinoma and adenocarcinoma of the lung. At autopsy, the
incidence of NBTE in each of these cell types is approximately 7%. The mitral valve is commonly involved,
and clinically significant emboli to the central nervous
system, kidneys, and coronary arteries have been
described in what previously was thought to be a syndrome of only pathologic interest at autopsy.92 Although
some patients may have heart murmurs, most do not.
Echocardiography picks up vegetations larger than 2 mm.
In a review of cerebrovascular complications in patients
with cancer, Graus and colleagues93 observed cerebral
embolic infarction in 42 of 86 patients with pathologically documented NBTE and careful autopsy examination
of the brain. NSCLC was the most common malignancy
in this group. Cerebral infarction was symptomatic in
32 (76%) of these patients ante mortem, and was associated with clinical evidence of other systemic emboli in
19 patients. The definitive diagnostic test is cerebral
angiography, which shows multiple arterial occlusions.
Tumor embolization to the lungs and brain is another
cause of emboli in cancer patients, in addition to
venous thrombosis and NBTE. Tumor emboli are an
unusual clinical event, although autopsy series have
reported tumor emboli in up to 23% of solid tumors.94
Lung cancer and breast cancer were the most common
malignancies in these patients, but in only one patient
was the tumor embolism correctly diagnosed ante
mortem.
The management of thromboembolic complications
in patients with lung cancer is difficult. Typically, such
patients are resistant to anticoagulation, especially with
warfarin. Long-term administration of subcutaneous
low molecular weight heparin (LMWH) may be a more
effective approach.95
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16 Quality of life and supportive care
Jean-Paul Sculier, Anne-Pascal Meert, Marianne Paesmans, Thierry Berghmans
Contents Introduction • Quality of life assessment • Critical care of the lung cancer patient
• Symptom management • Management of treatment complications
INTRODUCTION
During the last two decades there has been great interest in the patient’s well-being, particularly among
oncologists and lung cancer specialists in particular.
Quality of life (QoL) assessment is a way to obtain
objective data in order to ‘measure’ the patient’s condition and to evaluate the effectiveness of therapies administered to improve his or her situation. Unfortunately,
there are considerable methodologic difficulties in
designing adequate universal instruments to give a
global measurement of QoL. Most of the investigations
performed so far in this field have in fact assessed the
symptoms of the patient in a semiquantitative way.
The specific anticancer treatment is in many situations the obvious solution to control the disease and
thus to improve the patient’s condition, but it can be
associated with side-effects and complications, may act
with some delay, or may not always be applicable or
effective. The aim of supportive care is to manage those
problems for which anticancer therapy is not effective
or sufficient. The field covered by supportive care is
very large, from critical care to terminal care, and
includes complications management, symptomatic
treatment, psychosocial support, and palliative care.
In the present chapter we will first review QoL assessment of lung cancer patients with an analysis of the
published data, indications and principles of critical
care in oncology, management of the most common
symptoms related to bronchial neoplasms (dyspnea,
pain), and treatment of the usual complications of anticancer treatment (emesis, febrile neutropenia).
QUALITY OF LIFE ASSESSMENT
Interest in QoL evaluation began in the mid-1980s and
has increased in oncology, and in particular for lung
cancer patients, due to the disappointing progress made
in improving survival – the traditional and true endpoint for phase III clinical trials – especially for advanced
unresectable non-small cell lung cancer (NSCLC).
Improvement in evaluation is due to the development
of validated instruments for measuring QoL. Up to now
there has been no significant improvement in length of
survival of these patients, so more attention is being
paid to identifying less toxic treatments, achieving better control of symptoms, and generally improving the
QoL of the patients. However, the incorporation of QoL
assessment in lung cancer clinical trials is a challenge,
due to the practical and theoretic difficulties of data
collection, data analysis, and interpretation of results.
The definition of QoL is clearly a multidimensional
concept and agreement was needed on the dimensions
to be included for measuring it, although, most often in
medical research, the concept is restricted to the dimensions directly related to the disease, its symptoms, and
its treatment. Research is then focused on health-related
QoL, with inclusion of dimensions like physical function and impairment of physical function due to disease
symptoms, occupational function, psychologic or emotional function, and social function. There is an association between this health-related QoL and the
Karnofsky performance index, introduced much earlier
(in 1949). However, the latter measure is clearly too
limited, although worsening in performance status is
correlated to a QoL deterioration and to an increase in
the lung cancer symptoms.
The problem of measuring QoL adequately (by the
patient himself as, due to the subjective nature of the
concept, external observers are poor raters) has been
solved by the development of validated instruments
proven to be both reproducible (an unchanged measure has to been obtained when the patient’s condition
is stable) and sensitive (able to capture any change in
the patient’s condition). In lung cancer, several diseasespecific instruments are available. The most frequently
used in advanced NSCLC in recent randomized clinical
trials include:
•
the European Organization for Research and
Treatment of Cancer (EORTC) Quality of Life
Quality of life and supportive care 237
•
•
Questionnaire, including a core (QLQ C30) completed by a lung cancer module assessing diseasespecific symptoms and toxicities (QLQ LC13),1
which has the advantage of being translated into
many languages;
the Lung Cancer Symptom Scale (LCSS);2 and
the Functional Assessment of Cancer Therapy–
Lung (FACT-L).3
These three tools assess different domains including
functional scales – physical, role, cognitive, emotional,
social – (5 for QLQ C30, 4 for LCSS, and 5 for FACT-L)
and symptom scales (e.g. fatigue, nausea and vomiting,
pain). A questionnaire has also been developed in
Japanese, called QOL-ACD (QoL questionnaire for
cancer patients treated with anticancer drugs).4 Other
validated instruments less frequently used include
the Rotterdam Symptom Check List (RSCL), the Functional Living Index–Cancer (FLIC), the Hospital Anxiety and Depression Scale (HADS), and the Daily Diary
Card (DDC).
These questionnaires need to be assessed both at
baseline and at several preordained time points during
the treatment period and the follow-up. The logistics
required for QoL assessments are therefore important
and adequate monitoring is necessary to ensure patient
compliance in completing the questionnaires.
Data analysis also leads to some difficulties, for several reasons. The most important one is that the investigators are faced with significant amounts of missing
data, which are most probably related to QoL itself. The
missing data are therefore not missing at random but
due to a process of information censoring. It has indeed
been shown that a progressive worsening in clinical status induces a parallel increase in missing data. This is
clearly illustrated in the trials reporting on QoL. Consequently, data analysis is most often restricted to the first
weeks of follow-up, when the rate of missing data is not
yet too high. One helpful approach to this problem is
to look at the time of QoL deterioration and make some
assumptions about the QoL of the patients with missing
evaluations. Some statistical methods have been developed to deal with this issue of information censoring,
but are not yet in frequent use in practice.
Another problem is that a QoL assessment generates
vast amounts of data due to its multifactorial definition
and due to the need to study it over a period of time.
To control the rate of false-positive results, significance
probabilities have to be adjusted. Another solution is to
perform data reduction and to use summary parameters, but this may result in a loss of information when a
patient’s evolution is not going in the same direction on
several scales.
Nevertheless, QoL proved to be a useful secondary
endpoint when assessing the value of chemotherapy
versus best supportive care in advanced NSCLC. Indeed,
after the results of several meta-analyses showed survival benefit for chemotherapy compared to best supportive care, the issue of the positive balance between
survival benefit and chemotherapy toxicity was raised,
and none of the trials included in the meta-analyses had
been successful in investigating QoL. Some further
studies5–12 were therefore conducted in this respect, all
including QoL as an endpoint, sometimes even as primary objective (four of them), despite the methodologic
difficulties described above.
In 5 studies, attention was paid to the problem of
information censoring. It was found that at least one
parameter of QoL improved in all these series; in particular, symptoms related to lung cancer such as pain or
dyspnea were found to be reduced in chemotherapytreated patients. The side-effects of chemotherapy did
not cause a significant deterioration in the QoL. The
study by Cullen et al,6 which compared MIC (mitomycin C, ifosfamide, cisplatin) versus best supportive care,
demonstrated a significant prolongation of life in chemotherapy treatment as well as a significant improvement in QoL in treated patients, and a deterioration
with standard treatment. Thus these studies reinforce
the case for the use of chemotherapy in patients with
advanced NSCLC.
QoL is now frequently considered as an endpoint in
trials comparing different chemotherapy regimens in
advanced NSCLC, and the results of QoL assessments
are particularly interesting when no survival benefit is
demonstrated (which is indeed not infrequent). In such
circumstances, information on the relative merits of different treatments derived from the symptom scales and
QoL domains might, in conjunction with evaluation of
the side-effects of the treatments, be vital for selecting
the best treatment.
A recent unpublished review analyzed whether the
use of more recent drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine) might be associated with a further
improvement in QoL in patients with NSCLC. Among
16 selected studies, 5 were found in which attention to
information censoring was paid. Socinski et al13 compared four courses of carboplatin and paclitaxel, given
by the same regimen until progression in 230 patients
with advanced NSCLC. No effect was found on survival,
and QoL demonstrated a similar deterioration in both
groups, with time. It was concluded that four courses
238 Textbook of Lung Cancer
of chemotherapy were as good as a more protracted
therapy. Bonomi et al14 compared cisplatin and etoposide to cisplatin combined with paclitaxel in 574
patients. Survival was slightly increased with paclitaxel
and QoL was improved, compared to the other arm, at
6 months’ evaluation, but not afterwards. Kelly et al
evaluated 408 patients randomized to carboplatin and
paclitaxel or to cisplatin and vinorelbine.15 No effect of
treatment on survival or QoL was seen. Rosell et al
compared carboplatin and paclitaxel to cisplatin and
paclitaxel in 618 patients.16 Survival was better with
cisplatin, as was the control of symptoms related to
lung cancer. Scagliotti et al compared carboplatin plus
paclitaxel to cisplatin combined with either gemcitabine
or vinorelbine in 607 patients; no differences in survival
were observed and no superiority of one of the three
treatment arms was noticed in terms of QoL.17
In an additional 11 studies, in which QoL was evaluated without taking into account possible information
censorship, a positive effect on survival was seen in
3/11 series and a difference between treatment arms
related to QoL was seen in 6/11 studies. At least two
other studies reported clearly that chemotherapy
improved symptoms of disease, but without any difference being detected between study arms.
The regimens that were associated with an improved
QoL including better palliation of symptoms, were cisplatin plus paclitaxel in four studies and cisplatin (or
carboplatin) plus docetaxel in one series; cisplatin and
gemcitabine in one series and gemcitabine and vinorelbine in one series. A final series showed improved clinical benefit with gemcitabine. There was no real QoL
assessment; however the considered endpoint was a
composite one including treatment effect on symptom
control, performance status, and weight.
In more recent randomized phase III trials looking at
first-line chemotherapy in advanced NSCLC we found
two18,19 without detectable survival difference but
with a better QoL in one of the tested arms. Paccagnella
et al,18 with QoL as primary endpoint, showed that patients
reported better improvement on some symptom scales
(nausea and vomiting, appetite loss, and constipation)
with carboplatin combined with mitomycin and vinblastine compared to the regimen with cisplatin subsitituted for carboplatin. Global QoL was found with Spitzer’s
scale, but not with the EORTC scale. Georgoulias et al19
found that a gemcitabine–docetaxel combination
significantly improved QoL compared to cisplatin–
vinorelbine. For these two studies, QoL might be the
key to selecting one of the two treatments for further
studies. Three other trials20–22 showed improvement in
survival accompanied by better QoL: Fossella et al in
favor of docetaxel–platinum combinations (cisplatin or
carboplatin) compared to cisplatin and vinorelbine,20
Kubota et al in favor of docetaxel plus cisplatin compared to cisplatin and vindesine,21 and Rudd et al identified gemcitabine and carboplatin as improving results
obtained with MIC.22
A trial published by Cella et al,23 testing two doses of
gefitinib in symptomatic patients who had received at
least two prior chemotherapy regimens, showed a rapid
improvement in symptoms and, interestingly, showed
that this symptomatic improvement was associated
with tumor response and survival. They suggested that
symptom improvement might precede response assessment detected using radiologic tools.
However, comparisons between studies are seldom
possible as there is as yet no consensus about the frequency of QoL evaluations and about which results to
present, usually with selective reporting due to the significant amount of data generated by QoL evaluations.
Nevertheless, QoL assessment can play its role in the
global interpretation of clinical trial results.
CRITICAL CARE OF THE LUNG CANCER PATIENT
Intensive care is becoming more and more important in
the management of cancer patients and major cancer
hospitals have developed intensive therapy units, not
only for surgical patients but also for medical patients.
However, there is limited information in the medical
literature about intensive care in oncology, especially
concerning description of the types of patients admitted
in such units. An international inquiry performed in
anticancer centers24 has shown that 70% of the cancer
hospitals have at least one intensive care unit (ICU) especially devoted to patients with neoplastic diseases. Whether
general, surgical, or medical, those units do not depart
from the recommended guidelines for intensive care, as
far as the number of beds, the nursing staff, and the main
critical care techniques performed are concerned.
Admission of patients in an ICU is usually based on
the following three principles.25 First, the patients have
to be ‘salvageable’: patients whose chances of being cured
or having their disease put into remission are minimal
should not be admitted or should not stay in an ICU.
Second, the patient’s ‘autonomy’ must be respected: a
patient who refuses intensive supportive therapy
because he or she understands the potential poor prognosis of the underlying cancer disease should not be
admitted in the ICU. Finally, as medical resources are
Quality of life and supportive care 239
limited, even in highly developed countries, ‘distributive justice’ should be taken into account: patients with
the best chances of benefiting from intensive therapy
should be admitted in priority.
The assumption that patients with active malignant
disease should not be admitted to an ICU often predominates in general hospitals and makes it very difficult for oncologists to undertake a fruitful collaboration
with intensivists for the management of the critically ill
cancer patients. This negative opinion is not supported
by scientific data. It results from a bias of many physicians, who refuse critical care to cancer patients although
they are willing to provide it to patients with serious
non-neoplastic diseases such as advanced heart failure
or liver cirrhosis, who do not have a better short- or
long-term prognosis.26 Recently, it has been shown that
the prognosis of the cancer patient admitted in ICU for
a severe complication is not related to the characteristics of the underlying malignancy but only to the physiologic perturbations induced by the complications as
measured by severity scores.27–29 These data were confirmed in the only study specifically performed on lung
cancer with 57 patients admitted to the ICU.30
There are four main reasons to admit a cancer patient
to the intensive care unit:31
(1) postoperative recovery for advantages that are the
same as those for any high-risk postoperative
patient (availability of continuous hemodynamic
monitoring, early identification of cardiovascular
and respiratory disturbances, facilities for respiratory support, and constant skilled nursing care);
(2) critical complications of the cancer disease and its
treatment; these complications are numerous and
can be very specific for oncology, and their management has always to take into consideration the
presence of a severe chronic underlying disease;
(3) intensive anticancer treatment administration and
monitoring, useful in various situations such as
increased risk for treatment administration related
to the patient’s condition, administration of intensive chemotherapy requiring patient monitoring,
treatment of unknown toxicity in phase I trial
requiring optimal safety conditions of surveillance,
and administration of treatment that frequently
results in acute severe toxicity; and
(4) acute disease (such as myocardial infarction or
severe asthma), possibly unrelated to the malignancy or its treatment.
Advances in knowledge have been obtained during
the last decade in the use of life-threatening support
techniques for oncologic patients. Cardiopulmonary
resuscitation has been shown to be as effective in cancer
patients as in non-cancer patients.32,33 Mechanical ventilation is associated with a relatively poor outcome,34
particularly if the patient is leukopenic at the time of
intubation.35 A major advance in the management of the
cancer patient with respiratory failure has been achieved
with the development of non-invasive ventilation.36 The
ICU mortality in these patients can be reduced by this
technique from about 70–80% to 50%.37 Extrarenal
expuration by continuous venovenous hemofiltration
has also been shown to be effective in cases of acute
renal failure occurring in ICU.38 In all these situations,
the short-term prognosis is never influenced by the
characteristics of the underlying neoplasm.
SYMPTOM MANAGEMENT
The signs and symptoms manifested by patients with
lung cancer depend on the localization of the tumor, its
locoregional spread, and the effects of metastatic growth.
Dyspnea, pain, and cough are common symptoms of
lung cancer patients, with frequencies of 59%, 48%,
and 71%, respectively.2
Pain
More than 50% of lung cancer patients will present
with pain during the evolution of their disease. The first
cause of pain is related to direct tumor involvement,
bone destruction, liver metastasis, nerve compression
or invasion, or soft tissue infiltration. Pancoast’s syndrome with shoulder pain, brachial plexopathy, and
Horner’s sign occurs in apical tumors invading the brachial plexus, the chest wall, and stellate ganglion. Pleural effusion can cause pleuritic pain. Persistent pain
after surgery, radiotherapy, or chemotherapy can also
occur. Finally, some non-cancer-related causes of pain
like infection have to be looked for.
Effective management of pain can be achieved in
approximately 90% of patients. A pain severity scale
from 0 (‘no pain’) to 10 (‘pain as bad as you can imagine’) may be helpful in titrating analgesics. Careful
description of the type of pain is also essential. Some
cancer lesions, such as bone or epidural metastases,
responsible for pain can be treated by radiotherapy,
chemotherapy, or sometimes by surgical debulking.
Any analgesic medication program should be as simple as possible and non-invasive.39 Except for a minority
of patients whose pain is clearly episodic, analgesics
should be given around the clock. Treatment is decided
240 Textbook of Lung Cancer
according to ascending steps. A non-opioid drug (paracetamol) should be used as first step. Non-steroidal antiinflammatory drugs (NSAIDs) are very effective but have
a number of side-effects (e.g. gastritis and gastrointestinal bleeding, renal failure). As second step, an opioid for
mild to moderate pain (e.g. tramadol, codeine) should be
added. The third step includes an opioid for moderate to
severe pain (e.g. morphine, hydromorphone, methadone, fentanyl). Oral morphine, as an immediate or sustained-release preparation, is the analgesic of choice for
moderate to severe cancer pain. A typical starting dose of
immediate-release morphine is 5 to 30 mg every four
hours, with a relatively rapid increase if necessary. When
an effective dose of short-acting morphine has been
established, the required dose for a long-acting preparation can be calculated, with an additional supply of
short-acting morphine if necessary. A consistent need for
this supplemental morphine will dictate an upward dose
adjustment of the sustained-release morphine. Transdermal preparations (e.g. fentanyl) can be more convenient,
and with fewer side-effects (e.g. constipation) than
morphine,40 but they are more expensive. Constipation
is a frequent side-effect of opioids that should be managed prophylactically (increased fiber consumption, mild
laxative). Initial nausea and somnolence are also frequent. An anti-emetic should be administered to all
patients who are started on opioids. The combination of
opioids and paracetamol or NSAID often provides more
analgesia than can be accomplished by either class of
drugs alone, and thus facilitates the use of lower opioid
doses with fewer related side-effects. A co-analgesic (corticoid, tricyclic antidepressant, or anticonvulsant) may
be added at each step. Indeed, gabapentine, carbamazepine, valproic acid, clonazepam, and phenytoin can
be used to manage neuropathic pain. Tricyclic drugs are
useful in a variety of neuropathic pain (dysesthetic or
burning pain). Corticosteroid administration can lead to
mood elevation, relief of visceral inflammation, and
reduction of cerebral or spinal cord edema when there is
symptomatic metastasis or spinal cord compression.
Bisphosphonate (pamidronate, zoledronate) can be
administered alone or as an adjunct to external radiation
therapy for bone metastases. Other non-pharmacologic
methods exist to manage pain for example cutaneous
stimulation, nerve blocks, maintenance of regular activity, avoidance of prolonged immobilization, psychosocial
intervention, and education.
including physiologic, psychologic, and social components. It is perceived as one of the most devastating,
distressing symptoms. Its major physical evidence is
tachypnea. Dyspnea is, with cough, the most commonly
reported symptom in lung cancer patients.
There are multiple causes of dyspnea and several may
co-exist. The most common cause of dyspnea in lung
cancer patients is the primary or metastatic disease, but
it may also be related to cancer treatment (lung resection,
anemia, chemotherapy or radiation-induced lung toxicities) or to non-cancer causes (lung infection, pulmonary
embolism, chronic obstructive pulmonary disease, heart
failure). Most of the time, the cause can be easily determined by history and physical examination. Chest imaging, oximetry, blood tests, and pulmonary functions are
useful in the assessment of dyspnea. The first aim should
be to correct the cause when possible and appropriate.
Palliative management of dyspnea in the cancer patient
is often complex and difficult.39 Oxygen may be helpful.
However, there are no large studies available and, except
for hypoxemic patients who feel less breathless on
oxygen,41 it is difficult to predict which patients will
benefit.42 As bronchospasm is one important reversible
cause of dyspnea in cancer patients, bronchodilatators
(β2-agonists, anticholinergics) and aerosolized steroids
are commonly used. Systemic steroids can be used for
patients with airflow obstruction, postradio- or chemotherapy pneumonitis, or lymphangitic carcinomatosis.
Opioids are efficacious in the management of dyspnea by
decreasing the perception of breathlessness. The advised
starting morphine dose is 10 mg po or 5 mg sc/4 hours
around the clock. If the patient already receives morphine
for pain, doses must be increased to relieve dyspnea.
Intravenous continuous morphine infusion is optional
for terminal patients with severe dyspnea. In this situation, patient and family members should be aware of the
risk of hypoventilation and death. Nebulized opioids
could also be tried in less severe cases, and with fewer sideeffects, although their efficacy has not been demonstrated.
Subcutaneous scopolamine, hyoscine, or atropine can be
beneficial in drying up upper airway secretions. Anxiolytics are needed when an anxious component is obvious
(lorazepam 0.5–2 mg/day; diazepam 2.5 mg/6 hours) or
for intractable dyspnea (midazolam 10 mg iv /day). Finally,
environmental issues are important: a calm atmosphere,
relaxation, breathing techniques, and psychosocial support can reduce the perception of breathlessness.
Dyspnea
Dyspnea is a subjective experience of difficult and
uncomfortable breathing. It is a complex symptom
Cough
Cough is observed in 70 to 90% of the patients with lung
cancer. Involvement of any part of the respiratory system
Quality of life and supportive care 241
can lead to cough, predominantly lung cancer originating in the airways. Radiation- or chemotherapy-induced
fibrosis must also be considered when evaluating the
causes of cough. Finally, non-cancer causes of cough (e.g.
respiratory infection, drugs, heart failure, gastro-esophagal
reflux, chronic bronchitis) must also be looked for.
The control of cough is of particular importance
because it leads to sleep disturbance, shortness of
breath, pain, and decreased quality of life. Pharmacologic palliative treatments of cough39 are often disappointing for example non-opioid cough suppressants
(e.g. dextromethorphan, levodroproprizine), cromoglycate, bronchodilatators if bronchospasm exists, corticosteroids (in case of radio-induced pneumonitis), and
nebulized lidocaine. Narcotics, acting via opioid receptors, are the most efficacious treatment for significant
cough. Codeine (15–30 mg/6 hours) and analogs can
be tried initially and, if insufficient, morphine (5–10
mg/6 hours) can be administered.
Depression and anxiety
Psychologic distress including depression is an essential
element of the quality of life of a cancer patient. Between
15 and 44% of lung cancer patients experience some
form of depression after diagnosis, increasing according
to disease extent and associated prognosis. After curative resection, the prevalence of depression is 4 to 8%.43
In unresectable lung carcinoma patients, about 15% of
the patients have some degree of suicidal ideation,44 for
which predisposing factors are pain and depressive disorder. Female gender, living alone, no children in the
role of confidant, nurses as confidants, are predictive
factors for psychologic distress in ambulatory lung cancer patients.45 For example, in 52 newly diagnosed lung
cancer patients undergoing radio- or chemotherapy,
4% had an affective disorder, 44% expressed feelings of
sadness, 29% feelings of fear, 8% feelings of guilt, 13%
had considered suicide, and 31% had thoughts of
death.46 In the same study, 52% of the patients had
insomnia and 19% concentrating difficulties.
Anxiety and depression can be related to the
announcement of the diagnosis, the numerous investigations, the treatments, the symptoms due to cancer or
its treatment, and the fear of death. In the cancer patient,
it can be difficult to discriminate between underlying
biological/organic and psychologic factors causing
depression. Moreover, somatic symptoms of depression
can be confused with constitutional symptoms due to
the cancer or its treatment (such as fatigue).
Supportive conversation and advice must be the firstline treatment, but anxiolytics and antidepressants
could be necessary. Finally, active anticancer treatments
play a psychologic role by improving performance status or quality of life, by alleviating symptoms, and by
giving hope.
Anorexia and weight loss
Cancer-associated cachexia/anorexia occurs in almost
any late stage cancer, but is particularly common in
lung cancer, even at an early stage. Cachexia is a consequence of both decreased food intake (resulting from
loss of appetite) and metabolic abnormalities (e.g.
release of tumor-induced cytokines). Contributing factors include altered taste, pain, dysphagia, asthenia,
and depression.
As removal of the underlying causes is rarely possible, supportive measures are required. Control of nausea and vomiting is the first therapeutic step. Nasogastric
tube feeding or parenteral alimentation must be discussed case by case, as their efficacy is relative. Forcing
patients to eat has no impact on well-being and survival. Patients have to be encouraged to eat frequent,
small, enjoyable meals and to take a lot of liquids (often
better tolerated than solid food).
Most appetite stimulants are not very effective.
Steroids (dexamethasone, prednisolone, or methylprednisolone) have some short-term benefit in stimulating appetite, but their impact on weight gain is not
defined.47 Due to their side-effects, caution is necessary
for prolonged use of steroids. Progestational agents (e.g.
megestrol acetate, medroxyprogesterone acetate) stimulate appetite and, at least for megestrol, have a positive
impact on weight. In some studies, megestrol acetate
was shown to improve quality of life.47 However, the
benefit of these drugs must be counterbalanced with an
increased risk of thromboembolic episodes. Other
drugs have been tested, some with promising results.
For example, in a randomized clinical trial, 58 patients
with advanced NSCLC were randomized to receive
either 10 30-hour adenosine triphosphate (ATP) iv
infusions every two to four weeks or no treatment. An
inhibition of weight loss and appetite stabilization was
noted in the ATP group.48 In contrast, nandrolone, pentoxifylline, and hydrazine sulfate are not effective.49
MANAGEMENT OF TREATMENT COMPLICATIONS
The main complications related to the medical
treatment of lung cancer are chemotherapy-induced
aplasia, mainly neutropenia but also anemia and
thrombocytopenia, and vomiting secondary to cisplatin
administration.
242 Textbook of Lung Cancer
Neutropenia
The relationship between neutropenia and the risk of
severe infections has been established by Bodey et al.50
The risk of developing infectious complications depends
on the duration and on the level of the neutropenia.
These two variables also predict the severity of the
infection. In addition to neutropenia, lung cancer
patients are predisposed to infection due to neoplastic
bronchial obstruction favoring obstructive pneumonia
and by concomitant COPD. The impact of infections on
survival in lung cancer patients has not been well established. No statistically significant survival difference
was observed between SCLC patients presenting with
lung abscess and the others.51 In a very old study, the
authors52 observed a significant reduction in median
survival in patients with pulmonary infections.
Few studies have assessed the type and microbiologic
nature of infection in lung cancer patients. Recently, we
found that the lung is the predominant site of infection
and that, among all microbiologically documented
infectious episodes, Gram-negative bacteria were the
most prominent pathogens, mainly Escherichia coli,
Haemophilus influenzae, Pseudomonas aeruginosa, and
Moraxella catarrhalis, although Streptococcus pneumoniae
and Staphylococcus aureus were frequently observed (7%
and 9%, respectively, of all documented pathogens).53
Few data are today available concerning infection in
neutropenic lung cancer patients. In cancer patients
from any origin presenting with febrile neutropenia,
Gram-negative microorganisms are the most common
pathogens, although an increase in Gram-positive bacteria has been demonstrated in recent years.
Febrile neutropenia (FN) is a life-threatening complication requiring prompt empiric antibiotic therapy.
Guidelines have been published by the Infectious Disease Society of America (IDSA) for the use of antimicrobials in patients with cancer, not specifically addressed
for lung cancer, and FN.54 Broad-spectrum β-lactams
or carbapenem are suggested as first-line therapy. Outside of specific situations, aminoglycosides (for shock,
Gram-negative bacteriemia, etc.) and glycopeptides
(for documented resistant Gram-positive infection or
clinical signs suggesting infection with resistant Grampositive organisms) are no longer needed routinely in
first-line antibiotic combinations, monotherapy being
as effective.55,56 Oral antibiotic therapy should be
considered for low-risk patients.54 The role of new fluoroquinolones with increased sensitivity against Grampositive pathogens remains to be validated in randomized
trials. In any case, given the importance of S. pneumoniae as a pathogen in patients with lung cancer, antibi-
otics should provide adequate coverage for this
bacterium.53
Some studies have assessed the role of antibiotic prophylaxis to reduce the incidence of FN in SCLC patients.
In this setting, prophylactic cotrimoxazole appeared
effective. In pooled results from three studies,57 a global
reduction of infection from 36 to 17% was observed, in
patients with bacteriemia as well as for non-bacteriemic
infectious episodes. In a more recent study by the
EORTC,58 163 chemonaive SCLC patients were randomized between prophylaxis with ciprofloxacine (750
mg, bid) plus roxithromycin (150 mg bid) and placebo.
Prophylaxis was associated with a statistically significant reduction in the incidence of FN (43% vs 24%,
p = 0.007), fewer microbiologically and clinically documented infections, fewer hospitalizations for FN, and
a reduction in the number of infectious deaths (6%
versus 0%, p = 0.022). Nevertheless, it is not clear
at the present time if this strategy has an impact on
the overall survival of lung cancer patients undergoing
chemotherapy.
Another way to reduce the duration of neutropenia
and the incidence of FN could be the administration of
colony-stimulating factors (CSFs). In a meta-analysis of
randomized studies assessing the role of CSF in SCLC,59
we did not observe any favorable impact of CSF on survival, whatever the type of chemotherapy, although dose
intensity was generally increased with CSF administration. Yet, a detrimental impact on survival was noted in
patients treated with concomitant radiochemotherapy,60
or those receiving high-dose concentrated chemotherapy.61 No significant difference in infection-related mortality was associated with CSF administration. The
duration of neutropenia below 500/mm3 was reduced
and a statistically significant reduction in the incidence of
FN was noted in two-thirds of the trials. No meaningful
conclusions could be drawn from two small randomized studies performed in NSCLC. CSF administration
has also been tested in addition to antibiotics in established FN. Although a shorter time to neutrophil recovery was evident, overall mortality was not influenced
significantly.62 These results did not support the routine use of CSF, either for preventing FN or in addition
to antibiotics for the treatment of FN, in patients with
lung cancer.
Vaccination against S. pneumoniae and influenza
viruses might be another way to prevent infections in
lung cancer patients. Few data are currently available.
In a small study, the majority of the patients responded
fully to influenza vaccination.63 Pneumococcal vaccination was unsuccessful to prevent infection in a small
Quality of life and supportive care 243
randomized study,64 but the number of patients was
limited and new vaccines have since been developed.
Nevertheless, vaccination should be considered for
lung cancer patients as such treatment is well tolerated
and could have a beneficial impact on infection at a
low cost.
Anemia
Platinum-based chemotherapy, as well as other agents,
is frequently associated with anemia. Guidelines from
the Cancer Care Ontario Program (www.cancercare.
on.ca) recommend the use of erythropoietin (EPO) to
reduce the incidence of symptomatic anemia in patients
receiving platinum-based chemotherapy, but also for
myelosuppressive regimens that do not contain platinum derivatives. In a recent meta-analysis, the transfusion requirement was reduced by 33% with EPO
administration,65 without significantly higher toxicity.
A beneficial effect on survival was suggested (hazard
ratio 0.81).
Currently, three EPOs are marketed: epoietin alpha,
r-huEPo, and darbepoietin alpha. All three have demonstrated their efficacy in lung cancer patients. Today,
there is no evidence that the effectiveness of these drugs
is different.66 Recommended initial dosages are either
150 IU/kg three times a week or 40 000 IU once a week
for epoietin alpha and r-huEPO, and the equivalent
weekly dose of 100 µg (USA) or 150 µg (Europe) for
darbepoietin alpha.
Thrombocytopenia
Severe, potentially lethal bleeding is a frequent problem
in oncology. However, platelet transfusion requirement
is ten times less frequent in solid tumors than in hematologic patients. Half of the incidents of bleeding are
confined to the skin or mucosa. Risk factors for lifethreatening bleedings in thrombocytopenic patients are
concomitant infection, invasion of main vessels, as it
can be seen in lung cancer, and coagulation disorders.
Randomized trials conducted in the 1970s have shown
the effectiveness of a prophylactic transfusion policy on
the occurrence of bleeding. The threshold below which
platelets have to be transfused has also been the subject
of randomized trials. A level of 10 000 platelets/mm3
has been shown to be as safe as 20 000/mm3, with the
advantage of requiring significantly fewer platelet transfusions in the absence of fever or infection, in the absence
of bleeding, and when invasive procedures were not
planned. There are no specific data for solid tumors
and we could only extrapolate these results to the lung
cancer patients.
Nausea and vomiting
It was the development of cisplatin-based therapy for
lung cancer patients which initiated a strong stimulus for
the control of nausea and vomiting. The initial regimens
that were able to control severe emesis caused by highdose cisplatin consisted of high doses (2–4 mg/kg)
of metoclopramide in association with dexamethasone
and lorazepam. These regimens were complicated by
a significant number of side-effects, such as extrapyramidal motor disturbances. The introduction of the
‘setrons’, 5-HT3 antagonists, made anti-emetic therapy
in patients treated with cisplatin much easier. Once
again, the addition of corticosteroids increased the
effectiveness of all the setrons. However, setrons are
essentially active in acute emesis, and did not demonstrate a superior efficacy in delayed emesis compared
with dexamethasone plus metoclopramide. The selective NK1 antagonist, aprepitant, is more effective for
controlling delayed emesis after cisplatin compared to
5-HT3 antagonists.
Different guidelines have been reported for the prevention and treatment of chemotherapy-induced nausea
and vomiting. As well as the recommendations made by
ASCO67 and by the Cancer Care Ontario Program (www.
cancercare.on.ca), a combination of 5-HT3 antagonist
plus a corticosteroid is recommended for the prevention
of acute emesis induced by chemotherapy with high
emetogenic potential. For patients receiving cisplatin, a
corticosteroid plus metoclopramide (or domperidone)
and eventually a 5-HT3 antagonist are recommended for
the prevention of delayed emesis. The role of aprepitant
is not yet well delineated, although the consensus from
the Multinational Association of Supportive Care in
Cancer suggests its use in addition to a 5-HT3 antagonist
and dexamethasone for acute emesis and to dexamethasone for delayed emesis.68 In lung cancer patients, caution must be used with aprepitant, which is an inhibitor
of CYP3A4 and could thus theoretically increase the
concentrations of drugs metabolized this way, including
the chemotherapeutic agents frequently administered in
these patients: docetaxel and paclitaxel, etoposide, ifosfamide, vinorelbine, vincristine, and vinblastine (www.
merck.com/product/hcp.html).
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1986; 68: 7–11.
Perlin E, Bang KM, Kassim OO. The impact of pulmonary
infections on the survival of lung cancer patients. Cancer 1960;
66: 593–6.
Berghmans T, Sculier JP, Klastersky J. A prospective study of
infections in lung cancer patients admitted to the hospital.
Chest 2003; 124: 114–20.
Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines
for the use of antimicrobial agents in neutropenic patients with
cancer. Clin Infect Dis 2003; 34: 730–51.
Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta
lactam monotherapy versus beta lactam–aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ
2004; 328: 668.
Vardakas KZ, Samonis G, Chrysanthopoulou SA et al. Role of
glycopeptides as part of initial empirical treatment of febrile
neutropenic patients: a meta-analysis of randomised controlled
trials. Lancet Infect Dis 2005; 5: 431–9.
Klastersky J. Les complications infectieuses du cancer bronchique. Rev Mal Resp 1998; 15: 451–9.
Tjan-Heijnen VC, Postmus PE, Ardizzoni A et al. Reduction of
chemotherapy-induced febrile leucopenia by prophylactic use
of ciprofloxacin and roxithromycin in small-cell lung cancer
patients: an EORTC double-blind placebo-controlled phase III
study. Ann Oncol 2001; 12: 1359–68.
Berghmans T, Paesmans M, Lafitte JJ et al. Role of granulocyte
and granulocyte-macrophage colony-stimulating factors in the
treatment of small-cell lung cancer: a systematic review of the
literature with methodological assessment and meta-analysis.
Lung Cancer 2002; 37: 115–23.
Bunn PAJ, Crowley J, Kelly K et al. Chemoradiotherapy with or
without granulocyte-macrophage colony-stimulating factor in
the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group [published erratum appears in J Clin Oncol 1995;
13 (11): 2860]. J Clin Oncol 1995; 13: 1632–41.
Pujol JL, Douillard JY, Riviere A et al. Dose-intensity of a fourdrug chemotherapy regimen with or without recombinant
human granulocyte-macrophage colony-stimulating factor in
extensive-stage small-cell lung cancer: a multicenter randomized
phase III study. J Clin Oncol 1997; 15: 2082–9.
Clark OA, Lyman GH, Castro AA et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a metaanalysis of randomized controlled trials. J Clin Oncol 2005; 23:
4198–214.
Anderson H, Petrie K, Berrisford C et al. Seroconversion after
influenza vaccination in patients with lung cancer. Br J Cancer
1999; 80: 219–20.
Klastersky J, Mommen P, Cantraine F, Safary A. Placebo controlled pneumococcal immunization in patients with bronchogenic carcinoma. Eur J Cancer Clin Oncol 1986; 22: 807–13.
246 Textbook of Lung Cancer
65. Bohlius J, Langensiepen S, Schwarzer G et al. Recombinant
human erythropoietin and overall survival in cancer patients:
results of a comprehensive meta-analysis. J Natl Cancer Inst
2005; 97: 489–98.
66. Schwartzberg LS, Yee LK, Senecal FM et al. A randomized comparison of every-2-week darbepoietin alfa and weekly epoietin
alfa for the treatment of chemotherapy-induced anemia in
patients with breast, lung, or gynecologic cancer. Oncologist
2004; 9: 696–707.
67. Gralla RJ, Osoba D, Kris MG et al. Recommendations for the
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2971–94.
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the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer
2005; 13: 85–96.
17 The cost and cost-effectiveness of lung
cancer management
William K Evans, Christopher J Longo
Contents Introduction • Types of economic evaluation • Methodologic issues • Other considerations
• The cost of lung cancer management • Estimating the costs of lung cancer in Canada
• The cost-effectiveness of lung cancer treatment • Lung cancer economics and health-care policy
• Conclusion
INTRODUCTION
Lung cancer is the second most common cancer in men
and women in North America, and the leading cause
of cancer death among both sexes in the industrialized world. In 2007, it is estimated that lung cancer
will be responsible for the deaths of over 180 000 individuals in North America.1,2 In the last decade there has
been a marked increase in the incidence of lung cancer in women.3 Worldwide, the problem of lung cancer
is escalating as the developing world succumbs to the
promotional activities of the tobacco industry. The
resulting worldwide epidemic of lung cancer is a major
public health concern, not only because of the enormous loss of life and the great morbidity it causes, but
also because of the large economic burden it places
on health-care systems and society in general.
Brown et al4 have extensively analyzed the economic burden of cancer in the United States based
largely on 1990 data sources. The total direct healthcare expenditures for cancer were estimated to be
US$ 27.5 billion, including the costs of hospital care
($17.9 billion), physician services ($6.6 billion),
nursing services ($1.3 billion), drugs ($1.1 billion),
and other ($0.5 billion). Soni5 more recently estimated the total direct health-care expenditures for
cancer at $62.2 billion (2004) using the Medical
Expenditure Panel Survey (MEPS). Although the data
from Soni on cancer expenditures are more current
than those available in Brown’s publication no breakdown across types of health services was described.
Indirect costs were estimated by Brown et al4 to be
$58.7 billion as a result of mortality costs and
$9.9 billion due to morbidity costs. Morbidity costs are
measured by lost income due to disability and absenteeism from work. In total, the direct and indirect costs
of cancer were estimated to total US$96.1 billion.
The percentage of health expenditure dedicated to
cancer appears to have changed very little in the
interval from 1963 to 1995. Although the percentage
due to cancer increased from a low of 4.35% in 1963
to a high of 6.01% in 1980, more recent figures from
Soni5 based on the MEPS data suggest the percentage
of health expenditures dedicated to cancer in 2004
had increased to 6.9%.
Based on expenditure data from the 1996 Surveillance, Epidemiology, and End Results (SEER) database, Brown has made estimates of the direct medical
care costs for all cancers and for the four most common tumor types in the United States. Expenditures
were estimated to be $6.0 billion for breast cancer,
$5.7 billion for colorectal, $4.7 billion for lung, and
$4.6 billion for prostate cancer. These four tumor
types, which together make up approximately 50%
of all cancer cases, accounted for 49.5% of the total
direct costs of cancer ($21 billion of $42.4 billion).
In California, a study of the long-term costs of treatment estimated that the cost per case for the common cancers ranged from a high of US$64 000 for
ovarian cancer to a low of $29 000 for prostate cancer.6
Breast, colon, and lung cancer were estimated to incur
long-term costs of $35 000, $42 000, and $33 000,
respectively.
From these analyses, it can be readily appreciated
that the cost of lung cancer care will be high in industrialized countries where there is a high incidence of
lung cancer and adequate resources to provide stateof-the-art clinical care. The impact of such a large
economic burden on the health-care systems of developing countries could easily overwhelm the financial
ability of a country to provide other types of appropriate care. Even in wealthy nations, fiscal constraint
is increasingly causing physicians and health-care
administrators to critically examine the value of healthcare interventions and the efficiency of health-care
delivery systems.
This concern about the value for money expended
is particularly relevant to the problem of lung cancer,
248 Textbook of Lung Cancer
where, despite recent advances, the overall prognosis
of the disease remains poor.3 New treatments for
lung cancer, particularly for early stage resected disease and locally advanced disease, add expense but
also improve survival. However, the reputation of the
disease as one with a poor prognosis can be a barrier
to the adoption of new therapies. Economic evaluations of the new treatment interventions for lung
cancer can shed light on their relative cost-effectiveness compared with other health-care interventions.
An understanding of the cost components of care can
also help to inform health-care providers on how to
deliver treatments in the most efficient fashion. This
chapter will describe some of the economic analyses
that have been conducted on lung cancer management throughout the world, particularly in the United
States and Canada. Although it is not possible to easily
extrapolate health economic evaluations directly from
one health-care system to another, there are lessons
that can be learned from a review of these studies.
Physicians have typically had little training and
only passing interest in health economics, and, therefore, may be relatively unaware of the types of health
economic analysis that can be done and their application to lung cancer. Therefore, prior to presenting
data from studies evaluating the economic burden of
lung cancer, the cost components of lung cancer
management, and the cost-effectiveness of treatment,
we will first provide some information on the types
of economic evaluation and costing methodologies
that are commonly employed.
TYPES OF ECONOMIC EVALUATION
There are four types of commonly used economic
evaluations (Table 17.1). Each involves a comparison
of the costs and consequences of alternative interventions. The main difference between each of these
evaluations is in the method used to measure the
consequences.
Cost-minimization analysis
Also called a ‘cost analysis’, cost-minimization analysis is the simplest form of economic evaluation. This
type of study assumes that the outcomes or effectiveness of the interventions are equal. Resource utilization is the only significant difference between the
options. The direct costs associated with each intervention are compared, and the least costly strategy is
the preferred choice. No assessment of the consequences of treatment is required. Although there are
some examples of cost minimization in the oncology
literature, including studies of staging procedures,7,8
radiotherapy techniques,9–11 and systemic therapy,12
this type of economic evaluation is not common
because cancer treatments rarely produce equivalent
survival or quality of life benefits.
Cost-effectiveness analysis
If the interventions being assessed are not of equal
effectiveness, a more sophisticated analysis is
required. Cost-effectiveness analysis includes a comparison of outcomes, as well as costs. In this form of
analysis, the effectiveness of alternatives is measured
in natural units, such as life years gained, cases successfully treated, or cases averted. These outcomes
are then related to the direct costs of the procedure
by calculating ratios of cost per unit of effectiveness,
such as cost per life year gained. Typically the results
are described as an incremental cost-effectiveness
ratio (ICER), since the analysis is a comparative one,
and presents both the incremental costs and the
incremental benefits.
Table 17.1 Types of economic analyses
Cost-minimization analysis
Cost-effectiveness analysis
Cost–utility analysis
Cost–benefit analysis
Compares strategies of equal effectiveness to determine
which is least expensive
Compares ratios of the incremental cost over the
incremental effectiveness of alternative strategies
Compares ratios of the incremental cost over the
incremental utility; a utility is a measure of the value
attributed to a health state, usually measured in quality
adjusted life years (QALYs)
Assigns monetary value to the health benefits of an
intervention; if the cost/benefit ratio is <1, the
intervention is attractive
The cost and cost-effectiveness of lung cancer management 249
Cost-effectiveness analysis has the advantage of
being easily understood. As a result, it is the most
common approach to economic evaluation in health
care.13 However, its value is limited by the fact that
only one measure of effectiveness can be related to
the cost of the interventions. A cost per life year gained
looks at survival, but not at toxicity, inconvenience,
or effects on quality of life. These are also important
considerations in cancer treatment. For example,
surgery for the primary treatment of a specific cancer
can be compared to radiation in terms of its costs per
life year gained, but this may lead to an invalid conclusion if their effects on quality of life are very different. Therefore, cost-effectiveness analysis can help
choose between similar treatments for a specific disease, but cannot help in choices across dissimilar
treatments and conditions.
More recently, new methodologies such as ‘net
health benefits’ or ‘net monetary benefits’ have been
introduced into cost-effectiveness analysis for health
care.14 These newer methodologies provide a more
appropriate way to deal with situations where costeffectiveness ratios might be misleading, as when
both costs and effects are negative and the resulting
ratio is positive. Standard cost-effectiveness formulas
do not deal with this scenario well, whereas the ‘net
benefit’ approach is straightforward.
Cost–utility analysis
A cost–utility analysis is similar to a cost-effectiveness
analysis, but it incorporates mortality and morbidity
data into a single multidimensional measure, usually
as a quality adjusted life year (QALY).15 The QALY is
a measure of the quantity of life gained by a treatment, weighted by the quality of that life. This is relevant in oncology because many anticancer treatments
are inconvenient and have substantial toxicities that
impair quality of life. Because the QALY is not disease-specific, it also allows comparisons between the
relative efficiency of health-care interventions for different conditions.
Quality of life is approximated by a utility, which
is a measure of preference for a given health state rated
on a scale where 0 equals death and 1 equals perfect
health. Theoretically, a utility is most accurately determined using a ‘standard gamble’ exercise, where a
subject in a particular health state finds the balance
between the chance of returning to perfect health
and the risk of possibly dying in the process. Other
techniques such as time trade-off and direct rating on
visual analog scales have also been employed.16 Alternatively, instruments such as the Health Utilities
Index17 and the EuroQoL18 can be administered alongside standard gamble exercises in order to relate their
scores to utilities. However, most quality of life instruments have not undergone such testing. An approach
often used to integrate quality and quantity of life
calculates the quality-adjusted time with and without
symptoms or toxicity (Q-TWiST).19 It is particularly
useful when looking at interventions that will have
health effects persisting beyond the duration of treatment, such as adjuvant chemotherapy.
There is controversy about whether utilities should
be derived from patients, their families, health-care
workers, or lay societal ‘jurors’ given detailed scenarios
describing the health state. Recent guidelines favor the
latter as being most consistent with the societal perspective in an economic analysis.20 However, there is
concern that people without relevant disease experience may not fully understand the health (disease)
state. Any of these approaches to defining utilities is
defensible, as long as it is clearly identified in the
report of the study.
Cost–benefit analysis
Cost–benefit analysis (CBA) differs in how it values
consequences of health-care programs. CBA values
programs in monetary terms, thus allowing a direct
comparison of a program’s incremental costs with its
incremental consequences. The result is either a net
cost or a net benefit of the program. One common
application of this methodology is to convert the
quality-adjusted life year in the denominator of an
analysis into a monetary equivalent to arrive at the
absolute benefit of the intervention. An intervention
is ‘cost beneficial’ if the benefits (measured in currency) are greater than the actual costs. Because these
analyses always produce a monetary outcome, it is
relatively easy to compare different potential uses of
resources. However, placing a monetary value on the
often intangible outcomes of health care, in particular the value of a life, is problematic. As a result, true
cost–benefit analyses are rare.
Each of these analytic techniques has its place. While
cost–utility analysis is ideal for comparing toxic treatment options, a cost-effectiveness analysis may be
adequate when deciding between two diagnostic
strategies.
METHODOLOGIC ISSUES
As the primary purpose of a cost-effectiveness analysis
is to introduce a consideration of resource consumption
250 Textbook of Lung Cancer
into medical decision-making, an economic evaluation begins by identifying all the consequences of
adopting one intervention over another.21 This
involves identifying the resources used (medical care
services, the cost of informal care-giving, and other
non-direct medical care costs) and the effects of the
treatment intervention on the health state. Both direct
and indirect health-care costs should be considered.
The term direct health-care cost refers to resource
use that is directly attributable to the medical intervention or treatment regimen. In health economics,
the term indirect refers to gains or losses in productivity related to the illness. Because indirect costs in
accounting terminology refer to overhead or fixed
costs of production, some health economists recommend the use of the term ‘productivity cost’ to define
the indirect cost associated with the morbidity or
mortality of an illness.21
Assessment of costs
Depending on the perspective taken, the resource
costs in an economic analysis can include:
•
•
•
•
direct treatment costs: the resources used by the
health sector to provide treatment (e.g. healthcare provider time, drugs, equipment, diagnostic tests, overhead);
direct non-treatment costs: the resources used by
patients and family to gain access to and participate in treatment, such as travel, parking, and
accommodation near a cancer treatment center.
Often these are measured by having patients
complete diaries of their out-of-pocket expenses.
indirect costs: costs such as lost work time for the
patient or caregiver, or the time of volunteers
assisting with treatment;
intangible costs: the costs of anxiety, uncertainty,
or pain caused by the treatment itself. These
have proven difficult to measure. Techniques,
such as ‘willingness to pay’ have been developed
to capture these ‘costs’, but can be affected by each
subject’s own economic circumstances.
The choice of time horizon for an economic evaluation is important to ensure that the analysis has considered all relevant resource utilization. If a new
treatment intervention has an impact on the natural
history of a disease, it can affect ‘downstream’ costs. For
example, when analyzing the cost of treating lung
cancer, up-front costs include the cost of physician visits, diagnostic tests and procedures, hospitalization,
as well as drugs and dispensing fees. Downstream costs
include the costs for treatment of long-term compli-
cations and terminal care. One of these downstream
costs, hospitalization for terminal care, has been found
in the Canadian health-care system to be the largest
single component of the management of cancer over
the entire course of the illness.22 Interventions that
can affect terminal care can have important impacts
on the lifetime costs of the disease23,24 that might be
missed if the time horizon only included the active
phase of disease treatment.
In addition to ensuring that all relevant resource use
has been considered, it is important to assess whether
the resource use has been quantified accurately and
valued credibly, and to know whether the analysis is
based on costs or charges. Charges for health care are
influenced by market forces, government regulations,
and taxation laws,25 and often bear little resemblance
to actual incremental resource costs.26 Medicare providers in the United States are required to provide
cost-to-charge ratios that can be used to estimate costs.
However, it is not clear how accurate these ratios are.
Another consideration is whether resource utilization data have been collected prospectively or retrospectively. Prospectively collected data, such as those
gathered during a clinical trial, are more likely to be
complete and to allow for timely availability of economic data to help decision-makers after an important
clinical result is found. However, the prospective collection of data may be expensive. Furthermore, care
in clinical trials is often more resource intense than in
routine practice. For example, trials usually take place
in expensive tertiary care teaching hospital settings,
and involve more frequent monitoring of blood tests
and use of imaging studies. As a result, retrospective data
or prospective data collected outside a clinical trial
can also be used effectively in many circumstances.
It is often necessary to estimate costs through the
use of a combination of empirical data and modeling.
Resource utilization data such as the number of hospital days might be derived from a clinical trial. These
data might then be adjusted to reflect anticipated
usual care. Last, the costs can be allocated to the
resources consumed to calculate the cost of delivering the intervention. By separating resource utilization from cost, local variations in costs or charges can
be assessed.
OTHER CONSIDERATIONS
Setting
Economic evaluations are relatively specific to the
health-care system in which they are performed.
The cost and cost-effectiveness of lung cancer management 251
Countries such as Canada have single-payer, universal
health-care systems in which the government funds
virtually the entire system. In contrast, health care in
the United States is funded by multiple payers, primarily private insurers, and providers compete for
contracts to manage the care of groups of individuals.
A third type of system, common in European countries, provides universal health care, but with patients
responsible for a co-payment.
Extrapolating the results of a study from one healthcare environment to another involves more than simply
adjusting the figures by the exchange rate. Costs for
a health-care intervention may be affected by differences in (1) demographics and disease incidence, (2)
clinical practice patterns, and (3) relative prices. Practice patterns may be influenced by the availability of
alternative treatments and diagnostic tests, as well as
incentives to professionals and institutions (e.g. salary
versus fee for service).27 There have been few studies
reported to date addressing this issue. Drummond et
al assessed misoprostal for the prevention of NSAIDinduced ulcers simultaneously in four countries
(Belgium, France, UK, USA) using identical methodology. They found misoprostol to be more cost-effective
in the United States despite the fact that the drug was
36% more expensive there, because it averted surgical procedures which were relatively more costly.28
Copley-Merriman et al29 made similar observations
when they found that the treatment of advanced
NSCLC with gemcitabine monotherapy saved more
money in the United States compared to standard
etoposide/cisplatin (excluding chemotherapy drug
costs) than in Germany or Spain because it averted
more costly hospitalization and anti-emetic use.
is said to be ‘sensitive’ to that variable. If not, it is
‘robust’. The question becomes not whether all estimates of resource use and survival were accurate, but
whether any errors would have a meaningful impact
on the results.
One of the challenges facing economists is estimating an appropriate range for sensitivity analysis for
parameters that have a high degree of uncertainty. If
patient level data are available, the use of 95% confidence intervals can be employed to determine the
‘best case’ and ‘worst case’ scenarios. In cases where
confidence intervals are not available, one form of
sensitivity analysis involves the use of non-parametric bootstrapping to derive confidence intervals for
the ‘incremental cost-effectiveness ratio’ (ICER).30–32
Bootstrapping resamples from the original data to
build an estimate of the sampling distribution, allowing the calculation of confidence intervals and hence
a plausible range of values.
Transparency
A concern with many economic papers is a lack of
transparency in the description of methods and
assumptions. Transparency refers to how easy it is to
see exactly what the authors of a study have done. After
reading the results of an economic analysis, the reader
should not be left with the impression that the study
was done in a ‘black box’. For optimal transparency,
it is best to report disaggregated data on costs, resource
use, and quality of life.33 Ideally, the numerator and
denominator of cost-effectiveness ratios should be
reported separately. Costs should be shown in the
format:
quantity⫻unit price⫽cost
Sensitivity analysis and uncertainty
Sensitivity analyses assess the effect of varying the
estimates of resource use (such as the number of treatments of a new drug, the number of hospital days for
treatment administration or for palliative care) and
effectiveness (e.g. the length of survival gained, utility
estimates) over a range of plausible possibilities. No
matter how accurately costs and benefits have been
quantified and valued, it is likely that certain assumptions will be required. Skeptics often attack these
assumptions to dismiss a study. The choice of which
parameters to include in a sensitivity analysis is
dependent on two factors: how much confidence the
researcher has in the reported parameter, and the
impact changing this parameter has on the final outcome. If altering the value of key parameters significantly changes the outcome of the study, the analysis
while effectiveness measures should be separated
from their utility weightings. Obviously, it is important to know the currency and year of the costs. However, reports should also identify instances of price
adjustment, such as the use of the consumer price
index to inflate prices from another time period, or
the date and exchange rate used to translate costs
from other countries.
Discounting
Costs and benefits that occur in the future should be
adjusted, or discounted, to their present value. This
is because of ‘time preference’. We generally prefer to
incur benefits sooner rather than later and costs later
rather than sooner. Thus, future costs and benefits
have less weight than current costs and benefits, and
252 Textbook of Lung Cancer
are usually accounted for by multiplying them by a
constant discount rate with the formula:
1
(1 + r )n
where r is the discount rate, and n is the number
of years.33 Such adjustment favors therapeutic
procedures that provide immediate benefit, while rendering preventive and screening programs, which
require immediate expenditure for future benefits,
less attractive.
There is a lack of consensus over what the appropriate discount rate should be. American guidelines
suggest 3%,20 while Canadian guidelines have recommended 5%34 and British recommendations have
been 6%.35 The choice of discount rate can seriously
affect the results of an evaluation,36 and so should be
subject to sensitivity analysis. Also there is debate as
to whether benefits and costs should be discounted
at the same rate, as empirical studies have demonstrated that people do not have the same preferences
for future health benefits as for future costs.37–40
Assessing effectiveness
Health-care benefits can be measured as:
•
•
•
direct benefits: monetary savings in treatmentrelated resource utilization;
indirect benefits: increased productivity; and
intangible benefits: alleviation of pain and suffering associated with health improvements.
As described previously, the type of study (costeffectiveness, cost–utility, etc.) will determine the
type of benefit considered.
Large, randomized controlled trials or meta-analyses
provide good measures of clinical effectiveness. However, extrapolation of economic and clinical data to
routine practice is not always straightforward. Controlled clinical trials usually test the efficacy of a procedure under strictly defined ‘ideal world’ conditions.
Differences in the demographic characteristics of the
population, variations in clinical practice, and availability of resources may mean that the procedure is
less effective in routine clinical management.41 For
example, we might expect an elderly patient with
multiple co-morbidities to have a very different experience with chemotherapy for advanced lung cancer
than the highly selected patients studied in most
clinical trials. A clinician must decide whether his
patient is likely to derive the same benefits as the
patients included in the study.
Similarly, the toxicity of therapy may differ between
the experimental and normal practice settings. The
complication rate reported in a trial of complex therapy given to highly selected patients in a tertiary care
setting might not be the same as that seen when the
treatment is moved into general practice. As a result
of the costs associated with these complications, the
treatment might prove to be more expensive than
predicted by the economic model.
When survival is the outcome of interest, it is important to accurately quantify the magnitude of this benefit. Because survival distributions are skewed, the
median survival is most often reported in cancer trials. However, this measure may disregard important
information when trying to determine the average
benefit a patient can expect from a therapy. For
example, an intervention that results in some cures
will create a long tail on the survival curve that contributes to the number of life years gained. Such an
intervention can be highly cost-effective, even if there
is little or no increase in the median survival time. As
a result, economic evaluations should use the area
between the survival curves to determine the average
benefit from treatment.
Assessing cost-effectiveness
The cost-effectiveness ratio (CE) is the incremental cost
of an intervention divided by its incremental benefits,
as given by the formula:
CE ⫽
C1 ⫺ C 2
($)
E1 ⫺ E 2 (eg. time )
where C represents the cost of each intervention and
E represents their effectiveness.
Many people use thresholds to decide whether an
intervention is cost-effective. Canadian authors have
proposed that interventions costing less than $20 000
per QALY be considered cost-effective.42 Americans
tend to set the threshold at approximately $50 000 per
QALY.25 However, these cut-off points are arbitrary.
Another type of decision rule is a ‘league table’.
Economic evaluations assume that resources are limited, and have alternative uses if not applied to the
intervention in question. Policy-makers must make
decisions that will maximize health by getting the
highest value for the resources consumed. Their decisions often reflect a ‘utilitarian’ philosophy of doing
the greatest good for the greatest number of people.
In order to do this, a technology must be assessed for
its efficiency relative to all other potential uses of the
same resources. Cost-effectiveness league tables such
The cost and cost-effectiveness of lung cancer management 253
Table 17.2 An example of a league table
Cost per life-year gaineda
Medical intervention
Liver transplantation
Screening mammography, <50 years old
Cholestyramine for high cholesterol
Routine use of non-ionic radiography contrast medium
Coronary artery bypass, two-vessel disease plus angina
Captopril for hypertension
Zidovudine for HIV infection
Renal dialysis, in-center benefit, men
Screening mammography, >50 years old
Hydrochlorothiazide for hypertension
Coronary artery bypass, left main disease plus angina
Smoking cessation counseling, men
237 000
232 000
178 000
72 000–243 000
106 000
82 600
82 000–88 500
42 000–80 300
20 000–50 000
23 500
17 400
1300
a
1992 US dollars.
With permission from Smith et al.46
as Table 17.2 rank interventions by cost per life year
or cost per QALY gained.
There are two major attractions to league tables:
they place results in the context of the cost-effectiveness of other technologies, and they offer an easy
mechanism to inform or justify resource allocation
decisions. Resources can then be spent on the most
cost-effective programs until the resources are
exhausted. There are numerous examples of league
tables published across specialties,43–45 and in oncology in particular.46
There are, however, many methodologic difficulties in creating league tables, necessitating caution
when using them for resource allocation.47 One major
problem is that they often group together studies that
were undertaken at different points in time. Cost-effectiveness figures can be adjusted to a base year, but
this requires assumptions of constancy of relative
costs, resource use, disease management, and treatment
efficacy over time. There may also be differences in
study methodology. These include the choice of treatment comparisons, the length of follow-up of patients,
the quality of life or utility instrument adopted, the
assumptions made, and the range and sources of costs
included.47 Such differences may affect the ranking
of various technologies within a league table, leading
to erroneous conclusions.
Both the threshold and league table approaches
assume that QALYs have the same value in all situations. However, empirical evidence tells us otherwise.
Society generally adheres to the ‘rule of rescue’: we
value interventions that will actually save a patient
from dying from a disease more than one that may
make many live a little longer. We are also more willing
to pay for an intervention that will save an identifiable life, such as an individual who requires a heart
transplant, than one for which a ‘statistical’ life may
be saved, as in prevention programs. Because of these
problems, neither league tables nor thresholds should
be seen as providing accurate answers to difficult
resource allocation decisions. Rather they should be
seen only as an aid to inform decision-makers.
Deciding whether to believe the results
Knowledge of the key methodologic principles that
well-conducted studies should follow21,48,49 is important in order to avoid inappropriately applying the
results of a poor study or using data that are not applicable in a certain setting. Because of this, American
guidelines have been published for reporting economic
studies,20 and useful strategies have been proposed
for critically appraising economic analyses.50,51
THE COST OF LUNG CANCER MANAGEMENT
Cost of NSCLC
A number of studies have examined the direct costs
associated with the diagnosis and treatment of lung
cancer.52–56 Evans et al53 calculated the average direct
care costs over five years for diagnosis and treatment
of NSCLC in Canada to be $19 778 in 1988 Canadian
dollars.54 The first year costs ranged from $6333 for
supportive care for stage IV disease, to $17 889 for
254 Textbook of Lung Cancer
surgery and radiotherapy in earlier stage lung cancer.
Hospital costs were found to dominate, accounting
for 36.8% of all costs. About one-third of the total
cost was for hospitalization during the initial diagnostic work-up. Terminal care accounted for about
half of the total cost, whether a patient received chemotherapy or not.
In the United States, Riley et al compared the Medicare payments for patients aged 65 and over with
common cancers.55 They found that lung cancer was
the most expensive cancer site for initial treatment at
$17 518 (1990 US$) due to high costs for hospitalization ($10 782, or 62%). However, because of the
relatively short survival of lung cancer patients, it
was among the least expensive in terms of total payments from diagnosis to death at $29 184.
Hillner et al looked at the cost of lung cancer for a
commercially insured cohort in Virginia.56 These
patients were younger, and fees were generally higher
than those for the Medicare population studied by
Riley et al.55 They found that the total cost of treatment from diagnosis to death was $47 941 (in 1992
US$), with inpatient hospital facility costs accounting for up to 65% of the total cost. Patients receiving
no active treatment still incurred significant costs
($26 597 in the first year after diagnosis). On average, patients spent 27.6 days in hospital in the last
six months of life.
Methodologic differences and different time frames
make it difficult to compare these studies; however
hospitalization consistently stands out as the dominant cost in all of them. Similar findings have been
seen in other tumor sites.57–59 This sort of research has
led to a shift of treatment to the ambulatory setting,
development of care maps and algorithms to expedite diagnostic work-up,60 and increased use of hospices for terminal care.61
Cost of SCLC
Less work has been published on the costs associated with the treatment of SCLC. Evans et al found
that direct care costs for the diagnosis and initial
treatment of SCLC ranged from $18 691 (1988
Canadian dollars) for the management of limited
stage disease, to $4739 for the supportive care
of patients with extensive disease who were not
candidates for chemotherapy.62 The average total
cost for treating SCLC was $25 988.22,62 This is comparable to the $18 234 (1990 Australian dollars) for
limited and $13 177 for extensive disease calculated
by Rosenthal et al.63 Again, hospitalization was the
dominant cost.
ESTIMATING THE COSTS OF LUNG CANCER
IN CANADA
Statistics Canada has developed information at the
population level on the economic burden of lung
cancer from the perspective of the government as the
payer in a universal health-care system.22,53,54 This
POpulation HEalth Model (POHEM) was developed
to provide a comprehensive microsimulation of
Canadian health, including such important diseases as
lung, breast, colon, and prostate cancer, cardiovascular disease, dementia, arthritis, and osteoporosis. The
model integrates risk factors for disease, diagnostic
and therapeutic approaches, health-care resource
utilization, and direct medical care costs. The lung
model within POHEM assigns a histologic cell type
(small cell versus non-small cell) and stage to each
patient in a simulated lung cancer population.22,53 It
then describes the treatment appropriate to cell type
and stage, and the anticipated progress and survival of
the cancer in response to treatment. Costs are assigned
according to tumor cell type and treatment option.
To develop this model, it was necessary to access
multiple databases for information on cancer incidence, tumor cell type, patient demographics, and
stage distribution. Questionnaire surveys of Canadian oncologists were undertaken to obtain information not accessible from provincial databases, such as
diagnostic tests used or follow-up practices. Information on the duration of hospitalization for diagnostic
work-up and initiation of therapy was obtained from
Statistics Canada’s national person-oriented hospital
morbidity database. Costs for hospital outpatient
chemotherapy treatment were extracted from an economic analysis done by the National Cancer Institute
of Canada following a clinical trial (BR5), which
compared chemotherapy and best supportive care in
advanced NSCLC.23,24
Costs were initially determined in 1988 Canadian
dollars, but have been updated periodically since the
original report.22,53,54 The economic analysis was performed from the perspective of the government as
payer in a universal health-care system. Since the fees
paid for physicians’ assessments and laboratory and
surgical procedures varied from province to province
in Canada, the fee schedule operative in the province
of Ontario under its health insurance plan was used as
the standard. Statistics Canada’s ‘Hospital Statistics’:
Preliminary Annual Report was used to determine
the average cost of hospitalization by type of hospital. The per diem rate for a Canadian teaching hospital at the time of this analysis was C$818.50.
The cost and cost-effectiveness of lung cancer management 255
Hospital costs for non-surgical care of lung cancer
cases, including terminal care, were derived from the
economic analysis of the National Cancer Institute of
Canada clinical trial of best supportive care versus
chemotherapy.24 These costs were inflated by the rate
that the national per diem rate for tertiary care facilities had inflated during the same time period. More
details of the costing methodology are included in
previous publications.22,53,54 The cost of diagnosis
and initial treatment for stage 1 and II lung cancer
(excluding relapse costs) was C$14 110. The cost of
combined-modality therapy (surgery and radiotherapy) for patients in stage 1 and II was C$17 889. For
non-surgical candidates, treated with radical radiotherapy, the initial cost of diagnosis and treatment
was estimated to be C$12 474. The costs of treating
stage IIIA and IIIB disease with radiation alone were
less, at C$11 714 and C$9347, respectively. The initial cost of diagnosis and care of stage IV (metastatic
disease) patients was C$6333. Further significant
costs would be incurred by these patients when they
relapsed and entered the terminal-care phase of their
illness (the last three months’ period to death), with
costs equalling C$10 331. Based on the fact that there
were 12 549 NSCLC patients in Canada in 1988, and
assuming that all would have access to appropriate
care as defined by the treatment algorithms, the total
cost of treatment for a cohort of patients with NSCLC
followed over five years would be C$240 236 000.53
A similar analysis for the 3075 SCLC cases according
to disease stage revealed that patients with limited
stage disease treated with combined-modality therapy
would incur costs of approximately C$18 500. Patients
with extensive disease would receive less radiotherapy and less chemotherapy, and therefore would incur
fewer costs. The total cost per case estimated in POHEM
was C$13 525. The terminal-care costs for extensive
disease patients were estimated to be C$9387, and
these costs would be added to those of the treatmentrelated costs during the year of the patient’s death.
Overall, the total burden incurred in managing all cases
of SCLC diagnosed in 1988 over five years would
total C$79 913 000.63
An analysis of the cost of the various components
of lung cancer management illustrates the value of
this type of cost analysis, in that it immediately makes
apparent the major sources of expenditure in the
health-care system for the management of lung cancer patients. For all stages of lung cancer, the use of
acute-care hospital beds accounts for more costs than
diagnostic tests, medications, and physician fees combined. Hospitalization during initial diagnosis and
management made up 35.8% of the total five-year
costs, and the cost of terminal care utilizing acutecare hospital beds was 38.7% of the total cost. Therefore, assuming the goal is to make the health-care
system as cost-efficient as possible, strategies need to
be developed that devolve inpatient care to ambulatory diagnostic assessment units for patients with a
presumptive diagnosis of lung cancer, and provide
more palliative care in the home environment or
through palliative care units.
THE COST-EFFECTIVENESS OF LUNG CANCER
TREATMENT
We performed a MEDLINE and EMBASE search
using OVID for the period 1996 to August 2007 to
identify recent studies based on the search terms costeffectiveness and lung cancer. This search identified
632 publications after removing duplicates. When the
search was restricted to NSCLC and cost-effectiveness,
the total number of publications was 178. These publications included systematic reviews, meta-analyses,
and commentaries. Below, we highlight some of the
early literature that is frequently referenced (1998 and
earlier), and in the next section we highlight more
recent publications (1999–2007).
Of interest is the fact that in the previous edition
of this book, we were only able to identify 15 economic
evaluations of lung cancer management.22,29,53,54,64–76
All but one of these studies included an evaluation of
the cost-effectiveness of chemotherapeutic alternatives in lung cancer treatment.64 The one exception
involved a comparison of two different radiotherapy
regimens for NSCLC: conventional radiotherapy
treatment versus continuous hyperfractionated accelerated radiotherapy. Despite the recognition of the
importance of quality of life effects on treatment choice,
only two studies incorporated estimates of patient’s
quality of life into quality-adjusted life years.74,76 All
studies used effectiveness data derived from clinical
trials, though not all were based on randomized evidence. Several studies examined resource consumption from those same trials,24,64,65,74–76 while others
adopted an approach whereby resource use estimates
were obtained from other sources (e.g. institutional
databases) and were combined with effectiveness data
within a modeling framework.27,65–67,69,71–73
The Canadian POHEM model has been used as a
framework within which to assess new interventions
for their cost-effectiveness. The costs of the survival
benefit associated with new treatments, such as
256 Textbook of Lung Cancer
chemotherapy for stage IV NSCLC, can be compared
against the costs and benefits of standard treatment.
Clinical practice guidelines in Canada recommend
that cisplatin-based chemotherapy be offered as a
treatment option for medically suitable patients to
improve survival, symptom control, and quality of
life.77 The cost-effectiveness of this approach was an
important understanding at a time of fiscal restraint
in health care, since many physicians and health-care
administrators questioned whether it was appropriate to offer relatively expensive and toxic agents that
only modestly impacted survival.
The National Cancer Institute of Canada (NCIC)
was the first to demonstrate in a cost analysis that
chemotherapy administration might actually reduce
the overall costs to the health-care system, primarily
by reducing the average length of hospital stay for
terminal care. Jaakkimainen et al undertook an economic analysis of the NCIC clinical trial (BR5) that
compared the use of vindesine-cisplatin (VP) chemotherapy and the combination of cyclophosphamide,
doxorubicin (Adriamycin) and cisplatin (CAP) versus best supportive care (BSC) in patients with stage
IV NSCLC.23,24 This study, which used primary
survival data from patients entered in the trial and
estimated costs from the two largest institutions contributing patients to the trial, demonstrated that CAP
was a dominant strategy, saving C$949 per case.
Vinorelbine-cisplatin was also a dominant strategy as
an ambulatory regimen, saving C$473 per case, and
was more cost-effective than the same chemotherapy
given as an inpatient regimen [C$5551 per life year
saved (LYS)].
We are now faced with a proliferation of promising
new drugs with encouraging activity in NSCLC. Each
of these drugs is, however, significantly more expensive that the older drugs. By using POHEM, information on the costs of the old standard therapies and
their outcomes can be compared with the costs of the
new agents and their survival benefits. Based on data
from a randomized trial of vinorelbine alone compared
with the combinations of vinorelbine-cisplatin and
vindesine-cisplatin,78 estimates of the cost-effectiveness
of these regimens relative to BSC were made in the
POHEM.69 Vinorelbine was a dominant strategy, saving C$1447 per case. Vinorelbine-cisplatin was also
a dominant strategy as an ambulatory regimen, saving C$473 per case, and was more cost-effective than
the same chemotherapy given as an inpatient regimen
(C$5551 per LYS).
Hillner and co-workers73,79 also undertook a costeffectiveness analysis of vinorelbine-cisplatin and
vindesine-cisplatin compared with vinorelbine alone
in stage IV, based on the same clinical trial reported
by Le Chevalier et al.78 They used American costs
(charges) and found that vinorelbine-cisplatin cost
US$17 700 per LYS relative to vinorelbine. Vindesinecisplatin had a cost-effectiveness ratio of US$22 100
per LYS relative to vinorelbine. Even in this comparison against vinorelbine alone as opposed to BSC,
the combination of vinorelbine-cisplatin was seen to
be cost-effective.
Evans undertook an economic evaluation of the
use of gemcitabine in the management of patients with
stage IV lung cancer. Based on phase II survival data
from the large EO18 trial,80 and estimates of drug
cost per treatment cycle ranging from C$800 to
C$1800, gemcitabine was observed to be cost-effective
over a range of sensitivity analyses.67 At the greatest
cost per cycle (C$1800), and with survival reduced by
50% compared with the EO18 results, the cost per
life year gained was estimated to be C$16 230.
Earle and Evans66 undertook a similar analysis of
paclitaxel alone compared with BSC, based on the
data from two phase II clinical trials.81,82 The total
costs of administering three cycles of chemotherapy
were C$8143 and C$3375 more than the strategy of
BSC. However, on the basis of the difference in survival duration between stage IV patients treated in
the BSC arm of a previous NCIC trial and those represented in the pooled phase II survival results, the
cost per life year gained was C$4778.
All of the chemotherapy regimens that were previously evaluated in POHEM were updated to current
costs and placed in a decision framework.81,82 Vinblastine-cisplatin, vinorelbine-cisplatin, and etoposide (VP-16)-cisplatin were all found to decrease the
cost of treatment per patient compared with BSC,
while increasing survival relative to BSC. Therefore,
these chemotherapy regimens can all be considered
dominant treatment strategies. This important observation is true in the Canadian health-care environment, but it may not reflect reality in other health-care
environments.
The important influence of the health-care environment on the outcome of economic analysis is seen in
the report of Lappas el al.83 They undertook a pharmacoeconomic analysis of the impact of paclitaxel-carboplatin and vinorelbine-cisplatin. To obtain survival
outcome data, they performed a meta-analysis of all
available clinical trial literature. US Medicare reimbursement figures were used to determine the total
expected cost. This was determined to be US$19 322
and US $20 790 for paclitaxel-carboplatin and
The cost and cost-effectiveness of lung cancer management 257
vinorelbine-cisplatin, respectively. Treatment with the
vinorelbine-containing regimen was 7% more costly
than the paclitaxel-containing regimen. Lower administration costs and less frequent adverse event management costs led to the lower overall cost and to the
recommendation that paclitaxel-carboplatin be the
preferred choice from an American pharmacoeconomic perspective. Estimates of the cost per case are
greater for paclitaxel-cisplatin or paclitaxel-carboplatin in the Canadian environment than for vinorelbine-cisplatin, even though generic pricing is now in
effect for paclitaxel and carboplatin in Canada. Relative to BSC, paclitaxel-cisplatin is a cost-effective intervention at C$5034 per LYS, but vinorelbine-cisplatin
is a dominant strategy.
Recent cost-effectiveness literature (1999–2007)
Cost-effectiveness literature for lung cancer continues
to inform decision-makers, and has recently been used
in the evaluation of lung cancer staging strategies,84,85
the management of chemotherapy-induced anemia,86
the use of G-CSF,87 and the use of chemotherapy in the
first-line lung cancer setting,88–94 and in the secondline setting.95–97
Verboom et al84 demonstrated that, despite the
increased cost of a PET scan, the potentially averted
surgeries and related costs more than offset the costs
of the additional tests and made it the dominant strategy (€9573 conventional, €8284 PET). Kelly et al85
demonstrated that FDG-PET imaging improved staging accuracy compared to CT scanning alone, and
reduced the need for more expensive invasive staging
methods. Kelly did not provide any cost-effectiveness
ratios, and did suggest that the cost-effectiveness is
still unclear in populations with N0–2 disease.
Chouaid et al86 presented findings at the 11th world
conference on lung cancer on the cost-effectiveness of
darbepoetin alfa in anemia management. Chouaid
included drugs, transfusions, and anemia management costs in creating the cost-effectiveness ratio and
reported that darbepoetin alfa was the dominant
strategy. Timmer-Bonte et al87 have also presented a
cost-effectiveness analysis for G-CSF as secondary
prophylaxis added to antibiotics in SCLC. Their economic analysis suggested that the mean incremental
costs associated with adding G-CSF was €681 (95%
CI ⫺36–1397) per patient. The entire treatment
period had a mean incremental cost of €5123 (95%
CI 3908–6337). The ICER was €50 per percent
decrease in the probability of febrile neutropenia (95%
CI ⫺2–433) in the first cycle of treatment. They
concluded that if policy-makers were willing to pay
€240 for each percent gain in effect (€3360 for a
14% reduction in febrile neutropenia) the addition of
G-CSF would be considered cost-effective.
In the first-line chemotherapy setting a number of
recent cost-effectiveness analyses have been reported.
Martoni et al88 undertook a cost-minimization analysis
of gemcitabine-cisplatin versus vinorelbine-cisplatin
in NSCLC, as no difference in efficacy were demonstrated. Martoni estimated that the vinorelbinecisplatin combination had an average cost of €882.24
versus €2900.91 for gemcitabine-cisplatin.
Sacristan et al89 undertook a cost-minimization
analysis of gemcitabine-cisplatin versus etoposidecisplatin in NSCLC. Again this was based on the fact
that no differences in efficacy were demonstrated.
Sacristan showed that the average cost per patient
was 584 523 pesetas for gemcitabine-cisplatin versus
589 630 pesetas for etoposide-cisplatin based on the
combined costs of chemotherapy, anti-emetics, hospitalization, medical visits, and transfusions. Further
analysis based on cost per response or cost per progression-free month was also presented, although
these endpoints are difficult to evaluate as there is
limited literature on the use of these measures of
cost-effectiveness.
Ramsey et al90 initially planned a cost-effectiveness
analysis of the Southwest Oncology Group Trial S9509
comparing vinorelbine-cisplatin to paclitaxel-carboplatin in NSCLC. However, upon determining that
no differences in efficacy existed, a cost-minimization
analysis was undertaken. Patient costs were calculated
based on a 24-month follow-up and showed that
vinorelbine-cisplatin had an average cost of $40 292
versus $48 940 for paclitaxel-carboplatin. Ramsey noted
that most of the difference related to drug acquisition
costs (difference $11 863).
Dooms et al91 presented one of the few cost–utility
analyses in lung cancer based on a comparison of
gemcitabine monotherapy with vindesine-cisplatin
in NSCLC. They incorporated utilities by transforming a visual analog scale for quality of life. An incremental cost of €1522 per patient and an incremental
QALY of 0.11 years resulted in an ICER of €13 386
per QALY, which the authors considered to be a
favorable outcome.
Chen et al92 presented what they claim to be a costeffectiveness analysis (although in effect they presented
a cost-minimization analysis) of paclitaxel-carboplatin
compared to paclitaxel-gemcitabine in NSCLC. They
included costs for admission fees, out-patient clinic
visits, emergency-room visits, and chemotherapy. The
authors reported differences in costs between the two
258 Textbook of Lung Cancer
therapies, with the paclitaxel-carboplatin regimen being
US$2214 less expensive overall, with no statistically
significant differences in efficacy being identified.
Billingham et al93 used data from the MIC2 trial
which compared mitomycin-ifosfamide-cisplatin to
best supportive care for NSCLC. They incorporated
non-parametric bootstrapping which produced a
cost differential of £2924 and a survival advantage of
2.4 months. These outcomes produced an ICER of
£14 620 per life year gained. The authors noted that
the main driver of increased costs was associated
with increased hospital in-patient days for chemotherapy-related issues.
Annemans et al94 undertook a cost-effectiveness
analysis comparing paclitaxel-cisplatin to teniposidecisplatin in advanced NSCLC. They included the costs
for drugs and chemotherapy administration, and consequences associated with anemia, thrombocytopenia, neutropenia, neuropathy, and arthralgia/myalgia.
Paclitaxel-cisplatin had a higher cost in all analyses
undertaken in a number of countries (The Netherlands,
Belgium, France, and Spain), with a net cost per patient
of US$2311. Paclitaxel-cisplatin did provide a better
response rate (37% versus 26%). The authors state that
the cost per extra responder for paclitaxel-cisplatin
was, on average, US$21 011.
In the second-line setting for NSCLC, two costeffectiveness studies have been published based on
the pivotal clinical trial comparing docetaxel to best
supportive care (BSC).95 Leighl et al96 used Canadian
costing and concluded that the incremental cost for
docetaxel was C$9577, with the lower-dose regimen
showing an incremental cost of C$10 804. Survival
benefits were 2 months in the primary analysis and
3.9 months in the low-dose analysis. The resulting
ICER was C$57 749 per life year gained in the primary analysis, and C$31 776 per life year gained in
the low-dose analysis. Sensitivity analysis included
increasing and decreasing survival outcomes by 20%
with resulting ICERs of C$18 374 to C$117 434. Holmes et al97 used United Kingdom costing (in pounds)
and reported an ICER of £13 863 in the low-dose
analysis, but did not include an analysis of the primary study as reported by Leighl et al. Sensitivity
analysis produced ICERs from £10 020 to £32 781,
based on 95% CI for mean differences in survival.
Bradbury et al98 undertook an economic analysis
based on the National Cancer Institute of Canada
study of erlotinib versus best supportive care after
cisplatin-based chemotherapy in advanced NSCLC.
Their analysis showed that the incremental costs were
C$12 303 with a corresponding benefit of 0.13 years
(1.56 months). The resulting ICER was C$95 869 per
life year gained (95% C$52 359–$429 149).
In some cases the cost-effectiveness analyses illustrated above can be roughly converted to cost-utility
estimates by assigning utilities to each of the chemotherapy regimens and to BSC. Oncologists working
as part of the Ontario Practice Guideline Initiative
have estimated utilities for the different chemotherapy regimens. The scale used ranged from 0 to 1,
where 0 represents death and 1 is perfect health. The
utilities for the chemotherapy regimens ranged from
0.5 to 0.7, with the utility estimate for best supportive care being 0.5. It is important to note, however,
that utility estimates are typically created through a
survey of the general public or patients, and hence
some bias in the utility assessment may occur with
physician estimates. With the incorporation of physician-estimated utilities into the calculation of costeffectiveness, the chemotherapy regimens actually
became more cost-effective compared with BSC.
Chemotherapy interventions for stage IV NSCLC
can be ranked for their cost-effectiveness based on
alternative threshold values.99 Depending on the
value that society is willing to pay for each unit of
outcome gained, the ranking of each intervention
will vary. In North America, the common threshold
has been estimated to be approximately C$50 000
per quality-adjusted life year, although this is not a
definitive value.100 Using this threshold, paclitaxel
followed by paclitaxel-cisplatin, vinorelbine-cisplatin
(ambulatory), and gemcitabine would be the preferred
regimens. If the threshold was for therapies costing
only C$10 000 per life year gained, vinblastine-cisplatin would be the preferred regimen, followed by
vinorelbine-cisplatin given on an ambulatory basis,
etoposide-cisplatin, and vinorelbine alone.
The cost-effectiveness for combined-modality therapy for stage IIIA and IIIB disease has been evaluated
using the POHEM.65 For stage IIIA, combinedmodality therapy consisting of pre- and postoperative chemotherapy and radiotherapy, as described by
Kris et al,101 was modeled for patients with clinically
evident N2 disease. For patients with stage IIIB disease, the costs associated with delivering two cycles
of vinblastine-cisplatin followed by radical radiotherapy (60 Gy in 30 fractions), as reported by CALGB,102
have been modeled.
Although the incremental cost per case was high,
particularly for combined-modality therapy for stage
IIIA disease (C$22 963 more than standard radiotherapy), the estimated life years gained were also substantial and the cost-effectiveness was C$14 958 per
The cost and cost-effectiveness of lung cancer management 259
life year gained. The combined-modality approach of
vinblastine-cisplatin followed by radical radiotherapy
for stage IIIB patients was more expensive than standard
Canadian radiotherapy (C$22 303 versus C$13 391).
However, the estimated number of life years gained
with combined-modality therapy was large, and resulted
in a cost-effectiveness ratio of C$3348 per life year
gained.
A report by Winton et al in 2005, from the National
Cancer Institute of Canada Clinical Trials Group
demonstrated a dramatic increase of 15% in absolute
5-year survival with the use of post-operative vinorelbine-cisplatin in patients with completely resected
Stage IB and II NSCLC.103 An economic analysis of
this trial showed the chemotherapy to be highly
cost-effective at C$10 096 per life year gained.104
The increased volume of economic and pharmacoeconomic literature brings with it some challenges. As
can be seen from the results shown here, the methodologies are often unclear, with cost-minimization
analyses sometimes presented as cost-effectiveness
analyses. The analyses are also less informative when
the comparator therapies chosen do not always represent current standards of care. Additionally, not all
the analyses used the same measure of effectiveness.
Although many used life years or quality-adjusted
life years, other less well established outcomes were
sometimes incorporated. When the incremental evaluations do not use consistent methodology, the current standard of care as the comparator, or a typical
effectiveness measure, the analysis becomes more
difficult to interpret for researchers and policy-makers alike. It is advised that readers be wary of published studies that use atypical methods, comparators,
or measures of effectiveness.
LUNG CANCER ECONOMICS AND
HEALTH-CARE POLICY
The expenditures associated with medical practice
are coming under increased scrutiny. Both public and
private payers are demanding increased efficiency
and ‘value for money’ in the provision of health-care
services. As a result, policy-makers in both Australia
and the Province of Ontario (Canada) have developed
formal guidelines for economic analyses that are to
be part of drug reimbursement submissions.105,106
Clinical practice guidelines have recommended
that it is ‘reasonable to offer cisplatin-based chemotherapy to medically suitable patients as a treatment
option’ for survival, symptom control, and quality of
life outcomes in metastatic NSCLC patients.77,107 As
Evans et al have reported,108 the average cost of managing a lung cancer patient from diagnosis to death
without palliative chemotherapy is just under
$20 000. Therefore, for all 17 128 cases diagnosed in
Canada in 1992, the total cost was ∼$350 million. Even
though palliative chemotherapy is considered costeffective,99 by virtue of lung cancer’s high incidence,
the cost of treating all advanced stage patients with
chemotherapy adds significantly to health-care budgets and manpower requirements.
Oncologists are still fairly conservative in their
management of advanced lung cancer.108 As well,
many patients are not candidates for systemic therapy because of biologic age, performance status, or
co-morbid conditions. Therefore, the actual impact
of a new treatment for lung cancer on national health
budgets is likely to be less than projected based on
total number of cases.
CONCLUSION
Because of its high incidence, lung cancer is a significant burden on health-care systems. Studies indicate that strategies to minimize hospitalization are
likely to have the greatest impact on these expenditures.53 Despite common perceptions to the contrary,
supportive care for advanced lung cancer is associated with significant cost, and many chemotherapeutic treatments are cost-effective relative to other
commonly accepted medical interventions. However,
decision-makers sometimes have trouble seeing past
the price of these interventions. Therefore, it is important to understand how to assess these technologies
in the broader context of the costs and consequences
associated with their use. Providing decision-makers
with useful information from methodologically sound
studies will help optimize use of health-care resources,
and ensure continuing access to care for lung cancer
patients in the future.
Despite evidence of the cost-effectiveness of lung
cancer treatment, there remains reluctance in the
medical community, even in North America, to adopt
some of these new approaches in the management of
lung cancer. Concern has been expressed about the
quality of life that accompanies such treatments.
However, even when this has been factored into the
economic evaluations, the quality-adjusted life years
gained remain in the range that is considered
acceptable for health-care interventions in Canada.42
The reluctance of some institutions to provide
260 Textbook of Lung Cancer
combined-modality therapy for locally advanced disease or chemotherapy for metastatic disease may relate
to the absolute cost of introducing these new treatments. Since there are a large number of patients who
potentially could receive these treatments, the total
fiscal burden could be quite large. In developing
countries, where there is a need to prioritize healthcare expenditures even more carefully, the absolute
cost of care for lung cancer patients may become a
significant factor in determining health policy. Choices
will need to be made between the introduction of
these new strategies and the withdrawal of previously
existing treatments for cancer or the treatment of
other illnesses. Before such decisions are taken, however, economic data derived from the cost of care in
that particular environment need to be determined.
Evaluations in North America have dispelled the myth
that the treatment of lung cancer is costly and not
cost-effective in this health-care environment.
Although caution must be exercised in extrapolating
this to other health-care jurisdictions, economic factors should probably not be a barrier to the delivery
of current best treatment practices. The comparative
cost-effectiveness data presented in this review may
be useful to those who must make the decisions
about which regimens or strategies to choose.
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18 The future
Giovanni Selvaggi, Giorgio Vittorio Scagliotti
Contents Introduction • Screening • Molecular profiling • New imaging techniques
• Staging • Prognostic factors • Radiotherapy • Pharmacogenomics • Targeted therapies
• Vaccines • Conclusions
INTRODUCTION
The global burden of lung cancer will undergo dramatic
changes in the near future, from the developed to the
developing world, with an impressive contribution of
the over 300 million new smokers in China, almost
exclusively males.1 War against tobacco is the answer to
stop lung cancer epidemics. The identification of predisposed individuals is the next step.
Trends in the prevalence of cigarette smoking strongly
predict lung cancer incidence and mortality rates, which
closely parallel incidence because of the high case fatality of lung cancer. In the United States, the prevalence
of cigarette smoking in males and females declined consistently until approximately 1990, establishing a plateau at 25%. The patterns of smoking prevalence
indicate that lung cancer mortality rates will continue
to decrease until approximately 2020, assuming a
30-year lag between smoking patterns and subsequent
lung cancer incidence. By 2030, lung cancer cases will
no longer have a predominance of gender.2
In the 1990s adenocarcinoma became more frequent
than squamous cell carcinoma.3 Hypotheses concerning
such histologic shift focused on changes in the characteristics of cigarettes and in the inhaled doses of carcinogens.
An increased puff volume might lead to higher deposition
of tobacco smoke in the alveoli of the lung. Higher nitrate
levels in tobacco smoke would lead to enhanced doses of
NNK, a tobacco-specific nitrosamine believed to be
responsible for adenocarcinoma’s higher incidence.4
Understanding the potential links between ethnicity
(e.g. Caucasian vs African Americans vs Asians), low
socioeconomic status, and lung cancer risk is essential
to modify the impact of lung cancer incidence in a vast
part of the population worldwide and to design effective prevention projects. Hints of a higher susceptibility
to lung cancer in women are also a major concern, with
immediate consequences on therapeutic chances offered
by newer targeted therapies.5
There is a need for predictive models to quantify the
risk of developing lung cancer in coming years. A simulation model was constructed in Finland on the basis of
how changes in smoking habits could impact directly
on lung cancer incidence in the future.6 A delay of
10 years in starting age of smoking had the same effect
on lung cancer incidence as cutting the number of
those starting by 50%. Postponement of the starting age
by 20 years would eliminate most of the lung cancer
cases caused by smoking. Persuading youths not to
start smoking represents a socio-economic priority.
Lung cancer has always been viewed as a smoker’s disease. However, the epidemiologic burden of non-smokers
with lung cancer is significant, especially in Asiatic countries. The recent descriptions of epidermal growth factor
receptor (EGFR) mutations being more common among
lung tumors of non-smokers suggest that this selected
group of patients should be examined further. Evidence
exists that lung cancer among non-smokers may be biologically different from that of smokers. Genetic and/or
environmental factors, other than smoking, could possibly
predispose to lung cancer. In the near future lung cancer
in non-smokers may be treated differently from lung cancer arising in smokers. Is it really a different disease?
In a study testing 265 lung cancer specimens the
likelihood of EGFR mutations in exons 19 and 21
decreased as the number of pack-years increased.7
Mutations were less common in people who smoked
for more than 15 pack-years or who stopped smoking
cigarettes less than 25 years ago. Such data could help
clinicians in assessing the likelihood of EGFR mutations on exons 19 and 21 in patients with lung adenocarcinoma when mutational analysis is not available.
SCREENING
The detection of lung cancer at an early stage must be
pursued to cut the mortality from this deadly disease,
The future 265
given the five-year survival of stage I patients in the
range of 65–70%.8 The best tool for detecting early lung
cancer has still to be defined. Studies failed to show the
utility of chest radiography alone or in addition to sputum cytology for lung cancer screening.9
Significant improvements in technology have facilitated the generation of low-resolution images of the
entire chest using low radiation exposure and within a
single breath hold, by the use of low-dose spiral computed tomography (CT). Low-dose CT improved the
likelihood of detecting lung cancer at an earlier stage,
with an estimated five-year survival rate of 60–80% in
the Early Lung Cancer Action Project (ELCAP) study,10
followed by other larger studies from Japan,11 USA, and
Europe.12 In these studies most screening-detected cancers were in stage I. Data from the I-ELCAP study on
over 30 000 volunteers13 showed that lung cancer
detected by annual spiral CT screening is largely curable. Screening resulted in a diagnosis of clinical stage I
lung cancer in 85% of cases, with an estimated 10-year
survival rate of 88%, reaching 92% in those cases who
underwent surgical resection within one month after
diagnosis.
The question of the real impact on lung cancer mortality by CT screening programs will be answered
through the National Lung Cancer Screening Trial from
the National Cancer Institute (NCI) on 25 000 volunteers, using multi-detector-row scanners.
Overdiagnosis could represent a potential drawback
of screening without a true stage shift: an increase in
early stage disease associated with a corresponding
decrease in late stage disease. It was reported that the
gene-expression profile of screen-detected lung carcinomas showed no difference from that of a matched
population with symptomatic lung cancer, suggesting
that the biologic aggressiveness of screening-detected
lung cancer does not differ from the ‘real’ lung cancer,
thus eliminating a source of bias against screening.14
Other issues to be addressed include false-positive rate,
the cost-effectiveness of these projects, and the risk of
radiation exposure with low-dose CT scans.
The rapid advances in imaging technology make it
very difficult to complete a randomized study, sufficiently powered to address the issue of decreased mortality with lung cancer screening, before new devices
come on the market. The CT scan remains the optimal
tool for detection of lung nodules. Current 64-slice
scanners provide images of structures and acquire data
so quickly that motion artifacts and volume-averaging
effects are generally negligible. Computer-aided detection (CAD) CT systems are commercially available and
will provide markedly improved detection of lung nodules. One recently published trial found that the mean
sensitivity for the detection of lung nodules on CT rose
significantly with the addition of CAD.15
Positron emission tomography (PET) might improve
diagnostic accuracy if it is introduced into a screening
program. No data are available yet and prospective
studies are ongoing. Size limitation (lesions below 7 mm)
and false-positive/negative rates have to be defined
when implementing PET as a screening tool for lung
cancer. The limitations of PET with regard to lesion size
have improved with the introduction of combined
PET-CT scanners; the ‘multislice’ CT component
improves the spatial resolution of PET images to a lower
limit of 6–7 mm. False negatives are known to occur
with well-differentiated tumors such as bronchioloalveolar carcinomas (which may produce ‘ground-glass’
opacities on CT scans) and adenocarcinomas.16
On the biologic side, genomics and proteomics are
opening new horizons in both early and advanced lung
cancer management. Mutations, microsatellite alterations, and methylation of promoter regions of specific
cancer-related genes can be detected in the serum of
patients with lung cancer, while genomic instability can
be seen in the bronchoalveolar lavage fluid.17,18 The
measurement of DNA changes in the serum holds great
potential for the development of serum markers for the
early detection of lung cancer.
Proteomics relies on the detection of antibodies
directed at known proteins considered to be involved
in lung carcinogenesis. A monoclonal antibody, HNRNP
A2/B1, showed an accuracy of 90% in predicting
patients who would eventually develop lung cancer
over the next few years.19 The introduction of matrixassisted laser desorption ionization (MALDI) mass spectroscopy allows the generation of a protein ‘profile’
based on the molecular weights and relative quantity of
all proteins in a sample. The proteins that are differentially expressed can then be identified and tested as
potential biomarkers to select patients likely to respond
to targeted therapies.20
MOLECULAR PROFILING
The model of carcinogenesis for lung cancer favors the
hypothesis of a step-wise progression of genetic and epigenetic abnormalities that eventually leads to the loss of
normal control mechanisms of cellular growth. Multiple
genetic and epigenetic hits influence oncogenes, tumor
suppressor genes, growth factors, and DNA repair genes,
266 Textbook of Lung Cancer
resulting in uncontrolled cell growth. Based on these
assumptions, a subcategory for smoke-damaged bronchial mucosa as an intermediate step in the pathway
from normal bronchial mucosa to squamous cell lung
cancer emerges by the finding of early molecular
changes. Epidemiology and early diagnosis could derive
benefit from such studies. One of the earliest changes is
the loss or inactivation of genetic material on the short
arm of chromosome 3 (3p). In lung cancer patients
with 3p changes in the tumor, 3p changes were also
detectable in non-malignant bronchial epithelium. The
loss of large portions of chromosomal material on 3p
gives way to inactivation of tumor suppressor genes,
including RARβ (retinoic acid receptor beta), RASSF1A
(Ras association domain family I), and FHIT (fragile histidine triad) gene (3p14.2).21 Another inactivation pathway occurs via epigenetic silencing by DNA promoter
hypermethylation. All these epigenetic and somatic
changes are progressively caused by smoking.22 Another
early alteration associated with increasing pack-years of
smoking is inactivation of tumor suppressor gene p16,
with consequent phosphorylation of the retinoblastoma
(Rb) protein and uncontrolled proliferation.23
Preneoplastic lesions of adenocarcinoma remain undefined. Based on morphologic findings, some adenocarcinomas might occur as a result of progression from
atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma.24 DNA histogram patterns of AAH are
intermediate between reactive hyperplasia of type II
pneumocytes and small-sized well-differentiated adenocarcinomas.25 Therefore, AAH could represent a
clonal cellular proliferation closely related to adenocarcinoma. Several genetic analyses revealed that up to
39% of AAH had k-ras mutations.26 However, none of
the tumors with EGFR mutations showed k-ras mutation simultaneously.27 EGFR mutation might be the
hallmark of malignant progression of AAH to invasive
adenocarcinoma. EGFR protein expression increased
significantly as lesions progressed from AAH to
BAC.28 The accumulation of multiple allelic losses as
well as p53, k-ras, and EGFR mutations may play
important roles in the multistage carcinogenesis of
adenocarcinoma.29
NEW IMAGING TECHNIQUES
PET with 18F-fluorodeoxyglucose (FDG) has recently
gained a top spot in the staging of lung cancer.30 PET
registered a superior performance in overall TNM
staging compared to magnetic resonance imaging
(MRI)31 in solid tumors. PET diagnostic accuracy will
increase dramatically with progress in gating techniques
and the development of new tracers. New tracers are
continually being tested, but a substitute for 18F-FDG is
far from clinical routine use. A new molecular imaging
probe, 18F-deoxyfluorothymidine (FLT), has been
developed. This is retained in proliferating tissues
through the enzyme thymidine kinase 1 (TK1), that
phosphorylates FLT to FLT-5 phosphate, which is
essentially trapped in tumor cells. However, compared
to FDG-PET, detection of primary and metastatic
NSCLC by FLT-PET is limited by the relatively low FLT
uptake of the tumor tissue.32 FLT-PET is unlikely to
provide more accurate staging information than FDGPET. Future studies should evaluate the use of FLT-PET
for monitoring the cellular apoptotic index in response
to chemotherapy. An FLT-PET scan acquired after the
first course of chemotherapy was useful for predicting
the efficacy of chemotherapy in advanced breast cancer.33
New receptor systems such as those using gastrin
and bombesin are being developed in the field of singlephoton tracers of SPET (single photon emission tomography). Also (99m)Tc-based agents might be useful to
identify hypoxia in cancer, angiogenesis, and apoptosis.
Dual-modality integrated imaging systems (SPET-CT
and PT-CT) allow us to improve the spatial definition
of areas of uptake, thus generating fusion images with
CT scanning data.
A newly developed high-energy probe (positron
emission probe, PEP), optimized for localizing PET
tracers in vivo, was tested successfully for preoperative
planning of the extent of neck dissection in patients with
head and neck cancer.34 With use of the PEP probe,
nodal metastases were identified in 20/21 patients with
a sensitivity of 95%.
An intriguing idea is to implement tracers aimed at
biologic targets such as EGFR and VEGFR. PET with
EGFR kinase-specific radiolabeled tracers could provide the means for imaging the heterogeneity of EGFR
expression and signaling activity in tumors before and
during therapy with EGFR TKIs.35
New gating techniques could help in detecting smaller
lung nodules with PET-CT imaging, especially in
patients with lung nodules detected during CT screening programs.
Another field of interest for PET is radiation therapy.
In the era of image-guided radiation therapy (IGRT),
target delineation could maximize efficacy while simultaneously decreasing toxicity by limiting radiation doses
The future 267
to the surrounding normal tissues. PET-CT has an
innovative potential in the evaluation of disease stage,
in target delineation for treatment planning, and in the
assessment of response to therapy.36
the execution of transbronchial biopsies (TBBs) with a
high diagnostic yield, almost twice that of flexible fiberoptic bronchoscopy under fluoroscopic guidance for small
peripheral pulmonary lesions beyond the optical reach
of the bronchoscope.40
STAGING
PROGNOSTIC FACTORS
The next revision of the current version of the TNM
staging system for lung cancer is under evaluation by a
special committee of the International Association for
the Study of Lung Cancer (IASLC). This will be a joint
effort with the American Joint Committee on Cancer
(AJCC) and the International Union Against Cancer
(UICC). A database with nearly 100 000 lung cancer
cases (both NSCLC and SCLC) originating from all over
the world, with a European predominance, is undergoing evaluation by a panel of experts. Final approval
from the UICC is expected to be effective in 2009.
Current American Thoracic Society (ATS) guidelines
for the staging of lung cancer suggest that contrast-enhanced CT should be considered the standard imaging
technique for the evaluation of the mediastinum.37
Lymph nodes with the short-axis diameter >1 cm on
CT must be considered malignant. However, CT is neither sensitive nor specific for detecting metastasis in the
mediastinum, since some benign nodes may be larger and
small lymph nodes may be malignant. A meta-analysis
showed that PET is more accurate than CT for mediastinal staging.38 Tissue proof of PET-positive mediastinal
nodes by mediastinoscopy is still recommended before
denying surgical resection. Less invasive procedures
such as bronchoscopic transbronchial needle aspiration
(TBNA) will be implemented in the future. A comparison of CT, PET, and direct real-time endobronchial
ultrasound (EBUS)-guided TBNA for detection of mediastinal lymph node metastases in 102 patients with
lung cancer39 showed a diagnostic accuracy of 60%,
72%, and 98%, respectively. EBUS-TBNA did not cause
any complications.
Standard flexible bronchoscopes used for diagnostic
or minimally invasive procedures cannot reach most
peripheral lung lesions due to the progressive narrowing branches of the bronchial tree. An ideal tool would
provide navigational information with real-time positioning of the tip of the forceps to reach for invisible
peripheral lesions. Electromagnetic navigation based on
virtual bronchoscopy and real-time three-dimensional
(3D) CT images allows an approach to the peripheral
lung masses. The SDBS (superDimension/Bronchus
system – superDimension, Hertzliya, Israel) safely allowed
So far the clinical staging system represents the standard for determining lung cancer prognosis. It is also
clear to every medical oncologist how, especially in the
adjuvant setting, there is a wide variety in prognosis on
an individual basis even within the same stage. Other
clinical and biochemical markers with more reliable
prognostic significance are badly needed. In stage I
NSCLC nearly 30% of patients will relapse after radical
surgical resection, and the ability to identify such subgroups of patients at higher risk for relapse may improve
health outcomes across the spectrum of disease.
Microarray technologies used to profile human cancers at the DNA, RNA, and protein levels have led to the
discovery of disease susceptibility genes, therapeutic
targets, and expression profiles predicting disease outcome and sensitivity or resistance to a given drug.
Genomics can be applied to lung cancer results from
gene expression arrays, single-nucleotide polymorphism (SNP) arrays, and high-throughput capillary
sequencing. Gene expression arrays offer the possibility
of simultaneous analysis of the transcription of several
thousands of genes in a semiquantitative manner, either
as cDNA or oligonucleotide arrays. Some profiling
scores are more accurate than others in defining lung
cancer based on the gene expression profiles.41–43 Pattern recognition software and clustering algorithms allow
identification of different groups of genes or tumor specimens with similar repertoires of expressed genes. Novel
histologic subtypes could be delineated with a direct
impact on prognosis and selection of the best treatment
options. Additionally, high-density SNP arrays allow
the detection of loss of heterozygosity (LOH), as well as
copy number changes and homozygous deletions.44
Mutations in the EGFR gene have been found using highthroughput sequencing. A consensus on such matters is
far from being reached.
The Lung Metagene Model predicted recurrence for
individual patients and was consistent across all early
stages of NSCLC, with an overall predictive accuracy of
almost 80%.45 Such predictive power could be of particular benefit in stage IA patients, actually excluded
from adjuvant protocols. If the risk for recurrence based
268 Textbook of Lung Cancer
on the genomic profile is believed to be high, adjuvant
chemotherapy could be proposed in a randomized
fashion to check for its real impact on survival.
In another model, microRNA expression analysis identified unique profiles, which could discriminate lung
cancer from non-malignant lung tissues. MicroRNA
expression profiles correlated with survival, including
stage I adenocarcinomas, hence they could be used as
diagnostic and prognostic markers of lung cancer.46
Genomic tools, as a strategy to refine prognosis and
to precisely select patients, should be utilized across all
stages. Data should be extensively collected and pooled
in a common database. It is of basic importance that the
results of all gene expression studies in lung cancer
should translate into a widely applicable clinical test to
facilitate early identification of patients at high risk in
routine daily practice. A new direction of research is to
identify the effects of mutations on gene expression patterns to clarify the molecular basis of oncogenic signaling and to develop drugs targeting these biomolecular
steps. Expression array data from a KRAS-mutant mouse
model of lung adenocarcinoma identified a KRAS mutation signature.47 Transferring that signature to human
adenocarcinomas correctly identified KRAS-mutant
lung tumors. Given the current lack of a potent, clinically available KRAS inhibitor, one intriguing possibility would be to find inhibitors against key mediators of
mutant KRAS function.
Cancer-specific copy number alterations and LOH
represent important changes found in lung cancer cells.
Amplified regions of the genome may include oncogenes, whereas deletions and regions of LOH may harbor
tumor suppressor genes. Techniques such as comparative genomic hybridization (CGH) and array-CGH are
rapidly evolving. Millions of SNP loci have now been
identified, making them good markers for studying
cancer genetics: arrays of 500 000 SNP loci are in progress. SNP arrays have been used successfully in genomewide screens for detecting LOH in lung cancer.48 The
use of SNP arrays has allowed the selection of regions
of copy number change, amplification (chromosomal
regions 12p11 and 22q11, Myc family) and homozygous deletion (CDKN2A and PTEN, chromosomes
3q25 and 9p23, containing arylacetamide deacetylase,
AADAC), succinate receptor 1 (SUCNR1), and protein
tyrosine phosphatase, receptor type D (PTPRD). It is a
fundamental aim to refine technologies so as to better
understand key molecular changes in NSCLC, to test
whether a gene that is overexpressed is also amplified
and/or mutated, and to define all the complex networks
of signaling pathways on which lung cancer cells rely to
proliferate. Both in vitro and in vivo models will facilitate the testing of specific targeted drugs in the different
subgroups of lung cancer created according to a molecular profile. Clinical trials should be planned to select
patients prospectively.
Protein microarrays may provide a map of known
cell signaling proteins. Identification of critical nodes,
or interactions, within the network is a potential starting point for drug development and, at the same time,
the design of individual therapy regimens.49 The availability of high-quality, specific antibodies or suitable
protein-binding ligands is the limiting factor for reliability of this technology. Post-translational modifications or protein–protein interactions of an individual
protein cannot be explained merely by measuring its
total concentration.
Circulating total DNA levels seem to correlate with
NSCLC stage; this strategy has the potential to assess
responses more accurately and quickly than radiologic
tests, and to confirm the prognosis of surgical resection
and therefore select patients for adjuvant therapy.50 Correlation of both total DNA baseline levels and temporal
trends during treatment with response to therapy and
overall survival is to be investigated in future studies.
RADIOTHERAPY
Stereotactic radiotherapy is a new and promising
approach to the treatment of early NSCLC or single
lung metastases. The consistency of the results, with
high local control rates of 80–100% and a very slight
incidence of symptomatic side-effects, is noteworthy.
Several authors who carried out hypofractionated stereotactic irradiation applied three to ten fractions, with
doses per fraction varying from 6 to 20 Gy.51,52 A recent
study used non-fractionated, single-dose irradiation (more
convenient for the patient) and obtained local control
rates of 90% with negligible side-effects. Two-year and
four-year survival rates were 63% and 39%, respectively,
with a median survival of 20 months. Stereotactic singledose irradiation could become an effective, non-invasive
alternative to conventional surgery in peripheral stage I
NSCLC.53
PHARMACOGENOMICS
It is quite evident in everyday practice how survival can
vary significantly between individual patients at the
same stage of disease. Thus there is an urgent need for
The future 269
factors to predict response to anticancer therapies.
These factors could be used prospectively to identify
subgroups of patients who would show a dramatic
response when treated with either standard chemotherapy regimens or targeted therapies, or a combination of
the two. Protocols designed to test the impact of a treatment driven by a tumor’s genetic profile represent the
next step of integration of clinical and basic research.
Increased expression of the ERCC1 (excision repair
cross-complementation group 1) gene is associated with
cisplatin resistance in a variety of human cancers including NSCLC.54 Therefore, low expression of ERCC1 by
the tumor could predict a benefit from cisplatin-based
chemotherapy. ERCC1 also seems to carry a prognostic
role per se, regardless of platinum therapy. In resected
patients with NSCLC, high ERCC1 expression predicts
a better survival; an intact DNA repair mechanism may
reduce the accumulation of genetic aberrations contributing to the malignant potential of cells. Future adjuvant
and neoadjuvant chemotherapy trials in NSCLC should
stratify patients according to their ERCC1 expression
levels. In advanced NSCLC patients treated with cisplatin plus gemcitabine, a response rate of 52% was seen in
tumors with low ERCC1 mRNA levels, while in those
with high ERCC1 levels the response rate was 36%. The
difference was not statistically significant; however, median
survival was 15 months for patients with low levels of
ERCC1 and only 5 months for those with high levels
(p <0.001).55 In a phase III trial 264 patients were randomized based on the ERCC1 levels: in the control arm
patients received docetaxel plus cisplatin, in the experimental arm they received either docetaxel plus cisplatin
if ERCC1 mRNA levels were low or docetaxel plus gemcitabine if ERCC1 levels were high. The response rate
for patients with low ERCC1 levels was 56% versus 40%
in the control arm (p = 0.02). When patients in the control arm were split according to the ERCC1 levels, those
with low ERCC1 levels had a response rate of 47% versus 26% in those with high ERCC1 levels. Time to progression and survival were significantly in favor of the
group with low ERCC1 levels.56
A recent retrospective report from 761 patients
within the adjuvant IALT trial showed that benefit from
cisplatin-based chemotherapy was associated with lack
of ERCC1, measured by immunohistochemistry (IHC)
as protein level in the tumor. On the other hand, among
patients who did not receive adjuvant chemotherapy,
high expression of ERCC1 was a positive predictive factor for survival.57
The ribonucleotide reductase M1 (RRM1) gene encodes
the regulatory subunits of RR, the molecular target of
gemcitabine. Lower expression of RRM1 predicted longer survival in gemcitabine-treated NSCLC patients.58
Moreover, low levels of RRM1 improved the prognosis
in NSCLC, especially if coupled with low ERCC1 levels.
The ERCC1 and RRM1 genes should be looked at as
reliable candidates for customized chemotherapy in
NSCLC patients treated with cisplatin/gemcitabine.59
Tumoral RRM1, as well as ERCC1 expression, is a major
predictor of response to cisplatin/gemcitabine.60
BRCA1 is a component of multiple DNA repair
pathways and functions as a differential regulator of
chemotherapy-induced apoptosis. BRCA1 abrogates
the apoptotic phenotype induced by a range of DNAdamaging agents, including cisplatin and etoposide, while
inducing dramatic responses to a range of antimicrotubule agents, including paclitaxel and vinorelbine.61 BRCA1
mRNA expression closely correlates with ERCC1 mRNA
expression, and predicts a more favorable outcome in
locally advanced NSCLC patients treated with cisplatin/
gemcitabine followed by surgery; median survival has
not been reached in patients with the lowest BRCA1
mRNA levels.62 Elevation of ERCC1 and BRCA1 is closely
related to high levels of RRM1, which is one of the principal mechanisms of resistance to gemcitabine.
Pooled data indicate that K-ras mutations could be
found in 20% of NSCLC, mainly in adenocarcinoma,
and predicted a poorer prognosis. Adjuvant chemotherapy with vinorelbine plus cisplatin, however, did not
confer any survival advantage in patients whose tumors
had K-ras mutations.63 K-ras mutations also have a role
in predicting lower response to EGFR tyrosine kinase
inhibitors (TKIs), such as erlotinib.64 Time to progression and survival were shorter for patients with K-ras
mutations receiving erlotinib than for those receiving
chemotherapy alone.
A proportion of NSCLCs shows overexpression of
estrogen and progesterone receptors; cross-talk between
estrogen receptors and EGFR pathways is another new
field of research. In NSCLC, EGFR expression is downregulated in response to estrogen and upregulated in
response to fulvestrant (an estrogen receptor antagonist), suggesting that the EGFR pathway is activated as
a consequence of estrogen depletion.65 Expression of
progesterone receptors was more frequently seen in
males, stage I disease, and adenocarcinomas, and had a
favorable prognostic impact.66
Thymidilate synthase (TS) is an enzyme involved in
DNA synthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine
monophosphate (dTMP).67 High TS levels are associated with poor prognosis or progression of disease stage
270 Textbook of Lung Cancer
in gastrointestinal, breast, and non-small cell lung carcinomas.68–70 TS is the target enzyme of 5-fluorouracil
(5-FU) and its expression is significantly related to the
response to 5-FU-based chemotherapy in gastric, colorectal, and breast carcinomas.71 Pemetrexed is a potent
inhibitor of TS, with a lower inhibitory potential for
glycinamide ribonucleotide formyltransferase (GARFT).
Pemetrexed is approved as a second-line chemotherapy
in advanced NSCLC and is currently undergoing phase
III clinical trials to be introduced as a first-line, platinumbased combination. Developments in the understanding of the mechanisms of resistance to pemetrexed and
the role of TS will likely improve its efficacy in selected
patients.
In vitro drug sensitivity data, coupled with Affymetrix microarray data, facilitated the development of gene
expression signatures that predicted sensitivity to individual chemotherapeutic agents. Each signature was
validated with response data from an independent set
of cell lines and was also able to predict sensitivity to
multidrug regimens.72 The development of gene
expression profiles that can predict response to commonly used cytotoxic agents is the key to maximizing
the efficacy of these agents and to finding the right way
to use them in combination with existing targeted
therapies.
Prospective clinical trials are still necessary to assess
whether the expression of RRM1, ERCC1, TS, and other
markers remains the same through all stages of disease.
Other key issues for the near future include better definitions of cut-off levels for such markers, the feasibility
of taking and immediately freezing core needle biopsies
for gene expression analysis, and research into new
molecular pathways that modulate response to anticancer agents.
TARGETED THERAPIES
Continuous progress in the understanding of tumor
biology has led to the identification of molecular pathways that drive tumor growth. Each step in the abnormal
signaling pathways represents a unique target for new
anticancer therapies. Future strategies will require the
selection of patients based on molecular targets peculiar
to each tumor and to each individual subject.
Agents targeting the EGFR family and the angiogenesis
process are the most promising options. The next
step forward will be achieved by successfully combining
such targeted therapies or by finding the most active
sequencing with chemotherapy regimens. Agents are
available which are able to block different growth pathways.
Investigations in several laboratories have demonstrated evidence of negative interactions between chemotherapeutic agents and EGFR TKIs in vitro and in
vivo. A schedule-dependent interaction between erlotinib and other chemotherapeutic agents active in the
G2/M phase (paclitaxel, vinblastine, and bortezomib) in
human NSCLC cell lines (H322 and A549) has been
demonstrated. In fact, pretreatment with erlotinib
caused G1 arrest and abrogated the action of chemotherapy, resulting in decreased cytotoxicity and decreased
apoptosis.73 Based on these results and those discussed
above, a model of sequence-specific interaction should
be evaluated. Intermittent dosing of chemotherapy and
EGFR TKIs was found to be superior to a continuous
concurrent dosing schedule.74
Data from interactions of chemotherapy and monoclonal antibodies are less clear, although there seems to
be an addictive effect. In the first-line treatment of
advanced stage NSCLC new clinical trials must be
designed with sequential schedules, such as administering chemotherapy for four cycles, followed by randomization to either an EGFR TKI or observation/
chemotherapy. One such study is a large phase III trial
in which patients with advanced stage NSCLC achieving disease control after platinum-based chemotherapy
are then randomized to erlotinib or placebo as maintenance therapy. A second trial will compare erlotinib
with pemetrexed or docetaxel in the second-line setting, and a third trial will compare erlotinib plus bevacizumab (a monoclonal antibody to vascular endothelial
growth factor, antiVEGF) with bevacizumab alone in
the first line as maintenance therapy after chemotherapy. Importantly, however, none of these trials will
select patients based on EGFR mutational status or
FISH copy number.
An interesting newer approach considers the combination of bevacizumab with other targeted therapies.
Results from a phase I/II study of bevacizumab plus
erlotinib in previously treated stage IIIB/IV NSCLC patients
showed encouraging median survival prolongation.75
VEGF can also play an important role in the response
to radiotherapy by enhancing endothelial cell survival,
a critical factor determining tumor radiation response.
Inhibition of VEGF impacts on tumor oxygenation and
proliferation. Preclinical studies of ZD6474 and other
antiangiogenic agents plus radiation therapy demonstrated the potential synergistic effect of the two modalities, pending the optimization of scheduling of these
combinations.76
The future 271
Identifying optimal dosing and scheduling of targeted therapies is another key issue. The availability of
surrogate markers of treatment effect could therefore
help in finding the right dosing and schedule. Plasma
VEGF level is one such marker. Increases in plasma
VEGF after administration of antibodies to VEGF receptors seem to be specific to antibodies, and were not
observed following VEGFR TKIs.77 Circulating endothelial progenitor cells (CEPCs), as well as markers released
by damaged endothelial cells (E-selectin and VCAM),
could be investigated.78 The normalization of elevated
CEPC levels after thalidomide treatment indicates the
importance of CEPC as a surrogate marker of response
to antiangiogenic therapy. In NSCLC patients, pretreatment circulating CEPC levels were significantly higher
compared with healthy controls, and a single measurement of CEPC by flow cytometry could be a useful tool
to predict the outcome of chemotherapy.79 Patients
with lower pretreatment CEPC levels respond better to
chemotherapy, presumably due to more ‘normal’ tumor
vessels. Patients with high pretreatment CEPC levels
could be treated with anti-VEGF therapy to lower CEPC
(i.e. ‘normalizing’ the vasculature) before shifting to
chemotherapy.
Protein kinases regulate almost all cellular processes
and represent key enzymes in the vascular endothelial
growth factor signaling cascade that can ultimately
induce tumor angiogenesis. The type C family of protein kinases (PKC) might become an important molecular target for cancer chemotherapy. PKC activation can
trigger signaling through the ras/extracellular signalregulated kinase (ERK) pathway, which may be involved
in the control of cellular proliferation and apoptosis.
PKC might regulate the phosphatidylinositol 3-kinase
(PI3K)/AKT pathway: cross-talk between PKC and the
PI3K/AKT pathway may be an attractive mechanism by
which PKC influences the apoptotic response. Enzastaurin, a potent novel PKC inhibitor, disrupts the
intrinsic phosphotransferase activity of PKC-β,80 and it
has been tested in human tumor xenografts, where it
decreased microvessel density and VEGF expression.81
Additionally, enzastaurin directly suppresses phosphorylation of GSK3β, ribosomal protein S6, and AKT,
thus supporting the notion that enzastaurin elicits an
antitumor effect by suppressing signaling through the
AKT pathway, directly inducing tumor cell death and
suppressing tumor cell proliferation. Data from a phase
I study indicate that enzastaurin 525 mg once daily is
the recommended phase II dose: evidence of early activity was seen with significant stable disease in a variety
of heavily pretreated solid cancers, including NSCLC.82
Given the distinct toxicity profile and molecular targets,
enzastaurin has the potential to be used in combination
with cytotoxic agents to enhance tumor cell killing.
VACCINES
NSCLC is a non-immunogenic cancer.83 However, preliminary results of recent vaccine studies designed
to enhance tumor antigen recognition have demonstrated encouraging efficacy in subsets of patients.84,85
Belagenpumatucel-L is a non-viral gene-based allogeneic tumor cell vaccine that demonstrates enhancement
of tumor antigen recognition as a result of transforming
growth factor beta-2 inhibition. In advanced NSCLC
patients at dose levels of 2.5 × 107 cells/injection, it
produced a surprising estimated two-year survival rate
of 47%. A correlation of positive clinical outcome with
induction of immune enhancement of tumor antigen
was observed.86
CONCLUSIONS
Targeted therapies offer a unique chance to strike cancer cells in a selective way. Targeting multiple pathways
simultaneously will be a way to overcome tumor growth
through alternate mechanisms. It is not clear which
agents should be combined in multitarget regimens. A
combination of COX-2 inhibitors (celecoxib) and gefitinib
in an unselected population of chemotherapy-naive
patients with advanced NSCLC had a lower response
rate and overall efficacy compared with historical controls of chemotherapy.87 An innovative strategy could
be to design an induction treatment with TKIs and
check for efficacy in a three to four week span to look
for sensitive patients. The correlation of EGFR mutations with responsiveness to small-molecule inhibitors of
EGFR further supports this idea. However, testing availability in everyday practice and costs of both genetic
tests and newer targeted therapies are an open issue.
Approaches that can measure early changes in the tumor,
such as functional imaging studies like PET, may be one
effective way to predict a response to therapy.
Novel therapeutic strategies should include maintenance treatment with targeted therapies and implementation of pharmacogenomic profiles in chemotherapy
clinical trials. Functional maps depicting the state of
key pathways within each patient’s tumor cells will
become the starting point to engineer individualized
therapies.
272 Textbook of Lung Cancer
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Appendix: Chemotherapy
Cristiana Sessa, Heine H Hansen
Contents • Glossary • Abbreviations • Alkylating agents • Platinum compounds • Antitumor
antibiotics • Antimicrotubule agents: Vinca alkaloids and taxanes • Topoisomerase II inhibitors:
Anthracyclines, anthracenediones, and epipodophyllotoxins • Topoisomerase I inhibitors:
Camptothecines • Antimetabolites: Antifolates and pyrimidine analogs • Miscellaneous agents
• Targeted therapy • Radiochemoprotectants • Growth factors and supportive treatment
GLOSSARY OF TERMINOLOGY USED IN CLINICAL
PHARMACOKINETICS
Absolute bioavailability is the fraction of drug
absorbed upon extravascular administration in comparison with the dose administered.
Area under the curve (AUC•) is a measure of the
quantity of unchanged drug absorbed and in the body,
calculated as the integral of drug plasma or blood levels
over time from zero to infinity.
Bioavailability (F) is the fraction of drug systematically
available, defined as both the fraction of the administered dose absorbed and the fraction of absorbed
dose reaching systemic circulation in the presence of a
first-pass effect.
Central compartment is the sum of all body regions
(organs and tissues) in which the drug concentration
is in instantaneous equilibrium with that in blood or
plasma. Blood or plasma is always part of the central
compartment.
Compartment is a mathematical entity that can be
described by a definite volume and a concentration of
drug contained in it. In pharmacokinetics, experimental data are explained by fitting them to compartmental
models.
Cumulative urinary excretion curves are plots of the
actual cumulative amounts of drug and/or its metabolites
excreted into urine versus time after administration.
Disposition is the loss of drug from the central compartment due to distribution into other compartments
and/or elimination and metabolism.
Dose or concentration dependence refers to a change
of one or more of the pharmacokinetic processes of
absorption, distribution, metabolism and excretion with
increasing dose or concentration.
Elimination (biological) half-life (t1/2) of a drug is
the time required for the drug levels (in blood,
plasma or serum) to decline by 50% after equilibrium
(between plasma and tissue) is reached. Loss of drug
from the body, as described by the biological half-life,
means the elimination of the administered parent drug
molecule (not its metabolites) by urinary excretion
(renal clearance), metabolism (metabolic clearance) or
other pathways of elimination (lung, skin, etc.). It
includes t1/2α (distribution) and t1/2β (terminal). For
drugs with a high tissue distribution (anthracyclines, platinum compounds), t1/2 also includes t1/2γ, which reflects
accumulation and slow release from third spare compartment. t1/2 may be influenced by dose, variation in
urinary excretion (pH), intersubject variation, age, protein binding, concomitant drugs, and liver and renal
functions.
Enzyme induction is an increase in enzyme content or
rate of enzymatic processes resulting in faster metabolism of a compound. It may increase clearance and
decrease biological half-life.
Enzyme inhibition is a decrease in the rate of metabolism of a compound, usually by competition for an
enzyme system. It may increase biological half-life and
decrease clearance of a drug.
First-pass effect is the phenomenon in which some
drugs are already metabolized (not chemically degraded)
between the site of absorption and reaching systemic
circulation. It may occur in the gut wall, mesenteric
blood and/or the liver, upon oral and deep rectal
administration.
*Adapted from Sessa C, Anticancer agents. In: Textbook of Medical Oncology, 2nd edn (Cavalli F, Hansen HH,
Kaye SB, eds). Martin Dunitz: London, 2000.
276
Textbook of Lung Cancer
Hepatic clearance (CLH) is the hypothetical volume of
distribution in liters of the unmetabolized drug that is
cleared in one minute via the liver. It depends upon
intrinsic hepatic clearance and liver blood flow.
Loading dose, Priming dose or Initial dose is the dose
used in initiating therapy so as to rapidly achieve therapeutic concentrations. The need for a loading dose
depends upon biological half-life, dosing interval and
therapeutic concentration to be achieved.
Mean residence time (MRT) is the average time that
the drug stays in the body or plasma.
Non-linear kinetics or Saturation kinetics refers to a
change in one or more of the pharmacokinetic parameters during absorption, distribution, metabolism or
excretion caused by saturation or overloading because
of increasing doses.
Peak concentration (Cmax) is the maximum concentration of a drug achieved in plasma or in blood after drug
administration.
Peripheral compartment is the sum of all body regions
(i.e. organs, tissues or parts of them) to which a drug is
eventually distributed, but is not in instantaneous equilibrium with the central compartment.
Plasma clearance (CL) can be defined as the volume of
plasma that is completely cleared of drug per unit time.
Protein binding is the phenomenon that occurs when a
drug combines with plasma protein to form a reversible
complex. Some drugs can be displaced from protein
binding by other compounds of higher affinity for the
protein-binding sites. Protein binding is of clinical significance (e.g. with regard to displacement, volume of
distribution and metabolism) when it exceeds 80–90%.
It is the unbound drug that is in equilibrium with the
biophase (FF).
Renal clearance (CLR) is the hypothetical plasma volume in liters (volume of distribution) of the unmetabolized drug that is cleared per unit time via the kidney.
Renal clearance is affected by renal blood flow, urinary
pH, and the net effects of tubular reabsorption and
secretion.
Steady-state concentration (Css) is the concentration
of drug in blood and tissue upon multiple dosing when
input and output are at equilibrium or during a constant-rate intravenous infusion.
Time to peak concentration (Tmax) is the time until
Cmax is reached from drug administration.
Total body clearance (CLb) is an overall measure of
the body’s drug removal rate. CLb is the result of all drug
removal processes, including renal clearance of the
unchanged drug and metabolic clearance. CLb is the
hypothetical volume of distribution in liters of the unmetabolized drug that is cleared per unit of time (l/min or
l/h) by any pathway of drug removal (renal, hepatic and
other pathways of elimination); it is a proportionality
constant relating absorbed dose and steady-state blood,
plasma and serum concentration.
Volume of distribution (Vd) is the hypothetical volume
of body fluid that would be required to dissolve the total
amount of drug at the same concentration as that found
in blood or plasma. It is a proportionality constant that
relates the amount of drug in the body to the serum or
plasma concentration.
ABBREVIATIONS
Drugs
5-CHO-FH4: 5-formyltetrahydrofolate (leucovorin)
5-FU: 5-fluorouracil
Ara-C: cytarabine
ATRA: all-trans-retinoic acid
BLM: bleomycin
CCNU: lomustine
CPT-11: irinotecan
CTX: cyclophosphamide
dFdC: difluorodeoxycytidine (gemcitabine)
DHAD: mitoxantrone
EPI: epirubicin
FT: ftorafur
HMM: hexamethylmelamine
HN2: mechlorethamine
HU: hydroxyurea
IFO: ifosfamide
LV: leucovorin
MGA: megestrol acetate
MMC: mitomycin C
MPA: medroxyprogesterone acetate
MTX: methotrexate
VCR: vincristine
VLB: vinblastine
VM-26: teniposide
VP-16: etoposide
Other abbreviations
ADA: adenosine deaminase
ADCC: antibody-dependent cell-mediated cytotoxicity
Appendix: Chemotherapy
AICAR: aminoimidazole carboxamide ribonucleotide
transformylase
ANC: absolute neutrophil count
AP: alkaline phosphatase
AR: androgen receptor
Ara-CTP: cytarabine triphosphate
Ara-U: uracil arabinoside
AST: aspartate transarinase
AUC: area under the curve, concentration X time
BM: bone marrow
CDC: complement-dependent cytotoxicity
CdR kinase: deoxycytidine kinase
CH2-FH4: reduced-folate cofactor
CHF: cardiac heart failure
CI: continuous infusion
CL: clearance
CNS: central nervous system
COPD: chronic obstructive pulmonary disease
Cr: creatinine
CR: complete remission
CSF: cerebrospinal fluid
Css: steady-state concentration
Cyd deaminase: cytidine deaminase
CYP450: cytochrome P450
dATP: deoxyadenosine triphosphate
dCTP: deoxycytidine-5′-triphosphate
dFdCTP: difluorodeoxycytidine triphosphate
dFdU: difluorodeoxyuridine
DHFR: dihydrofolate reductase
DL: dose-limiting
dNTP: deoxynucleotide triphosphate
DPD: dihydropyrimidine dehydrogenase
dTTP: deoxythymidine triphosphate
DVT: deep venous thrombosis
F-DHU: 5-fluorodihydrouracil
FdUMP: 5-fluoro-2′-deoxyuridine 5′-monophosphate
FH4: reduced folates
FPGS: folylpolyglutamate synthethase
FUMP: 5-fluorouridine 5′-monophosphate
FUTP: 5-fluorouridine 5′-triphosphate
GAR: glycinamide ribonucleotide transformylase
G-CSF: granulocyte colony-stimulating factor
GFR: glomerular filtration rate
GM-CSF: granulocyte–macrophage colony-stimulating
factor
H2O2: hydrogen peroxide
HAI: intrahepatic arterial infusion
277
HGPRTase: hypoxanthine–guanine phosphoribosyl
transferase
HSR: hypersensitivity reaction
HZ: herpes zoster
IFN: interferon
IL: interleukin
i.t.: intrathecal
LFTs: liver function tests
LVEF: left ventricular ejection fraction
MDR: multidrug resistance
mFBP: membrane folate-binding protein
MMR: mismatch repair
MTD: maximum tolerated dose
MTIC: 5-(3-methyl-1-triazeno)-imidazole-4-carboxamide
NAD: nicotinamide adenine dinucleotide
N&V: nausea and vomiting
NSAID: non-steroidal anti-inflammatory drug
NV: normal value
O−2: superoxide
O6-AT: DNA-O6-alkylguanine-DNA alkyltransferase
OH: hydroxyl radical
PALA: N-phosphonocetyl-l-aspartate
PB: premature beats
PBSC: peripheral blood stem cell support
PDGF: platelet-derived growth factor
PE: pulmonary embolism
PEG: polyethylene glycol
P-gp: P-glycoprotein
PK: pharmacokinetics
PKC: protein kinase C
plt: platelets
PRPP: phosphoribosyl pyrophosphate
PS: performance status
PT: prothrombin time
pts: patients
PTT: partial thromboplastin time
RAR: retinoic acid receptor
RBC: red blood cells
RIA: radioimmunoassay
RNR: ribonucleotide reductase
RT: radiotherapy
TE: thromboembolic
Topo: topoisomerase
TS: thymidylate synthase
VOD: veno-occlusive disease
WBC: white blood cells
PO well absorbed;
biphasic plasma disappearance with T1/2β of
4–6.5 h after 6–80 mg/
kg; renal excretion of
metabolites; high degree
of interpt. Variation in
metabolism; only CTX
measured in CSF.
Hepatic CYP450
activation to highly
reactive metabolites
(acrolein: bladder
irritant; phosphoramide mustard:
alkylating moiety)
causing DNA-interstrand cross-links.
Cyclophosphamide
(CTX) Endoxana®
Cyclic phosphamide
ester of HN2.
Special populations
Renal impairment
Cr CL <20 ml/min: ↓
dose 50–75%.
Chemical transformation
into highly reactive
compounds, rapidly
bound to tissues; degradation by spontaneous
hydrolysis; PK not
studied.
Pharmacology and dose
modifications
Prototype of bifunctional alkylating
agent: covalent bond
of the alkyl group to
N7 of guanine with
formation of DNAinterstrand crosslinks between two
guanines located in
the opposite strands.
Mechanism of action
Meclorethamine (HN2)
Mustargen®
Nitrogen mustard
Name, chemistry, relevant
features
ALKYLATING AGENTS
With CYP450
inducers: potential but of
unknown clinical
relevance (barbiturates) or
blockers (glucocorticoids);
detoxification
with MESNA.
Drug interactions
Toxicity
IV HD: 7000 mg/m2
(MTD) (IV hydration +
MESNA).
Thrombocytopenia;
SIADH (more common
at > 50 mg/kg); cardiotoxicity (↑ incidence in
case of prior anthracyclines, large single
infusions, glutathionedepleting agents).
Local vesicant on
Neutropenia and
extravasation.
thrombocytopenia
In case of leakage:
(after about 8 days,
infiltration of the area
for 10–20 days); acute
with sterile isotonic Na severe prolonged N &
thiosulfate (1/6 molar)
V; phlebitis; rare
and application of ice
severe allergic reaccompresses for 6–12 h. tions; maculopapular
IV: 0.4 mg/kg (10–12
rash.
2
mg/m ) every 4–6
weeks; 6 mg/m2 days 1
and 8 every 4 weeks
(MOPP).
PO: 50–100 mg/m2
DL neutropenia after
8–14 days, recovering
daily
within 10 days; N & V
2
(delayed with IV
IV: 1000–1500 mg/m
therapy); alopecia;
every 3 weeks
hemorrhagic cystitis
(prevented by adequate
pre- and
posthydration).
Route, schedule, and
recommendations
278
Ifosfamide (IFO)
Mitoxana®
Analogue of CTX;
oxazophosphorine HN2.
In comparison with
CTX, slower hepatic
activation to acrolein
and active ifosforamide mustard
(which causes
DNA-interstrand
cross-links) and
higher proportion of
inactive dechloroethylated metabolites.
Special populations
Renal impairment
Cr CL < 20 ml/min ↓
dose 50–75%.
High degree of interpt.
intrapt. variability of PK
and metabolism. T1/2
15 h, 60% of dose as
unchanged drug in urine
after single doses of 5 g/
m2.
Induction of IFO metabolism after 3 days of IV
bolus or CI treatment
with increase of CL due
to production of dechloroethylated species;
decreased urinary
fraction (12–18% of
dose) of unchanged IFO
after repeated doses.
Comparable serum AUCs
and urinary fractions of
IFO and metabolites after
IV bolus and CI administration; no effect of DXM
on IFO metabolism.
see CTX
With nephrotoxic
drugs: (DDP) ↑
renal damage
With CNS active
agents: (including
narcotics, some
antiemetics): ↑
CNS toxicities,
methylene-blue to
reverse and
prevent CNS
toxicities.
IV HD (CI): 3–4 g/m2
on days 1–4 (MTD).
Adequate hydration
before, up to 72 h
after to avoid hemorrhagic cystitis.
IV: short (1–3 h inf.)
or CI: 1.2–1.5 g/m2
days 1–3 or days 1–5
every 3–4 weeks; 24 h
CI: 5 g/m2.
(Continued)
DL hemorrhagic
cystitis prevented with
hydration and
MESNA; 50% myelosuppression with
cumulative anemia;
>50% N & V; >80%
alopecia; 12% CNS
toxicity with confusion, lethargy, seizures, hallucinations,
possibly due to
inactive metabolites, ↑
CNS toxicity in
elderly/pts with renal
impairment; 60%
nephrotoxicity
(tubular), ↑ risk in
children.
Similar toxicities, but
of ↑ incidence
and degree.
279
Toxicity
PO: N & V if given
undiluted; in case of V
within 1 h, redose IV.
False ↑ of urinary
chetones.
HSR with skin reaction, itching, edema,
rare anaphylaxis.
Route, schedule, and
recommendations
IFO IV short infusion:
60% daily total dose
divided in 3 doses
(each 20%) 15 min
before (always IV), 4
and 8 h later (40%
single dose if given
PO).
IFO CI: same equal
dose (directly mixed),
continue up to 12 h
after the end of IFO.
CTX-HD (>10 mg/kg)
2–3 h infusion: 100%
daily total dose in
repeated doses each
20% total dose, first
dose always IV 15 min
before CTX, then every
6 h from start up to
24 h from end.
Drug interactions
Incompatible in
solution with DDP;
does not affect the
antitumor activity
of other cytotoxic
agents.
Caution
↑ risk of urinary
toxicity in pts with
prior pelvic RT,
urinary infection,
and prior hemorrhagic cystitis.
Pharmacology and dose
modifications
Dimerization in blood to
the inactive disulfide
dimesna, reduced back to
mesna in renal tubules
and excreted in urine;
10% protein bound.
40% and 30% urinary
excretion of free-thiol
mesna after IV and PO
administration; lower but
more prolonged (between
12 and 24 h) urinary
excretion of free-thiol
mesna after PO administration than IV.
Mechanism of action
Selective urinary tract
protectant for oxazophosphorine-type
alkylating agents by
binding of the SH
moiety to acrolein.
Name, chemistry, relevant
features
Mesna
Sodium mercaptoethane
sulfonate
Uromitexan®
IV formulation.
280
Polyfunctional
alkylating agent with
three aziridine
groups. Intracellular
release of aziridine
and generation of
ethylenimonium ions
acting as monofunctional alkylating
agents; the different
functional groups
induce DNA-interstrand cross-links.
Still unknown,
possibly DNA alkylation; structurally
similar to triethylenemelamine.
Thiotepa
N, N′, N″-triethylenethiophosphoramide; can be administered by any parenteral route.
Hexamethylmelamine
Altretamine
Hexalen®
Triazene ring with dimethylamino groups at each of the
three carbons.
Ethylenimines
40% protein bound; rapid
activation by CYP450 to
main metabolite TEPA,
less cytotoxic and with
longer terminal T1/2 (5 h);
24% of dose excreted in
24 h urine. Possible
metabolic saturation at
highest doses studied
(6–7 mg/kg). Advantages
of IT over IV administration still to be verified.
After IV, CSF levels
equivalent to those in
plasma.
Special populations
Liver impairment
No guideline available but
use with caution.
>90% protein bound;
variable PO absorption
with T1/2 of 0.5–3 h. Rapid
demethylation by
microsomal CYP450;
T1/2β 3–10 h; 60–70% of
dose in 24 h urine as
metabolites.
IV bolus: 0.3–0.4
mg/kg every 1–4 weeks
IV HD: 500–1125 mg/m2
(MTD: 1000 mg/m2)
Intrapleural, intrapericardial: 60 mg at ≥1 week
interval.
Intravesical: 30–60 mg/
week ×4.
IT: 15 mg at ≥1 week
interval.
PO: single agent, 260
mg/m2 on days 1–14
every 4 weeks; combination, 150–200
mg/m2 on days 1–14
every 4 weeks (four
divided daily doses).
Inhibition of
pseudocholinesterase
activity with ↑ effect
of succinylcholine.
↑ absorption from
body cavities in
presence of infiltration/inflammation of
mucosa
(radiotherapy).
With CYP450
inducers: (phenobarbitone) with ↓
antitumor effect.
With concomitant
IMAO: severe
orthostatic hypotension.
(Continued)
DL N & V ↓ if
taken after meals;
cumulative CNS
somnolence,
mood disorders,
hallucinations,
dizziness; peripheral neuropathy
mainly sensory;
reversible mild
leukopenia.
Dose related and
cumulative
myelosuppression
with short WBC
and longer Pt
nadir; DL
mucositis,
hyperpigmentation of skin,
hepatotoxicity;
confusion,
somnolence. Rare
myelosuppression.
Lower abdominal
discomfort,
bladder irritability.
281
Glucosamine-1methyl nitrosourea;
water soluble.
Streptozocin
Zanosar®
Chloroethylcyclohexylnitrosourea.
CCNU
Lomustine®
Nitrosoureas
Name, chemistry,
relevant features
DNA methylation;
carbamoylation of
proteins through
isocyanate molecules; inhibition
of O6-AT; inhibition of key
enzymes in gluconeogenesis.
Mechanism of action
Special populations
Renal impairment
Cr CL <25 ml/min: ↓
dose by 50–75%.
Rapid and extensive
metabolism; no intact
drug after 3 h; prolonged
T1/2 of metabolites.20% of
dose in 24 h urine as
metabolites; BBB rapidly
crossed.
Rapid absorption,
decomposition and
metabolism in liver with
parent drug never
detectable; Cmax of
metabolites within 3 h.
50% of dose in 12 h
urine as degradation
products; >30% plasma
levels in CSF.
Pharmacology and dose
modifications
↑ risk of nephrotoxicity with potentially
nephrotoxic drugs; ↑
risk glucose intolerance with corticosteroids;↑ effect of
DNA-reactive anticancer agents through
inactivation of 06-AT;
prolongation of the
T1/2 of DOX requiring
its dose reduction.
Drug interactions
Toxicity
Delayed (after 3–6
weeks) potentially
cumulative myelosuppression; acute N & V;
mild reversible hepatic
toxicity; ↑ risk of second
malignancy after longterm therapy.
Rare, cumulative (after
1100 mg/m2) pulmonary
fibrosis, possible delayed
onset (>10 years after) in
cured children having
received cranial RT.
Local vesicant on
DL cumulative nephroextravasation.
toxicity due to tubular
damage with proteinuria,
IV (30–60 min inf.):
glycosuria, and hyposingle agent: 1 g/m2 every
phosphatemia; acute
week ×4–6 weeks with
severe cumulative
4-week rest; combination;
N & V; occasional
500 mg/m2 on days 1–5
diarrhea and hepatoxicity
every 6 weeks.
with ↑ LFTs and hypoWarning
albuminemia; acute
Adequate hydration
hypoglycemia; burning
before and after each
pain in the vein; mild
course and monitoring of myelosuppression and
renal function (serial
hepatotoxicity.
urinalysis for proteinuria).
PO: 100–130 mg/m2
(single agent) every 6–8
weeks on empty stomach.
Route, schedule, and
recommendations
282
Imidazotetrazine
derivative; analog
of DTIC; methyl
derivative of
mitozolamide.
Temozolomide
Temodal®
Imidazotetrazines
Prodrug; converted
to cytotoxic MTIC
through chemical
process (instead of
metabolic activation
as for DTIC). ↑
induction of
O6-alkylguanine
adducts with
depletion of O6-AT;
schedule-dependent antitumor
activity.
Special populations
Renal impairment
No guideline available but
caution in pts with severe
impairment.
100% F reduced by food,
rapidly absorbed within 1 h;
T1/2β 1.8 h, linear PK. Wide
tissue distribution; crosses BBB
(30% ratio CSF/plasma AUC).
No accumulation with daily
dosing; clearance not affected
by anticonvulsants (with
exception of valproic acid), H2
blockers, barbiturates, DXM but
5% lower in women with
greater myelosuppression.
Possible synergism
with antitumor
agents with similar
mechanism of
action to deplete
O6-AT; possible
synergism with
ionizing radiations.
(Continued)
PO: 150–200 mg/m2 on days DL myelotoxicity
(mainly neutropenia
1–5 every 4 weeks (fasting,
and thrombocytopenia)
single-dose).
with delayed nadir >20
Heavily pretreated pts: 150
days and recovery in
mg/m2 on days 1–5 every 4
7–14 days; 50%
weeks; non-heavily pretreated
N & V (severe 10%);
adult and pediatric pts: 200
30% fatigue and
mg/m2 on days 1–5 every 4
malaise.
weeks. Dose reductions by
50 mg/m2 daily according to
ANC/Pt nadirs, do not
reduce below 100 mg/m2.
283
Special population
Age
↑ risk neurotoxicity
in >65 years due to ↓
renal function.
Renal impairment
Cr CL 50–70 ml/min:
use Mannitol and
increase hydration to ↑
diuresis.
Cr CL <50 ml/min: use
with caution.
Could delay excretion of
drugs eliminated through
kidneys (MTX, BLM,
IFO).
90% protein bound;
active species produced
within the cell by
aquation hydrolysis.
Triphasic disappearance
of total platinum with
T1/2γ of 5.4 days and
high tissue distribution.
90% renal excretion
mainly by glomerular
filtration; 40% of dose
excreted in 24 h urine;
poor CSF penetration.
DNA binding of
aquated species
with formation of
DNA inter-/
intrastrand crosslinks; binding to
SH groups of
critical enzymes.
Mechanisms of
resistance include
↓ cellular drug
accumulation,
cytosolic inactivation by thiol-containing
compounds,
enhancement of
DNA repair,
overexpression of
some proto-oncogenes and loss of
DNA MMR
enzymes.
Cisplatin (DDP)
Cis-diamminedichloroplatinum (II)
Inorganic planar coordination
complex.
IV (30–60 min inf.):
standard dose
50–100 mg/m2 every
3 weeks; 20 mg/m2
on days 1–5 every 3
weeks, with pre-/
posthydration to ↑
diuresis and prevent
renal toxicity.
Route, schedule, and
recommendations
With taxanes: ↑ incidence
of peripheral neuropathy. HD: 120 mg/m2
single day every 3
weeks, 40 mg/m2 on
days 1–5 every 3
weeks (with hypertonic saline; nephroprotective agents).
IP: 90–270 mg/m2
(with pre-/posthydration).
With concomitant
SH-containing agents
(sodium thiosulfate,
amifostine, glutathione):
↓ renal toxicity.
With concomitant
nephrotoxic drugs
(aminoglycosides,
amphotericin B): ↑ renal
toxicity.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant features
PLATINUM COMPOUNDS
Same toxicities but ↑
incidence and
degree; dose-dependent high-frequency
hearing loss and
myelotoxicity
(anemia); rare, focal
encephalopathy and
retinal toxicity.
Dose-dependent,
early (after 1–24 h)
severe and delayed
(after 24–120 h) N
& V; acute tubular
damage with hypomagnesemia; cumulative subclinical
tubular damage with
↓ Cr CL; cumulative
peripheral sensory
neuropathy (paresthesias, sensory
loss) slowly reversible; 30% irreversible.
Toxicity
284
Second-generation platinum
compound; 10-fold more
water soluble than DDP.
Carboplatin (CBDCA)
1,1-Cyclobutanedicarboxylato
(2-)-0, 0-platinum (II).
Carboplatin NP
Paraplatin®
Same as that of
DDP; slower
reactivity with
DNA and lower
potency than
DDP; mechanisms
of resistance
possibly similar to
those of DDP.
Special population
Renal impairment
Doses are based on Cr
CL as estimate of GFR
(Calvert formula).
Lower relative rate of
activation than DDP;
T1/2 of ultrafilterable
platinum of 170 min;
triphasic disappearance
of total platinum with
T1/2β and T1/2γ of 1.5 h
and 5.8 days; 30%
plasma levels in CSF
after IV treatment; 70%
of dose as parent in
24 h urine; plasma
clearance of ultrafilterable species correlated
to GFR.
Dose modifications
Calvert formula
Adults: total dose (mg) =
target AUC × (GFR* +
25); pretreated pts AUC:
4–6 mg/ml/min;
untreated pts AUC: 6–8
mg/ml/min.
Children: total dose: (mg)
= target AUC × (GFR* +
0.36 × BW (kg)).
*GFR as estimated by
51
Cr-EDTA or 24 h urine
collection or CockcroftGault equation).
HD: Single agent,
2000 mg/m2 (MTD)
(with hydration);
combination, AUC
11–20 mg/ml × min.
Standard dose
adult untreated pts/
Calvert formula;
single agent, AUC
6–8 mg/ml/min
every 3–4 weeks;
combination, AUC
4–5 mg/ml/min
every 3–4 weeks
(without hydration)
IV (30–60 min inf):
(Continued)
DL hepatotoxicity,
nephrotoxicity with
loss of serum electrolytes, reversible
vision loss.
DL cumulative
thrombocytopenia
after 2–3 weeks,
recovering within 2
weeks; moderate
N & V after 6–12 h;
myelotoxicity,
cumulative peripheral neuropathy;
allergic reactions
after very high
cumulative doses, no
cross-reactivity with
DDP; transient ↑
hepatic enzymes.
285
Drug interactions
Additive or synergistic
effects in vitro and in vivo
with 5-FU, TS inhibitors,
CPT11.
Incompatible with normal
saline, alkaline solution
(5-FU).
Pharmacology and dose
modifications
95% protein bound; at
the end of inf. 50%
accumulated (nonexchangeable) in RBC
and 50% in plasma
(33% ultrafilterable);
triphasic disappearance
of ultrafilterable
platinum with T1/2β and
T1/2γ of 16.3 h and 273
h; 54% of dose in 48 h
urine. High CL by
tissue binding and renal
CLR (34%) correlated
with GFR. Extensive
non-enzymatic
biotransformation to
cytotoxic/non-cytotoxic
species. ↑ AUC of
ultrafilterable platinum
if Cr CL <60 ml/min.
No need of ↓ dose if Cr
CL > 20 ml/min. No
accumulation of total
plasma platinum with
repeated administrations.
Mechanism of action
Same as that of
DDP with bulkier
DNA adducts;
activity in cancer
cell lines and
murine models
resistant to DDP
because of deficiency of MMR
activity and
enhanced replicative bypass.
Name, chemistry, relevant features
Oxaliplatin
Eloxatin®
Trans-1-diaminocyclohexane
oxalatoplatinum.
Toxicity
DL peripheral
neuropathy (mainly
hands/feet and
perioral) of 2 types:
Type 1: acute early
onset, reversible
within 14 days,
sensory, enhanced
by cold contact;
Type 2: persistent >
14 days paresthesia,
dysesthesia, and
deficit in propioception with functional
impairment, cumulative, reversible at
discontinuation
(complete recovery
only in 41% within
8 months).
Incidence overall
neuropathy single
agent: 82%, persistent 19%, with
functional impair
ment 12%; 10% and
50% of risk of
developing it after 6
and 9 cycles; 65% N
& V (gr 3–4 11%),
30% diarrhea (gr
3–4 4%), 10%
neutropenia. Rare:
HSR.
Route, schedule, and
recommendations
IV (2 h inf.):
single agent,
130 mg/m2 every
3 weeks;
combinations,
85 mg/m2 every
2 weeks.
286
*mg = unit.
IV bolus:
10–20 mg/m2*
per week.
IM, SC: same dose
as IV, with antipyretics/steroids to
prevent fever.
IV CI: 5–10 mg/m2
on days 1–4 every
3 weeks.
Intrapleural:
60–120 U (50% of
dose in the systemic circulation).
Avoid NSAID
against chest pain.
↑ risk of pulmonary toxicity with
hyperoxia, concomitant RT, nephrotoxic drugs with ↓
excretion of BLM.
10% protein bound;
T1/2 of 2–3 h; rapid
tissue inactivation,
lower in skin and
lung with 50% of
dose in 24 h urine,
mainly as inactive
species. Cmax with IM
administration after
30–60 min, 1/3 of
that after IV; 45%
systemic absorption
after intrapleural
administration.
DNA binding with
production of single and
double-strand breaks;
DNA damage affected by
specific repair enzymes,
glutathione, ionizing
radiation. BLM inactivated by BLM hydrolase;
pulmonary toxicity due
to low enzyme concentration and high O2
tension. When used
intrapleurally acts as
sclerosing agent.
Bleomycin sulfate
(BLM)
Mixture of sulfur-containing glycopeptides;
formed by a DNAbinding fragment and
an iron-binding
portion. Activation
through O2 binding.
Special population
Renal impairment
Cr CL ≤30 ml/min:
↓ dose by 50%.
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
ANTITUMOR ANTIBIOTICS
(Continued)
IV: acute DL stomatitis; 50%
fever and chills; 50% cumulative skin hyperpigmentation.
Mild to moderate alopecia.
Rare, HSR (1% of lymphoma
pts) and Raynaud’s phenomenon.
Low-dose hypersensitivity
pneumonitis responsive to
steroids. 10% late chronic
pneumonitis up to irreversible
interstitial fibrosis (dry cough,
dyspnea, rales, basilare infiltrates), ↑ incidence for cumulative dose >250 U, age
>70 years, COPD, thoracic RT,
hyperoxia during surgical
anesthesia; role of steroids
uncertain.
Toxicity
287
Special population
PK unchanged
if liver/renal
impairment.
DNA intercalation of the 5% protein bound; by
Dactinomycin
RIA, biphasic disapplanar multiring phe(DACT)
®
pearance with T1/2 of
noxazone between
Cosmegen Lyovac
guanine-cytosine
base
35 h, longer in case
Phenoxazine pentapeppairs with inhibition of
of liver impairment;
tide antibiotic.
RNA synthesis.
minimally metaboRadiosensitizer.
lized, does not cross
BBB; 30% of dose in
urine and feces as
intact drug within 1
week.
Purple antibiotic
isolated from Streptomyces caespitosus.
Unexpected hepatic
toxicity after
hepatotoxic agents
(halothane, enflurane).
Rapid plasma disap- With concomitant
DOX: ↑ risk of
pearance due to
cardiotoxicity.
tissue distribution
and liver metabolism;
T1/2β: 25–90 min;
<10% of dose in 24 h
urine, 23% hepatic
extraction with HAI
administration.
Activation to bifunctional alkylating agent
with formation of DNA
interstrand cross-links
and oxygen free radicals.
Activation by chemical
reducing agents, enzymatic reduction, exposure to acidic pH.
Possible preferential
activation in hypoxic
environment.
Mitomycin C (MMC)
Mitomycin C Kyowa®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Delayed (after 3–8 weeks)
cumulative leuko- and thrombocytopenia, cumulative
anemia; partial alopecia. Rare:
HUS with thrombocytopenia,
renal and cardiac failure: ↑ risk
for cumulative dose >50 mg,
exacerbated by RBC transfusions, rarely reversible, steroids
ineffective (52% lethal). Rare,
severe interstitial pneumonitis
with lung infiltrates.
Local vesicant on
extravasation.
DL myelotoxicity with leukoand thrombocytopenia in 1
week and nadirs up to 3 weeks.
IV (bolus): single
Severe prolonged (up to 24 h)
agent, 500 µg
N & V; 30% stomatitis and
(max. 15 µg/kg) on
diarrhea; alopecia; late radiadays 1–5 every 4
tion recall toxicity (mainly skin,
weeks; combinabut also GI, liver, lung).
tion, 500 µg on
Immunosuppression.
days 1–2.
Local vesicant on
extravasation.
IV bolus: single
agent, 20 mg/m2
every 6–8 weeks;
combination,
10 mg/m2 every
6–8 weeks.
Intravesical:
20 mg × 3 per
week.
Toxicity
Route, schedule, and
recommendations
288
Mechanism of action
Sulfate salt of a dimeric
alkaloid from Catharantus
rosea.
As VLB with formyl side
chain on vindoline.
Vincristine sulfate (VCR) Same as that of VLB.
Vincristine NP
Oncovin®
vinca alkaloids
Vinblastine sulfate (VLB)
Vinblastine NP
Velbe®
Binding to a specific
site on tubulin with
prevention of polymerization, inhibition
of microtubule
Sulfate salt of a dimeric
assembly and mitotic
alkaloid from Vinca rosea;
spindle formation.
formed by two multiringed
Involved in MDR
units (catharanthine and
phenomenon through
vindoline) with methyl side
P-gp overexpression.
chain on vindoline.
Name, chemistry, relevant
features
ANTIMICROTUBULE AGENTS
Special population
Liver impairment
Bilirubin up to 3 mg/ml:
50% ↓ dose.
Special population
Liver impairment
↓ Dose if obstructive liver
disease.
48% protein bound;
rapidly distributed into
tissues with triphasic
disappearance; liver
metabolism with 70% of
dose in 72 h feces.
80% protein bound;
rapidly distributed into
tissues with triphasic
disappearance (T1/2γ 19–25
h); partially metabolized in
liver to deacetyl VLB; 80%
of dose excreted
unchanged in bile.
Pharmacology and dose
modifications
↑ accumulation
of MTX in
tumor cells.
Drug interactions
Toxicity
IV bolus: 0.4–1.4 mg/m2
(maximum 2 mg total
dose) per week.
IV CI: single agent, 0.5
mg/m2 on days 1–5;
combination, 0.4 mg/m2
days 1–4 (VAD regimen) every 3 weeks.
Local vesicant on
extravasation.
(Continued)
DL cumulative neurotoxicity, with peripheral neuropathy
(paresthesias, loss of
deep tendon reflexes);
less frequent, autonomic effects with
abdominal pain and
constipation; ↑ incidence if underlying
neurological problems);
20% alopecia. Rare:
SIADH.
DL leucopenia after
5–10 days, recovering
2
IV (bolus): 4 mg/m for within 7–14 days. Neurotoxicity with constistarting, increased to
pation and abdominal
6 mg/m2 per week.
Prophylaxis of constipa- pain; less frequent,
peripheral neuropathy,
tion: use lactulose.
jaw pain, urinary
retention ↑ incidence if
underlying neurological problems; stomatitis
and mild alopecia.
Local vesicant on
extravasation
Route, schedule, and
recommendations
289
Mechanism of action
Vinorelbine (NVB)
Navelbine®
Same as VLB; ↓
activity on axonal
microtubules with
Semisynthetic derivative of
possibly ↓ neurotoxVLB with structural modifiicity.
cations on the catharanthine ring.
Name, chemistry, relevant
features
Special population
Liver impairment
Bilirubin > 2 × NV: ↓ dose
by 50%.
80–90% protein bound;
rapid tissue distribution
with triphasic disappearance (T1/2γ 27–40 h); high
liver uptake; hepatic
metabolism by CYP3A in 2
metabolites, 1 active
(desacetyl metab.); main
hepatic excretion. PK
unchanged by age; F, mean
27% ± 14; Cmax after 1.5 h
and large first pass effect.
No food effect on os
absorption.
Pharmacology and dose
modifications
Potential
interactions
with inducers/
inhibitors of
CYP3A.
Drug interactions
IV (5–10 min inf.):
single agent, 30 mg/m2
weekly with ↓ dose
according to myelotoxicity; combination, 25
mg/m2 weekly with
cisplatin every 4 weeks.
PO soft-gel capsules: 60
mg/m2 per week per 3
weeks, then ↑ 80 mg/m2
per week if no severe
neutropenia.
Local vesicant an
extravasation.
Route, schedule, and
recommendations
DL non-cumulative
neutropenia (90%;
36% G 4) after 7–10
days, recovering within
7–14 days; 25%
peripheral neuropathy
(paresthesia) with
decreased deep tendon
reflexes; 35% constipation; 40% N & V (2%
severe); 12% alopecia;
10% chemical phlebitis; 27% fatigue.
PO: 50% N & V (15%
severe); >50% diarrhea;
6% G2–4 neutropenia.
Toxicity
290
Promotes microtubule
assembly of tubulin
dimers and stabilizes
microtubule dynamics
Diterpene from
with inhibition of cell
bark and leaves of
proliferation, blockade
Taxus brevifolia;
of mitosis, and inducpoorly water
tion of apoptosis.
soluble, need of
Resistance related to
vehicle with 50%
P-gp overexpression and
polyoxyethylated
mutations of tubulin,
castor oil (Cremoslower rate of microtuphor EL) and
bule assembly, overex50% ethanol.
pression of Bcl-2.
↑ in vitro cytotoxicity
after longer exposure
time.
In vitro sensitizing effect
to ionizing radiation.
Effective in vitro concentrations
(≥0.1 µmol/1)
achieved in humans
at the end of infusion.
Taxanes
Paclitaxel
Taxol®
Special populations
Liver impairment
Liver enzymes >2 <10 × NV
or bilirubin 2–5 × NV: ↓
dose to 90 mg/m2 (3 h inf.).
Renal impairment
no need of dose ↓.
>90% protein bound; rapid
tissue uptake with triphasic
plasma disappearance and
extensive liver metabolism at
the taxane ring through
CYP2C8 and CYP3A4; main
metabolite inactive 6-OH
paclitaxel. High biliary
secretion and low intestinal
absorption of paclitaxel and
metabolites. Non-linear PK
in humans, mainly caused by
Cremophor EL; Cmax and
AUC not proportional to
dose, because of saturable
distribution, metabolism, and
elimination. Neutropenia
related to the time plasma
concentrations of ≥0.05–0.1
µmol/l are maintained. Does
not cross BBB.
After IP treatment: low Vd,
slow peritoneal CL, prolonged significant IP and
plasma concentrations.
In vitro effects on
metabolism of
concomitant
CYP450 isoenzyme substrates
(cyclosporin,
steroids, macrolide antibiotics,
benzodiazepines,
barbiturates,
anticonvulsant
drugs, fluconazole).
With doxorubicin:
↑ incidence of
CHF with paclitaxel (3 h inf.)
and DOX (bolus
>380 mg/m2
cumulative dose).
With cisplatin: ↑
peripheral
neuropathy.
With concomitant
EIAs: ↓ Css and ↓
systemic toxicity
in pts receiving
96 h infusion
paclitaxel.
(Continued)
DL mucositis, onicolysis.
DL abdominal pain.
DL non-cumulative neutropenia (50% G 4) after 7–10
days recovering in 1 week;
total alopecia (within 2–4
weeks); 60% dose-dependent myalgia (8% severe)
after 2–3 days for 3–4
days; 60% dose-dependent
cumulative peripheral
neuropathy (3% severe),
slowly reversible; 41% HSR
(<2% severe); 12%
hypotension; 23% ECG
abnormalities (sinus
HD (+G-CSF): good
bradytachycardia, PB)
risk pts 200–250 mg/
2
usually asymptomatic, not
m every 3 weeks.
requiring interventions;
IV weekly (1–3 h inf.):
radiation recall skin
90–100 mg/m2 per
reaction. Schedule-depenweek.
dent neutropenia and
IV CI (96 h): 140 mg/
m2 (without premedica- mucositis, ↑ with 24 h
infusion.
tion).
DL cumulative peripheral
IP: 82.5–125 mg/m2
neuropathy, onicolysis.
every 3 weeks.
Premedication: steroids,
histamine H1- and
H2-receptors antagonists (day 1; day 1).
IV 3 h inf.: 175 mg/m2
every 3 weeks.
IV 24 h inf.: 135 mg/m2
every 3 weeks.
291
Special population
Liver impairment
AP >2.5 × NV and transaminases >1.5 × NV: ↓ dose by
25%; bilirubin, AP ↑ >6 ×
NV or transaminases >3.5 ×
NV: discontinue.
Weekly: 36 mg/m2 per
week × 3 every 4
weeks.
DL: non-cumulative neutropenia (80% G 3–4, 11%
febrile neutropenia) after 8
days, recovering within 1
week; 76% total alopecia
(within 2–4 weeks), 62%
asthenia (5% severe), 50%
cumulative sensory neuropathy (4% severe), 47%
skin reactions (5% severe),
39% diarrhea (5% severe),
15% acute HSR (2%
severe); 64% fluid retention (6% severe) due to
capillary protein leak
syndrome, after a median
cumulative dose of ≥400
mg/m2.Steroids useful to ↓
severity of skin reactions
and of fluid retention (after
a median dose of 800 mg/
m2), and to avoid severe
HSR. Rare: radiation recall
phenomena, ischemic
colitis.
DL fatigue and asthenia;
rare peripheral edema and
neuropathy; uncommon
mild neutropenia and
onicolysis.
Premedication: DXM 8
mg b.i.d. for 3 days
(from day –1).
IV (1 h inf.):
single agent,
60–100 mg/m2
every 3 weeks;
combination,
75–100 mg/m2
every 3 weeks.
Specific substrates of CYP450
3A isoenzymes
(erythromycin,
ketoconazole,
nifedipine) could
modify CL.
>90% protein bound; linear
PK up to 115 mg/m2 with
triphasic plasma disappearance (T1/2β and T1/2γ 38 min
and 12 h); extensive liver
metabolism with oxidations
of the C 13 side chain and
production of inactive
metabolites; high interpt.
variability of metabolism and
PK. 74% of dose excreted in
feces as metabolites, 5% in
urine; CL ↓ 27% in pts with
↑ transaminases; CL is
independent predictor of
severe and febrile neutropenia in population of PK
study.
Same mechanisms of
action and resistance of
paclitaxel. Scheduleindependent antitumor
activity; in vitro sensitizing effect to ionizing
radiation.
Docetaxel
Taxotere®
Semisynthetic
paclitaxel derivative from needles
of Taxus baccata;
more water
soluble than
paclitaxel; Tween
80 in the
solution.
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
292
Mechanism of action
Hydroxyl daunorubicin; anthracycline antibiotic
constituted by
water-soluble
aminosugar
(daunosamine)
linked to planar
anthraquinone
nucleus (adriamycinone) site of
electron transfer
reactions.
Same structure as
DNR with
hydroxyacetyl
group C8.
Doxorubicin
(DOX)
Doxorubicin Rapid
Dissolution
Cytotoxicity due to: 1.
DNA intercalation of
aglycone between base
pairs with inhibition of
nucleic acid synthesis; 2.
Topo II inhibition; 3.
Generation of hydroxyl
radicals (relevant mainly
for cardiac toxicity)
through (a) redox cycling
of quinone with production of O2−, H2O2, and
OH− which bind to DNA
and cell membrane lipids;
(b) formation of drug–
metal (Fe2+, Cu2+) complexes which catalyze and
bind to DNA and cell
membranes. Cardiomyopathy possibly related to 3
because of destruction of
detoxifying glutathione
peroxidase by DOX and
relative deficiency of
scavenging enzymes in
heart. Involved in MDR
phenomenon through
P-gp overexpression and
Topo II alterations.
Anthracyclines, anthracenediones
Name, chemistry,
relevant features
TOPOISOMERASE II INHIBITORS
Special populations
Liver impairment
Bilirubin >1.25–2.0 × NV:
↓ dose by 50%.
Bilirubin >2.0–4.0 × NV:
↓ dose by 25%.
No verified guidelines for
abnormal transaminases:
caution suggested.
75% protein bound with
rapid tissue distribution;
triphasic plasma disappearance (T1/2γ DOX and
metabolites: 25–28 h).
Main metabolite DOXOL
produced by ubiquitous
(mainly liver) aldoketo
reductase, less active than
DOX; 7-deoxyaglicones,
inactivation species produced mainly in liver,
conjugated and excreted
into bile and urine. 40% of
dose excreted in bile and
5% in 7-day urine.
Pharmacology and dose
modifications
With dexrazoxane: ↓ risk of
cardiotoxicity
(see p.323).
With MMC,
CTX, paclitaxel,
Ca antagonists:
↑ risk of
cardiotoxicity.
With MDR
modulators:
↓ CL through
P-gp inhibition.
With CYP450
inducers: ↑ CL.
Compatible with
IV BLM, VLB,
VCR, CTX;
incompatible
with DXM,
5-FU, heparin.
Drug interactions
IV bolus intermittent:
Cumulative dose: ≤450
mg/m2; 300–100 mg/m2
if cardiac risk factors.
Warning
Recommended maximum
cumulative dose (doseassociated <10% risk of
CHF).
Cardiac risk factors
(combination CT, prior
mediastinal RT, age >70
years, pre-existing heart
disease).
Local vesicant on extravasation.
IV bolus intermittent:
single agent, 60–75 mg/
m2 every 3 weeks; combination, 50–60 mg/m2
every 3 weeks.
IV bolus weekly: 20 mg/m2
per week.
IV CI (72–96 h) (central
IV line): 60 mg/m2 every
3 weeks.
Route, schedule, and
recommendations
(Continued)
Cardiotoxicity:
Dose independent:
reversible, acute (after
hours or days): arrhythmias (with non-specific
ST segment and T-wave
changes, AV blocks, A
tachyarrhythmia; more
rarely, acute pericarditis/
myocarditis.
Dose-related: irreversible
cumulative, delayed,
chronic cardiomyopathy
with CHF responsive to
diuretics, digitalis, ACE
inhibitors. Serial determinations of LVEF by
MUGA/ECHO to
DL neutropenia after
10–14 days recovering in
1 week; acute dose-dependent N & V; total
alopecia within 3 weeks;
hyperpigmentation of
skin and nails; radiation
recall; venous flare
reactions. Rare,
stomatitis.
Toxicity
293
Mechanism of action
Pharmacology and dose
modifications
Drug interactions
Route, schedule, and
recommendations
IV bolus weekly and IV
CI: Cumulative dose:
≤700 mg/m2; 550 mg/m2
if cardiac risk factors.
77% protein bound;
Do not mix hepa- Local vesicant on extravaEpirubicin (EPI) 1 and 2 same as those of
extensive liver metabolism rin or fluoroura- sation.
DOX; 3 less prominent
Pharmorubicin®
with EPI and 13-OH
due to ↑ glucuronides
cyl; do not mix
IV (10–15 min, inf.):
Epimer of DOX
production escaping redox derivative (epirubicinol)
with other drugs
standard dose, single
with 4′-OH on
with formation of inactive in the same
cycling and free radical
agent: 90 mg/m2 every 3
daunosamine in
glucuronides rapidly
formation. Involved in
syringe; avoid
weeks; combination:
equatorial rather
excreted. Triphasic plasMDR phenomenon.
prolonged
60–75 mg/m2 every 3
than axial position;
matic disappearance with
contact with
weeks.
↑ lipophilicity, ↑
T1/2γ of 40 h; 50% of dose alkaline pH
β-glucuronidation
solution because Warning
excreted in the bile in 4
to inactive comRecommended maximum
days and <20% into urine. of hydrolysis.
pounds with ↓
With cimetidine: cumulative dose (doseSpecial populations
cardiotoxicity, ↑
associated <10% risk of
↑ AUC by 50%
Liver impairment
CL and ↓ potency.
CHF).
and ↓ decrease
Bilirubin 1.2–3 mg/dl or
plasma clearance Cardiac risk factors
AST 2–4 × N: ↓ dose by
(combination CT, prior
by 30%; avoid
50%. Bilirubin >3 mg/dl or
concomitant use. mediastinal RT, age >70
AST >4 × NV: ↓ dose by
years, pre-existing heart
75%.
disease).
Name, chemistry,
relevant features
Acute side-effects comparable to those of DOX
with dose ratio of
DOX:EPI of 1:1.2 for
hematological, 1:1.5 for
non-hematological
toxicities, 1:1.8 for
cardiotoxicity.
Dose-related cumulative
delayed cardiotoxicity as
for DOX; serial LVEFS by
MUGA/ECHO (baseline,
300–400 mg/m2, 600–
700 mg/m2, then after
each dose) to minimize
the risk of cardiotoxicity
(4% at ≥950 mg/m2, 15%
at 1000 mg/m2).
More frequent stomatitis.
minimize the risk of
cardiotox (baseline, 300,
450 mg/m2, then after
each dose). Discontinue
treatment if ≥10% ↓ of
baseline to a level below
normal. Endomyocardial
biopsy findings predictive of subsequent CHF.
Toxicity
294
Doxorubicin HCI Longer circulation times;
higher concentrations in
liposome
®
tumor tissues in animal
Caelyx
models than DOX, possiDOX encapsulated
bly due to enhanced
in pegylated
permeability and
(STEALTH®)
retention.
liposomes.
HD (30–60 min. inf.)
days 1–2: total dose
single agent, 120–150
mg/m2; combination, 120
mg/m2 + CSF or 200 mg/
m2 + PBSC.
Linear PK up to 20 mg/m2; No drug interac- Local vesicant on extravation studies. Do sation.
T1/2: 74 h. In comparison
IV: infuse initially at 1
to DOX: higher CL (0.030 not mix with
mg/min to minimize risk
other drugs.
l/h/m2), lower Vd (1.93 l/
of reactions.
m2 equal to plasma volAIDS-KS: 30 min inf. 20
ume), greater AUC, similar
mg/m2 every 3 weeks;
metabolism.
solid tumors: 60 min inf.
Special populations:
50 mg/m2 every 4 weeks.
Age
Warning
No differences.
Cumulative cardiotoxic
Liver impairment
dose not defined: in
At cycle 1: bilirubin 1.2–3
metastatic frontline pts
mg/dl: ↓ dose by 25%; bilimonitor cardiac functions
rubin >3 mg/dl: ↓ dose by
after >600 mg/m2 in
50%.
naive and 450 mg/m2 in
At second cycle if first
DOX-pretreated pts.
cycle well tolerated: ↑ dose
by 25%.
Single agent, combination:
≤900 mg/m2;
≤540 mg/m2 if risk
factors.
(Continued)
Dose-dependent cumulative skin toxicity with
palmar-plantar erythrodysesthesia, possibly due
to preferential accumulation in flexure, pressure
areas, palms (40% at 50
mg/m2, 17% G 3),
usually appearing after
2–3 cycles, recovering in
2–4 weeks, steroids
benefit unknown; ↓
incidence at ≥4 week
intervals and by avoiding
pressure, high temperature for 1 week after
treatment; pyridoxine
possibly useful.
Secondary AML: cumulative risk 0.2 and 0.8% at
3 and 5 years when used
with other DNA-damaging cytotoxics.
DL mucositis; 90% G 4
neutropenia; severe
N & V; total alopecia.
295
Name, chemistry,
relevant features
Mechanism of action
Renal impairment
Cr CL 30–156 ml/min: no
modifications.
Pharmacology and dose
modifications
Drug interactions
Route, schedule, and
recommendations
34% asthenia; 30%
stomatitis (G3–4 9%);
20% alopecia; 10%
infusion reactions
(occasional HSR); 5%
G3–4 N & V; 10% G3
neutropenia (solid
tumors); <10%, cardiacrelated AE, lower risk of
cardiotoxicity compared
to DOX at cumulative
equiactive doses; evaluation of long-term cardiac
effects ongoing.
Toxicity
296
Etoposide (VP16)
Vepesid®
Topo II inhibition
with stabilization of
the DNA–TOPO II
Semisynthetic derivative
complex and
of podophyllotoxin with
production of DNA
epipodophyllotoxin
double-strand
linked to a glucopyranobreaks. Cytotoxicity
side with methyl group;
phase and schedule
made more water-miscidependent; lower
ble by organic solvents
repeated doses more
(Tween 80, polyethylene
effective than higher
glycol).
single.
Involved in MDR
phenomenon
through P-gp
overexpression and
Topo II alterations
(↓ activity, point
mutations).
Epipodophyllotoxins and aminoacridines
Special populations
↓ Cr CL, ↓ albumin, age
>65 years: ↓ dose.
95% protein bound;
biphasic disappearance
with T1/2 of 6–8 h; linear
PK also at high doses. 44%
of dose in feces and 56%
(mainly parent compound)
in urine of 5 days; hepatic
metabolism with production of less active hydroxy
acid metabolites,
glucuronide and/or sulfate
conjugates in urine.
Dose-dependent, variable F
(50–75%) up to 200 mg
total dose; lower
at >200 mg.
Measurable CSF levels of
parent compound and
metabolites after high
doses.
With DDP,
HD-CBDCA,
cyclosporin A:
↓ CL.
With concomitant EIAs:
↑ CL.
IV (30–60 min.
inf.): 100–120 mg/
m2 on days 1–3 or
on days 1–5 every
3–4 weeks.
IV HD (500 mg/h
inf.): single agent,
60 mg/kg (preparatory for BMT), 3000
mg/m2 (MTD);
combination:
400–800 mg/m2 on
days 1–3.
IV (72 h CI): 150
mg/m2 daily.
PO: 100 mg (50 mg
× 2) daily, in
untreated pts, days
1–14; pretreated
pts, days 1–10
every 4 weeks.
(Continued)
DL non-cumulative neutropenia
after 10–12 days, recovering
within 7–10 days; N & V; less
frequent, exacerbation of preexisting VCR neuropathy,
diarrhea. Rare hypotension,
flushing.
High dose: DL myelotoxicity,
mucositis, severe N & V.
PO: DL neutropenia after
3 weeks, recovering in 1 week;
mild to moderate N & V; total
alopecia after repeated cycles.
All schedules: ↑ risk of secondary
monoblastic leukemia with
balanced 11q 23 translocations,
short latency period, no preleukemic phase for cumulative doses
of ≥2 g/m2. High-dose DDP,
alkylating agents, RT as additional risk factors.
297
Same as etoposide with a
thenylidene group on
the glucopyranoside.
Teniposide (VM26)
(Vumon®)
Same as that of
etoposide.
Special populations
Liver impairment
Bilirubin 1–2.5 mg/dl:
↓ dose by 50%.
Bilirubin >2.5 mg/dl:
↓ dose by 75%.
>99% protein bound;
triphasic disappearance
with T1/2γ of 20 h; 86%
eliminated by hepatic
metabolism (metabolites
mostly unknown), 20% of
dose in 24 h urine; ↓ CLR
than etoposide.
Same as that of etoposide.
Same as that of
etoposide.
Etoposide phosphate
Etopophos®
Water-soluble prodrug
of etoposide, completely
converted to etoposide
in vivo.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Same as that
of etoposide.
Drug
interactions
IV (5 min inf.)
(solution of higher
concentration than
for etoposide):
50–100 mg/m2 on
days 1–3 or 1–5.
IV HD: highest safe
dose: 1000 mg/m2
(2 h inf.) on days 1
and 2.
IV (30–60 min.
inf.): single agent,
60 mg/m2 on days
1–5 every 3–4
weeks; combination
(children ALL), 165
mg/m2 × 2 per week
× 4 (with Ara C).
Route, schedule, and
recommendations
DL neutropenia after 7–10 days,
recovering within 1 week;
moderate N & V; alopecia;
mucositis; chemical phlebitis.
Rare type I HSR.
Secondary leukemias as after
etoposide.
Comparable to those expected
from etoposide.
3% HSR (chills, rigors, bronchospasm, and dyspnea); 2% flushing; 3% skin rashes.
Toxicity
298
Hydrochloride trihydrate; semisynthetic
derivative of camptothecin. Water-soluble
precursor of the lypophilic metabolite SN38.
Irinotecan (CPT-11)
(Campto®)
Camptothecines
Name, chemistry, relevant
features
Topo I inhibition
with production of
single-strand DNA
breaks. Antitumor
activity not schedule
dependent.
Converted primarily
in liver to active and
inactive metabolites
by at least 2 known
pathways: 1. By
carboxylesterase to
SN38, 1000-fold
more potent, subsequently inactivated
by glucuronidation
to SN38G. Both
CPT11 and SN38
undergo pH-dependent reversible
hydrolysis from
active form lactone
(closed ring) to
carboxylate (inactive
open ring). 2. By
CYP3A to oxidative
metabolites: APC
Mechanism of action
TOPOISOMERASE I INHIBITORS
High interpt. variability due
to individual variations of
metabolic pathway activity
(see Mechanism) and polymorphism of UGT enzyme
(responsible for SN38
glucuronidation).
Protein binding: 50% CPT11,
95% SN38.
For both, linear PK up to 350
mg/m2, unchanged after
repeated cycles. SN38 AUC
values <10% of CPT; excretion 28% total urinary with
CPT11 and SN38 as main
products; 24% fecal excretion.
Relationship between AUC
(CPT11 and SN38) and % ↓
of ANC.
Special populations
Guidelines for 3-week schedule only
Liver impairment
Bilirubin >1 mg/dl: keep dose
<145 mg/m2; bilirubin NV but
AST >3 × NV: start dose at
225 mg/m2, then ↑ if
Pharmacology and dose
modifications
No PK interactions with
DDP, 5FU, etoposide
and OXA.
In vitro ↓ CYP3A
metabolism with
CYP3A4 substrates
(loperamide, ketoconazole, ondansetron) of
unknown clinical
relevance.
With EIAs: ↑ CL
(phenytoin, carbamazepine, phenobarbital,
pyrimidone, felbamate).
With Valproate: ↓ SN38
glucuronidation.
Drug interactions
Toxicity
(Continued)
Diarrhea principal of
2 types.
Type 1: early-onset
diarrhea-cholinergic
syndrome (EOD-CS)
(during or within
24 h from infusion),
associated with
rhinitis, salivation,
miosis, diaphoresis,
preventable by
atropine (IV or SC
LOD treatment:
0.25–1 mg).
treat at first
Type 2: late-onset
episode of loose
diarrhea (LOD)
stools with
(>24 h) lasting for
loperamide (4 mg
5–7 days.
immediately, then
Single agent G3–4
2 mg every 2 h
toxicity by schedule:
until diarrhea free
Intermittent: 22%
for 12 h), and
LOD, 22% neutropehydrate.
nia, 15% asthenia,
14% N&V, 12%
EOD-CS, 12% CNS
symptoms, 5%
anorexia.
All schedules: IV
90 min inf.
Single agent:
every 3 weeks:
300–350 mg/m2;
weekly: 125 mg/
m2 × 4, every
6 weeks.
Combination:
every 2 weeks:
180 mg/m2
Route, schedule, and
recommendations
299
Mechanism of action
Pharmacology and dose
modifications
(500-fold less potent
than SN38) and
NPC, excreted in
bile
no toxicity.
Gilbert’s syndrome with mutation of UGT1A1
↓ dose to 200 mg/m2 every 3
weeks.
Renal impairment
Cr >1.6–3.5 mg/dl: start at
225 mg/m2, then ↑ if no
toxicity.
50% of drug as carboxylate
Topo I inhibition
Topotecan
(80% after 18 h) at the end of
with production of
(Hycamtin®)
short infusion; wide tissue
single-strand DNA
9-Dimethylaminomethyldistribution; biphasic disapbreaks; pH-depen10-hydroxycamptothecin;
dent hydrolysis with pearance of lactone (T1/2β 3 h)
water-soluble semisynpredominance of
with linear PK highly variable.
thetic derivative of
lactone (active
Main renal excretion (60–70%
camptothecin.
species) at pH <7.0; total drug in 24 h urine);
less active open-ring. 30–40% penetration into CSF
Active N-desmethyl in children; positive correlametabolite in plasma tion between total AUC and
produced by CYP.
% ↓ of ANC.
Higher antitumor
Special population
activity in experiRenal impairment
mental models after
Cr CL 20–39 ml/min: ↓ dose
CI/repeated than
by 50%; no data in case of
single bolus adminisCrCL <20 ml/min.
trations.
Liver impairment
No need of ↓ dose.
Name, chemistry, relevant
features
Same as those of CPT
11.
With cisplatin: ↑ neutropenia if Topotecan
given after DDP.
With EIAs: ↑ CL
(concomitant with
phenytoin).
Warning
Concomitant anticonvulsant therapy: allowed
gabapentin, lamotrigine;
NOT allowed: phenytoin, carbamazepine,
phenobarbital, pyrimidone, felbamate.
Drug interactions
If G-CSF used,
start at least 24 h
from last dose.
IV (30 min inf.):
single agent, 1.5
mg/m2 on days
1–5 every 3
weeks; combination, 0.75 mg/m2
on days 1–5 every
3 weeks.
Route, schedule, and
recommendations
DL neutropenia (78%
G4) after 10–12 days,
recovering in 1 week;
37% severe anemia
after 15 days; 27%
severe thrombocytopenia after 15 days;
32% diarrhea; 54%
cumulative fatigue;
60% mild to moderate N&V; 49%
dose-related cumulative alopecia.
Weekly: 7% EOD-CS;
31% LOD, 31%
neutropenia, 16% N,
14% asthenia, 12% V,
7% anorexia, 2%
CNS symptoms.
Toxicity
300
Special populations
Renal impairment
↓ re-treatment interval to
4 weeks and reduce dose
according to Cr CL ml/
min. Cr CL 55–65: ↓
dose by 25%; Cr CL
25–54: ↓ dose equivalent
to ml/min (e.g. if 30 ml/
min, give 30% full dose);
Cr CL <25: discontinue.
Warning
Avoid concomitant use
of: folates, tubular
secreted drugs (e.g.
NSAIDs), and highly
protein-bound drugs
(e.g. warfarin).
Serial checks of liver
and renal function tests.
IV (15 min. inf.): 3 mg/
m2 every 3 weeks.
93% protein bound;
triphasic disappearance
with T1/2β and T1/2γ of
1.7 h and 198 h; long
T1/2γ due to intracellular
deglutamation and
release from tissues.
Not metabolized.
Excreted unchanged in
urine (40–50%) and 15%
in feces, about 50%
retained in tissues.
Potent and selective inhibitor
of TS, forms polyglutamates,
100-fold more potent than
parent compound and
retained within cells.
Quinazoline
folate analog
With MTX: see also
high-dose MTX.
With 5–FU (short
infusion): 20–200 mg/m2
on days 1–5.
90% absorption after PO
up to <50 mg total dose,
then 75%; Tmax 0.5 h.
Crosses BBB, rescue
delayed for ≥24 h after IT
treatment.
Route, schedule, and
recommendations
Provides cells with FH4
depleted because of DHFR
inhibition by MTX.
Drug interactions
Antifolates
Leucovorin (LV)
5-CHO-FH4;
reduced form of
folic acid (racemic mixture);
active L-LV.
Raltitrexed
Tomudex®
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
ANTIMETABOLITES
(Continued)
DL prolonged diarrhea
(38%, 10% G 3–4) and
neutropenia (13%);
49% asthenia (5% G
3–4); 58%
N & V (9% G 3–4);
16% ↑ LFTs, 12%
mucositis (2% G 3–4);
6% alopecia.
Toxicity
301
60% protein bound;
triphasic plasma disappearance with T1/2γ of
8–10 h, longer if ↓ Cr CL
and third space fluid
collections. 60–100%
urinary excretion after
high-dose MTX through
glomerular and tubular
processes with drug CLR
comparable to Cr CL;
40% of drug in 24 h
urine as 7-hydroxy-MTX,
poorly soluble in acidic
pH. Biliary excretion
<10% drug clearance.
Well absorbed after PO
doses of ≤25 mg/m2,
erratic F at higher doses
and in children. With HD
(8 g/m2) therapeutic
concentrations achieved
in CSF and maintained
much longer than with
IT. After IT administration, T1/2 of 12–18 h with
delayed CL and ↑
myeloneurotoxicity if
active meningeal disease.
HD or IT treatment for
meningeal prophylaxis;
through Ommaya reservoir (therapeutic).
Tight-binding inhibitor of
DHFR with depletion of
intracellular FH4, necessary
for synthesis of purines
(through GAR and AICAR
transformylases) and thymidylate (through TS) with
inhibition of DNA and RNA
synthesis. MTX and FH2
polyglutamated by FPGS,
higher in some tumors than
in normal cells. DHFR, GAR,
AICAR and TS directly
inhibited by polyglutamates.
MTX enters cells through
reduced folate carrier and
mFBP, with higher affinity for
FH4 than for MTX. Mechanisms of resistance to MTX
include impaired membrane
transport, defective polyglutamation, and alteration of
DHFR due to ↑ expression or
↓ binding affinity. High-dose
therapy based on different
distribution of transport
carrier systems between
tumor and normal cells, with
passive diffusion of MTX into
tumor cells and selective
rescue of normal cells by LV.
LV intracellularly converted
to 10-CHO-FH4, which
Methotrexate
(MTX)
Folic acid analogue; 4-amino,
10-methyl analog
of aminopterin.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Standard dose
IV (bolus): 30–50 mg/m2
per week.
HD
↑ toxicity with
salicylates, sulfonamides, phenytoin
due to protein
binding displacement; with
probenecid,
penicillins, cephalosporins, aspirin,
NSAIDs due to
inhibition of
tubular secretion.
With antitumor
agents: ↓ toxicity of
asparaginase if
MTX given first; ↑
therapeutic activity
of 5FU, VCR or
AraC if MTX given
first; ↑ levels of
6-MP if MTX given
first.
With RT: ↑ risk of
soft tissue necrosis
and osteonecrosis.
Warning
Implement: (1) IV fluids
and urinary alkalinization: keep urinary pH >7;
↑ diuresis at least 12 h
before and up to ≥48 h
after, monitor Cr CL
(must be ≥60 ml/min).
(2) MTX plasma levels
monitoring to guide
duration and amount of
(3). (3) LV rescue: start
2–24 h after MTX until
MTX levels are <5 × 10−8
M.
Jaffe regimen
Dose: 50–250 mg/kg 6 h
inf
Rescue: Start 2 h from the
end of MTX with LV 15
mg/m2 IM every 6 h × 7,
then according to MTX
level at 48 h for 8 doses.
MTX level LV mg/m2
at 48 h
≥5 × 10−7 M
15
≥1 × 10−6 M 100
≥2 × 10−6 M 200.
Repeat after 48 h and
Route, schedule, and
recommendations
Drug interactions
PO: chronic toxicities,
hepatic fibrosis,
interstitial infiltrates.
IT: acute chemical
arachnoiditis; 10%
subacute neurotoxicity
(motor paralysis,
cranial nerve palsies);
chronic demyelinating
encephalopathy
(dementia, limb
HD: Acute: reversible
nephrotoxicity; N & V;
maculopapular rash
(up to 5 days after);
oral stomatitis (after
3–7 days) preceding
myelotoxicity, both
reversible within 2
weeks; ↑ LFTs reversible within 2 weeks;
fever. Transient
encephalopathy with
paresis, aphasia, and
seizures within 6 days,
recovering in 72 h.
Leukothrombocytopenia after 4–14 days;
stomatitis; diarrhea; ↑
toxicity in dehydrated,
malnourished pts.
Toxicity
302
L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4
-oxo-1Hpyrrolo[2,3-d]
pyrimidin-5-yl)
ethyl]benzoyl]
disodium salt.
Pemetrexed
(Alimta®)
Linear PK; ↓ CrCL results
in ↓ CLp and ↑ AUC. Not
metabolized to an appreciable extent, 70–90%
excreted unchanged in
24 h urine.
T1/2β 3.5 h, small Vd, CL
not affected by PO folic
acid, IM vitamin B12 or
concomitant DDP.
Inverse relationship
between severity of
neutropenia and AUC; ↓
ANC nadir also occurring
in presence of baseline ↑
cystathionine and ↑
homocysteine levels
(markers of vitamin B12
and folate deficiency);
vitamin supplementation
effective in ↓ toxicity.
Simultaneous inhibition of TS
(primary target), DHFR and
GARFT (secondary targets)
reverted by thymidine and
hypoxanthine in combination; enters cells through
mainly reduced folate carrier
and mFBP; polyglutamated
by FPGS, with >100-fold
greater affinity for TS than
monoglutamate. In mice
dietary folic acid protects
from toxicity without ↓
efficacy.
Special population
Renal impairment CrCL
≥45 ml/min: no dose
adjustment;
CrCL <45 ml/min: no
data available but caution.
Special populations
Age
↑ sensitivity in elderly
due to ↓ renal function.
Renal impairment
Cr CL ≤80 ml/min: ↓
dose; Cr CL <50 ml/min:
discontinue.
Liver impairment
No need of ↓ dose.
competes with polyglutamated species for DHFR; the
dose of LV to rescue normal
cells depends on MTX
concentration; MTX cytotoxicity depends on drug
concentration and duration of
exposure.
Therapeutic concentrations:
1 × 10−6 mol/l.
Warning
Do not use preservativecontaining solutions.
No interaction
IV (10 min inf) every 3
with aspirin, or
weeks: 500 mg/m2 with
DDP.
vitamin supplementaWith NSAID: ↓ CL tion (vitamin B12 IM
(20%) and ↑ AUC 1000 µg, 1–3 weeks
(20%) with ibubefore and every 9
profen.
weeks during study;
folic acid PO 350–1000
Caution
µg starting 1–3 weeks
Concomitant
NSAID use in renal before and continuing
impairment (CrCL until 30 days after
discontinuation).
45–79 ml/min);
avoid NSAIDs with Skin rash prophylaxis:
short T1/2 for 2 days PO DXM 4 mg b.i.d.
before, the day of, days 1 to 2.
and 2 days following pemetrexed
administration. No
information for
long-acting
NSAIDs; avoid
NSAIDs with long
T1/2 for 5 days
before, the day of,
and 2 days following pemetrexed
administration.
continue up to
<5 × 10−8 M.
PO: 15–20 mg/m2 × 2
per week.
IT: >3 years old: 12 mg
total dose every 2–7
days.
(Continued)
G3–4 toxicities in with
NSCLC pts receiving
vitamin supplementation: 5% neutropenia,
4% anemia, 2%
thrombocytopenia, 2%
ALT elevation, 5%
fatigue, 3% nausea, 2%
febrile neutropenia, 1%
stomatitis, 1% rash,
0.5% diarrhea.
spasticity; ↑ with
concomitant
cerebral RT).
303
Uracil analog with fluorine atom substituted for
H at C5 of the pyrimidine
ring.
5-Fluorouracil (5-FU)
Pyrimidine analogs
Name, chemistry, relevant
features
Intracellular activation to: 1. FdUMP
with inhibition of TS
(ternary complex
with CH2-FH4) and
inhibition of DNA
synthesis and repair;
2. FUMP, metabolized to FUTP, with
incorporation into
RNA, altering RNA
functions; 3. FdUMP
phosphorylated to
FdUTP with incorporation into DNA.
1. Is probably the
principal mechanism
with long T1/2 (6 h) of
ternary complex.
Resistance due to
deletion of activating
enzymes, relative
deficiency of CH2FH4, alterations in
TS, ↑ activity of
catabolic enzymes.
Pattern of 5FU
metabolism different
in different normal
tissues and tumor
types; mechanism of
Mechanism of action
Erratic F, also because of
first-pass effect. After IV
bolus T1/2β 6–20 min
with <1 µM (cytotoxic)
within few hours; nonlinear PK at higher doses,
with ↓ non-renal CL due
to saturation of catabolism. Crosses BBB; Tmax 30
min. Rapid catabolism
(50% of dose) in liver and
in tissues to F-DHU by
DPD; main biliary excretion of 5FU and catabolites; extensive catabolism
also extrahepatic. 50% of
dose cleared through liver
first-pass after HAI or IV
portal infusion. After i.p.
treatment 300:1 gradient
between i.p.:IV concentrations due to slow
peritoneal absorption and
rapid liver metabolism
with low systemic
toxicity.
Improvement of therapeutic index by adapting
5FU dose to AUC in H &
N pts receiving 5FU (96 h
inf.) and DDP in a
Pharmacology and dose
modifications
Incompatible in
solution with any
acidic agent; incompatible with diazepam, AraC, DOX,
MTX.
With LV: stabilization
of the FdUMP-TSfolate ternary complex; with
dipyridamole (inhibitor of thymidine
uptake): ↓ dTTP and
↑ FdUMP; with MTX
(if given before 5FU):
↑ FUMP and FUTP;
with IFN and with
cisplatin: mechanism
of synergism still
uncertain; with
allopurinol (300 mg
t.i.d.): (selective
inhibition of 5FU
anabolism in normal
tissues), to prevent
toxicity; with delayed
high-dose uridine to
prevent myelosuppression.
Drug interactions
HD
IV (bolus): 375 mg/m2
on days 1–5, 1 h after
LV (30 min inf.) 500
mg/m2 on days 1–5
every 3 weeks.
IV (CI) 1000 mg/m2 on
days 1–5 every
3–4 weeks.
Combination with LV
Low dose
IV (bolus): 425 mg/m2
on days 1–5 immediately after LV (bolus)
20 mg/m2 on days 1–5
every 4–5 weeks.
Protect from light
IV (bolus) single
agent: 400–500 mg/m2
(12 mg/kg) on days
1–5 every 3–4 weeks;
500 mg/m2 per week
(15 mg/kg).
Maximum recommended daily dose =
800 mg.
Route, schedule, and
recommendations
Toxicity and clinical
efficacy partly related to
schedule of administration.
DL neutropenia (31% G
3–4) after 9–14 days; 7%
stomatitis; 6% diarrhea
(IV fluids and ↓ dose at
subsequent cycles if >3
discharge/day), excessive
lacrimation. Less frequent, skin hyperpigmentaton, radiation recall
with erythema, moderate
alopecia; transient
blurring of vision, eye
ocular toxicity with
lacrimation, nasal discharge. Rare, neurologic
disturbances with somnolence and cerebellar
ataxia (more frequent
after high-dose and LV
combination); cardiac
toxicity with chest pain,
ECG changes consistent
with myocardial ischemia, ↑ serum enzymes,
(↑ risk in pts with
pre-existing heart disease).
Toxicity
304
Tegafur (FT) and uracil in
a molar ratio of 1:4. FT is
5-FU linked to furan ring
(dehydroxylated ribose
sugar), to be administered
with LV.
UFT
Uftoral®
FT activated to 5-FU
in liver, inactivated to
F-DHU by DPD;
uracil supposed to
inhibit subsequent
catabolism in liver
with possibly higher
concentrations in
tumor than in blood
or normal tissues.
cytotoxicity also
related to drug
concentration and
time of exposure.
FT: 52% protein bound.
Rapid variable absorption;
Tmax 0.3–3 h; after 5 days
AUC and Css of 5-FU
after UFT equivalent to
those achieved with CI of
5-FU; no accumulation
after repeated doses;
<20% FT excreted in
urine.
Special populations
Liver impairment
Omit if bilirubin >4 ( NV
Pharmacogenomic
↑ risk of life-threatening
toxicities at standard
doses in DPD-deficient
persons; present in some
degrees in 3% of patients.
multicentric randomized
study.
With halogenated
antiviral agents:
severe myelosuppression and CNS toxicity.
DL GI toxicity (2%
diarrhea, 3% N & V, 5%
anorexia, mucositis);
3.5% asthenia; fatigue;
leukopenia.
PO: 300 mg/m2 daily
on days 1–28 plus LV
90 mg daily on days
1–28 every 5 weeks
(daily doses of both
drugs divided into 3
doses given every 8 h)
1 h before or 1 h after
meals.
(Continued)
IV + LV: ↑ frequency of
myelosuppression, stomatitis and neurological
disturbances. CI: DL
stomatitis and diarrhea;
slowly reversible handfoot syndrome (34% G
3–4) incidence related to
duration of infusion,
pyridoxine (50–150 mg
per day) possibly useful;
20% epigastric pain and
gastric ulcerations; ↑
frequency of cardiac
toxicity.
HAI or IV portal: mild
mucositis and GI symptoms; biliary sclerosis
with cholestatic jaundice;
catheter-related complications (thrombosis of the
gastroduodenal artery
with necrosis of intestinal
epithelium, hemorrhage,
perforation).
Prolonged CI: 200 mg/
m2 per day until
toxicity (×4–5 weeks).
HAI or IV portal
infusion i.p. 500 mg/l
PO not recommended.
305
Prodrug of 5-FU;
transformed to 5-FU
or to FdUMP. Similar
mechanism of action
as that of 5-FU.
Floxuridine (FUDR)
2-Deoxy-5-fluorodeoxyuridine; deoxyribonucleoside of 5–FU.
Mechanism of action
Name, chemistry, relevant
features
Drug interactions
Special population
↓ dose in pts with liver
impairment, prior pelvic
RT, prior alkylators.
Guidelines not available.
Narrow margin of
Given by HAI, higher
first-pass extraction (90%) safety CI.
than 5-FU (40%) with ↓
systemic toxicity; PK data
not available.
Special population
PK in liver/renal
impairment not
studied.
Undergo microsomal
oxidation by CYP2A6.
Pharmacology and dose
modifications
Toxicity
Catheter-related complications and drug-related
hepatic toxicity as those
of HAI and IV portal
Warning
5-FU: N & V, diarrhea,
Contraindications
stomatitis, localized
Poor nutritional state, ↓
erythema, ↑ LFTs,
BM function, potengastritis, cramps, abdomitially serious infections.
nal pain, intra-/extraheCaution
patic sclerosis, BM
Possibility of severe
depression,
toxic reaction: deliver
GI ulceration.
first course as inpatient. Discontinue therapy
promptly in case of first
signs of cardiac ischemia,
stomatitis, initial leucopenia, intractable vomiting,
and diarrhea.
Caution
In pts with history of
heart disease. In pts
receiving drugs affecting
CYP2A6 activity.
CI HAI: 0.2 mg/kg
on days 1–14 every
4 weeks.
Warning
Give the highest dose
of UFT in the morning
and lower doses in the
afternoon or evening if
the total number of
UFT capsules cannot
be evenly divided.
Route, schedule, and
recommendations
306
Xeloda®
5-Deoxy-5-fluoro-N[(pentyloxy) carbonyl]cytidine; rationally
designed oral fluoropyrimidine carbamate.
Capecitabine
Same as that of 5FU;
tumor-selective agent
with ↓ risk of toxicity
than with systemic
5FU. 5′-DFUR in
tumor converted by
Thd Pase to 5-FU,
further catabolized by
DPD; efficacy in
xenografts correlated
with ratio of Thd
Pase to DPD; tissue
distribution of
activating enzymes in
monkeys, but not in
rodents, comparable
to humans.
In xenografts, 5FU
concentrations in
tumor > than in
plasma and healthy
tissues and > than
after equitoxic doses
of 5FU. Antitumor
activity correlated
with total dose given.
Special populations
Age
No impact on PK, but
monitor >80 years for ↑
risk of diarrhea.
Renal impairment
Cr CL 30–50 ml/min: ↓
dose by 25%; Cr CL
<30 ml/min: discontinue.
Liver impairment
Unknown.
Pharmacogenomic
As with 5FU ↑ risk of G4
toxicities at standard
doses in persons with
DPD deficiency (3%
incidence).
<60% protein binding;
rapid (Tmax 1–2 h); rapid
and almost complete
absorption of unchanged
drug in fasting conditions,
70% with food. Selectively metabolized in liver
to 5′-DFCR by carboxylesterase then converted
to 5′-DFCR by cytidine
deaminase in liver and
tumor. 5′-DFCR is then
activated to 5FU mainly
in liver and at tumor site
(see mechanism). 84% of
dose in urine 24 h, 96%
over 7 days. In xenografts
↑ antitumor activity of
combinations of capecitabine than of combinations of 5FU.
Warning
Do not use in pts with
known hypersensitivity
to 5FU.
PO intermittent schedule, single agent and
combination same dose:
2500 mg/m2 daily in
2 divided doses for
2 weeks, followed by 1
week rest, every 3
weeks. Each dose taken
with water
12 h apart within
30 min from end of
meal.
(Continued)
DL 50% diarrhea (severe
15%), 54% hand-foot
syndrome (severe 17%),
48% hyperbilirubinemia
(severe 23%), 43% N
(severe 4%), 41% fatigue
(severe 8%), 35% abdominal pain (severe 10%),
27% V (severe 4%); 25%
stomatitis (severe 3%),
13% neutropenia (severe
3%), neurological
(<10%).
307
Synergism with
antitumor agents
producing DNA
breaks because of
inhibition of DNA
repair (alkylating
agents, DDP, VP16,
AMSA); synergism
with RNR inhibitors
(thymidine, HU,
fludarabine) because
of ↓ dCTP pools.
Incompatible with
heparin, insulin,
MTX, 5FU, penicillin,
and methylprednisolone.
13% protein bound; after
IV bolus Cmax 10 µM after
100 mg/m2, proportionally higher up to 3 g/m2
(2 h inf.) (>100 µM).
Rapid plasma elimination
with T1/2α of 10–15 min
and T1/2β of 30–150 min;
70–80% of dose in urine
as Ara-U; Ara-U predominates in plasma with T1/2β
of 3–6 h. After CI of
0.1–2 g/m2 daily proportional increase of Css up
to 5 µM; rapid increase of
plasma levels with toxicity
at higher doses due to
saturation of deamination.
After SC or CI, >2-fold
higher AUC than after IV
bolus. Crosses BBB with
Css CSF 20–40% of those
in plasma within 24 h of
CI.
After 50 mg/m2 IT, Cmax
of 1 mM with >0.1 µM
for 24 h, T1/2β of 3 h.
Drug concentration and
duration of exposure
primary determinants of
toxicity.
Activated to Ara-CTP
in tumor cells by
sequential kinase
activity; degraded to
inactive Ara-U by
widely distributed
deaminases. Ara-CTP
acts by inhibiting
DNA polymerase and
DNA repair and by
incorporation into
DNA; possible
differentiating effects
on leukemic cells at
lower doses. Cytotoxicity dependent on
duration of exposure
and rate of DNA
synthesis. Enters cells
by facilitated nucleoside transport system
at standard doses, by
passive diffusion at ↑
doses. Resistance due
to deficiency of CdR
kinase, ↑ of dCTP
pools, ↑ cytidine
deaminase activity, ↓
nucleoside transport
sites, ↓ intracellular
retention of Ara CTP.
Cytarabine (cytosine
arabinoside; Ara-C)
Cytosar®
Deoxycytidine antagonist
with arabinose instead of
deoxyribose.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Toxicity
High-dose
IV (3 h inf.
>200 mg/m2): 2–3 g/m2
b.i.d. days 1–6.
HD: 20% neurotoxicity
with reversible cerebellar
(10%) and cerebral
dysfunction (somnolence,
confusion); ↑ risk if >36
g/m2 total dose, >50 years
old, ↑ creatinine; repeat
neurological examination
daily; ↓ incidence with
longer infusion. Severe
myelotoxicity; mucositis;
total alopecia; diarrhea;
typhlitis and necrotizing
colitis. Conjunctivitis
(prophylactic steroids
drops up to 48 h after last
dose), sometimes hemorrhagic, with slowly
reversible visual acuity
Standard dose
SD: DL myelosuppresIV (12 h inf.): 100 mg/ sion with biphasic
m2 b.i.d. days 1–5 or 7. leukopenia; initial nadir
after 7–9 days, second
nadir after 12–15 days,
recovering within 2–3
weeks. Frequent acute GI
toxicity (N & V, abdominal pain, diarrhea);
stomatitis and intrahepatic cholestasis. Flu-like
syndrome with rashes,
myalgia, fever, appearing
6–12 h post-treatment.
Route, schedule, and
recommendations
308
Cytarabine liposome
DepoCyt®
As cytarabine;
sustained-release
formulation, direct
Cytarabine encapsulated
administration into
into spherical multivesicuCSF.
lar lipid-based particles
(Depo Foam) for IT
administration only.
Depo Foam particles
release drug by erosion
and are biodegradable and
metabolized.
In AML or ALL pts,
Ara-C uptake,
Ara-CTP formation
and retention in
blasts are determinant
of response.
After 50 mg IT, CSF peak
levels of free cytarabine
within 5 h; T1/2α ∼ 10 h,
T1/2β ∼ 141 h; free
cytarabine concentration
>0.02 µg/ml for >14 days;
negligible systemic
exposure due to rapid
Ara-U conversion in
plasma.
Special po]pulations
Renal impairment
At high dose, ↓ dose if ↑
Cr because of ↑ risk of
neurotoxicity.
Prophylaxis: DXM b.i.d.
4 mg days 1–5, 2 mg
day 6, 1 mg day 7.
Maintenance: every 4
weeks.
Induction and
consolidation: every
2 weeks.
IT (1–5 min bolus): 50
mg.
Low dose
SC or IV (bolus or CI):
5–20 mg/m2 daily ×
2–3 weeks.
IT: 30 mg/m2 × 2 per
week until CR, then
one additional dose.
(Continued)
IT: fever, headache,
chemical arachnoiditis
with vomiting, seizures
with transient paraplegia.
Rare: myelopathic
syndrome.
Acute neurotoxicity
within 5 days from
treatment: 25% headache;
18% chemical arachnoiditis (neck rigidity or
pain, meningism), ↓ with
steroids prophylaxis, ↑
with concomitant RT/CT;
19% nausea, 17% vomiting, fever, back pain;
transient ↑ of CSF
proteins and WBC after
administration.
DL myelosuppression.
problems. Rare: pulmonary toxicity with noncardiogenic edema.
309
Mechanism of action
Gemcitabine (d FdC)
Gemzar®
Intracellularly activated to dFdCTP by
CdR kinase with
2′2′-Difluorodeoxycytidine;
accumulation and
fluorine-substituted Ara-C
prolonged retention.
analogue.
Inhibition of DNA
synthesis through
incorporation into
DNA (masked chain
termination) and
inhibition of RNR
with depletion of
dNTP which compete
with dFdCTP for
incorporation into
DNA (self-potentiating mechanism).
Depletion of dNTP
lead also to: 1. ↑ rate
of dFdC phosphorylation; 2. ↓ activity of
cytidine deaminase,
self-potentiating
mechanisms.
Name, chemistry, relevant
features
Special populations
Renal impairment
↑ risk of HUS, monitor
closely.
Cytotoxicity reversed
by exogenous deoxycytidine; synergistic
effect in vitro/in vivo
of concomitant DDP
and RT.
Low protein binding;
linear PK; for 30 min inf.,
biphasic disappearance
with T1/2 of 8 min due to
tissue inactivation by
cytidine deaminase
(mainly liver and kidney)
to dFdU; 77% of dose as
dFdU in urine. Saturable
accumulation process of
dFd CTP; ↑ intracellular
concentrations possibly
achieved by longer drug
exposure; longer infusion
associated with ↑ Vd and
longer T1/2.
With warfarin: ↑
anticoagulant effect of
warfarin.
With radiosensitizer:
no available guidelines but ↓ dose if
concomitant RT and
avoid concomitant
use in NSCLC.
Drug interactions
Pharmacology and dose
modifications
IV (30 min inf): single
agent, 1000 mg/m2 per
week × 7 followed by 1
week rest, then weekly
× 3 every 4 weeks;
1000 mg/m2 per week
× 3 every 4 weeks;
combination with DDP,
1250 mg/m2 days 1, 8
every 3 weeks or 1000
mg/m2 days 1, 8, 15
every 4 weeks.
Route, schedule, and
recommendations
DL non-cumulative
myelotoxicity (25% G3–4
neutropenia, 5% thrombocytopenia); 75% ↑
LFTs, 10% G3–4; 65%
mild to moderate N & V;
40% mild ‘flu-like
syndrome’, 1.5% severe;
30% maculopapular rash;
30% peripheral edema.
15% alopecia; 8%
diarrhea; 7% stomatitis; ↑
non-hematological
side-effects after more
frequent administrations.
Rare: severe pulmonary
effects including edema,
interstitial pneumonitis
(1%), or ARDS: discontinue drug, steroids might
be effective; HUS in
presence of anemia with
evidence of microangiopathic hemolysis, elevation of bilirubin or LDH,
severe thrombocytopenia
and/or ↑ Cr.
Toxicity
310
Special populations
Renal impairment
According to GFR ml/
min: GFR >50: 100% of
dose; GFR 10–50: ↓ dose
by 50%; GFR <10:
discontinue.
(Continued)
DL leukopenia, after a
median of 10 days,
recovering at discontinuation; maculopapular
rash and facial erythema;
LFTs abnormalities;
drowsiness; transient
renal function abnormalities.
CML
PO: 20–30 mg/kg daily;
discontinue if WBC
<2.5 × 109/1 or Pt <100
× 109/1.
Radiosensitizer: 80 mg/
kg as a single dose,
every 3 days from at
least 7 days before
radiation.
With RT: radiation
recall reactions
independent from
timing of RT (may be
before, concomitant
or even after HU
administration).
With didanosine: ↑
incidence of pancreatitis and neurotoxicity.
With Ara-C: modulation of Ara-C activity,
with ↑ production of
Ara-CTP and incorporation into DNA.
With 5FU: antagonist
effect, with ↓ FdUMP
due to inhibition of
RNR.
Additive effect with
5FU and LV because
of ↓ dUMP pool
competing with
FdUMP for binding
to TS.
Well absorbed; Tmax 1 h,
50% of dose transformed
in liver and excreted in
urine and as respiratory
CO. T1/2 3.5–4 h.
Degraded by urease of
intestinal bacteria; metabolism unknown; 55%
excreted by renal route.
Crosses BBB and third
space fluids with peaks in
3 h.
Enters cells by
passive diffusion;
inhibits RNR with
depletion of ribonucleotides and
inhibition of DNA
synthesis and repair.
Radiation sensitizer.
Hydroxyurea (HU)
Hydroxycarbamide/
Hydroxyurea
NP
Hydrea®
CH4N2O2
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
MISCELLANEOUS AGENTS
311
Weak MAOI: avoid
concomitant use of
sympathomimetic
drugs (isoproterenol,
ephedrine), tricyclic
antidepressants,
gingseng, tyraminerich foods (dark beer,
cheese, red wine,
bananas), MOA and
Special populations
COMT inhibitors (↑
Renal and liver impairment
effect with headache,
No guidelines available
hypertensive crisis,
but ↓ dose.
tremor, palpitations).
With alcohol: disulfiram-like reaction
(severe G1 toxicity,
headache).
With antitumor
agents: possible
interaction through
inhibition of CYP450
system and depletion
of O6-AT.
Completely absorbed with
peak concentrations in
plasma and in CSF in 1 h.
Rapidly concentrated and
metabolized (T1/2β 10
min) in liver and kidney
with 75% of dose
excreted as metabolites in
24 h urine.
Prodrug; generates
several reactive free
radicals, with direct
damage to DNA
through autooxidation, chemical
decomposition, and
CYP450-mediated
metabolism; generates
also methyldiazonium
with monofunctional
alkylating activity.
Also DNA methylation mainly at N7-O6
of guanine with
extent of O6 methylation correlated to
O5-AT activity.
Procarbazine
N-methylhydrazine;
structure similar to MAO
inhibitors.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
DL delayed myelosuppression (mainly thrombocytopenia after up to 4
weeks); acute GI toxicity
(N & V, diarrhea), with
tolerance after continued
administration; flu-like
syndrome at the beginning of treatment; allergic
reactions with skin rash
and pulmonary infiltrates
(controlled with low-dose
cortisone); CNS disturbances (paresthesia,
headache, insomnia). Late
toxicities: azospermia,
anovulation, ↑ incidence
of second tumors after
MOPP + RT.
PO: 100 mg/m2 daily
days 1–14 every 4
weeks (MOPP regimen).
Warning
Start at low dose and
then escalate daily to
minimize GI toxicity.
Toxicity
Route, schedule, and
recommendations
312
a-(N-phtalimido)
glutarimide.
Thalidomide
Thalomid®
Immunomodulatory
agent with anti-inflammatory activity;
antiangiogenic effects.
Mechanism of action
not fully understood:
in humans ↓ suppression of excessive
TNFα production
and down modulation of selected
adhesion molecules.
Special population
No data available.
Protein binding
None known; avoid
unknown; F not estabconcomitant
lished; Tmax 3–6 h,
sedatives.
dose-proportional AUC,
Cmax less proportional
suggesting PO solubility
in aqueous media may
hinder absorption rate, fat
meals ↑ Tmax to 6 h;
distribution unknown,
crosses BBB; metabolism
unknown, liver metabolism minimal, undergoes
non-enzymatic hydrolysis;
mechanism of excretion
mostly unknown: T1/2 5–7
h, CL 1.1 ml/min, 0.7%
unchanged drug in 48 h
urine.
(Continued)
Most commom: 48%
fatigue, 43% drowsiness
Multiple myeloma: initial
and somnolence, 28%
dose 200 mg, then
dizziness, 22% tremor,
increase after 14 days
22% incoordination, 22%
to 400 mg daily, in
peripheral edema; 25%
absence of severe
generalized skin rash
side-effects.
(pruritic, macular,
Administer at bedtime to
erythematous; not dose
minimize dizziness and
related, reversible, can be
somnolence.
rechallenged at lower
Anticoagulant prophydoses); 22% depression
laxis: PO warfarin 1 mg
GI (59% constipation,
daily, suggested in pts
11% nausea); 15% TE.
receiving concomitant
Most severe: peripheral
CT.
neuropathy (up to 28%)
Warning
can be irreversible after
Do not start if ANC
chronic use (cumulative
>750/mm3.
dose not known) or if
Discontinue at earliest
severe; starts with symsymptoms of peripheral metrical paresthesias of
neuropathy, if clinically hands and feet, progressappropriate.
ing to cramps, postural
tremor, ↓ muscle
Teratogen
reflexes, palmar eryCan cause severe
thema, and brittle nails.
defects in humans,
Rare: hallucinations,
male and female
delayed skin ulcers,
contraception must be
Stevens–Johnson
implemented.
syndrome.
PO daily
313
Mechanism of action
Recombinant,
humanized, IgG1
MAB against the
extracellular
domain of the
erb-B2 receptor
(HER2).
Herceptin
Trastuzumab®
Binds to HER2
with inhibition of
proliferation and
mediation of
ADCC. HER2
protein overexpression tested by ICH
assays (e.g.
HercepTest); HER2
gene amplification
tested by FISH
assays (e.g.
PathVysion).
Monoclonal antibodies
Name, chemistry,
relevant features
TARGETED THERAPY
Dose-dependent PK
with ↑ T1/2 and ↓ CL at
higher doses; at the RD
terminal T1/2 5–8 days,
Vd 44 ml/kg; ↓ serum
concentration in
presence of high levels
of shedded Ag.
Pharmacology and dose
modifications
In vitro, in vivo
synergistic effects
with DDP, VP16,
and docetaxel;
additive with paclitaxel,
anthracyclines,
NVB.
Drug interactions
Toxicity
Most common: mild, less
frequently moderate: 42%
asthenia, 36% fever, 32% chills,
26% ↑ cough, 26% headache,
25% diarrhea, 23% dyspnea,
IV every 3 weeks: loading
20% infections, 18% rash,
dose: 90 min inf. 8 mg/
14% insomnia.
kg; maintenance: 90
Most serious: cardiomyopathy
min inf. 6 mg/kg.
5% severe CHF (responsive to
Warning
cardiac medications) with
Pre-existing cardiac
dyspnea, peripheral edema and
conditions or with prior
↓ LVEF; discontinue treatment
cardiotoxic
in pts with symptomatic CHF;
therapies: baseline
in combination with
cardiac assessment
anthracyclines 19%.
(EKG + Echo or Muga). HSR including anaphylaxis and
pulmonary symptoms mainly
Pre-existing pulmonary during initial infusion, rechalcompromise
lenge with steroids and antihisDo not administer
tamines. Infusion reaction
as an IV push or bolus. during first infusions with
Do not mix or dilute
chills, fever, nausea, vomiting,
with other drugs; do
hypotension (40% mild to
not mix with Dextrose
moderate); pulmonary events
solutions.
most frequent in elderly.
IV weekly: loading dose:
90 min inf. 4 mg/kg;
maintenance: 30 min
inf. 2 mg/kg.
Route, schedule, and
recommendations
314
Recombinant
chimeric
human IgG1
MAB
against the
extracellular
domain of EGFR
Cetuximab
Erbitux®
Specific, high-affinity binding to the
extracellular
portion of EGFR;
competitive antagonist of TGFα
resulting in:
1. Inhibition of
EGFR function
with ↓ cell proliferation, induction
of apoptosis, ↓
tumor angiogenesis, ↓ DNA repair.
2. Internalization
of EGFR with
downregulation.
Cetuximab also
exhibits ADCC. In
vitro additive
effects with cytotoxics, biological
agents, RT.
Synergistic activity
of combination of
Cetuximab plus
CPT11 in CRC
xenografts refractory to single agent
CPT11. Overexpression of EGFR
tested by ICH
assays.
Special populations
Age
No age effect.
Other
Not studied in
children, in pts with
renal and in pts with
moderate to severe liver
impairment
(AST and/or ALT >2.5
NV, or bilirubin
>1.5 × NV).
Linear increase of
Cmax and AUC up to
400 mg/m2;
dose-dependent CL
with plateau at
200 mg/m2 of
0.02 l/h/m2, possibly
due to a saturable
excretion pathway at
low doses; Tmax 1–2 h,
Vss 1.9–2.9 l/m2, T1/2
66–97 h at the RD
400/250 mg/m2; Css
achieved after 3 weeks
of treatment.
No PK interaction
with CPT11, DDP,
Gemcitabine, Paclitaxel, Docetaxel.
(Continued)
Immunogenicity: 4% HACA, not
clinically relevant.
Most common: acne-like rash
(88%, G3–4 14%), correlated
with response to treatment,
occurring mostly during the
Premedication with
first week, lasting for >90 days
antihistamine.
in 50% of pts, resolving in 50%
of pts within 30 days after
Skin reactions: prolong
discontinuation.
retreatment interval, ↓
dose, and symptomatic Other common G 3–4; 11%
asthenia, 10% dyspnea, 7%
topical steroids.
abdominal pain. 4% HSR,
occurring at first infusion in
Warning
Resuscitation equipment 80% of cases, mainly moderate,
with fever, chills, rash, dyspnea,
available. Monitor HR,
BP during the infusion, cough, back pain; controlled by
↓ infusion rate; if severe disconup to 1 h after.
tinue treatment permanently.
IV 2 h inf.: 400 mg/m2
day 1, then IV 1 h inf.
250 mg/m2 weekly.
315
Recombinant
humanized IgG1
MAB anti-VEGF.
With CPT11
(potential): 33% ↑
concentration of
SN-38 in pts
receiving
bevacizumab in
combination with
Special populations
CPT11/LV/5FU and
Age, gender
↑ of G3–4 diarrhea;
No adjustment required
extent and reasons of
for age, gender.
interaction uncerOther
tain.
No information
available in pts with
renal or liver
impairment.
T1/2 20 days; time to
Css 100 days; CL
1.2–2.66 1/day; higher
in males and in pts
with high tumor
burden.
Binds to
VEGF inhibiting
biological activity
in vitro and in vivo
by preventing the
interactions of
VEGF to the cell
surface receptors
Flt-1 and KDR.
Causes ↓ of
microvascular
growth and
metastatic spread
in murine colon
xenograft models.
Bevacizumab
Avastatin®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Toxicity
In combination with:
CPT11/LV/5FU.
IV (90 min infusion)
5 mg/kg once every
14 days until disease
progression. Start
treatment at least 28
days after surgery.
Post-bevacizumab
surgery: at least 20 days
after last administration.
Most common: (NB incidence
refers to the combination): 37%
leukopenia, 34% diarrhea, 10%
asthenia.
Most serious: GI perforation:
2–4% (potentially fatal), 1%
wound healing complications
(15% if surgery after bevacizumab; hemorrhage: 4–31%
G3–4 usually massive
hemoptysis (in NSCLC pts),
rare GI, subarachnoid and
Warning
stroke; TE: possibly ↑; hyperDo not administer as an
tension: 60–67% (placebo
IV push or bolus.
43%), G3–4 7–10% (placebo
Do not freeze; do not
2%); proteinuria: 2–4% G3,
shake.
rare (0.5%) nephrotic synDiscontinue permanently:
drome; CHF: 2%, ↑ risk (14%)
in case of GI perforawith concomitant DOX; HSR <
tion, wound dehiscence,
3%.
serious bleeding,
Immunogenicity: data uncertain
nephritic syndrome,
hypertensive crisis, HSR due to different assays.
(no data on rechallenge).
Temporary suspension:
in case of severe
proteinuria.
Route, schedule, and
recommendations
316
Binds to CD20
(human
B-lymphocyteImmunoradiotherarestricted differenpic agent; murine
tiation Ag, Bp35) a
IgG2a lambda MAB
transmembrane
against CD20,
phospho protein
covalently bound to
expressed on
iodine-131.
pre-B cells, mature
B cells, and in 90%
NHL B cells.
CD20 is not
internalized upon
binding, nor shed
or found in the
blood.
Mechanisms of
action not fully
elucidated, may
include triggering
of apoptosis (with
the contribution of
131
I), CDC and
ADCC. 7 weeks
from end of
treatment no
circulating CD20+
cells.
Tositumomab
Bexxar®
Special populations
Renal impairment
Not studied; 131I CL
might be ↓, leading to
↑ exposure.
After predosing with
unlabeled MAB ↓
splenic targeting and ↑
terminal T1/2. In pts
with high tumor
burden, splenomegaly,
or BM involvement, ↑
CL, Vd, and ↓ terminal
T1/2; elimination by
decay and urinary
excretion (98%).
Vaccines: not studied, but caution.
Anticoagulants and
drugs affecting Pt
function: potential
pharmacological
interaction with ↑ of
bleeding.
Two-step regimen: step
1 dosimetry, then after
7–14 days therapeutic
step.
Dosimetry:
Tositumomab 450 mg
IV (inf. 60 min),
followed by 131I
Tositumomab IV
(inf 20 min), monitor
postinfusion with
SPECT at 1 h, 2–4 and
7–10 days. If acceptable
biodistribution proceed
to therapy (single
course): Tositumomab
450 mg IV (inf. 60 min)
followed by 131I Tositumomab (35 mg Tositumomab) at therapeutic
doses according to Pt
count/mm3.
Do not treat if Pt <
100 000/mm3 Pt.
Maximum dose of 131I
Tositumomab: 75 cGy.
(Continued)
Secondary malignancies: 4.2
and 10.7% AML a/o myelodysplasia at 2 and 4 years, respectively, in patient previously
treated with APC, onset average
27 months; other
malignancies 5%.
Most common: 46% asthenia,
36% N (with V 15%); 29%
infusion-related effects (chills,
fever, rigor, hypotension,
dyspnea, bronchospasm,
sweating), during or within
48 h from therapy; 9–17%
hypothyroidism, 15% abdominal pain, 14% anorexia.
Most serious: pancytopenia
severe (G3–4) prolonged: 63%
neutropenia, 53%
thrombocytopenia, 29%
anemia; nadir 4–7 weeks,
recovering in 30 days (90 days
in 5% of pts); 45% infections,
12% hemorrhage; 6% HSR
(bronchospasm and angioedema), risk ↑ in pts with
HAMA.
317
Name, chemistry,
relevant features
Mechanism of action
Pharmacology and dose
modifications
Drug interactions
Warning
Resuscitation equipment
available.
HSR: discontinue
treatment and treat
appropriately.
Premedication with
acetominophene and
antihistamine suggested
but value not known.
Thyroid protective
therapy: initiate 24 h
before and for 14 days
after. Assess thyroid
status before treatment
and monitor annually.
Route, schedule, and
recommendations
Toxicity
318
Gefitinib
Iressa®
Selective EGFR-TK
inhibitor, which
blocks autophosSynthetic
phorylation of
anilinoquinazoline.
EGFR; EGFR
N-(3-chloroinhibition
4-fluorophenyl)maintained for
7-methoxy-624 h gives need of
(3-morpholinochronic treatment
propoxy)
for antitumor
quinazolin-4-amine. effect. No
correlation between
EGFR expression
and xenograft
sensitivity.
In vitro synergistic
effect with
radiation; at higher
doses proapoptic
effect mainly in
combination with
CT.
Small molecules
Special populations
No relationship with
body weight, age,
gender, ethnicity, renal
function.
Liver impairment
Not observed in pts
with mild to severe
LFTs alteration due to
liver mets. No data
available for noncancer-related
impairment.
90% protein bound. F
60%; slow absorption
with Cmax at 3–7 h.
Plasma Css achieved
within 10 days, with
56% and 30% interpt./
intrapt. variability.
Terminal T1/2 48 h.
Extensively distributed:
Vdss 1400 1 after IV.
Extensively metabolized by CYP, principally by 3A4; excretion
in feces (86%), renal
elimination (parent and
metabolites) <4%.
With CYP3A4
inhibitors or
inducers:
itraconazole
(inhibitor) ↑ 85%
AUC rifampicin
(inducer) ↓ 88%
AUC.
With drugs ↑ gastric
pH: potential reduction of plasma
concentrations.
With warfarin: INR
elevations and/or
bleeding events.
(Continued)
Very common: 48% G1–2
diarrhea, 12% G1–2 V, 56%
G1–2 pustular skin rash, rarely
Interrupt treatment
itchy.
temporarily (maximum
Common: 30% G1–2 ↑ AST/
14 days): for G 3–4:
ALT, 7% anorexia, 6% G1
diarrhea, ↑ LFTs, skin
asthenia, 2% conjunctivitis
rashes; any grade eye
alopecia.
symptoms.
Uncommon (0.1 to <1%):
Discontinue treatment
corneal erosion; G3–4 ILD, fatal
for acute onset or
in 34% of cases, as interstitial
worsening of pulmonary pneumonitis and alveolitis with
symptoms (dyspnea,
cough and fever, acute onset,
cough, fever).
higher mortality in case of
concurrent idiopathic
pulmonary fibrosis. ILD has
occurred in pts with prior RT
(31% of cases), prior CT (57%),
no previous therapy (12%).
PO: 250 mg fixed daily
dose.
319
N-(3-ethynylphenyl)-6,7-bis(2methoxyethoxy)-4quinazolinamine,
monohydrochloride.
With CYP3A4
>90% protein bound;
inducers: ↓ plasma
rapid absorption after
concentration.
oral administration
with Tmax 3–4 h; F in
humans not clarified,
T1/2 24 h, Css plasma
concentration
1.20 mg/ml; no drug
accumulation after
daily dosing
150 mg.
Metabolism: predominantly liver through
CYP3A4 and 3A5;
principal active metabolite OSI–420; by other
P450 systems also in
tumor tissues.
Excretion 90% in feces.
Direct and
reversible
inhibition of HER1/
EGFR TK, and
EGFR-dependent
proliferation at
nanomolar
concentrations. In
animals, 0.5 µg/ml
plasma
concentrations
result in EGFR
inhibition
associated with
antiproliferative
activity; after oral
administration,
maximum
inhibition 1 h,
>70% for >12 h.
Erlotinib
Tarceva®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Toxicity
Possible relationship between
skin toxicity and antitumor
effects, to be confirmed by
phase III analysis.
Most common: DL 39% diarrhea
PO: 150 mg daily
uninterrupted schedule. (≥G3 4%), 61% cutaneous rash
(≥G3 5%), 21% nausea, 21%
Treatment for skin rash:
pulmonary disorders (≥G3 2%),
steroid creams, topical
18% fatigue (≥G3 2%), 13%
antibiotics and systemic
acne, 11% vomiting, 10%
antihistamines have
headache, 8% dry eye, 8%
been tried.
dry mouth.
Route, schedule, and
recommendations
320
Competitive
inhibitor of Bcr-Abl
TK, constitutively
4-[(4-Methyl-1activated in Ph+
piperazinyl)
CML. Inhibits also
methyl]-N-[4-methTK of c-Kit, PDGF,
yl-3-[[4-(3and SCF. Inhibits
pyridinyl)-2-pyrimproliferation and
idinyl]
induces apoptosis
amino]-phenyl]
in vitro and in vivo
benzamide
Ph+ CML cells.
methanesulfonate.
Mechanism of
resistance not fully
elucidated,
includes AAG
binding, mutation
a/o amplification
(resulting in ↑
expression of
Bcr-Abl TK) of the
Bcr-Abl gene.
Imatinib mesylate
Gleevec®
Special populations
Age
Edema more frequent
in elderly; no pediatric
data.
Liver impairment
No guidelines, suggested: bilirubin
>3 × NV and AST 5 ×
NV: withhold, then if
bilirubin <1.5 × NV
and AST <2.5 × NV:
resume at ↓ doses.
95% protein bound; F
98%, Tmax 2–4 h, high
fat meals ↓ absorption;
linear and dose-dependent PK (25–1000 mg).
T1/2 parent and major
active metabolite,
respectively, 18
and 40 h.
Metabolized mainly by
CYP3A4, N-demethylated piperazine
derivative main active
human metabolite;
eliminated 13% in 7
days urine and 68% in
feces (mostly as metabolites); CL 8–14 1/h
with <40% interpt.
variability allowing
fixed dosing.
With CYP3A4
inhibitors
(ketoconazole,
grapefruit juice,
erythromycin, etc.):
↑ plasma
concentration.
With CYP3A4
inducers (DXM, St
John’s wort,
rifampicin,
phenytoin, etc.): ↓
plasma
concentration.
With CYP3A4
substrates
(cyclosporin,
triazolo benzodiazepine, etc.): ↑
plasma concentration
of substrate.
With CYP2D6
substrates (CTX,
beta-blockers,
morphine, etc.): ↑
Plasma concentration
of substrate.
With warfarin: ↑
anticoagulant effects.
With acetaminophen:
potential ↑
hepatotoxicity.
GIST: 400–600 mg
daily.
PO daily.
CML
Chronic phase: 400 mg
daily; accelerated phase:
600 mg daily.
↑ to 600 and 800 (400
× 2) respectively daily,
in absence of severe toxicity, if: disease progression or failure to
achieve hematological
response after 3
months, or failure to
achieve cytogenetic
response after 6–12
months, or loss of
previous hem or cytogenetic response.
(Continued)
Common: 55% fluid retention
(severe 1%), 42% N (15% V),
30% diarrhea, 32% rash, 35%
muscle cramps, 30% headache,
28% arthralgia, 23% abdominal
pain, 15% dyspepsia;
hematological: 19% hemorrhage (G3 1%), 12% ≥G3
neutropenia, 7% thrombocytopenia, 3% liver toxicity.
321
Natural retinoid;
related to retinol
(vitamin A);
differentiating
agent.
86% headache in 50% due to ↑
intracranial pressure
(pseudotumor cerebri, espeIntermittent PO
cially in children), early signs:
schedule (to overcome
papilledema, N & V, visual
metabolic induction);
disturbances; 77% skin and
45 mg/m2 daily, in two
mucosal toxicity (dryness,
divided doses, days
itching, peeling, cheilitis); 70%
1–14 every 3 months.
bone pain, arthralgia; 50% ↑
Administer in fed
LFTs slowly reversible; 25%
conditions.
edema, fatigue, fever and rigors;
17% ocular disorders; 25%
Monitor LFTs:
temporary withdrawal if RA-APL syndrome (usually
during first month) with
>5 × NV.
leukocytosis, fever, hypotenRA-APL syndrome: HD
sion, dyspnea, RX lung infilIV steroids at first
trates, fluid retention, CHF,
suspicion.
DIC-like syndrome (differential
diagnosis with APL). Teratogenic: avoid pregnancy.
Maintenance regimen
only
With CYP450
inducers: ↑ catabolism; unproven
clinical relevance.
With CYP450
inhibitors (e.g.
ketoconazole): ↑
T1/2 of unproven
clinical relevance.
>95% protein bound;
Tmax, 1–2 h; F 50%
affected by biliar pH
and high fat meal; high
interpt. variability of
absorption and plasma
levels. T1/2 <1 h,
undetectable after 10 h;
metabolized by CYP450
to 4-OXO-ATRA then
glucuronidated; 60%
excretion in urine, 30%
in feces.
Induces its own
metabolism: ↑ CL after
2 weeks chronic dosing
due to ↑ catabolism
and ↑ tissue
sequestration.
Differentiating
effect through
binding to cytosolic
and nuclear
receptors (RARs)
with induction of
transcription of
genes involved in
growth inhibition
and differentiation.
ATRA most active
among natural
retinoids in reversing changes of
epithelial-derived
malignancies.
Tretinoin (alltrans-retinoic acid,
ATRA)
Vesanoid®
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
322
2% protein bound;
minimal tissue binding;
T1/2α 15 min, T1/2 β 140
min; 42% excreted in
urine.
Cardioprotection
observed in >65 years
old and in pts with
LVEF low normal.
Cleared from plasma in
10 min; retained in
normal tissues; T1/2 9
min; 4% urinary excretion. High
concentration of free
thiol in BM, declining
within 2.5 h.
Cardioprotection:
intracellular hydrolysis to ring-opened
chelating agent with
removal of Fe2+ and
Cu2+ from DOXcomplexes and ↓ of
O2 free radicals
generation.
Dexrazoxane
Zinecar®
Prodrug; selectively
dephosphorylated in
normal tissues by
Cytoprotective
AP to free thiol
thiophosphate
which acts (a) by
compound.
binding to reactive
Indications: (1) to ↓
molecules of DDP
the cumulative renal
and (b) as a free
toxicity associated
radical scavenger of
with repeated
free radicals generadministrations of
ated by DDP and
DDP in pts with
RT.
ovarian and NSCL
Higher uptake and
cancers; (2) to ↓
metabolism in
incidence of modernormal cells due to
ate to severe xerostohigher pH and AP
mia in pts with
concentration.
H&N receiving
postsurgery RT
(1.8–2 Gy) to >75%
of both parotid
glands.
Amifostine
Ethyol®
Indication: continuation of DOX after
≥300 mg/m2 cumulative dose in pts in
whom
continued therapy
is indicated.
Bispiperazinedione;
cyclic derivative of
EDTA.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
RADIOCHEMOPROTECTANTS
Caution
In pts with preexisting cardiovascular/cerebrovascular
conditions.
With antihypertensives:
hypotension,
to be interrupted at
least 24 h before
Amifostine.
IV (15 min inf.): a
maximum of 30 min
should elapse within the
start of inf. and DOX
administration.
Dosage ratio to DOX:
10:1 (500 mg/m2: 50 mg/
m2).
With DOX: ↓
incidence and severity
of DOX cardiomyopathy. Does not influence PK of DOX.
HSR, severe cutaneous
reaction: discontinue
treatment.
Warning
Incidence of side-effects
↑ with longer infusion.
Antiemetic prophylaxis
with steroids and 5HT3
antagonists.
With CT:
IV (15 min inf.): 910 mg/
m2 30 min before DDP
(≥100 mg/m2) (keep pts
in supine position during
and after treatment).
With RT:
IV (3 min inf.):
200 mg/m2 15–30 min
before RT (keep pts in
supine position during
and after treatment).
Do not mix with other
drugs during infusion.
Warning
Cardiac function must be
monitored serially.
Route, schedule, and
recommendations
Drug interactions
DL toxicities: emesis (92%) and
hypotension (62%) at the end of
infusion, lasting 5 min.
Less frequent: sneezing, warm
flush, mild somnolence,
hypocalcemia (<1%).
Rare: HSR, serious cutaneous
reactions, more frequent in pts
receiving RT.
May add to chemotherapy myelotoxicity: serial CBC monitoring.
Urticaria 2%, pain on injection
site 7%.
Toxicity
323
Recombinant made
by gene-modified
mammalian cells
with human gene.
Glycoprotein
hormone for
erythropoiesis,
produced primarily
in peritubular
interstitial cells of
kidney; ↑ production due to ↑ gene
transcription if
kidney/liver
hypoxia.
Delayed incomplete
Not known.
absorption with sustained levels after SC.
T1/2 3–10 h, detectable
in plasma up to 24 h;
Tmax between 5 and
24 h after SC dosing;
hepatic metabolism
with desialyzation, 10%
excretion in urine.
Binds on specific
receptors on
committed
erythroid
progenitor cells,
stimulates
proliferation and
differentiation of
erythroid cells with
negative feedback
on hypoxic
stimulus. Inverse
correlation between
erythropoietin
plasma levels and
Hb concentration if
normal kidney
function.
Recombinant
human
erythropoietin
(rHuEPO)
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
GROWTH FACTORS AND SUPPORTIVE TREATMENT
Toxicity
Absolute contraindications: uncontrolled
hypertension, severe
cardiac/peripheral
arteriopathies, recent
TIA, DVT.
Warning
EPO likely to be
ineffective if erythropoietin plasma levels
>500 mU/ml.
Check hematocrit (Ht)
weekly, 25% dose
titration up or down,
discontinue if Ht >35%.
Exacerbation of pre-existent
hypertension with need of
CT-associatcd anemia:
weekly monitoring of BP; mild
150–300 mU/kg 3 times
arthralgia, local pain injection,
a week for 8 weeks.
pure red cell aplasia due to
Zidovudine-associated
neutralizing Ab to native
anemia: 100 mU/kg 3
erythropoietin; ↑ incidence of
times a week.
CVC thrombosis; potential
Supplemental iron if
stimulation of growth of some
serum ferritin <100 µg/l tumors.
or serum transferrin
saturation <0%.
SC
Route, schedule, and
recommendations
324
Differs from
rHuEPO for a
5-chain, instead
of a 3-chain
oligosaccharide,
with ↑ molecular
weight.
Darbepoetin alfa
(Aranesp)
Same mechanism
as endogenous
erythropoietin with
↑ Hb within 2–6
weeks after
starting.
Special populations
No age effect.
Linear PK within
Not known.
0.45–4.5 µg/kg with no
accumulation. After SC
administration slow
rate-limiting absorption
with T1/2 49 h (27–89
h), Cmax between 71
and 123 h; 37%
bioavailability in
chronic renal failure
pts.
Absolute
contraindications:
uncontrolled
hypertension, known
hypersensitivity.
Warning
EPO likely to be ineffective if erythropoietin
plasma levels
>500 mU/ml.
Supplemental iron
if serum ferritin <100
µg/l or serum transferrin
saturation <20%.
Keep Hb around 12 g/
dl; ↓ dose for ↑ Hb
>1 g/dl over 2 weeks;
discontinue if Hb
>14 g/dl, then restart at
50% dose.
SC: start with 2.25 µg/
kg once a week; check
Hb weekly, increase to
4.5 µg/kg once a week
for ↑ Hb <1 g/dl after 4
weeks; discontinue after
4 weeks for ↑ Hb still
>1 g/dl.
(Continued)
↑ risk of cardiovascular events,
exacerbation of pre-existing
hypertension with need of
weekly monitoring of BP.
Rare: severe allergic reaction
requiring discontinuation.
Most common: 23% hypertension, 21% myalgia, 16%
headache, 15% diarrhea, 11%
edema, 11% arthralgia, 11%
fluid retention, 10% back pain,
9% fatigue, 9% fever, 8% CNS,
8% rash, 6% TE, 1.3% PE.
325
Recombinant
glycoprotein
hormone necessary
to maintain
adequate numbers
of circulating PMN;
produced by
E. coli-inserted
G-CSF gene.
T1/2β 3.5 h; Tmax 2–8 h; With lithium: ↑
distributed into plasma ANC release, ↑
and BM, metabolized in frequency CBC.
liver and kidney.
By binding on
specific receptors
induces proliferation of granulocyte
progenitor cells, ↑
PMN chemotaxis,
phagocytosis and
intracellular killing.
Filgrastim
Neupogen®
G-CSF
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Paracetamol to control
bone pain.
Autologous or allogenic
BMT and in AML: start
the day of BM infusion,
>24 h after CT, >12 h
after total body irradiation, up to ANC
1500/mm3 for 3 days.
PBPC reinfusion: 5 µg/kg
daily starting up to 5
days after, up to ANC
10 000/mm3.
PBPC mobilization: 10
µg/kg (or 480 µg/day)
daily.
SC
CT-induced neutropenia:
5 µg/kg daily (or 300
µg), starting 1–5 days
after CT for 14 days or
up to ANC
5000–10 000/mm3;
check counts bi-weekly.
Route, schedule, and
recommendations
Exacerbation of pre-existing
inflammatory conditions.
20% bone pain, mainly medullary and iliac, due to ANC
expansion in BM, leg pain,
musculoskeletal pain; transient
↑ AP/LDH.
Rare: HSR, ARDS in neutropenic septic pts; sickle cell
crises in pts with sickle cell
disease.
Toxicity
326
Covalent conjugate
of filgrastim and
monomethoxypolyethylene glycol.
Pegfilgrastim
Neulasta®
Same as filgrastim
Special populations
No age effect.
↓ CL and prolonged
With lithium: ↑
persistence; as comANC release, ↑
pared to filgrastin
frequency CBC.
larger intrapt. variability with T1/2β of 15–80
h. Non-linear PK, ↓ CL
for ↑ dose, serum clearance related to ANC
count and body weight.
Long-lasting effect.
Warning
Must be given: at least
24 h after CT; at least
14 days prior to subsequent CT. Avoid use in
weekly or <3 weeks CT
schedules.
Absolute
contraindication:
known hypersensitivity.
Approved indication: ↓
incidence of infection.
SC
Adults and children ≥45
kg: 6 mg once per cycle.
Children <45 kg: dose
not defined (<6 mg).
(Continued)
26% mild to moderate medullary bone pain, 12% requiring
non-opioid analgesics, 19% ↑
LDH, 9% ↑ AP.
Rare: splenic rupture, ARDS,
sickle cell crises, HSR.
327
Mechanism of action
IL-11 (Oprelvekin) Stimulation of
proliferation of
Neumega®
HSC and
Recombinant
megakaryocyte
polypeptide,
progenitor cells,
thrombopoietic
induction of
growth factor for
megakaryocyte
prevention of severe
maturation.
thrombocytopenia
Stimulation of
and reduction of
osteoclastogenesis.
transfusions need
after
myelosuppressive
CT.
Name, chemistry,
relevant features
Drug interactions
Warning
In pts with CrCL <15
ml/min, doubling of
Cmax AUC and ↑ >20%
mean plasma volume,
with ↓ RBC volume
resulting in dilutional
anemia, prirmirely due
to Na and water
retention (beginning
after 3–5 days,
reversible within
1 week after
discontinuation).
After SC administration No interaction with
80% bioavailability.
filgrastim.
Tmax 3 ± 2 h, T1/2γ 7 h
with no accumulation
after repeated
administrations; low
urinary excretion.
Dose-dependent effect,
beginning 5–9 days
after start, continuing
up to 7 days from end,
recovering to baseline
within 14 days.
Pharmacology and dose
modifications
Absolute
contraindication: prior
hypersensitivity.
Caution in pts with:
pre-existing papilledema, prior/concomitant CHF, aggressive
hydration, atrial
arrhythmias. Safety of
chronic dosing not
established.
Warning
Discontinue at least 2
days before restarting
CT.
Monitor periodically Pt
count, fluid balance,
and electrolytes.
SC daily
Adults: 50 µg/kg, start
6-24 h after completion
of CT, continue up to
postnadir value of
50 000/mm3 Pt (usually
for 10–21 days).
Children: recommended
dose not defined, higher
doses used with ↑
side-effects, mainly
papilledema see toxicity.
Route, schedule, and
recommendations
Adults: 59% peripheral edema
due to fluid retention, 48% dyspnea, 41% headache, 36%
fever; 25% skin rash; cardiac:
dizziness, 14% palpitation, 20%
tachycardia, 15% arrhythmia;
1% papilledema.
Children: ↑ incidence due to ↑
doses up to 125 µg/kg; cardiac:
84% tachycardia, 24%
radiographic evidence of
cardiomegaly; 58% conjunctival
injection, 16% papilledema
after repeated courses, 11%
periosteal changes.
Rare (all pts): HSR including
anaphylaxis, after first or
subsequent doses.
Toxicity
328
Bisphosphonates
Pamidronate
Aredia®
aminohydroxypropylidenebiphosphate
Zoledronic acid
Zometa®
Inhibition of bone
resorption due to:
(1) direct
inhibition of
osteoclastic
activity;
(2) binding to Ca
phosphate crystals
in bone blocking
its dissolution and
bone/cartilage
resorption; (3)
inhibition of tumor
factors activating
osteoclasts and
bone resorption.
If renal impairment
after long-term use,
discontinue treatment
until recovery, repeat
examinations every
3–4 weeks.
Caution
No data in pts with Cr
>3 mg/dl or >245
µmol/l): ↑ inf. time.
Special populations
Renal impairment
Withhold treatment: if
Cr baseline normal and
Cr ↑ by 0.5 mg/dl; if
Cr baseline abnormal
and Cr ↑ by 1 mg/dl.
Re-introduce only if
recovery to 10%
baseline.
Zoledronic acid: 56%
protein bound; 44 ±
18% dose as parent
compound in 24 h
urine; triphasic plasma
disappearance with
T1/2α 0.23 h, T1/2β 1.75 h,
T1/2γ 167 h.
Pamidronate: not
metabolized but
exclusively eliminated
through renal excretion
(46%); CLR closely
correlated to renal
function.
Zoledronic acid
With loop diuretics,
aminoglycosides,
thalidomide: possible
↑ renal damage.
Pamidronate: none
known.
Warning
Do not mix with
Ca-cantaining
solution, administer
through a separate
line.
Zoledronic acid (Z) IV
Osteolytic lesions
15 min inf. 4 mg every
4 weeks.
Hypercalcemia
Hydrate to daily
diuresis 2 1/day. Titrate
dose to serum Ca
values.
Pamidronate (P) IV
Osteolytic lesions 90 mg
every 4 weeks. Inf
duration: 2 h inf.
(diluted in 250 ml NS
0.9%); 4 h inf. (diluted
in 500 ml NS 0.9%).
Hypercalcemia
Hydrate to daily diuresis 2 1/day. Titrate dose
to serum Ca values.
Maximum effect within
3–7 days, at least 7 days
within retreatments if
no activity.
Gr 3–4 (%) P Z
Hypocalcemia 2 1, hypophosphatemia 38 53
Hypomagnesemia 1 0
Renal deterioration <1 <1
Nausea 45 43
Vomiting 30 30
Fatigue 37 36
Diarrhea 25 32
Pyrexia 28 30
Myalgia 24 21
Paresthesia 14 12
Rash 11 11.
Rare: scleritis
within 6 h to 2 days
after P.
329
List of drugs
1. Alkylating agents
1.1 Nitrogen mustard
Meclorethamine
Cyclophosphamide (CTX)
Ifosfamide (IFO)
Mesna
1.3 Ethylenimines
Thiotepa
Hexamethylmelamine
1.4 Nitrosoureas
CCNU
Streptozocin
1.6 Imidazotetrazines
Temozolomide
2. Platinum compounds
Cisplatin (DDP)
Carboplatin (CBDCA)
Oxaliplatin
3. Antitumor antibiotics
Bleomycin sulfate (BLM)
Mitomycin C (MMC)
Dactinomycin (DACT)
4. Antimicrotubule agents
4.1 Vinca alkaloids
Vinblastine sulfate (VLB)
Vincristine sulfate (VCR)
Vinorelbine (NVB)
4.2 Taxanes
Paclitaxel
Docetaxel
5. Enzyme inhibitors: topoisomerase II inhibitors
5.1 Anthracyclines, anthracenediones
Doxorubicin (DOX)
Epirubicin (EPI)
Doxorubicin HCl liposome
5.2 Epipodophyllotoxins
Etoposide (VP16)
Etoposide phosphate
Teniposide (VM26)
6. Enzyme inhibitors: topoisomerase I inhibitors
6.1 Camptothecines
Irinotecan (CPT-11)
Topotecan
8. Antimetabolites
8.1 Antifolates
Leucovorin (LV)
Raltitrexed
Methotrexate (MTX)
Pemetrexed
8.2 Pyrimidine analogues
5-Fluorouracil (5-FU)
UFT
Floxuridine (FUDR)
Capecitabine
Cytarabine (cytosine arabinoside; Ara-C)
Cytarabine liposome
Gemcitabine (d FdC)
9. Miscellaneous agents
Hydroxyurea (HU)
Procarbazine
Thalidomide
10. Targeted therapy
10.1 Monoclonal antibodies
Herceptin
Cetuximab
Bevacizumab
Tositumomab
332 List of drugs
10.2 Small molecules
Gefitinib
Erlotinib
Imatinib mesylate
Tretinoin (all-trans-retinoic acid, ATRA)
11. Radiochemoprotectants
Dexrazoxane
Amifostine
13. Growth factors and supportive treatment
Recombinant human erythropoietin (rHeEPO)
Darbepoetin alfa
Filgrastim
Pegfilgrastim
IL-11 (Oprelvekin)
Biophosphonates
Index
Note: Locators in italics denote tables and illustrations.
18
F-fluoro-2-deoxy-D-glucose positron emission tomography, clinical
diagnosis 88, 89, 90
5-fluorouracil (5-FU) 304–5
abbreviations 276–7
drugs 276
abdominal ultrasound, staging 107
aberrant anti-growth signaling, molecular biology 26–9
acupuncture, smoking cessation 48
adenocarcinoma
BAC 63–5
classification 63
defining 63
histopathology 63–5
molecular profiling 266
pathoradiologic correlations 64
prognostic correlations 64–5
variants 63
adenosquamous carcinoma
defining 68
histopathology 68
adjuvant chemotherapy after surgical resection 147–52
meta-analyses 152
Adjuvant Lung Project Italy (ALPI trial) 148
Adjuvant Navelbine International Trialists Association (ANITA)
trial 152
adrenal metastases, clinical diagnosis 78–9
advanced NSCLC
bevacizumab 165
chemotherapy 158–65
erlotinib 164
first-line therapy 158–9, 161–2
second-line therapy 163–4
targeted therapies 164–5
three-drug combinations 161, 162
air pollution 6–7
alkylating agents 278–83
ALPI trial see Adjuvant Lung Project Italy
altered fractionation radiation therapy, NSCLC 141–2
alternative therapies, smoking cessation 48
amifostine 323
aminoacridines 297–8
anemia 243
angiogenesis, molecular biology 30–1
angiogenic factors, targeting 31
animal models, MM 195–7
ANITA see Adjuvant Navelbine International Trialists Association trial
ANNA-1 see antineuronal nuclear
autoantibodies-1-associated syndromes
ANNA-2 see type 2 antineuronal nuclear autoantibodies
anorexia, symptom management 241
anthracenediones 293–6
anthracyclines 293–6
anti-angiogenic agents, MM 201
anti-Ri antibodies, clinical diagnosis 83
antibiotics, antitumor 287–8
antifolates 301–3
antimetabolites 301–10
antimicrotubule agents 289–92
antineuronal nuclear autoantibodies-1-associated (ANNA-1)
syndromes, clinical diagnosis 83
antitumor antibiotics 287–8
anxiety, symptom management 241
APC see argon plasma coagulation
apoptosis, lung cancer 24–6
apoptotic pathways, targeting 25–6
Ara-C 308–9
argon plasma coagulation (APC), bronchoscopic treatment 211–12
asbestos, MM 191
atypical/typical carcinoid tumors 69–70
availability, tobacco policy 36
BAC see bronchioloalveolar carcinoma
basaloid carcinoma
differential diagnosis 66–8
cf LCNEC 66–7, 68
cf NSCLC 68
cf SCLC 66–7
334 Index
bevacizumab 316
advanced NSCLC 165
biomarkers, MM 198
bisphosphonates 329
bleomycin sulfate (BLM) 287
bone metastases, clinical diagnosis 80
bone scintigraphy, staging 107
bones, clubbing, fingers/toes 83–4
brain metastases
clinical diagnosis 79–80
complications 224–5
bronchioloalveolar carcinoma (BAC) 63–5
bronchoscopic treatment 210–17
advantages 213, 215
APC 211–12
cryotherapy 212
disadvantages 213, 215
EC 211–12
economic aspects 215
endobronchial brachytherapy 212
extraluminal tumors 214–15
indications 210
laser resection 211
mechanical obstruction removal 210–11
palliation of lung tumors 210–17
PDT 212–14
recommendations 215
results 214
stenting 214–15
techniques to remove endobronchial tumors 210–14
bronchoscopy
clinical diagnosis 91
staging 104
bronchus cancer, incidence 13–16
bupropionSR, smoking cessation 47
CALGB 9633 trial see Cancer and Leukemia Group B 9633 trial
camptothecines 299–300
Canada, costs 254–5
Cancer and Leukemia Group B (CALGB) 9633 trial 151–2
capecitabine 307
carbon monoxide
expired air 42
smoking cessation 42
carboplatin (CBDCA) 285
vs cisplatin 160
carcinogenesis 1–5
carcinogens, tobacco smoke 1–5
carcinoid tumors
differential diagnosis 70
histopathology 69–70
immunohistochemistry 69–70
typical/atypical 69–70
carcinosarcoma, histopathology 69
cardiac tamponade, complications 223–4
care, supportive see supportive care
causative agents, lung cancer 1–5
CBA see cost-benefit analysis
CCNU 282
central nervous system metastases, clinical diagnosis 79–80
cervical mediastinoscopy, staging 107–8
cessation, smoking see smoking cessation
cetuximab 315
chemotherapy
adjuvant chemotherapy after surgical resection 147–52
advanced NSCLC 158–65
agents used 184–7
bevacizumab 165
chemotherapy followed by radiotherapy 155
combined-modality therapy 137–41
concurrent chemoradiotherapy 155–7
docetaxel 163–4
elderly patients 163
erlotinib 164
first-line therapy 158–9, 161–2
induction chemoradiotherapy before surgery 154
induction chemotherapy before surgery 152–4
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
induction chemotherapy, restaging after 113–15
locally advanced unresectable (IIIA and IIIB) NSCLC 154–8
MM 199, 200
non-cisplatin-containing 159–61
NSCLC 147–69
platinum-based 158–9
poor performance patients 163
preoperative (neoadjuvant) chemotherapy 152–4
regimens, common 184–7
SCLC 184–9
second-line therapy 163–4, 187
topoisomerase inhibitors 184–7
two drugs vs one drug 161, 162
chest pain 220–1
see also Pancoast’s syndrome
symptom management 239–40
chest radiography
clinical diagnosis 84–5
staging 103–4, 109–13
children, tobacco policy 39
chromosomal abnormalities
3p 28–9
MM 192–3
cigarettes, changing, tobacco policy 38–9
cisplatin (DDP) 284
vs carboplatin 160
non-cisplatin-containing chemotherapy 159–61
classification
adenocarcinoma 63
histopathology 61–3
lung tumors 61–3
MM 194
SCC 61
SCLC 65
staging 97–102
TNM Classification of Malignant Tumors 97–102
clinical approach, smoking cessation 41
clinical diagnosis 75–96
18
F-fluoro-2-deoxy-D-glucose positron emission
tomography 88, 89, 90
adrenal metastases 78–9
ANNA-1 83
ANNA-2 83
anti-Ri antibodies 83
bone metastases 80
brain metastases 79–80
bronchoscopy 91
Index
central nervous system metastases 79–80
chest radiography 84–5
clubbing, fingers/toes 83–4
CT 86–8, 93
Cushing’s syndrome 82
diagnostic techniques 89–92
differential diagnosis 66–8, 70
ECOG 84, 85, 102–3
ectopic adrenocorticotropic hormone syndrome 82
endoscopic ultrasound 91–2
evaluation 75, 92–3
flexible fiberoptic bronchoscopy 91
future developments 93
GGOs 87–8
history 75–84
hypercalcemia 80
imaging 84–9
Karnofsky Performance Scale 84, 85
Lambert–Eaton myasthenic syndrome 82–3
liver metastases 79
local effects 75–6
magnetic resonance imaging 88
metastatic effects 78–80
MM 194, 200
neurologic syndromes 82–3
Pancoast’s syndrome 78, 79
paraneoplastic effects 80–4
physical examination 84, 85
pleural effusion 77
presentation aspects 75–6
regional extension effects 76–8
SIADH 80–2
skeletal metastases 80
SPN 86–7
sputum examination 90–1
superior vena cava syndrome 77–8
surgery, thoracic 92
techniques 89–92
thoracic surgery 92
TTNA 91
ultrasound 91–2
V/Q scans 88–9
clinical history and examination, staging 102–3
clinical presentation, MM 197
clonidine, smoking cessation 48
clubbing, fingers/toes, clinical diagnosis 83–4
combination therapies, MM 201–2
combined-modality therapy
NSCLC 137–41
patient selection 142
toxicity 142
complications 218–35
anemia 243
brain metastases 224–5
cardiac tamponade 223–4
chest pain 220–1
Cushing’s syndrome 228
DIC 232–3
digital clubbing 231–2
ectopic adrenocorticotropic hormone syndrome 228
extrathoracic 224–6
hemoptysis 219–20
HPO 231–2
humoral hypercalcemia 228–30
hypercalcemia 228–30
infections 218–19
Lambert–Eaton myasthenic syndrome 230
marantic endocarditis 233
nausea/vomiting 243
NBTE 233
neurologic syndromes 230–1
neutropenia 242–3
Pancoast’s syndrome 220–1
paraneoplastic cutaneous syndromes 231–2
paraneoplastic endocrine syndromes 226–8
paraneoplastic hematologic syndromes 232–3
paraneoplastic musculoskeletal syndromes 231–2
paraneoplastic neurologic syndromes 230
paraneoplastic syndromes 226–33
paraneoplastic vascular syndromes 232–3
PCD 230
peripheral neuropathy 230–1
pleural effusion 221–2
SCC 225–6
SIADH 226–8
superior sulcus tumors 220–1
SVCS 77–8, 222–3
thrombocytopenia 243
thromboembolic 232–3
tumor embolization 233
complications management, supportive care 241–3
computed tomography (CT)
clinical diagnosis 86–8, 93
future 264–5
future developments 93
GGOs 87–8
screening 53–60, 88
SPN 86–7
staging 104–7, 110
concurrent chemoradiaton, vs sequential
chemoradiation 139–40
cost-benefit analysis (CBA) 249
cost-effectiveness
lung cancer management 247–63
lung cancer treatment 255–9
cost-effectiveness analysis 248–9
cost-minimization analysis 248
cost-utility analysis 249
costs
assessing 250
assessing cost effectiveness 252–3
assessing effectiveness 252
bronchoscopic treatment 215
Canada 254–5
direct non-treatment 250
direct treatment 250
discounting 251–2
economic evaluation types 248–9
health-care policy 259
indirect 250
intangible 250
league tables 252–3
lung cancer economics 259
lung cancer management 247–63
methodologic issues 249–50
NSCLC 253–4
335
336 Index
costs (Continued)
SCLC 254
sensitivity analysis 251
setting 250–1
time horizon 250
transparency 251
uncertainty 251
cough, symptom management 240–1
CPT-11 see irinotecan
cryotherapy, bronchoscopic treatment 212
CT see computed tomography
cultural background, tobacco policy 36–7
Cushing’s syndrome
clinical diagnosis 82
complications 228
cyclophosphamide 278
cytarabine (cytosine arabinoside; Ara-C) 308–9
cytarabine liposome 309
cytology, MM 198
d FdC see gemcitabine
dactinomycin (DACT) 288
darbepoetin alfa 325
DDP see cisplatin
depression, symptom management 241
developing countries, tobacco policy 39
dexrazoxane 323
diagnosis, clinical see clinical diagnosis
diagnostic techniques, clinical diagnosis 89–92
DIC see disseminated intravascular coagulation
differential diagnosis
basaloid carcinoma 66–8
carcinoid tumors 70
LCNEC 66–7
SCLC 66–7
digital clubbing, complications 231–2
direct non-treatment costs 250
direct treatment costs 250
discounting, costs 251–2
disseminated intravascular coagulation (DIC), complications 232–3
docetaxel 292
second-line therapy 163–4
doxorubicin (DOX) 293–4
doxorubicin HCI liposome 295–6
DRR see digitally reconstructed radiograph
drugs, abbreviations 276
duration of smoking 17
dyspnea, symptom management 240
early disease, NSCLC 136–7
Eastern Cooperative Oncology Group (ECOG)
clinical diagnosis 84, 85, 102–3
staging 102–3
EC see electrocautery
ECOG see Eastern Cooperative Oncology Group
economic aspects see costs
ectopic adrenocorticotropic hormone syndrome
clinical diagnosis 82
complications 228
EGFR see epidermal growth factor receptor
elderly patients
chemotherapy 163
treatment, SCLC 187
electrocautery (EC), bronchoscopic treatment 211–12
endobronchial brachytherapy, bronchoscopic treatment 212
endoscopic ultrasound, clinical diagnosis 91–2
environmental agents 6–7
environmental tobacco smoke (ETS) 5–6
EPI see epirubicin
epidemiology 10–19
1930s onwards 10–12
1950s 12–13
1960s onwards 16–18
descriptive 13–16
etiology, 1950s 12–13
MM 190–1, 202
public health success 10–12
epidermal growth factor receptor (EGFR)
NSCLC 21–2
overexpression 21–2
signaling 21–2
targeted therapies 270–1
epipodophyllotoxins 297–8
epirubicin (EPI) 294–5
ERCC1 gene see excision repair cross-complementation group 1 gene
erlotinib 320
advanced NSCLC 164
ethylenimines 281
etiology, lung cancer 1–9
1950s 12–13
genetic susceptibility 7
etoposide (VP16) 297
etoposide phosphate 298
ETS see environmental tobacco smoke
evaluation, clinical diagnosis 75, 92–3
excision repair cross-complementation group 1 (ERCC1) gene,
future 269–70
experimental treatments, tumor suppressors 29
extraluminal tumors, bronchoscopic treatment 214–15
febrile neutropenia (FN) 242–3
females
lung cancer susceptibility 7–8
prevalence of smoking 17–18
filgrastim 326
financial aspects see costs
first-line therapy
advanced NSCLC 158–9, 161–2
duration 161–2
timing 161–2
flexible fiberoptic bronchoscopy, clinical diagnosis 91
floxuridine (FUDR) 306
FN see febrile neutropenia
FUDR see floxuridine
future 264–74
CT 264–5
ERCC1 gene 269–70
imaging 266–7
MALDI 266
molecular profiling 265–6
PET 266–7
pharmacogenomics 268–70
prognostic factors 267–8
radiotherapy 266–7, 268
RRM1 gene 269–70
screening 264–5
Index
staging 267
targeted therapies 270–1
tobacco policy 39–40
vaccines 271
future developments
clinical diagnosis 93
CT 93
screening 93
future directions
MM 200–2
radiotherapy 181–2
SCLC 181–2
gefitinib 319
gemcitabine (d FdC) 310
gender differences
incidence, lung cancer 61
lung cancer susceptibility 7–8
prevalence of smoking 17–18
gene therapy, MM 199
genetic susceptibility, lung cancer etiology 7
GGOs see ground-glass opacities
giant cell carcinoma, histopathology 68–9
global transcriptional profiling, MM 194–5
glossary, clinical pharmacokinetics 275–6
ground-glass opacities (GGOs), clinical diagnosis 87–8
growth factor receptors, overexpression 21–3
growth factors
targeting 24
VEGF 270–1
growth factors/supportive treatments 324–9
growth signals
EGFR overexpression 21–2
lung cancer 20–4
health-care policy, costs 259
health warnings, tobacco policy 36
hematologic parameters, staging 104
hemoptysis, complications 219–20
herceptin 314
hexamethylmelamine 281
histopathology
adenocarcinoma 63–5
adenosquamous carcinoma 68
carcinoid tumors 69–70
carcinosarcoma 69
classification, lung tumors 61–3
giant cell carcinoma 68–9
LCNEC 67–8
lung tumors 61–74
MM 198
NSCLC 67–8
pulmonary blastoma 69
sarcomatoid carcinoma 68–9
SCC 61
SCLC 65–7
spindle cell carcinoma 68–9
historical background, epidemiology 10–19
history
clinical diagnosis 75–84
clinical history and examination 102–3
HN2 see meclorethamine
HPO see hypertrophic pulmonary osteoarthropathy
337
HU see hydroxyurea
humoral hypercalcemia, complications 228–30
hydroxyurea (HU) 311
hypercalcemia
clinical diagnosis 80
complications 228–30
hypertrophic pulmonary osteoarthropathy (HPO),
complications 231–2
hypnosis, smoking cessation 48
IALT trial see International Adjuvant Lung Cancer trial
ifosfamide (IFO) 279
IL-11 (oprelvekin) 328
imaging
see also screening
18
F-fluoro-2-deoxy-D-glucose positron emission tomography 88,
89, 90
bone scintigraphy 107
chest radiography 84–5, 103–4, 109–13
clinical diagnosis 84–9
CT 53–60, 86–8, 93, 104–7, 110
future 266–7
MRI 88, 111–13
PET 109–11
scintigraphic scans 107
staging 103–7
V/Q scans 88–9
imatinib mesylate 321
imidazotetrazines 283
immunobiology, MM 195
immunotherapy, MM 199, 201
incidence
bronchus cancer 13–16
gender differences 61
lung cancer 1, 13–16, 61
trachea cancer 13–16
indirect costs 250
induction chemoradiation, NSCLC 140–1
induction chemoradiotherapy before surgery 154
induction chemotherapy
plus adjuvant surgery, SCLC 171–4
restaging after 113–15
before surgery 152–4
infections, complications 218–19
intangible costs 250
intensive care 238–9
International Adjuvant Lung Cancer trial (IALT trial) 148–51
International Staging System (ISS) 97–102
irinotecan (CPT-11) 299–300
ISS see International Staging System
Karnofsky Performance Scale, clinical diagnosis 84, 85
Lambert–Eaton myasthenic syndrome
clinical diagnosis 82–3
complications 230
large cell neuroendocrine carcinoma (LCNEC)
cf basaloid 66–7
cf basaloid carcinoma 68
differential diagnosis 66–7
histopathology 67–8
cf NSCLC 67–8
cf SCLC 66–7
338 Index
laser resection, bronchoscopic treatment 211
LCNEC see large cell neuroendocrine carcinoma
league tables, costs 252–3
legislation, tobacco policy 36–7
leucovorin (LV) 301
liver metastases, clinical diagnosis 79
local effects, clinical diagnosis 75–6
locally advanced disease
see also advanced NSCLC
defining 137
NSCLC 137–41
lung tumors
classification 61–3
histopathology 61–74
LV see leucovorin
magnetic resonance imaging (MRI)
clinical diagnosis 88
staging 111–13, 114
MALDI see matrix assisted laser desorption ionization mass
spectroscopy
malignant mesothelioma (MM) 190–206
animal models 195–7
anti-angiogenic agents 201
asbestos 191
biomarkers 198
chemotherapy 199, 200
chromosomal abnormalities 192–3
classification 194
clinical diagnosis 194, 197–8, 200
clinical presentation 197
combination therapies 201–2
course 197
cytology 198
epidemiology 190–1, 202
etiologic agents 191–2
future directions 200–2
gene therapy 199
global transcriptional profiling 194–5
histopathology 198
immunobiology 195
immunotherapy 199, 201
management 198–200
mesothelial tissues 191
NF2 gene 194
oncogenes 193
p16INK4a 193–4
pathobiology 194
pathogenesis 191–4
radiology 197
radiotherapy 199, 200
surgery 199–200
SV40 virus 191–2, 195–6
therapy, future 200–2
transcription factor p53 193
treatment summary 209
tumor biology 202
tumor suppressor genes 193–4
WT1 194
marantic endocarditis, complications 233
matrix assisted laser desorption ionization (MALDI) mass
spectroscopy, future 266
mechanical obstruction removal, bronchoscopic treatment 210–11
meclorethamine (HN2) 278
mediastinal exploration, staging 107–8
mediastinal needle biopsy, staging 108–9
Medical Expenditure Panel Survey (MEPS) 247–8
mesna 280
mesothelioma, malignant see malignant mesothelioma
metastasis
brain metastases 179–80
molecular biology 31–2
prophylactic cranial irradiation, NSCLC 142–3
prophylactic cranial irradiation, SCLC 179–80
metastatic effects, clinical diagnosis 78–80
metastatic process, targeting 32
methotrexate (MTX) 302–3
mitomycin C (MMC) 288
MM see malignant mesothelioma
MMC see mitomycin C
molecular alterations, lung cancer 20
molecular biology
aberrant anti-growth signaling 26–9
angiogenesis 30–1
apoptosis 24–6
growth signals 20–4
lung cancer 20–34
metastasis 31–2
replicative potential 29–30
telomerases 29–30
tissue invasion 31–2
molecular profiling
adenocarcinoma 266
future 265–6
monoclonal antibodies 314–18
mortality data, lung cancer 61, 75
motivation stages, smoking cessation 41–2
MRI see magnetic resonance imaging
MTX see methotrexate
mutations, Tp53 26–7
Myc amplification 23–4
National Cancer Institute of Canada (NCIC) JBR10 trial 151
nausea/vomiting 243
NBTE see non-bacterial thrombotic endocarditis
NCIC JBR10 trial see National Cancer Institute of Canada JBR10 trial
neurologic syndromes
clinical diagnosis 82–3
complications 230–1
neuropeptides, overexpression 23
neutropenia 242–3
new drugs, smoking cessation 48
NF2 gene, MM 194
nicotine replacement therapy (NRT)
smoking cessation 42–7
tobacco policy 37–8
nitrogen mustard 278–80
nitrosoureas 282
non-bacterial thrombotic endocarditis (NBTE), complications 233
non-cisplatin-containing chemotherapy 159–61
non-platinum doublets, vs platinum 160–1
non-small cell lung cancer (NSCLC)
adjuvant chemotherapy after surgical resection 147–52
advanced NSCLC, chemotherapy 158–65
altered fractionation radiation therapy 141–2
cf basaloid carcinoma 68
Index
chemotherapy 147–69
chemotherapy followed by radiotherapy 155
chemotherapy for advanced NSCLC 158–65
chemotherapy for locally advanced unresectable (IIIA and IIIB)
NSCLC 154–8
combined-modality therapy 137–41
concurrent chemoradiaton 139–40
concurrent chemoradiotherapy 155–7
costs 253–4
differential diagnosis 67–8
early disease 136–7
EGFR overexpression 21–2
first-line therapy 158–9, 161–2
histopathology 67–8
induction chemoradiation 140–1
induction chemoradiotherapy before surgery 154
induction chemotherapy before surgery 152–4
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
inoperable stage III treatment 208
cf LCNEC 67–8
locally advanced disease 137–41
palliative therapy 143
patient selection 142
preoperative (neoadjuvant) chemotherapy 152–4
prognostic indicators 115–17
prophylactic cranial irradiation 142–3
radiotherapy 136–46
second-line therapy 163–4
sequential chemoradiation 138–40
single-modality therapy 137
stage IA treatment 208
stage IB–IIIA treatment 208
stage IV (and IIIB with pleural effusion) treatment 208–9
superior sulcus tumors 141
surgery 123–35
targeted therapies 164–5
toxicity 142
treatment 123–69
treatment summary 208–9
nortriptyline, smoking cessation 47–8
NRT see nicotine replacement therapy
NSCLC see non-small cell lung cancer
NVB see vinorelbine
oncogenes
MM 193
targeting 24
oncogenic viruses 7
oprelvekin (IL-11) 328
outcome factors, lung cancer 75
overexpression
EGFR 21–2
growth factor receptors 21–3
neuropeptides 23
oxaliplatin 286
p16INK4a
MM 193–4
Rb signaling 27–8, 29
packet labeling, tobacco policy 36
paclitaxel 291
pain
see also Pancoast’s syndrome
chest 220–1
symptom management 239–40
palliation of lung tumors, bronchoscopic treatment 210–17
palliative therapy
NSCLC 143
radiotherapy 143, 181
SCLC 181
pamidronate 329
Pancoast’s syndrome 220–1
clinical diagnosis 78, 79
MRI 111
superior sulcus tumors 141, 220–1
paraneoplastic cerebellar degeneration (PCD),
complications 230
paraneoplastic cutaneous syndromes, complications 231–2
paraneoplastic effects, clinical diagnosis 80–4
paraneoplastic endocrine syndromes, complications 226–8
paraneoplastic hematologic syndromes, complications 232–3
paraneoplastic musculoskeletal syndromes,
complications 231–2
paraneoplastic neurologic syndromes, complications 230
paraneoplastic syndromes, complications 226–33
paraneoplastic vascular syndromes, complications 232–3
passive smoking 5–6
pathobiology, MM 194
pathogenesis, MM 191–4
patient selection
combined-modality therapy 142
NSCLC 142
toxicity 142
PCD see paraneoplastic cerebellar degeneration
PDT see photodynamic therapy
pegfilgrastim 327
pemetrexed 303
peripheral neuropathy, complications 230–1
PET see positron emission tomography
pharmacogenomics, future 268–70
photodynamic therapy (PDT), bronchoscopic treatment 212–14
physical examination, clinical diagnosis 84, 85
platinum-based chemotherapy 158–9
platinum compounds 284–6
platinum, vs non-platinum doublets 160–1
pleural effusion
clinical diagnosis 77
complications 221–2
policy, tobacco see tobacco policy
pollution, air 6–7
poor performance patients, chemotherapy 163
poor-prognosis patients, treatment, SCLC 187
positron emission tomography (PET)
future 266–7
staging 109–11
preoperative (neoadjuvant) chemotherapy, NSCLC 152–4
presentation aspects, clinical diagnosis 75–6
prevalence, lung cancer 1, 10
procarbazine 312
prognosis 117
prognostic correlations, adenocarcinoma 64–5
prognostic factors, future 267–8
prognostic indicators 115–17
NSCLC 115–17
promotion abolition, tobacco policy 36
339
340 Index
prophylactic cranial irradiation
NSCLC 142–3
SCLC 179–80
proteases, targeting 32
pulmonary blastoma, histopathology 69
pyrimidine analogs 304–10
quality of life (QoL) 236–46
assessing 236–8
critical care 238–9
intensive care 238–9
supportive care 236–46
radiochemoprotectants 323
radiography see imaging
radiology, MM 197
radiotherapy
altered fractionation radiation therapy 141–2
brain metastases 179–80
chemotherapy followed by radiotherapy 155
combined-modality therapy 137–41
concurrent chemoradiaton 139–40
concurrent chemoradiotherapy 155–7
current recommendations, SCLC 180–1, 182
future 266–7, 268
future directions 181–2
induction chemoradiation 140–1
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
MM 199, 200
NSCLC 136–46
palliative therapy 143, 181
prophylactic cranial irradiation 142–3, 179–80
SCLC 177–83
sequential chemoradiation 138–40
thoracic irradiation, SCLC 177–9
radon 6
raltitrexed 301
Ras mutations 22, 23
Rb signaling, p16INK4a 27–8, 29
recombinant human erythropoietin (rHuEPO) 324
regimens, common, SCLC 184–7
regional extension effects, clinical diagnosis 76–8
regulation of the product, tobacco policy 37
replicative potential, telomerases 29–30
restaging after induction chemotherapy 113–15
rHuEPO see recombinant human erythropoietin
ribonucleotide reductase M1 (RRM1) gene, future 269–70
rimonabant, smoking cessation 48
RRM1 gene see ribonucleotide reductase M1 gene
salvage surgery, SCLC 174–5
sarcomatoid carcinoma, histopathology 68–9
SCC see spinal cord compression; squamous cell carcinoma
scintigraphic scans, staging 107
SCLC see small cell lung cancer
screening 53–60, 88
CT 53–60, 88, 93
current evidence 53–5
current status 53–60
discussion points 56–7
future 264–5
future developments 93
recent developments 57–8
recommendations, professional societies 56–7
technical innovations 55–6
second-line therapy
advanced NSCLC 163–4
chemotherapy 163–4
SCLC 187
sensitivity analysis, costs 251
sequential chemoradiation
vs concurrent chemoradiaton 139–40
NSCLC 138–40
SIADH see syndrome of inappropriate antidiuretic hormone
single-modality therapy, NSCLC 137
skeletal effects, clubbing, fingers/toes 83–4
skeletal metastases, clinical diagnosis 80
small cell lung cancer (SCLC)
agents used 184–7
cf basaloid carcinoma 66–7
chemotherapy 184–9
classification 65
combined 65–6
costs 254
defining 65
differential diagnosis 66–7
extensive disease treatment 207–8
future directions 181–2
growth factor receptors overexpression 22–3
histopathology 65–7
induction chemotherapy plus adjuvant surgery 171–4
cf LCNEC 66–7
limited disease treatment 207
palliative therapy 181
primary surgery 171, 172
radiotherapy 177–83
recurrent disease treatment 208
regimens, common 184–7
salvage surgery 174–5
second-line therapy 187
surgery 170–6
surgery plus postoperative chemotherapy 171, 172
survivin 25–6
targeted therapies 187
thoracic irradiation 177–9
topoisomerase inhibitors 184–7
treatment 170–89
treatment summary 207–8
small molecules 319–22
smoke-free environments, tobacco policy 36
smokers, changing, tobacco policy 37–8
smoking cessation 41–52
acupuncture 48
alternative therapies 48
bupropionSR 47
cancer patients 49
carbon monoxide 42
clinical approach 41
clonidine 48
hypnosis 48
motivation stages 41–2
new drugs 48
nortriptyline 47–8
NRT 42–7
rimonabant 48
Index
smoking reduction 48–9
vaccines 48
varenicline 47
weight gain 49–50
smoking reduction, smoking cessation 48–9
SND see systematic nodal dissection
solitary pulmonary nodule (SPN), CT 86–7
spinal cord compression (SCC), complications 225–6
spindle cell carcinoma, histopathology 68–9
SPN see solitary pulmonary nodule
sputum examination
clinical diagnosis 90–1
sputum cytology 90
sputum cytometry 90–1
squamous cell carcinoma (SCC)
classification 61
defining 61
histopathology 61
variants 61
staging 97–115
abdominal ultrasound 107
bone scintigraphy 107
bronchoscopy 104
cervical mediastinoscopy 107–8
chest radiography 103–4, 109–13
classification 97–102
clinical history and examination 102–3
CT 104–7, 110
ECOG 102–3
future 267
hematologic parameters 104
imaging 103–7
ISS 97–102
mediastinal exploration 107–8
mediastinal needle biopsy 108–9
MRI 114
PET 109–11
process 99–102
restaging after induction chemotherapy 113–15
scintigraphic scans 107
SND 112–13, 114
system 97–102
TEMLA 108
tests 102–13
TNM Classification of Malignant Tumors 97–102
transesophageal fine needle aspiration 109
ultrasound 107
VAMLA 108
stenting, bronchoscopic treatment 214–15
streptozocin 282
superior sulcus tumors
see also Pancoast’s syndrome
NSCLC 141, 220–1
superior vena cava syndrome (SVCS)
clinical diagnosis 77–8
complications 222–3
supportive care
complications management 241–3
critical care 238–9
intensive care 238–9
QoL 236–46
symptom management 239–41
surgery
adjuvant chemotherapy after surgical resection 147–52
MM 199–200
NSCLC 123–35
SCLC 170–6
thoracic, clinical diagnosis 92
survivin, SCLC 25–6
SV40 virus, MM 191–2, 195–6
SVCS see superior vena cava syndrome
symptom management
anorexia 241
anxiety 241
cough 240–1
depression 241
dyspnea 240
pain 239–40
supportive care 239–41
weight loss 241
syndrome of inappropriate antidiuretic hormone (SIADH)
clinical diagnosis 80–2
complications 226–8
systematic nodal dissection (SND), staging 112–13, 114
targeted therapies
advanced NSCLC 164–5
EGFR 270–1
future 270–1
SCLC 187
VEGF 270–1
targeting
angiogenic factors 31
apoptotic pathways 25–6
growth factors 24
metastatic process 32
oncogenes 24
proteases 32
telomerases 30
tax, tobacco policy 36–7
taxanes 291–2
techniques
clinical diagnosis 89–92
endobronchial tumors removal 210–14
telomerases
replicative potential 29–30
targeting 30
telomere maintenance 30
TEMLA see transcervical extended mediastinal lymphadenectomy
temozolomide 283
teniposide (VM26) 298
TGFβ signaling, aberrant 28
thalidomide 313
thiotepa 281
thoracic irradiation, SCLC 177–9
thoracic surgery, clinical diagnosis 92
three-drug combinations, advanced NSCLC 161, 162
thrombocytopenia 243
thromboembolic complications 232–3
time horizon, costs 250
tissue invasion, molecular biology 31–2
TNM Classification of Malignant Tumors, staging 97–102
tobacco policy 35–40
availability 36
basic policy 36–9
children 39
341
342 Index
cigarettes, changing 38–9
cultural background 36–7
developing countries 39
future 39–40
health warnings 36
legislation 36–7
NRT 37–8
packet labeling 36
promotion abolition 36
regulation of the product 37
smoke-free environments 36
smokers, changing 37–8
tax 36–7
tobacco smoke, carcinogens 1–5
topoisomerase I inhibitors 299–300
topoisomerase II inhibitors 293–8
topoisomerase inhibitors, SCLC 184–7
topotecan 300
tositumomab 317–18
toxicity
combined-modality therapy 142
patient selection 142
Tp53 see transcription factor p53
trachea cancer, incidence 13–16
transcervical extended mediastinal lymphadenectomy (TEMLA ),
staging 108
transcription factor p53 (Tp53)
MM 193
mutations 26–7, 28
transesophageal fine needle aspiration, staging 109
transparency, costs 251
transthoracic needle aspiration (TTNA), clinical diagnosis 91
treatment, cost-effectiveness 255–9
treatment, NSCLC
chemotherapy 147–69
radiotherapy 136–46
summary 208–9
surgery 123–35
treatment, SCLC 170–89
chemotherapy 184–9
elderly patients 187
poor-prognosis patients 187
radiotherapy 177–83
summary 207–8
surgery 170–6
tretinoin 322
triplets, advanced NSCLC 161, 162
TTNA see transthoracic needle aspiration
tumor biology, MM 202
tumor embolization, complications 233
tumor suppressor genes, MM 193–4
tumor suppressors, experimental treatments 29
tumors, lung
classification 61–3
histopathology 61–74
type 2 antineuronal nuclear autoantibodies (ANNA-2), clinical
diagnosis 83
typical/atypical carcinoid tumors 69–70
UFT 305–6
UFT adjuvant trials 151
ultrasound
abdominal 107
clinical diagnosis 91–2
staging 107
uncertainty, costs 251
V/Q scans see ventilation-perfusion scans
vaccines
future 271
smoking cessation 48
VAMLA see video-assisted mediastinoscopic lymphadenectomy,
staging
varenicline, smoking cessation 47
vascular endothelial growth factor (VEGF), targeted
therapies 270–1
VCR see vincristine sulfate
VEGF see vascular endothelial growth factor
ventilation-perfusion (V/Q) scans, clinical diagnosis 88–9
video-assisted mediastinoscopic lymphadenectomy (VAMLA),
staging 108
vinblastine sulfate (VLB) 289
vinca alkaloids 289–90
vincristine sulfate (VCR) 289
vinorelbine (NVB) 290
viruses, oncogenic 7
VLB see vinblastine sulfate
VM26 see teniposide
vomiting see nausea/vomiting
VP16 see etoposide
weight gain, smoking cessation 49–50
weight loss, symptom management 241
Wilms’ tumor gene (WT1), MM 194
workplace exposure 6–7
WT1 see Wilms’ tumor gene
Lung
Hansen
Textbook of
Cancer
Textbook of Lung Cancer, Second Edition, published in association with the European
Society for Medical Oncology, is a comprehensive and multidisciplinary text, which
examines all aspects of this disease, with contributions from a multinational team
of authors on etiology, epidemiology, molecular biology, pathology, smoking,
detection and management, clinical features, staging and prognostic factors, surgery,
radiotherapy and chemotherapy. It provides essential information and guidance for
specialist trainees in oncology, and for the many physicians and specialists involved in
Table of contents
Etiology of lung cancer • Epidemiology of lung cancer • Molecular biology of lung cancer
• Tobacco policy • Smoking cessation programs • Current status of early lung cancer
screening • Histopathology of lung tumors • Clinical diagnosis and basic evaluation
• Staging, classification and prognosis • Treatment of non-small cell lung cancer
• Treatment of small cell lung cancer • Malignant mesothelioma • Summary of treatment
• Therapeutic bronchoscopy for palliation of lung tumors • Complications to lung cancer
• Quality of life and supportive care • The cost and cost-effectiveness of lung cancer
management • The future • Appendix: Chemotherapy
About the editor
Heine Hansen MD FRCP is Professor of Clinical Oncology at the Finsen Center,
National University Hospital, Copenhagen, Denmark.
Also available:
ESMO Handbook of Cancer Prevention
Edited by Schrijvers, Senn, Mellstedt, Zakotnik (ISBN: 9780415390859)
ESMO Handbook of Principles of Translational Research
Edited by Mellstedt, Schrijvers, Bafaloukos & Greil (ISBN: 9780415410915)
Lung Cancer – Translational and Emerging Therapies
Edited by Pandya, Brahmer & Hidalgo (ISBN: 9780849390210)
Image-Guided Radiotherapy of Lung Cancer
Edited by Cox, Chang & Komaki (ISBN: 9780849387838)
Lung Cancer
the field of lung cancer.
Textbook of
Second Edition
Cancer
Second Edition
Edited by
Heine Hansen
Textbook of Surgical Oncology
Edited by Poston, Beauchamp & Ruers (ISBN: 9781841845074)
Lung Cancer Therapy Annual 6
Edited by Hansen (ISBN 9780415465458)
Second
Edition
www.informahealthcare.com
Lung
Textbook of
Published in association with
the European Society for Medical Oncology
Hansen
Textbook of
Cancer
Textbook of Lung Cancer, Second Edition, published in association with the European
Society for Medical Oncology, is a comprehensive and multidisciplinary text, which
examines all aspects of this disease, with contributions from a multinational team
of authors on etiology, epidemiology, molecular biology, pathology, smoking,
detection and management, clinical features, staging and prognostic factors, surgery,
radiotherapy and chemotherapy. It provides essential information and guidance for
specialist trainees in oncology, and for the many physicians and specialists involved in
Table of contents
Etiology of lung cancer • Epidemiology of lung cancer • Molecular biology of lung cancer
• Tobacco policy • Smoking cessation programs • Current status of early lung cancer
screening • Histopathology of lung tumors • Clinical diagnosis and basic evaluation
• Staging, classification and prognosis • Treatment of non-small cell lung cancer
• Treatment of small cell lung cancer • Malignant mesothelioma • Summary of treatment
• Therapeutic bronchoscopy for palliation of lung tumors • Complications to lung cancer
• Quality of life and supportive care • The cost and cost-effectiveness of lung cancer
management • The future • Appendix: Chemotherapy
About the editor
Heine Hansen MD FRCP is Professor of Clinical Oncology at the Finsen Center,
National University Hospital, Copenhagen, Denmark.
Also available:
ESMO Handbook of Cancer Prevention
Edited by Schrijvers, Senn, Mellstedt, Zakotnik (ISBN: 9780415390859)
ESMO Handbook of Principles of Translational Research
Edited by Mellstedt, Schrijvers, Bafaloukos & Greil (ISBN: 9780415410915)
Lung Cancer – Translational and Emerging Therapies
Edited by Pandya, Brahmer & Hidalgo (ISBN: 9780849390210)
Image-Guided Radiotherapy of Lung Cancer
Edited by Cox, Chang & Komaki (ISBN: 9780849387838)
Lung Cancer
the field of lung cancer.
Textbook of
Second Edition
Cancer
Second Edition
Edited by
Heine Hansen
Textbook of Surgical Oncology
Edited by Poston, Beauchamp & Ruers (ISBN: 9781841845074)
Lung Cancer Therapy Annual 6
Edited by Hansen (ISBN 9780415465458)
Second
Edition
www.informahealthcare.com
Lung
Textbook of
Published in association with
the European Society for Medical Oncology
Textbook of Lung Cancer
Textbook of Lung Cancer
Second Edition
Edited by
Heine Hansen MD FRCP
Finsen Center
National University Hospital
Copenhagen
Denmark
© 2008 Informa UK Ltd
First published in the United Kingdom in 2000
Second edition published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ.
Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in
England and Wales number 1072954.
Tel: +44 (0)20 7017 5000
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of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing
Agency, 90 Tottenham Court Road, London W1P 0LP.
Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad
to acknowledge in subsequent reprints or editions any omissions brought to our attention.
The Author has asserted his right under the Copyright, Designs and Patents Act 1988 to be identified as the Author of this Work.
Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate
responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences
arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure
discussed herein, please consult the prescribing information or instructional material issued by the manufacturer.
A CIP record for this book is available from the British Library.
Library of Congress Cataloguing-in-Publication Data
Data available on application
ISBN-10: 0 415 38510 5
ISBN-13: 978 0 415 38510 7
Distributed in North and South America by
Taylor & Francis
6000 Broken Sound Parkway, NW, (Suite 300)
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Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401
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Contents
List of Contributors
vii
Preface
xi
Color plate
1. Etiology of lung cancer
Aage Haugen, Steen Mollerup
xiii
1
2. Epidemiology of lung cancer: a century of great success and ignominious failure
Peter Boyle, Sara Gandini, Nigel Gray
10
3. Molecular biology of lung cancer
Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot
20
4.
35
Tobacco policy
Nigel Gray
5. Smoking cessation programs
Philip Tønnesen
41
6. Current status of lung cancer screening
James L Mulshine
53
7. Histopathology of lung tumors
Elisabeth Brambilla, Sylvie Lantuejoul
61
8. Clinical diagnosis and basic evaluation
John J Mullon, Eric J Olson
75
9. Staging, classification, and prognosis
Michael Dusmet, Peter Goldstraw
97
10. Treatment of non-small cell lung cancer
10.1 Treatment of NSCLC: surgery
Robert J Korst
123
10.2 Treatment of NSCLC: radiotherapy
Merideth MM Wendland, William T Sause
136
vi Contents
10.3 Treatment of NSCLC: chemotherapy
Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias
147
11. Treatment of small cell lung cancer
12.
11.1 Treatment of SCLC: surgery
Hisao Asamura, Riken Kawachi
170
11.2 Treatment of SCLC: radiotherapy
Christopher M Lee, William T Sause
177
11.3 Treatment of SCLC: chemotherapy
Heine H Hansen, Morten Sørensen
184
Malignant mesothelioma
Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney
190
13. Summary of treatment
Heine H Hansen
207
14. Therapeutic bronchoscopy for palliation of lung tumors
Paul WA Kunst, Pieter E Postmus, Thomas G Sutedja
210
15. Complications of lung cancer
Vincenzo Minotti, Michele Montedoro, Maurizio Tonato
218
16. Quality of life and supportive care
Jean-Paul Sculier, Anne–Pascal Meert, Marianne Paesmans, Thierry Berghmans
236
17. The cost and cost-effectiveness of lung cancer management
William K Evans, Christopher J Longo
247
18.
The future
Giovanni Selvaggi, Giorgio Vittorio Scagliotti
264
Appendix: Chemotherapy
275
List of drugs
331
Index
333
Contributors
Sophia Agelaki MD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Hisao Asamura MD
Division of Thoracic Surgery
National Cancer Center Hospital
Tokyo
Japan
Thierry Berghmans MD
Department of Critical Care and
Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Peter Boyle MD
International Agency for Research on Cancer
Lyon
France
Elisabeth Brambilla MD PhD
Deptartment of Pathology
Michallon Hospital
CHRU Grenoble
National Institute for Health and
Medical Research
University Fourier Grenoble
Grenoble
France
Jenette Creaney MD
School of Medicine and Parmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Michael Dusmet MD FMH
Department of Thoracic Surgery
Royal Brompton Hospital
London
UK
Williams K Evans MD FRCPC
Department of Oncology
McMaster University
Hamilton, Ontario
Canada
Sara Gandini MD
Division of Epidemiology and Biostatics
European Institute of Oncology
Milan
Italy
Vassilis Georgoulias MD PhD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Peter Goldstraw MD
Department of Thoracic Surgery
Royal Brompton Hospital
London
UK
viii List of Contributors
Nigel Gray AO MBBS FRACP FRACMA
Tobacco Unit
International Agency for Research on Cancer
Lyon
France
Christopher J Longo PhD MSc BA
DeGroote School of Business
McMaster University
Hamilton, Ontario
Canada
Heine H Hansen MD
The Finsen Center
National University Hospital
Copenhagen
Denmark
Anne–Pascal Meert MD
Department of Critical Care and
Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Aage Haugen PhD
Department of Chemical and Biological
Working Environment
National Institute of Occupational Health
Oslo
Norway
Vincenzo Minotti MD
Department of Medical Oncology
Santa Maria Della Misericordia Hospital
Perugia
Italy
Riken Kawachi MD
Division of Thoracic Surgery
National Cancer Center Hospital
Tokyo
Japan
Steen Mollerup PhD
Department of Chemical and Biological
Working Environment
National Institute of Occupational Health
Oslo
Norway
Robert J korst MD
Daniel and Gloria Blumenthal Cancer Center
Valley Health System
Valley Hospital
Paramus, NJ
USA
Michele Montedoro MD
Department of Medical Oncology
Santa Maria Della Misericordia Hospital
Perugia
Italy
Peter WA Kunst MD PhD
Department of Pulmonary Diseases
HAGA Hospital
The Hague
The Netherlands
Sylvie Lantuejoul MD PhD
Department of Pathology
Michallon Hospital
CHRU Grenoble
National Institute for Health and Medical Research
University J. Fourier Grenoble
Grenoble
France
Christopher M Lee MD
Department of Radiation Oncology
University of Utah School of Medicine
Huntsman Cancer Hospital
Salt Lake City, UT
USA
John J Mullon MD
Division of Pulmonary and Critical Care Medicine
Mayo Clinic College of Medicine
Rochester, MN
USA
James L Mulshine MD
Rush University Medical Center
Chicago, IL
USA
Anna Nowak MD
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Eric J Olson MD
Division of Pulmonary and Critical Care Medicine
Mayo Clinic College of Medicine
Rochester, MN
USA
List of Contributors ix
Marianne Paesmans MSc
Data Center
Institut Jules Bordet
Brussels
Belgium
Athanasios G Pallis MD PhD
Department of Medical Oncology
University Hospital of Heraklion
Heraklion
Greece
Helle Pappot MD
Department of Oncology
Copenhagen University Hospital
Copenhagen
Denmark
Pieter E Postmus MD PhD
Department of Pulmonary Diseases
Vrije Universiteit University Medical Center
Amsterdam
The Netherlands
Hans Skovgaard Poulsen MD DMSc
Department of Radiation Biology
Copenhagen University Hospital
Copenhagen
Denmark
Thomas Tuxen Poulsen MSc
Department of Radiation Biology
Copenhagen University Hospital
Copenhagen
Denmark
Bruce WS Robinson MBBS MD FRACP
FRCP DTM&H FCCP
National Research Centre for Asbestos
Related Diseases
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
Cleo Robinson MD
National Research Centre for Asbestos
Related Diseases
School of Medicine and Pharmacology
Sir Charles Gairdner Hospital
Perth, WA
Australia
William T Sause MD
LDS Hospital Radiation Center
Salt Lake City, UT
USA
Giorgio V Scagliotti MD
Department of Clinical and Biological Sciences
University of Turin
Orbassano, Turin
Italy
Jean-Paul Sculier MD PhD
Department of Critical Care and Thoracic Oncology
Institut Jules Bordet
Brussels
Belgium
Giovanni Selvaggi MD
Department of Clinical and Biological Sciences
University of Turin
Orbassano, Turin
Italy
Morten Sørensen MD
The Finsen Center
National University Hospital
Copenhagen
Denmark
Tom G Sutedja MD PhD
Department of Pulmonary Diseases
Vrije Universiteit University Medical Center
Amsterdam
The Netherlands
Maurizio Tonato MD
Regional Cancer Center
Poloclinico Hospital
Perugia
Italy
Philip Tønnesen MD
Department of Pulmonary Medicine
Gentofte University Hospital
Hellerup
Denmark
Merideth MM Wendland MD
Department of Radiation Oncology
Huntsman Cancer Hospital
University of Utah
Salt Lake City, UT
USA
Preface
Since the publication of the first issue of this textbook
in 2000, the epidemiologic features of smoking have
undergone continuous changes and the worldwide
intensification of the battle against tobacco consumption is changing the geographic pattern. In the USA,
some western European countries, and Australia, the
incidence of lung cancer is decreasing among males,
while the disease continues to increase among females.
In the southern and eastern parts of Europe, lung cancer is on a rapid rise, and a similar pattern is seen in
highly populated countries like China, Indonesia, and
Japan. Other regions of the world, such as the Middle
East, Africa, and South America, show the same dismal
picture.
Worldwide, the annual number of new cases of lung
cancer is estimated at more than one million and is
expected to increase to ten million in 2025. Fortunately,
the political efforts to reduce the use of tobacco are
getting increasing attention in many countries and the
statistics are now showing the first positive results.
Among the epidemiologic changes we also see a
change in the histopathologic pattern, with a relative
decrease in squamous cell carcinoma and a rise in adenocarcinoma. Lately, important new information as
regards the biology of lung cancer is emerging, including new treatment approaches. The result is a slow, but
steady improvement of the overall management of lung
cancer based on an increasing use of combined modality therapy, consisting of surgery, chemotherapy, and
radiotherapy applied concurrently or sequentially in
early stage disease. Furthermore, new techniques are
gaining ground, both within surgery and radiotherapy,
and targeted medical therapy is being offered to more
and more patients.
The textbook brings up-to-date information about
lung cancer, based on worldwide experience, for the
use of the many physicians involved in this field.
Heine H Hansen
Color Plates
(a)
(c)
(b)
Figure 8.5
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma in the left upper lobe (a), with contralateral hilar metastasis
(b). (c) Coronal 18F-FDG-PET without CT fusion, demonstrating no extrathoracic involvement. Transbronchial needle aspirate of the right
hilar lymph node confirmed metastatic adenocarcinoma with stage IIIB NSCLC assigned.
xiv Color Plates
(a)
(c)
(b)
Figure 8.6
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma involving the left upper lobe with ipsilateral mediastinal
lymph node metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without CT fusion demonstrating mediastinal and
extrathoracic (left adrenal) involvement. CT-guided biopsy of the left adrenal confirmed metastatic adenocarcinoma with stage IV NSCLC
assigned.
Color Plates xv
Figure 9.13
The nodal chart established by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC)
in 1997.3
Figure 11.2.2
Anterior-posterior digitally reconstructed radiograph (DRR) illustrating a typical radiation portal which includes the primary tumor mass
and adjacent hilar/mediastinal lymph nodes.
xvi Color Plates
Figure 11.2.3
Conformal radiotherapy planning techniques allow escalated radiation doses to be delivered safely with simultaneous sparing of
surrounding critical structures. In this example, a combination of anterior-posterior and oblique fields (four fields in total) are utilized to
decrease radiation dose to the nearby spinal cord.
Figure 11.2.4
Right lateral digitally reconstructed radiograph (DRR) illustrating a typical portal used for prophylactic cranial irradiation.
1
Etiology of lung cancer
Aage Haugen, Steen Mollerup
Contents Introduction • Carcinogens in tobacco smoke • Environmental tobacco smoke • Air pollution,
radon, workplace exposure, and viruses • Genetic susceptibility and lung cancer etiology • Females and
lung cancer susceptibilty
INTRODUCTION
Lung cancer, which was rare at the beginning of the
20th century, is now a global problem. It is the most
frequent cancer in the world.1 Presently, 1.2 million
people die of lung cancer each year and the global incidence of lung cancer is increasing. A major contribution to this trend comes from the former socialist
economies and developing countries where smoking
rates are still high. Consequently, lung cancer will
remain a major cause of cancer death worldwide in the
21st century even though the prevalence of tobacco use
has declined in many high-income countries.
That carcinogens in tobacco smoke play a major
role in lung cancer is unquestionable. About 85–90%
of lung cancer patients are smokers.2 However, lung
cancer also occurs in people who have never smoked,
and this implies that factors such as environmental
tobacco smoke (ETS), environmental and domestic
air pollution, work-related risk factors, radon exposure,
and viruses may also have an impact on lung cancer
incidence rates. In addition, since fewer than 20% of
smokers will develop lung cancer in their lifetime, inherited predisposition may be an important component.
CARCINOGENS IN TOBACCO SMOKE
Lung carcinogenesis is mediated through an interaction
between several putative carcinogens. A smoker inhales
gas-phase smoke (so-called ‘mainstream smoke’) as well
as particulates (tar). Cigarette smoke is a complex mixture of compounds and more than 4000 compounds
have been identified in tobacco mainstream smoke3–7
(Table 1.1). Studies have led to the identification of
60–70 carcinogens: polycyclic aromatic hydrocarbons
(PAHs), heterocyclic hydrocarbons, N-nitrosamines,
aromatic amines, N-heterocyclic amines, aldehydes,
various organic compounds, inorganic compounds such
as hydrazine and some metals, and free radical species.
Table 1.2 lists likely causative agents for lung cancer.
Available evidence indicates that carcinogenic PAH
compounds and the tobacco-specific carcinogen NNK
(4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone)
are of major importance in lung cancer induction in
smokers.8 Most studies on tobacco smoking genotoxicity in the lung have focused on these compounds. They
are strong carcinogens and tobacco contains relatively
high amounts of PAHs and N-nitrosamines. However,
compounds such as aldehydes, butadiene, and benzene, which appear to have lower carcinogenic potential, are found in much higher quantities in tobacco
smoke.
PAHs are formed by incomplete combustion of
tobacco during smoking. PAHs, particularly benzo(a)
pyrene, induce tumors of the lung in laboratory animals by various routes of administration. Furthermore,
studies have demonstrated that human lung tissue can
metabolize PAHs to reactive metabolites that can interact with DNA, forming mutagenic DNA adducts.9 DNA
adduct formation is thought to be the primary initiating
event in carcinogenesis and may be predictive of
lung cancer risk.10,11 PAH–DNA adducts have been
detected in human lung samples, and increased levels
of PAH–DNA adducts in human lung tissue of smokers
and ex-smokers relative to non-smokers have been
reported in several studies.9 The major adduct formed
by activated benzo(a)pyrene, the (+)-anti-benzo(a)
pyrene-guanine adduct, is premutagenic, mispairing
with A and generating primarily G-to-T transversions.
The role of PAHs in lung cancer is consistent with data
on mutational analysis of the TP53 gene with the demonstration of a large number of G-to-T transversions at
certain bases (hotspots) in this gene in smokers’ lung
tumors.12 In vitro studies have shown a direct molecular link between benzo(a)pyrene and the development
of lung cancer. Exposure of human epithelial cell cultures to the reactive diol epoxide metabolites of this
carcinogen resulted in the formation of adducts and
TP53 hotspot mutations, similar to that observed in
lung tumors in smokers.13
2 Textbook of Lung Cancer
Table 1.1 Carcinogens in cigarette smoke
Agent
Amount in mainstream
cigarette smoke
IARC evaluation of
carcinogenicity
In animals
Polynuclear aromatic hydrocarbons
Benzo[a]anthracene
20–70 ng
Benzo[b]fluoranthene
4–22 ng
Benzo[j]fluoranthene
6–21 ng
Benzo[k]fluoranthene
6–12 ng
Benzo[a]pyrene
8.5–11.6 nga
Dibenz[a,h]anthracene
4 ng
Dibenzo[a,i]pyrene
1.7–3.2 ng
Dibenzo[a,e]pyrene
Present
Indeno[1,2,3-cd]pyrene
4–20 ng
5-Methylchrysene
ND-0.6 ng
Heterocyclic hydrocarbons
Furan
20–40 µgb
Dibenz(a,h)acridine
ND–0.1 ng
Dibenz(a,j) acridine
ND–10 ng
Dibenzo(c,g)carbazole
ND–0.7 ng
Benzo(b)furan
Present
N-Nitrosamines
N-Nitrosodimethylamine
0.1–180 ngb
N-Nitrosoethylmethylamine
ND–13 ng
N-Nitrosodiethylamine
ND–25 ngb
N-Nitrosopyrrolidine
1.5–110 ngb
N-Nitrosopiperidine
ND–9 ng
N-Nitrosodiethanolamine
ND–36 ngb
N′-Nitrosonornicotine
154–196 nga
4-(Methylnitrosamino)110–133 nga
1-(3-pyridyl)-1-butanone
Aromatic amines
2-Toluidine
30–200 ngb
2,6-Dimethylaniline
4–50 ng
2-Naphthylamine
1–22 ngb
4-Aminobiphenyl
2–5 ngb
N-Heterocyclic amines
A-α-C
25–260 ng
MeA-α-C
2–37 ng
IQ
0.3 ng
Trp-P-1
0.3–0.5 ng
Trp-P-2
0.8–1.1 ng
Glu-P-1
0.37–0.89 ng
Glu-P-2
0.25–0.88 ng
PhIP
11–23 ng
In humans
IARC group
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2A
2B
2B
2B
2A
2A
2B
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2B
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2A
2B
2A
2B
2B
2B
2Bc
2Bc
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
Sufficient
Sufficient
2A
2B
1
1
2B
2B
2A
2B
2B
2B
2B
2B
(Continued)
Etiology of lung cancer 3
Table 1.1 Continued
Agent
Amount in mainstream
cigarette smoke
Aldehydes
Formaldehyde
10.3–25 µga
Acetaldehyde
770–864 µga
Phenolic compounds
Catechol
59–81 µga
Caffeic acid
<3 µg
Volatile hydrocarbons
1,3-Butadiene
20–40 µgb
Isoprene
450–1000 µg
Benzene
12–50 µgb
Nitrohydrocarbons
Nitromethane
0.5–0.6 µg
2-Nitropropane
0.7–1.2 ngc
Nitrobenzene
25 µg
Miscellaneous organic compounds
Acetamide
38–56 µg
Acrylamide
Present
Acrylonitrile
3–15 µg
Vinyl chloride
11–15 ng
1,1-Dimethylhydrazine
Present
Ethylene oxide
7 µg
Propylene oxide
0–100 ng
Hydrazine
24–43 ng
Urethane
20–38 ngb
Metals and metal compounds
Arsenic
40–120 ngb
Beryllium
0.5 ng
Nickel
ND–600 ng
Chromium (hexavalent)
4–70 ng
Cadmium
41–62 ngb
Cobalt
0.13–0.20 ng
Lead (inorganic)
34–85 ng
Radio-isotope polonium-210
0.03–1.0 pCi
IARC evaluation of
carcinogenicity
In animals
In humans
IARC group
Sufficient
Sufficient
Limited
2A
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2B
Limited
Sufficient
2A
2B
1
Sufficient
Sufficient
Sufficient
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
2B
2A
2B
1
2B
1
2B
2B
2B
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
Sufficient
Sufficient
Sufficient
Sufficient
Sufficient
Limited
1
1
1
1
1
2B
2A
1
Modified from Hoffmann and Hoffmann,4 this table shows components of unfiltered mainstream cigarette smoke, with amounts given per cigarette.
Virtually all these compounds are known carcinogens in experimental animals. In combination with data on cancer in humans and – in some cases –
other relevant data, IARC Monograph classifications for these agents have been established as Group 2B (possibly carcinogenic to humans), Group 2A
(probably carcinogenic to humans), or Group 1 (carcinogenic to humans).
Abbreviations: ND, not detected; A-α-C, 2-amino-9H-pyrido[2,3-b]indole; IQ, 2-amino-3-methylimidazo-[4,5-b]quinoline;
Trp-P-1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b]indole; Glu-P-1, 2-amino6-methyl[1,2-a:3′2″-d]imidazole; Glu P-2, 2-aminodipyridol[1,2-a:3′,2″-d]imidazole; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine;
pCi, picoCurie.
a
Data from Swauger et al (2002) (for ‘full-flavor’ cigarettes).5
b
Data from US Department of Health and Human Services (1989).6
c
Corrected value (see Fowler and Bates, 2000).7
4 Textbook of Lung Cancer
Table 1.2 Causative agents in cigarette smoke
Carcinogens
Major risk factors
PAHs
Nitroso compounds
Tumor promoters/
co-carcinogens
Catechol
Phenol
Aldehydes
Oxidative radicals
Minor risk factors
Polonium-210
Aldehydes
Butadiene
Ni, Cd, Cr
Oxidative radicals
The concentration of nitrosamines found in tobacco
products is relatively high, and except for some occupational exposure situations, heavy smokers have the
highest exposure to N-nitroso compounds. The socalled tobacco-specific N-nitrosamines (TSNAs), principally the nicotine-derived NNK, are the strongest
respiratory carcinogens identified in tobacco products.
Adenocarcinoma of the lung is the main type of lung
cancer induced by NNK, and both benign and malignant tumors are formed in rats, mice, and hamsters.14
Moreover, human lung tissue metabolically activates
NNK, although less effectively than rodent lung tissue.
This activation is mediated by P450 monooxygenases,
cyclooxygenases, and lipooxygenases. Metabolites of
NNK have been reported in urine from smokers, and
NNK and N′-nitrosonornicotine (NNN)-specific DNA
adducts have been reported at increased levels in the
lungs of smokers.8,15 A high frequency of G-to-A transitions in the TP53 gene is consistent with the mutational
spectrum expected from NNK.12 NNK might also exert
its biologic activity through cell surface receptors such
as nicotine acetylcholine receptors (nAchRs) and
β-adrenergic receptors.16 Adenocarcinoma has now
overtaken squamous cell carcinoma as the most common lung cancer type, consistent with the role of NNK
in lung carcinogenesis. NNK concentrations in mainstream smoke have increased while those of benzo(a)
pyrene have decreased since the 1960s.
There are relatively high levels of metals in cigarette
smoke (Figure 1.1). At least 30 metals have been
identified.3,4 The contribution of these metals to increased
lung cancer risk is poorly understood. Experimental evidence indicates that many metals are effective initiators
of the carcinogenic process, but can also be potential
promoters during carcinogenesis. This is particular true
for tobacco smoke, where exposure to multiple agents
occurs. Cigarette smoke contains a substantial amount
of chromium, cadmium, and nickel. It is known that
chromium accumulates in the lung and tobacco smoking is the main source of cadmium exposure in humans.
It has been reported that chromates are carcinogenic in
rats, inducing lung tumors after instillation.17 Cadmium
chloride aerosols produce lung adenocarcinoma and
squamous cell carcinoma in rats,18 and nickel subsulfide yields lung cancer in rats upon inhalation.19 Because
of their relatively high levels in cigarette smoke, these
metals may play a role in lung carcinogenesis. They are
likely to contribute to lung cancer induction by multiple mechanisms such as inducing DNA damage (single
strand breaks, cross-linking of DNA and proteins), and
they could potentiate the genotoxicity of other DNAdamaging agents and enhance mutagenesis. Many studies have demonstrated that reactive oxygen species are
implicated in metal carcinogenesis.
Table 1.2 lists other constituents of tobacco-smoke
that could be involved in lung cancer induction. However, less importance has been attributed to these compounds in comparison with PAH and NNK. Inhalation
studies of formaldehyde and acetaldehyde have demonstrated that they are respiratory carcinogens in the
rat.20 These compounds are weak carcinogens, but the
levels are relatively high in cigarette smoke.
Polonium-210 (210Po) is a natural constituent of cigarette smoke and will deposit in the lungs of smokers,
emitting alpha particles.21 The content of several carcinogens in tobacco has been reduced due to changes
in tobacco processing methods and new cigarette filters, but this is not the case with the 210Po concentration, neither in tobacco nor in tobacco smoke. Radiation
exposure may induce lung cancer both alone and in
interaction with other carcinogens in tobacco. Animal
studies have shown that 210Po is a strong pulmonary
carcinogen in rats and Syrian golden hamsters.22
Cigarette smoke contains large amounts of free radicals and is known to induce oxidative damage. Both gas
and particulate phases are highly oxidized, and damage
the lung. Alkenes (i.e. unsaturated aliphatic hydrocarbons), nitrosamines, aromatic and heterocyclic hydrocarbons, amines, and catechol and hydroquinone are
all well known sources of reactive oxygen species such
as hydroxyl radicals, superoxides, and peroxides.23 Damage can also result from the activation of phagocytic cells
that generate reactive oxygen species (ROS).24 Cigarette
smoke is a strong inflammatory stimulus that induces
Etiology of lung cancer 5
Causative agents in cigarette smoke:
PAH, NNK, 210Po, Cr, Cd,
Ni, aldehydes, oxidative radicals
Phase 1
(activation)
Susceptibility:
Variation in
metabolism and
DNA repair
Nutrition
Immunologic
status
P 450
DNA-damaging
metabolites
Chronic exposure
DNA
repair
Days
DNA
repair
10–30 years
Excretion
Synergistic effect:
Asbestos
Chloromethyl ethers
Mustard gas
Radioactive ore
Preneoplastic
cells
Initiated cells
Normal cells
Phase 2
(detoxification)
Progression
Lung
cancer
DNA
repair
Months
Genetic changes:
TP53, KRAS, EGFR, inactivation of FHIT/RASSF1/SEMA3B (3p), INK4, RB
Activation of CCDN1; MYC1 - amplification
LOH (2q, 5q, 9q, 18q, 22q)
Figure 1.1
Lung carcinogenesis.
proinflammatory cytokines and recruits activated macrophages and neutrophils to lung tissue.25 Neutrophils
play an important role in the defense of the lung through
a variety of activities and generate oxidative radicals
when exposed to PAHs and aromatic amines. The oxidative capacity of neutrophils is therefore important
as a potential cause of oxidative damage to the lung.
Several epidemiologic studies have associated lung
inflammatory diseases such as asthma, bronchitis, and
chronic obstructive pulmonary disease (COPD) with an
increased risk of lung cancer development.
DNA is an important target for ROS. In order for
ROS to induce DNA damage, a sufficient concentration
must be available to overwhelm the antioxidant capacity of the lung. Products that result from oxidative damage to both lipids and DNA have been detected in
smokers at higher levels than in non-smokers. Although
the direct role of such products in carcinogenesis is
unclear, 8-oxoguanine (8-oxo-G), a frequent product of
oxidative damage, has miscoding properties associated
with the cancer induction process.26 Studies indicate
that unrepaired 8-oxo-G gives rise to G-to-T transversions. The most abundant genetic change induced as a
consequence of oxidative damage is GC-to-AT transition. Apart from oxidative modification of DNA bases,
free radicals are also able to induce single strand
breaks.
Nicotine is the agent in tobacco capable of producing
addiction, or nicotine dependence, and exists at high
concentrations in the blood of smokers. Direct involvement of nicotine in the development of lung cancer has
not yet been shown, but nicotine does appear to play an
important role and may have multiple sites of action. It
is absorbed rapidly when smokers inhale. Specific,
high-affinity nAChRs are found on human lung cancer
cells of all histologic types as well as in normal lung
tissue.27 Chronic exposure to nicotine can lead to the
activation of growth-promoting pathways upon its
interaction with nAChRs, and may also affect apoptosis
and angiogenesis.28
ENVIRONMENTAL TOBACCO SMOKE
Environmental tobacco smoke (ETS), or passive
smoking, is a mixture of exhaled mainstream smoke
and sidestream smoke diluted with ambient air. Cigarettes generate a large amount of ETS and affected individuals are exposed to the same carcinogens as an active
smoker. However, the relative proportions of the particular compounds may differ between mainstream and
sidestream smoke. For example, due to filters, concentrations of PAHs such as benzo(a)pyrene and benzo(a)
anthracene in the sidestream are approximately 10-fold
6 Textbook of Lung Cancer
higher than those in mainstream smoke. Benzene, formaldehyde, hydrazine, butadiene, N-nitrosamines, aniline, 2-naphthylamine, and 4-aminobiphenyl may
also be present at higher concentrations in sidestream
smoke.29
Many epidemiologic studies, which were evaluated
by the IARC in 2004,3 have shown an increased lung
cancer risk in never-smokers exposed to ETS. This is
particularly true for spouses of active smokers, where
ETS-exposed never-smoking females and males have an
excess risk of lung cancer in the order of 20 or 30%,
respectively. Never-smokers exposed to ETS in the
workplace may also be at an increased risk (12–19%).
Experimental studies have confirmed the carcinogenic
potential of ETS. Thus, concentrations of tobaccosmoke-related compounds adducted to biologic macromolecules such as proteins, and to a lesser extent DNA,
have been found to be increased in individuals exposed
to ETS.3 Also, lung tumors from ETS-exposed nonsmoking individuals show TP53 and KRAS mutations
similar to those found in tumors from smokers, although
at a lower frequency.30,31
AIR POLLUTION, RADON, WORKPLACE EXPOSURE,
AND VIRUSES
The different incidence rates for lung cancer among
non-smokers in different countries suggest that environmental agents can modify the risk. Air pollution is a
complex mixture of different gaseous and particulate
components that may pose a moderate risk factor for
lung cancer. Numerous air pollutants resulting from
heavy traffic, burning of fossil fuels, and industrial
plants are potential contributors to the incidence of
lung cancer. These include PAH, formaldehyde, benzene, ethylene oxide, petroleum vapors, and metals. An
association between lung cancer and air pollution has
been reported in studies from cities. Urban residents
with the highest exposure levels seem to have an
increase in lung cancer in the range of 1.5 times that of
rural residents.32 In a large European prospective study,
it was found that residence in proximity to heavy-traffic
roads or exposure to NO2 concentrations greater than
30 µg/m3 can increase the risk of lung cancer.33 In the
case of NO2, the lung cancer risk ratio has shown an
exposure–response relationship.34 In other studies, particulate matter (fine particles), SO2, and black smoke
have all been associated with a moderate increase in the
risk of lung cancer. However, analysis is complicated
due to the fact that air pollution is a complex mixture,
with numerous air pollutants that vary during the year
and over time. Since the lung has a large respiratory
volume (500–600 liters of air/h) with a large surface
area (75–85 m2), and a large blood perfusion, exposure
to toxic compounds in the ambient air could lead to
lung toxicity and lung cancer development even at low
levels.
Radon, a naturally reactive but chemically inert gas
found ubiquitously in the environment, emanates as a
toxic gas from the soil and from building material of
terrestrial origin, such as stone, bricks, and concrete.
High levels of radon exposure occur in occupational
settings, particularly in uranium mines. People are also
subjected to residential radon exposure, which may be
increasing due to the tendency to reduce ventilation
rates in indoor air. The carcinogenicity of radon is
attributable mainly to its short-lived, radioactive, alphaemitting daughters, polonium-214 and polonium-218.35
In miners, increasing risk of lung cancer is associated
with increasing cumulative exposure to radon.36 There
is also compelling evidence that indoor radon is an
important contributor to the risk of lung cancer.37 The
dose–response relation between residential radon exposure and excess risk of lung cancer appears to be linear
with no threshold. Overall estimates have been made
that radon may contribute to 9% of all lung cancers,
and the available data suggest that the risks of lung
cancer from exposure to radon and smoking are at least
additive.
Workplace exposure plays an important role in the
causation of lung cancer. The evidence for lung cancer
induction by occupational exposure to metals such as
beryllium, chromium, nickel and arsenic is convincing
and well documented.38 High exposure to PAH occurs
in several occupations, such as those involved in aluminium production, coke production, and coal gasification, iron and steel workers, bus drivers (because of
diesel engine exhaust), roofers, and asphalt workers.
The lung is the major target organ among PAH-exposed
workers.39 Although occupational exposure to asbestos
is no longer an issue in most developed countries, in
several developing countries exposure is widespread
and may be a significant etiologic factor for lung cancer.
As in most other exposure scenarios, tobacco smoking
is the main cause of lung cancer in asbestos-exposed
workers, and the relative risk seems to be higher among
non-smokers compared to smokers.40 Crystalline silica,
which may be inhaled in occupational settings, has been
classified as a lung carcinogen, with an apparent linear
dose–response relationship without any threshold.41
It is important to note, however, when assessing the
Etiology of lung cancer 7
etiology of lung cancer associated with occupational
exposure, that a significant confounder to be considered is tobacco smoking.
Oncogenic viruses may be involved in the etiology of
lung cancer. Some evidence has been provided for the
involvement of human papilloma viruses, but detection
rates of the viruses in bronchial carcinomas are highly
variable, ranging from 0 to 100% in different studies.42
Regarding other oncogenic viruses such as Epstein–
Barr virus, human cytomegalovirus, human herpes
virus-8, and simian virus 40, the evidence is scarce.43
repair genes involved in different repair pathways show
associations.
There is increasing knowledge of the genetic defects
that give rise to the observed variation in, and, more
importantly functional significance of these allelic variants. However, there are numerous conflicting reports
on the association between different polymorphisms
and lung cancer risk. Larger studies are needed in
this area.
FEMALES AND LUNG CANCER SUSCEPTIBILITY
GENETIC SUSCEPTIBILITY AND LUNG
CANCER ETIOLOGY
Host factors may influence individual susceptibility to
tobacco smoke. This may be illustrated by the fact that
only 1 in 10 lifetime smokers will develop lung cancer.
Several epidemiologic studies have indicated that there
are genetic factors modifying the risk of individuals to
lung cancer. Some degree of familial aggregation of lung
cancer is evident in most family studies. One study has
reported linkage to chromosome 6q in lung cancer families, strongly supporting the existence of a gene for
lung cancer.44 The human genome project has resulted
in increasing information becoming available on the
existence of polymorphisms in human genes. Susceptibility to lung cancer may be modulated by host-specific
factors including differences in carcinogen metabolism
and detoxification, DNA repair, cell cycle control, cell
signaling, apoptosis, and inflammation pathways. Several studies have been designed to evaluate a large
number of sequence variants among multiple genes
of drug-metabolizing enzymes.45 Procarcinogens in
tobacco smoke are activated by several forms of cytochrome P450 (phase I) and detoxified by glutathione
S-transferase (GST), NADPH:quinone oxidoreductase
(NQO), N-acetyl-transferase (NAT), and others (phase
II). Many of these genes exhibit allelism and there is
accumulating evidence that some CYP, GST, NQO, and
NAT genotypes are associated with an altered risk of
lung cancer.
The removal and repair of DNA damage plays a key
role in protecting the integrity of the genome from the
insults of genotoxic agents such as PAH and NNK found
in tobacco smoke. Lung cancer patients were reported
to have a lower DNA repair capacity, and recent studies
have assessed the relationship between single nucleotide polymorphisms (SNPs) in several DNA repair
genes and the risk of lung cancer.45–47 Several DNA
The relative lung cancer burden from women is
increasing, partly due to their changing smoking
habits. Although controversial, the increase in lung
cancer among females is possibly also partly due to a
higher susceptibility to tobacco smoke carcinogens.
Several studies have reported the relative risk of lung
cancer among females to exceed that of males by a
factor of 1.5 to 2.5.48–50 Although not all epidemiologic
studies have been able to confirm that females are at
increased risk,51,52 it is clear that biologic factors
involved in lung cancer development differ between
the sexes. Experimental studies have indicated sex
differences in PAH metabolism, DNA repair capacity,
and cell proliferation potential that may support this
hypothesis.
By analyzing the TP53 gene mutational spectra in a
large number of lung cancer cases, G:C-to-T:A hotspot
mutations were found at a higher frequency among
female smokers compared to female never-smokers.
Similar differences were not found among males.53
Since G:C-to-T:A transversions are associated with
exposure to PAH, this indicates a specific role for PAH
in generating this particular signature mutation in
women. Women have also been reported to have
increased levels of pulmonary tobacco-smoke-induced
DNA damage in the form of PAH-related adducts.54 The
DNA-adduct level may be a predictor of cancer risk.55
Higher DNA-adduct levels among females coincide
with a higher level of expression of the smoking-induced
cytochrome P450 1A1 (CYP1A1), which is an important
gene in the metabolic activation of PAH.56 Estrogens
and their receptors have been hypothesized to be
involved in these sex differences by interfering with the
transcription-activating activity of the aryl hydrocarbon
receptor (AHR). AHR is a ligand-activated transcription
factor with high affinity for PAH. In studies with lymphocytes isolated from lung cancer patients, it was
found that females might also have a lower capacity to
8 Textbook of Lung Cancer
repair DNA damage,57 which may result in increased
susceptibility to the manifestation of mutations.
One report has indicated that pulmonary expression
of the gastrin-releasing peptide receptor (GRPR), which
is involved in lung development during fetal stages, is
more frequent among women than men.58 The GRPR
gene is induced by smoking and is located on a region
of the X-chromosome that appears to escape X-chromosome inactivation in females. Activation of the GRPR has
been associated with an increased proliferative response
in human airway epithelial cells. Thus, this represents a
model where smoking may induce the gene to a higher
extent among women.
In summary, tobacco smoking (active smoking or
exposure to environmental tobacco smoke) plays a
major etiologic role in lung carcinogenesis. More than
60 compounds in tobacco smoke have been identified
as carcinogenic. Other etiologic factors of minor, but
still significant importance for the disease are air pollution, radon, workplace exposure, and viruses. Genetic
differences in susceptibility to lung cancer are apparent
and sex differences may be involved.
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2
Epidemiology of lung cancer: a century of
great success and ignominious failure
Peter Boyle, Sara Gandini, Nigel Gray
Contents Introduction • Phase I: public health success, 1930s onwards • Phase II: understanding
etiology, losing ground in incidence and mortality • Phase III: descriptive epidemiology of
lung cancer • Phase IV: public health failure, 1960s onwards
INTRODUCTION
The present century has witnessed a remarkable
epidemic of lung cancer. The words of Adler,1 published in 1912, today make salutary reading:
Is it worthwhile to write a monograph on the subject of primary malignant tumours of the lung? In
the course of the last two centuries an ever-increasing literature has accumulated around this subject.
But this literature is without correlation, much of it
buried in dissertations and other out-of-the-way
places, and, with but a few notable exceptions, no
attempt has been made to study the subject as a
whole, either the pathological or the clinical aspect
having been emphasised at the expense of the other,
according to the special predilection of the author.
On one point, however, there is nearly complete
consensus of opinion, and that is that primary malignant neoplasms of the lungs are among the rarest
forms of the disease. This latter opinion of the
extreme rarity of primary tumours has persisted for
centuries.
Lung cancer is currently the most common form of
cancer worldwide. It is the most common cause of cancer
death in men in North America and in virtually all
European countries, west and east, and it is increasingly
common as a cause of death in developing populations
in Asia, Latin America, and Africa, although comparable high-quality data are not available from many of
these populations. From being virtually an unknown
and rare disease at the beginning of the last century,
public health has documented the development of a
true epidemic of lung cancer through the 20th century,
and has failed to alleviate the situation by positive
actions. Knowing the cause, which has been the case for
lung cancer since at least the middle of the last century,
has been of little value in public health terms, since
there has been no real action taken to reduce the impact
of this serious disease.
In viewing the century of lung cancer epidemiology,
there are a number of distinct phases that can be identified. Initially (phase I), there was the great success of
epidemiology, the basic science of public health, in establishing the causal link between cigarette smoking and
lung cancer risk. Following this period, from the mid1950s onwards, there was a period (phase II) where
there was an increasing understanding of the etiology of
lung cancer, and simultaneously public health began
losing ground as smoking rates led to great increases in
the incidence and mortality of the disease, particularly
among men in developed countries. The association
between tobacco smoking and lung cancer became
widely known, and many groups actively took up the
movement towards tobacco control. During this period
(phase III), the situation stabilized while activists and
scientists united to try to bring the adverse effects of
tobacco smoking to general attention and thereby to
take actions designed to reduce smoking and its harmful side-effects. It quickly became clear that a great deal
of ground had been lost, and during phase IV large
increases in lung cancer among women became apparent, indicating the great failure of public health to curb
the development of the habit among women.
PHASE I: PUBLIC HEALTH SUCCESS, 1930s ONWARDS
The association between tobacco smoking and the
development of lung cancer appears to have been
suggested in the UK in 1927.2 The first interview study
on tobacco smoking and lung cancer seems to have
been reported from Vienna,3 where lung cancer rates
Epidemiology of lung cancer: a century of great success and ignominious failure 11
had risen dramatically. Fleckseder3 found 51 smokers
among 54 patients with lung cancer. Thirty-seven of
these smoked between 20 and 90 cigarettes daily, while
excessive smoking of pipes, cigars, or both was rarer.
The same association was alluded to in a report from
the USA4 on a study primarily of a series of
79 patients treated by total pneumonectomy. A report
from Cologne followed one year later,5 based on the
postmortem records of 96 patients. The patients (or
more usually the relatives of fatal cases) were interviewed as to patient’s occupation, tobacco consumption, and exposure to specific ‘inhalants’.
Reanalysis of Muller’s5 data shows a relative risk of
3.1 among moderate smokers, 2.7 among heavy smokers,
16.8 among very heavy smokers, and 29.16 among
excessive smokers. Within the limitations of the study
(e.g. small numbers, especially among non-smoking
cases, and possible inaccuracies in elucidation of precise smoking histories), these results were noticeably
similar to results obtained from later case–control studies in the USA and, apart from a lack of increase among
heavy smokers, there is the possible appearance of a
dose–response relationship.
A study of smoking habits and occupation based on
195 postmortem records of lung cancer cases from the
Pathology Institute at Jena for the years 1930–1941 was
reported: usable replies were obtained from relatives of
93 men and 16 women. Of the women, 13 were nonsmokers.6 The authors attempted to collect control
information by interviewing 700 men in Jena between
the ages of 53 and 54, the average age of the lung cancer
patients at death (53.9 years). This was a study performed
in Germany towards the end of the Second World War,
and only 270 men from Jena responded to the questionnaire. The authors showed great insight in concluding that wartime conditions (particularly the rationing
system) may have favored results from non-smokers.
They reported a statistically significant difference
between non-smokers and heavy smokers among lung
cancer patients on the one hand and normal patients on
the other. Realizing the possible errors on their material, they concluded that there was a considerable probability that lung cancer was far more frequent among
non-smokers than expected. Their data are such that an
approximate relative risk can be calculated: the risk
relative to non-smokers was 1.90 among light smokers,
9.05 among moderate smokers, and 11.34 among
heavy/excessive smokers. Again there appears to be a
moderate dose–response relationship.
The rapid escalation in lung cancer during the 1940s
reached a level that permitted more and larger studies
to be conducted and, in 1950, five major contributions
were made to the literature.7–11
The data presented by Wynder and Graham10 are
capable of transformation to calculate the relative risks
(the concept of which was unknown for a few more
years). Setting the risk among non-smokers at 1.0, there
is to some extent or other a dose–response relationship
with increasing levels of smoking in all age groups.
Together with the study of Wynder and Graham,10 the
fifth paper published on this subject during the year
represented a significant contribution not only to knowledge about smoking and cancer but also to the methodology of retrospective epidemiologic studies.11
This well-planned, controlled, and well-conducted
study was initially reported,11 and completed and published more extensively two years later. It is this latter
report12 that we shall discuss here. Doll and Hill12 did
not discuss cigar smoking, but calculated that use of
one ounce of pipe tobacco was the equivalent of 26.5
cigarettes, and one ounce per week was equivalent to
smoking four cigarettes per day. Non-smokers were
defined as people who had never consistently smoked
as much as one cigarette per day for as long as one
year.11
The strongest difference between cases and controls
(for both males and females) was found to be the average amount smoked daily over the 10 years preceding
the patient’s illness. Qualitatively similar results were
also obtained using the amount smoked immediately
before the patient’s illness, the maximum amount ever
smoked regularly, the total smoked since smoking began,
and the average amount smoked daily over the 10 years
preceding the patient’s illness, over the penultimate 10
years and over the whole of the patient’s life since the
age of 15 (even after allowance had been made for
recorded changes in smoking habit).
Patients who recognized that they inhaled were found
no more frequently in the lung cancer group than in the
control group, although those cases with growths of
central origin inhaled less frequently than normal. It
also appeared that lung cancer patients more frequently
had a history of preceding pneumonia or chronic bronchitis, while other respiratory illnesses were referred to
with approximately equal frequency by the two
groups.
Doll and Hill’s reports11,12 contained a remarkable
amount of information, but the fundamental finding in
men was a highly significant difference between the
proportions of non-smokers and of smokers in the disease group and in the control group. A less marked
series of differences was reported for women. Highly
12 Textbook of Lung Cancer
significant differences were also shown between the proportions of both groups smoking different average
amounts, i.e. between heavy and light smokers, and this
result held for males and females. It is apparent from
the raw data that there is a dose–response relationship
present.
Less marked but nevertheless distinct differences
were found when the duration of smoking was considered rather than the amount smoked. Lung cancer
cases, as a group, began to smoke earlier; they continued to smoke longer and gave up less often and, when
they did, did so for shorter periods. In males, all these
differences were statistically significant, but, although
the differences were in the same direction in women,
they did not reach the commonly accepted (5%) level
of statistical significance.
These five studies,7–11 but mainly the impact of
two,10,11 alerted the medical and scientific community
to the serious health hazards associated with cigarette
smoking. Once alerted, the public response to these
studies was a significant, but brief, drop in the per
capita consumption of cigarettes in both the USA and
the UK.
PHASE II: UNDERSTANDING ETIOLOGY, LOSING
GROUND IN INCIDENCE AND MORTALITY
Throughout the 1950s, a mass of information was
published demonstrating the association between lung
cancer and cigarette smoking, using data derived
from retrospective studies. Many concentrated on inhalation and, while some studies demonstrated a higher
occurrence of inhalation among lung cancer patients
than among controls, others failed to detect this
association.
The US Surgeon General was moved by the weight of
evidence associating smoking with cancer of the lung,
as well as of other sites, to produce an official statement
on ‘Smoking and Health’ on behalf of the US Government.13 This created a worldwide reaction, since it
implicated a frightening link between cigarette smoking
and a variety of fatal diseases in a document of impeccable scientific authority.
This report weighed the available evidence, and considered that it had been established that cigarette smoking was causally related to lung cancer in men, and judged
cigarette smoking in the USA a sufficiently important
health hazard to warrant remedial action.
In the 15 years that passed from that initial report,
the body of evidence increased, and extended to include
women,14 in whom lung cancer had increased fivefold
in two decades in the USA. The Secretary for Health of
the time (Mr Joseph Califano) concluded ‘that smoking
is the largest preventable cause of death in America’.
An important factor in the causal relationship between
smoking and lung cancer is the demonstrated dose–
response relationship. In epidemiologic studies, the dose
has been measured by:
•
•
•
•
•
•
•
•
•
the number of cigarettes smoked per day at interview;
the maximum number of cigarettes smoked per
day;
the age when smoking commenced;
the degree of inhalation of tobacco smoke;
the total number of years smoked;
the total lifetime number of cigarettes smoked;
the tar and nicotine levels of the brand of cigarettes
used;
the number of puffs per cigarette;
the length of the unburned portion of cigarette.
A variety of combinations of these variables can be
converted into dosage scores.
Lung cancer mortality ratios exhibit an inverse relationship with the age of initiation of the smoking habit.
Those who develop the habit at school have a much
higher risk of lung cancer than those who begin smoking at age 25+, in whom the risk is only four to five
times that of non-smokers.
Available data show a strong dose–response relationship between self-reported inhalation of cigarette smoke
and lung cancer mortality. Those who inhale deeply
have risks double those of smokers who do not. The
American Cancer Society 25 State Study15 reported a
mortality ratio among non-smokers of 1.0, a mortality
ratio of 8.0 among smokers who stated that they did
not inhale, and elevations in this risk among those who
inhaled slightly (8.9), moderately (13.1) and deeply
(17.0). Similar results were reported from a Swedish
study:16 although the mortality ratios among nonsmokers (1.0), non-inhalers (3.7), light inhalers (7.8),
and deep inhalers (9.2) were smaller in magnitude, the
same steady pattern was found.
Although it has been suggested for some time that
the risk of developing lung cancer increases with the tar
and nicotine content of cigarettes there has not been
any substantial evidence to suggest that individuals
who switch to lower-tar and lower-nicotine cigarettes
experience less lung cancer mortality.17 It has been proposed that, if the tar and nicotine contents of tobacco
Epidemiology of lung cancer: a century of great success and ignominious failure 13
were reduced, smokers might increase the number of
cigarettes smoked per day and effectively vitiate any
benefit. On the other hand, those who switch to low-tar
and low-nicotine brands might inhale smoke more
deeply than smokers of high-tar and high-nicotine cigarettes, and thus exposure to tar and nicotine might be
reduced.
The relationship of tar and nicotine was carefully
examined with respect to lung cancer in a major study,18
in which 897 825 men and women were classified by
levels of tar and nicotine smoked. Brands were considered to be high in nicotine if they contained between
2.0 and 2.7 mg of nicotine and high in tar if they contained between 25.8 and 35.7 mg of tar. The medium
levels of tar and nicotine were set at 17.6 and 25.7 mg
and at 1.2 and 1.9 mg, respectively. Low tar and nicotine levels were all those below these limits.
The risk in the high-tar and high-nicotine group of
makes was set at 1.0, and the relative risks in the
medium group (risk ratio, RR = 0.95) and low group
(RR = 0.81) were appreciably lower. Similar results were
found for females: high (RR = 1.0), medium (RR = 0.79),
and low (RR = 0.60). These results take into account the
daily cigarette consumption.
In other words, for men smoking the same number of
cigarettes per day, there appears to be an almost 20%
reduction in the risk of developing lung cancer with the
use of cigarettes low in tar and nicotine. In females,
keeping the number of cigarettes smoked per day constant, there appears to be a 40% reduction in risk. The
amount of tar and nicotine taken into the body per day
obviously depends on the number of cigarettes smoked
as well as on the tar and nicotine content of individual
cigarettes. Hammond therefore performed a second
analysis comparing subjects who smoked 1–19 high-tar
and -nicotine cigarettes per day with those who smoked
20–39 low-tar and -nicotine cigarettes per day. Setting
the risk to be 1.0 among the high categories of both
males and females, Hammond found risks of 1.6 (males)
and 2.1 (females) among the groups who smoked
20–39 low-tar and -nicotine cigarettes. He concluded
that the number of cigarettes smoked per day was relatively more important than the tar and nicotine
content.15,18
All these early observations were regarding forms of
cancer and forms of tobacco smoking that were the
most common at the period. Cigarette smoking
increased heavily in Europe during the last years of
Napoleon,19 and the habit spread during the Crimean
War, accelerated around 1900 and reached many men,
and increasingly women, during the First World War
(1914–1918). In many countries, such as the USA and
the UK, women began to reach the same smoking levels
as men during the Second World War (1939–1945).
Subsequent to this period, cancer was becoming
more frequent, and was developing into an international disease that was to become, by the latter part of
the 20th century, a significant global public health
problem. An increasing number of forms of cancer
became linked with cigarette smoking: initially oral
cancers, then lung cancer, bladder cancer, laryngeal
cancer, esophageal cancer, pancreatic cancer, acute
myeloid leukemia, cervical cancer, kidney cancer, and
gastric cancer. Several of these are of unusually high
frequency in international populations.20
PHASE III: DESCRIPTIVE EPIDEMIOLOGY
OF LUNG CANCER
The main tobacco-related site is the lung. Lung cancer
rates in self-reported non-smokers from various studies
are of the order of only 10–15 per 100 000. The IARC
monograph Tobacco Smoking21 gave estimates of the
proportions of lung cancer deaths attributable to
tobacco smoking in five developed countries (Canada,
England and Wales, Japan, Sweden, and the USA):
these ranged between 83% and 92% for males, and
between 57% and 80% for females.
The most recent, international, cancer incidence data
are available for the period around 1990. The highest
incidence rate in men is recorded among the AfroAmerican population of New Orleans in the USA, where
the average, annual, age-standardized rate per 100 000
person-years is 110.8 (Table 2.1). Other Afro-American
populations in the USA also have remarkably high lung
cancer rates in men. Rates are also high among the
Maori population of New Zealand, where the incidence
rate is 99.7 per 100 000 (Table 2.1). The incidence rate
is high in Lower Silesia (Poland) and in the west of
Scotland (Table 2.1). There are virtually no regions of
the world where the annual incidence rates are low: the
lowest incidence rates are reported from a variety of
population groups from the developing world
(Table 2.2).
Among women, the highest rates are found in
the Maori population group of New Zealand (72.9 per
100 000) (Table 2.3). High rates are also found among
a variety of populations of North America – both AfroAmerican and Caucasian. Notably high rates are
reported from the west of Scotland, where incidence
rates are high in men as well as in women (Table 2.3).
14 Textbook of Lung Cancer
Table 2.1 Highest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990
Registry
Cases
ASRa
USA, New Orleans: Black (1988–1992)
USA, Central Louisiana: Black (1988–1992)
USA, Detroit: Black (1988–1992)
USA, San Francisco: Black (1988–1992)
New Zealand: Maori (1988–1992)
USA, SEER:b Black (1988–1992)
USA, Atlanta: Black (1988–1992)
Poland, Lower Silesia (1988–1992)
Canada, Northwest Territories (1983–1992)
UK, Scotland, west (1988–1992)
USA, Los Angeles: Black (1988–1992)
USA, Connecticut: Black (1988–1992)
Italy, Ferrara (1991–1992)
USA, New Orleans: White (1988–1992)
Italy, Trieste (1989–1992)
842
172
2263
1003
387
4964
892
7213
126
8877
1925
422
597
1707
897
110.81
105.62
103.23
101.49
99.73
99.11
97.26
95.52
90.26
88.90
88.74
86.15
85.73
84.01
82.73
a
Average, annual, age-standardized rate per 100 000 person-years.
Surveillance Epidemiology and End Results Program (National Cancer Institute).
b
Table 2.2 Lowest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990
Registry
Cases
ASRa
India, Karunagappally (1991–1992)
Thailand, Kohn Kaen (1990–1993)
Peru, Lima (1990–1991)
Costa Rica (1988–1992)
India, Bombay (1988–1992)
Singapore: Indian (1988–1992)
India, Madras (1988–1992)
Peru, Trujillo (1988–1990)
India, Trivandrum (1991–1992)
USA, New Mexico: American Indian (1988–1992)
Ecuador, Quito (1988–1992)
India, Bangalore (1988–1992)
Mali, Bamako (1988–1992)
Uganda, Kyadondo (1991–1993)
India, Barshi, Paranda and Bhum (1988–1992)
58
355
635
686
1867
83
789
47
69
24
172
495
38
20
11
17.04
17.02
15.89
15.63
14.48
14.33
12.64
11.93
10.63
10.32
10.13
8.06
5.28
4.24
1.26
a
Average, annual, age-standardized rate per 100 000 person-years.
The finding of the incidence rate among women in
Tianjin, China, among the 15 highest incidence rates
recorded, is the first clear indication of the rising epidemic of lung cancer, and other cancers, resulting from
the increasing prevalence of cigarette smoking during
recent decades (Table 2.3). There are some regions of
the world where the incidence rate among women is
still truly low (Table 2.4).
In men in all European countries, except Portugal,
lung cancer is now the leading cause of cancer death. In
the USA (and in all European countries except a few
Scandinavian countries), it is also the commonest tumor
Epidemiology of lung cancer: a century of great success and ignominious failure 15
Table 2.3 Highest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990
Registry
Cases
ASRa
New Zealand: Maori (1988–1992)
Canada, Northwest Territories (1983–1992)
Canada, Yukon (1983–1992)
USA, San Francisco: Black (1988–1992)
USA, Detroit: Black (1988–1992)
USA, New Orleans: White (1988–1992)
USA, San Franciso: non-Hispanic White (1988–1992)
USA, Detroit: White (1988–1992)
USA, Central California: non-Hispanic White (1988–1992)
USA, Los Angeles: non-Hispanic White (1988–1992)
UK, Scotland, west (1988–1992)
USA, SEER:b Black (1988–1992)
USA, Hawaii: White (1988–1992)
USA, Seattle (1988–1992)
China, Tianjin (1988–1992)
326
80
39
562
1213
1115
3906
4772
2267
6674
5086
2558
340
4413
3870
72.93
65.56
47.62
44.33
42.02
41.19
40.42
40.17
39.48
38.58
38.47
38.46
37.94
37.62
37.00
a
Average, annual, age-standardized rate per 100 000 person-years.
Surveillance Epidemiology and End Results Program (National Cancer Institute).
b
Table 2.4 Lowest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990
Registry
Cases
Malta (1992–1993)
France, La Réunion (1988–1992)
France, Tarn (1988–1992)
Spain, Albacete (1991–1992)
Spain, Tarragona (1988–1992)
Algeria, Setif (1990–1993)
Spain, Granada (1988–1992)
Spain, Zaragoza (1986–1990)
India, Karunagappally (1991–1992)
India, Madras (1988–1992)
India, Trivandrum (1991–1992)
India, Bangalore (1988–1992)
Mali, Bamako (1988–1992)
Uganda, Kyadondo (1991–1993)
India, Barshi, Paranda and Bhum (1988–1992)
18
46
60
19
72
33
92
116
10
142
14
103
13
4
3
ASRa
3.35
3.34
3.19
3.14
3.09
2.88
2.71
2.66
2.59
2.37
1.89
1.67
1.53
0.41
0.33
a
Average, annual, age-standardized rate per 100 000 person-years.
in terms of incidence (although the recent inflation of
prostate cancer incidence figures with very early detection of cases is taking prostate cancer above lung cancer
in terms of the incidence of the disease). The range of
geographic variation in lung cancer mortality in Europe
is threefold in both sexes – the highest rates being
observed in the UK, Belgium, the Netherlands, and the
former Czechoslovakia, and the lowest rates being
reported in southern Europe and in Norway and Sweden.22 This overall pattern of age-standardized lung
cancer mortality rates does not reveal the important
and diverging cohort effects occurring in various countries: for instance, some of the countries in which there
are now low rates, such as those in southern Europe
16 Textbook of Lung Cancer
and parts of eastern Europe, experienced a later uptake
and spread of tobacco use, and now appear among the
most elevated rates in the younger age groups. This
suggests that these same countries, including Italy,
Greece, France, Spain, and several countries in eastern
Europe, will have the highest lung cancer rates in men
at the beginning of the next century, in the absence of
rapid intervention.
The importance of adequate intervention is shown
by the low lung cancer rates in Scandinavian countries,
which have adopted, since the early 1970s, integrated
central and local policies and programs against
smoking.23,24 These policies may have been enabled by
the limited influence of the tobacco lobby in these
countries. The experience in Finland provides convincing evidence of the favorable impact, after a relatively
short delay, of well-targeted large-scale interventions on
the most common cause of cancer death and of premature mortality in general.
With specific reference to women, current rates in
most European countries (except the UK and Ireland)
are still substantially lower than in the USA, where lung
cancer is now the leading cause of cancer death in
females. In several countries, including France, Switzerland, Germany, and Italy, where smoking is now
becoming commoner in young and middle-aged
women, overall national mortality rates are still relatively low, although appreciable upward trends have
been registered over the last two decades. This is particularly worrisome in perspective, since smoking prevalence has continued to increase in subsequent
generations of young women in these countries. Thus
the observation that lung cancer is still relatively rare in
women, with smoking at present accounting for only
approximately 40–60% of all lung cancer deaths, cannot
constitute a reason for delaying efficacious interventions
against smoking by women. The currently more favorable situation in Europe compared with the USA,
together with the observation that smoking cessation
reduces lung cancer risk after a delay of several years,
should, in the presence of adequate intervention, enable
a major lung cancer epidemic in European women to
be avoided.
A proportion of lung cancers, varying in various
countries and geographic areas, may be due to exposures at work, and a small proportion to atmospheric
pollution.25 The effect of atmospheric pollution in
increasing lung cancer risk appears to be chiefly confined to smokers. Lung cancer risk is elevated in atomic
bomb survivors,26 in patients treated for ankylosing
spondylitis,27 and in underground miners whose bron-
chial mucosa was exposed to radon gas and its decay
products: this last exposure was reviewed and it was
concluded that there was ‘sufficient evidence’ that this
occupational exposure caused lung cancer.28 A greater
risk of lung cancer is generally seen for individuals who
are exposed at an older age. Investigation of the interaction with cigarette smoking among atomic bomb survivors suggests that it is additive,29 but the data from
underground miners in Colorado are consistent with a
multiplicative effect.30
In conclusion, the overwhelming role of tobacco
smoking in the causation of lung cancer has been
repeatedly demonstrated over the past 50 years. Current lung cancer rates reflect cigarette smoking habits of
men and women over past decades,31–33 but not necessarily current smoking patterns, since there is an interval of several decades between the change in smoking
habits in a population and its consequences on lung
cancer rates. Over 90% of lung cancer may be avoidable
simply through avoidance of cigarette smoking. Rates
of lung cancer in central and eastern Europe at present
are higher than those ever before recorded elsewhere;
lung cancer has increased tenfold in men and eightfold
in women in Japan since 1950; there is a worldwide
epidemic of smoking among young women,34 which
will be translated into increasing rates of tobacco-related disease, including cancer, in the coming decades;
there is another epidemic of lung cancer and tobaccorelated deaths building up in China as the cohorts of
men in whom tobacco smoking became popular reach
ages at which cancer is an important hazard.35 Many
solutions have been attempted to reduce cigarette
smoking, and increasingly many countries are enacting
legislation to curb this habit.36
PHASE IV: PUBLIC HEALTH FAILURE, 1960s
ONWARDS
Thus it has been clear for the entire second half of the
20th century that cigarette smoking causes lung cancer.
Current low levels of smoking among physicians and
research scientists in many countries have led many of
them unconsciously to overlook tobacco smoking as an
important cause of cancer.37 There is, however, a very
substantial body of evidence from many sources that
indicates the carcinogenicity of tobacco smoking. Not
only does cigarette smoking greatly increase the risk of
lung cancer in smokers, but the risk of oral cavity cancer, laryngeal cancer, esophageal cancer, bladder cancer, pancreatic cancer, and kidney cancer is also
Epidemiology of lung cancer: a century of great success and ignominious failure 17
increased. The risk of cancer of the cervix and stomach
may also be increased, although the evidence for this is
much less consistent.38 These forms of cancer can be
expected to rise in women as a result of their increased
levels of cigarette smoking.
There is at present a worldwide epidemic of tobaccorelated disease: not only does smoking cause increased
levels of many different common forms of cancer, it
also increases the risk of cardiovascular disease. As
mentioned in the previous section, deaths from lung
cancer, the tumor most strongly linked to cigarette
smoking, have increased in Japan by a factor of 10 in
men and 8 in women since 1950. In central and eastern
Europe, more than 400 000 premature deaths are currently caused each year by tobacco smoking. In young
men in all countries of central and eastern Europe, there
are current levels of lung cancer that are greater than
anything seen before in the Western countries, and
these rates are still rising. In Poland – a country severely
hit by the tobacco epidemic – the life-expectancy of a
45-year-old man has been falling for over a decade now
owing to the increasing premature death rates from
tobacco-related cancers and cardiovascular disease.39
Tragically, cigarette smoking is still increasing in central
and eastern Europe and also in China, where an epidemic of tobacco-related deaths is building up quickly.
Tobacco smoking is also the most easily avoided risk
factor for cancer.
The most important determinant of risk of lung cancer is the duration of smoking: long-term cigarette
smokers have a 100-fold increased risk compared with
never-smokers. The content of cigarettes (low tar) produces only a threefold variation in risks between the
extremes. (‘Low tar’ is frequently taken to include a
number of features, including filter-tips as well as the
active tar yield.) Lung cancer is the major tobacco-related tumor and the leading cause of cancer death in
men in almost every developed country. Incidence rates
are around 10–15 per 100 000 in non-smokers and
between 80 and 100 per 100 000 in the highest-incidence population groups such as Afro-Americans, and
rates exceeding 200 per 100 000 have been reported in
cities of central and eastern Europe. Since lung cancer
is frequently fatal, mortality rates are high, and consequently so are the social costs.
Women around the world have taken up the cigarette smoking habit with gusto. For many years, it
appeared that their lung cancer rates were low and that
tobacco was not having the same effect as on men. This
complacency, which crept in during the two decades
from the mid-1960s especially, is now exposed as false:
nor is there evidence that the effect of cigarette smoking
on lung cancer risk is greater in women than in men.
The dominance of the effect of duration of smoking
means that a long period of time will pass between the
exposure (large numbers of women smoking) and the
effect (high levels of lung cancer). Lung cancer now
exceeds breast cancer as the leading cancer cause of
death in women in the USA, Canada, Scotland, and several other countries. In Canada, breast cancer mortality
has remained at least constant for nearly four decades,
while lung cancer death rates have increased between
three- and fourfold during the same period. While the
higher case-fatality of lung cancer may be one factor in
the mortality rates overtaking breast cancer, there is,
increasingly, evidence that there are regions of the
world where the gap in the incidence rate is now closing. For example, in Glasgow, an area where lung cancer has been historically high, by 1990 the incidence
rate for lung cancer (115 per 100 000) exceeded that
for breast cancer (105 per 100 000) in 1990.40 Among
international cancer registries, there are some where the
incidence of lung cancer now exceeds the incidence of
breast cancer, and others where there is still a gap. In
the SEER (Surveillance Epidemiology and End Results)
Program of the US National Cancer Institute, the incidence of lung cancer in both Black and White women
increased by over 90% between 1973–1977 and 1988–
1992: the increase in the incidence of breast cancer was
around 25% in both racial groups (comparison made
between incidence rates age-adjusted using the 1970
US population). It is a great worry that there does not
appear to be any end in sight to this increase in lung
cancer risk internationally: it is programmed to continue for several decades to come.
Part of the complacency over the effect on women
was also due to the strong tendency for women to
smoke brands of cigarettes that were lower in tar and
nicotine content than those smoked by men: it was
assumed that these would have less of a risk for lung
cancer than the higher-tar cigarettes that men generally
smoked. Marked changes in the rates of the major histologic cell types of lung cancer can now
be seen, with particular increases in the risk of
adenocarcinoma.41,42 The changes seen are compatible
with increased risk of adenocarcinoma due to increasing
levels of smoking of ‘light’ cigarettes (low-tar, low-nicotine). It appears that abandoning high-tar cigarettes
(15–45 mg tar) may have some impact on reducing
squamous-cell carcinoma risk, but this is now being
balanced by ‘light’ cigarettes increasing the risk of adenocarcinoma.
18 Textbook of Lung Cancer
Cigarette smoking kills half of all those who
adopt the habit, with 50% of these deaths occurring in
middle age and each losing an average of 20 years of
non-smoker’s life expectancy.43 It kills in over 24 different ways, with the lung being the commonest cancer
site.43 Lung cancer rates have been declining in men
and increasing in women: cigarette smoking in men has
been declining while it has been increasing in women.
These two trends are closely related. The move to ‘light’
cigarettes, which is increasingly common, now appears
to be linked to increases in adenocarcinoma of the lung,
and shows no sign of being linked to a reduced risk
overall. There is no such thing as a ‘safe cigarette’.
Smokers should be urged and helped to stop smoking;
children and young adults should be convinced not to
smoke. Tobacco can become an addictive drug: it
should be left alone.20
ACKNOWLEDGMENTS
It is a pleasure to acknowledge that this work was conducted within the framework of support from the Associazione Intaliana per la Ricerca sul Cancro (Italian
Association for Research on Cancer).
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3
Molecular biology of lung cancer
Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot
Contents Introduction • Growth signals and lung cancer • Apoptosis in lung cancer • Aberrant
anti-growth signaling • Replicative potential and telomerases • Angiogenesis • Tissue invasion
and metastasis • Conclusion
INTRODUCTION
It becomes more and more important to understand the
biology of lung cancer as new therapeutic agents are
emerging in the field of clinical oncology. These agents
are often referred to as targeted therapy or biologic
therapy. New advances in molecular technologies are
providing insight into the pathobiology of lung cancer
development. It is now known that clinical lung cancers have accumulated numerous clonal genetic and
epigenetic alterations as a multistep process.1 In many
research laboratories molecular studies are these days
performed in an integrated approach with clinical
investigators to find new ways for early diagnosis, risk
assessment, prevention, and treatment for this frequent
and deadly disease. In the following, the spectrum of
molecular alterations in lung cancer are described as
hallmarks of cancer, subdivided as suggested by Hanahan and Weinberg:2
•
•
•
•
•
•
abnormalities in self-sufficiency
signals;
evading apoptosis;
insensitivity to anti-growth signals;
limitless replicative potential;
sustained angiogenesis;
tissue invasion and metastasis.
of
growth
GROWTH SIGNALS AND LUNG CANCER
In tumor cells, activated (proto)oncogenes often encode
molecules involved in aberrant growth factor signaling,
either by directly promoting cell growth, by mimicking
other growth factors, or by neutralizing growth inhibitory signals. Growth factors are proteins that bind to
receptors (usually on the cell surface) and trigger
activation of cellular proliferation and/or differentiation.
Normal cells depend on external growth stimulating
signals to proceed from quiescence to proliferation
and these growth stimuli are often provided by neighboring cells in the immediate microenvironment,
for instance by release of diffusible growth factors
or expression of cell adhesion molecules. These interrelations between the cell and its environment allow
for establishment of normal tissue homeostasis with
a tight regulation of tissue modeling, growth, and
regeneration.
Tumor cells have lost their dependency on growth
stimulatory signals from the external environment and
are fully capable of proliferating independently. This
phenotype of growth autonomy is attained by a variety
of molecular changes and gene mutations within the
cell, typically characterized by a state of growth factor
self-sufficiency, where the cell itself produces the
required growth factors and receptors, resulting in a
self-stimulatory autocrine signaling loop. Aberrant
expression and signaling by a number of growth factors
and cognate receptors have been identified, which
increase the cellular proliferative potential in lung cancer. In non-small cell lung cancer (NSCLC) these
include upregulation/mutation of certain receptor
tyrosine kinases (RTKs), in particular the epidermal
growth factor receptor (EGFR, ErbB1) and other members of the ErbB RTK family. In small cell lung cancer
(SCLC) overexpression of insulin-like growth factor I
(IGF-I) and its receptor as well as a number of neuronal
growth stimulators is frequently observed.
An overview of the changes in expression and signaling of central growth factors and receptors, signal transducers, and transcription factors in lung cancer is
presented below and summarized in Table 3.1. The
section will conclude with a presentation of related
experimental therapeutic strategies developed to target
these mediators for future treatment of lung cancer.
Molecular biology of lung cancer 21
Table 3.1 Growth signals and lung cancer
Signaling mediators involved in activating growth signaling in lung cancer
Aberrant activation/mutation frequency
Oncogene
NSCLC (%)
SCLC (%)
References
EGFR
HER2-Neu
IGF-I
C-Kit/C-Met
K-ras
Neuropeptides
C-myc
50–90
∼30
—
—
∼20–30
16–47
up to 50
—
—
>95
Up to 70
—
All
10–40
3, 4
33
9
12, 13
15
17
23, 24
Epidermal growth factor receptor overexpression
and signaling in NSCLC
Overexpression of EGFR occurs in 50–90% of all
NSCLC and is particularly common in squamous cell
carcinoma,3,4 whereas EGFR overexpression is rare in
SCLC. The receptor is membrane associated and contains three main regions: an extracellular ligand binding
domain, a hydrophobic membrane spanning region,
and a cytoplasmic part holding the catalytic tyrosine
kinase activity. Upon ligand binding, EGFR undergoes
a conformational change, leading to dimerization of the
receptor and activation of the intracellular catalytic
domain by phosphorylation of tyrosine residues. The
phosphorylated tyrosine residues serve as binding sites
for a number of different downstream signaling molecules and adaptors within the cell. Three major signaling pathways downstream of EGFR are outlined
in Figure 3.1. One of the most intensively studied
cascades is the Ras/Raf/ERK pathway (the right-hand
pathway in Figure 3.1). The effects of this pathway are
diverse (for a review see reference 5), with a large number of Ras effectors, but in general Ras signaling upon
EGF stimulation has been associated with increased cell
growth and proliferation. One of the three ras genes,
Kirsten-ras (K-ras, p21-ras), is mutated in ∼30% of
NSCLC. The oncogenic impact of this mutation in lung
cancer is discussed further below.
Another central pathway in EGFR signaling involves
activation of PI3-kinase and AKT (PKB). This pathway
generally serves to promote cell survival, by inhibition
of various cell cycle regulators such as glycogen synthase kinase 3 (GSK3) and the pro-apoptotic protein
BAD (Figure 3.1, the middle pathway).
A final key pathway activated by EGFR involves
the activation of phospholipase C-γ (PLC-γ), resulting
in hydrolyzation of phosphoinositide 4,5-bisphosphate
(PIP-2) to generate inositol-3-phosphate (IP3) and
diacylglycerol (DAG) (Figure 3.1, the left-hand pathway). This results in the release of calcium ions from intracellular stores, which affects cell motility and migration
by interfering with the activity of actin-modulatory
proteins. The activation of PLC-γ also activates
protein kinase C (PKC), which causes attenuation of
EGFR signaling by a negative feedback mechanism.
The different pathways by which activated EGFR
exerts its proliferative, migratory, and anti-apoptotic
effects, and the fact that many of the involved signaling
modulators have been found to cross-react between
pathways, provide a central, yet complex, role for EGFR
in cell transformation. In NSCLC, increased EGFR signaling is obtained by an increased gene copy number
and by activating mutations within the EGFR gene.6
One mutated EGFR variant termed EGFRvIII, commonly found in various malignancies including ∼16%
of NSCLC, has gained increasing interest in recent
years. EGFRvIII lacks the extracellular ligand-binding
domain, rendering the receptor incapable of binding
any ligands, yet the receptor is constitutively active
and fully capable of activating downstream modulators.7 In recent years, novel activating mutations within
the tyrosine kinase domain of EGFR have been identified in NSCLC. These mutations have gained massive
interest, since they have been found to correlate with
increased response to treatment with EGFR tyrosine
kinase inhibitors.8
Another member of the ErbB family is HER2-Neu
(ErbB2), which is overexpressed in ∼30% of NSCLC.
No ligands for Her2-Neu have yet been identified but
the receptor is a central dimerization partner for the
other RTKs of the ErbB family. To date, results are
22 Textbook of Lung Cancer
EGFR dimer
EGF
EGF
Membrane
DAG
PKC
PIP2
Raf
IP3
Ras
PLC-γ
TK
TK
PI3K
SOS
SHC
Ca2+
MEK
GRB2
AKT
Ca2+
Ca2+
Ca2+
Cytosol
GSK3
BAD
ERK
Nucleus
Altered gene expression
- Increased cell growth and proliferation
- Downregulation of apoptotic response
- Increased cell motility/migration
Figure 3.1
EGFR signaling. Upon ligand binding EGFR dimerizes, resulting in a complex signaling response within the cell. Oncogenic EGFR signaling
occurs through three major pathways: the Ras/ERK (right-hand), the PI3-kinase AKT (middle), and the phospholipase C-γ (left-hand)
pathways, resulting in an increased malignant potential of the cells. For further explanation see text.
conflicting with regard to Her2-Neu overexpression
and prognosis in NSCLC.
Overexpression of other growth factor receptors
and ligands
The expression level of the mitogen IGF-I is elevated in
the majority of SCLC, resulting in a self-stimulatory
autocrine loop involving the IGF-I receptor which is
commonly co-expressed in this malignancy.9 IGF signaling proceeds through binding of IGF ligands (IGF-I
and II) to cell surface RTKs (IGF-IR and -IIR). The biologic activity of the signaling system is modulated by
binding of IGF binding proteins present in the extracellular fluids and serum to the IGF ligands. As for EGFR,
activated IGF-IR signaling is complex but primarily
occurs through the Ras/Raf/ERK and the PI3-kinase/
AKT pathways. A correlation between significantly
elevated IGF-I serum levels and lung cancer risk has
been reported, but results of other studies are
conflicting.10,11
The RTK c-Kit and its ligand stem cell factor (SCF) is
another receptor/ligand system, upregulated in more
than 80% of SCLC tumors.12 A study of c-Kit expression in SCLC patients identified c-Kit as a marker for
Molecular biology of lung cancer 23
increased survival13 – an observation which appears
contradictory to the oncogenic properties of c-Kit signaling. However, the patients enrolled in this study were
receiving chemotherapy targeting actively dividing
cells, and since activation of c-Kit induces cell proliferation, the active receptor may render the malignant
cells more susceptible to cytotoxic treatment, thereby
improving overall survival.
c-Met is yet another RTK often overexpressed in
SCLC. Signaling through this receptor system has
been reported to be associated with tumor growth and
metastasis. In contrast to the c-Kit/SCF system, the
c-Met ligand hepatocyte growth factor (HGF) is rarely
co-expressed with the receptor in SCLC,12 but is
expressed and secreted from surrounding normal lung
fibroblasts. This observation indicates a paracrine rather
than autocrine activating loop of c-Met expression in
lung cancer. The importance of paracrine c-Met signaling for lung cancer pathogenesis has been investigated
further in a study where c-Met-expressing lung cancer
cells were transplanted into HGF-overexpressing
mice, resulting in increased metastatic potential of the
transplanted cells.14
Activating Ras mutations
As mentioned, mutations of the intracellular membraneassociated signaling mediator Ras (Figure 3.1, green
pathway) with a high overrepresentation of mutations
in the K-ras gene are detected in up to 30% of NSCLC,15
but rarely in SCLC patients. Ras protein becomes
activated by the binding of guanine triphosphate (GTP),
allowing for transmission of growth stimulatory signals
to the cell nucleus. Downregulation of Ras signaling
occurs by hydrolysis of GTP to GDP, mediated by the
GTPase-activating protein (GAP). In NSCLC and other
malignancies, activating point mutations in the K-ras
gene result in resistance to GAP activity, thereby trapping the Ras protein in a constitutively active state,
capable of continuous growth promoting signaling.
Controversy exists as to whether K-Ras mutations serve
as a marker for poor prognosis in lung cancer, but a
global meta-analysis correlated the presence of pointmutated constitutively active Ras in NSCLC with a poor
prognosis.16
G-protein-coupled receptors, resulting in activation of
various downstream signaling pathways including PLC,
PI3-kinase, and certain kinases, involved in cellular
focal adhesion. Gastrin releasing peptide (GRP) signaling via the GRP receptor (GRP-R) has become one of
the most intensively studied neuropeptide signaling
pathways in SCLC, since different studies have shown
that blocking GRP or GRPR activity inhibits SCLC cell
growth in vitro and in vivo, whereas GRP addition
to SCLC cells induces cell proliferation.18,19 The concentration of the GRP precursor pro-GRP is highly elevated in the majority of SCLC patients and levels
decrease upon tumor resection, indicating that proGRP serum levels may serve as a detection and monitoring marker for patients with this disease. Other
neuropeptides highly expressed in lung cancer include
bradykinin, neuron specific enolase and L-Dopa decarboxylase. Whether these molecules play an oncogenic,
growth-promoting role in lung cancer and/or whether
they may potentially serve as clinical markers remains
controversial.
In recent years, the expression of the neuroendocrine
transcription factor Achaete–Scute homolog 1 (ASH1)
in SCLC has gained increased attention. ASH1 is normally expressed in neuronal progenitor cells during
early fetal development of various tissues including the
central nervous system and the lung. Expression is virtually absent in the normal adult organism, but ASH1
is reactivated and highly expressed in SCLC and in
other lung tumors with a neuroendocrine phenotype,
including a minority of large cell and adenocarcinomas.
High expression of ASH1 seems to correlate with poor
differentiation of these lung tumors, since expression is
virtually absent in fully differentiated carcinoid tumors.20
Furthermore, ASH1 expression is tightly linked to classic neuroendocrine markers including L-Dopa decarboxylase. Although future research is clearly necessary
to clarify the role of ASH1 in lung cancer pathogenesis,
many studies suggest ASH1 expression as a critical
pathogenic factor in neuroendocrine lung tumors. The
overexpression of ASH1 induces lung tumors and cell
hyperplasia in mouse models,21 and one study reported
significant inhibition of SCLC cell growth after ASH1
knock out in vitro and in vivo.22
Overexpression of neuropeptides
Highly elevated expression of different neuropeptides
is a hallmark of SCLC and many of these markers
have also been detected in some (mainly poorly differentiated) NSCLC tumors.17 Neuropeptides exert their
effect via binding to seven transmembrane (7TM)
Amplification of myc
Members of the c-myc, N-myc, and L-myc (proto)oncogene family are commonly amplified in SCLC and
NSCLC, resulting in overexpression of Myc transcription factors.23,24 Myc protein competes with other transcription factors to bind Max, resulting in activation
24 Textbook of Lung Cancer
and repression of a number of genes. Although the contributions of myc amplification to lung cancer pathogenesis remain to be elucidated, recent studies point to
a role for myc in promoting cell cycle progression by
activation of key cell cycle molecules responsible for
entry into the S-phase of the cell cycle (for a review of
myc signaling in lung cancer see reference 25). In combination with loss of tumor suppressor genes such as
Rb (the properties of which will be discussed in a later
section), myc has been shown to significantly contribute to decreased cell cycle arrest and deregulated tumor
growth.26
Experimental therapeutic targeting of growth
factors and oncogenes in lung cancer
In the previous sections, a number of different growth
factors and oncogenes of importance for lung cancer
biology have been presented. Knowledge gained about
the properties of these molecules has allowed for
the development of novel therapeutics targeting
key activating, growth promoting, and tumorigenic
pathways.
A research area of major focus in recent years has
been therapeutic targeting of EGFR in NSCLC. There
are two general strategies for inhibiting signaling via
EGFR. One is to prevent binding of ligand by blocking
the ligand binding site (commonly with a monoclonal
antibody) and the other is to directly inhibit receptor
signaling by blocking activity of the cytoplasmic tyrosine
kinase domain. Belonging to the first group, cetuximab
is a humanized monoclonal EGFR antibody, which is
presently under development and testing for treatment
of NSCLC. The results of a recently published phase
I/II clinical trial have shown an effect of cetuximab
in combination with chemotherapy of NSCLC,27 and
further clinical studies are ongoing at present.
The two most clinically advanced RTK inhibitors
are erlotinib and gefitinib, and erlotinib recently
obtained FDA approval for second-line treatment
of NSCLC. As previously mentioned, a number of
mutations in the RTK domain of EGFR have been
identified in NSCLC.8 Importantly, the presence of
RTK mutations seems to correlate positively with the
response to treatment with gefitinib, suggesting that
these mutations may serve as classifiers for selecting the
patients who will benefit from EGFR-RTK inhibiting
treatments.
As previously mentioned, the gene encoding the
growth promoting Ras protein is mutated in up to 30%
of NSCLC, making this protein a potential target for
therapeutic intervention. Cytoplasmic Ras protein is
inactive and must be associated with the plasma membrane to contribute to cell signaling. For this association
to occur, synthesized Ras protein is post-translationally
modified by addition of a farnesyl group. Farnesylation
is mediated by a specific enzyme – the farnesyl
transferase – and targeting this reaction with farnesyl
transferase inhibitors has been investigated clinically
for treatment of lung cancer and other malignancies.
Despite promising preclinical data and reported
responses in patients with breast cancer and certain
leukemias, the results of the use of farnesyl transferases
for treating lung cancer have been disappointing, with
lack of tumor regression in all of the clinical studies
reported to date.28
The monoclonal antibody imatinib targets a number
of RTKs including c-Kit and has been evaluated in two
recent phase II studies for treatment of SCLC. Disappointingly, both studies report no inhibitory effect on
tumor growth, even in patients with c-Kit-positive
tumors.29,30 Apart from the clinical studies reported to
date, a number of preclinical investigations have shown
promise for anti-growth-signaling targeted therapy
of lung cancer. Therapeutic blockade of IGF-I signaling
by an IGF-IR-specific tyrosine kinase inhibitor has
been reported to enhance the sensitivity of SCLC cells
to chemotherapy in vitro, correlating with inhibition of
the anti-apoptotic PKB signaling pathway.31 Finally,
therapeutics have been developed which target neuronal markers overexpressed in lung cancer, primarily
SCLC. However, a phase I clinical trial using an antibody targeting GRP in patients with SCLC reported no
significant therapeutic response.32 In contrast, recent
pre-clinical data showed growth suppression of SCLC
cells after knockout of ASH1 in vitro and in vivo.22
APOPTOSIS IN LUNG CANCER
Apoptosis is a morphologically and biochemically
distinct form of cell death that occurs under various
physiologic and pathologic conditions triggered by
extrinsic and intrinsic cellular and molecular damage. It
is characterized by the activation of a specific event of
molecular processes followed by certain morphologic
changes such as shrinkage of the cell, condensation
of chromatin, and disintegration of the cell into small
fragments.
Today many of the key players in cellular apoptosis
regulation have been identified and activators and
inhibitors have been characterized and can therefore be
targeted by therapeutic agents. Apoptosis is activated
Molecular biology of lung cancer 25
by a family of intracellular cysteine proteases called caspases. They are synthesized as zymogens and activated
by proteolytic cleavage. They are divided into two distinct classes, initiator caspases, which include caspases
P8, P9, and P10, and effector caspases, which include
caspases P3, P6, and P7.
Current knowledge suggests that there are two separate pathways of caspase activation. One starts with
binding of an extracellular ligand to its cell surface
receptor. The ligands are TNF, FasL, and Trail, and
their respective receptors are TNFRI, FAS, and DR4 and
DR5. The ligand binding triggers initiator caspase activation through a death inducing signaling complex
(DISC), resulting in caspase-P8 activation of effector
caspases, either directly or through BCL-2 interacting
domain (BID)-mediated release of cytochrome c from
mitochondria (Figure 3.2). The other caspase activation
pathway starts with release of cytochrome c from the
intermembrane space of mitochondria. Two proapoptotic family members, BAX and BAK, appear to facilitate cytochrome c release by participating in the
Death
ligand
Death receptor
pathway
Mitochondrial
pathway
Membrane
Death receptor
PROCASP 8/10
FADD
Mitochondria
BID
BID
DISC
Cytochrome c
CASP 8 (CASP10)
PROCASP 9
EXECUTIONER PATHWAY
CASP3,6,7
APOPTOSIS
CASP 9
APAF1
Apoptosome
Figure 3.2
Apoptosis. Major pathways to apoptosis: two pathways lead to
apoptosis, an extrinsic pathway through death receptors and an
intrinsic pathway through the mitochondria. The two pathways
overlap and interact.
formation of a pore that releases mitochondrial intermembrane space proteins. After its release, cytochrome
c binds to apoptotic protease activating factor-1 (APAF-1).
APAF-1 binds to procaspase-9 forming a multiprotein
complex, called an apoptosome, which activates effector caspases through caspase-9 (Figure 3.2).
Anti-apoptotic factors such as Bcl-2-related proteins
antagonize BAX and BAK. In addition, IAP (inhibitor of
apoptosis protein) binds and inhibits apoptosomerelated caspases. However, this inhibition can be
relieved by the release of another mitochondrial protein, called Smac/Diablo, which binds to the IAP and
releases active caspases. The most widely studied IAP
is survivin. Activators and inhibitors are influenced
by several other proteins including p53, RB, PTEN,
Raf-ERK, PI3K-PKB, and Hsp70.33,34
The apoptotic pathways and possible defects have
not been studied much in human lung cancer, and
therefore only sporadic, non-conclusive data are available. However, recently it has been shown that DR4
and DR5 are upregulated in NSCLC, and overexpression of DR5 correlates with a poor prognosis in patients
with NSCLC. Bcl-2 expression is higher in SCLC compared with NSCLC. Furthermore, data have indicated
that the BAX:Bcl-2 ratio might be of importance for
resistance to apoptosis. Caspase-8 and caspase-10 might
be deregulated, and differences in deregulation in SCLC
compared with NSCLC especially concerning caspase-8
have been observed, resulting in deregulation of DISC.
Others have found that the apoptosome signaling might
be blocked. In addition, it has been indicated that
downregulation of caspase-3 is correlated with a poor
prognosis in patients with NSCLC.33,35
Survivin is increased in most NSCLC and it has been
shown that absence of its expression might be associated with improved prognosis. In addition, previously
unpublished microarray data show that survivin is
upregulated in SCLC in human cell lines, xenografts,
and resected tumors from patients (Figure 3.3)36
(Poulsen HS, unpublished data).
Targeting apoptotic pathways
Treatment with TNF has been undertaken. However,
due to pronounced general toxicity, its potential as a
therapeutic drug is limited. Recently TRAIL agonists
have been approved for clinical trials but no data are
presently available.
Small molecule inhibitors of Bcl-2 have been developed and are at the moment being tested in preclinical
trials. In addition, antisense constructs against survivin
have been produced and tested in phase I clinical trials.
26 Textbook of Lung Cancer
250
Microarray signal
200
150
100
50
Normal tissues
SCLC cell lines and xenografts
SCLC tumor 1
SCLC tumor 2
SCLC tumor 3
SCLC tumor 4
SCLC tumor 5
SCLC tumor 6
CPH 54A
CPH 54A Xeno
CPH 54B
CPH 136A Xeno
GLC 2
GLC 3
GLC 3 Xeno
GLC 14
GLC 14 Xeno
GLC 16
GLC 19
GLC 26
GLC 28
DMS 53
DMS 79
DMS 92
DMS 114
DMS 153
DMS 273
DMS 273 Xeno
DMS 406
DMS 456
H69
H69 Xeno
NCI 417
NCI 417 Xeno
MAR H24
MAR H24 Xeno
MAR 86H
Fetal brain
Brain
Adrenal gland
Colon
Heart
Kidney
Liver
Lung
Pancreas
Prostate
Salivary gland
Skeletal muscle
Small intestine
Spleen
Stomach
Testes
Thyroid
Trachea
0
Tumors
Figure 3.3
Survivin in SCLC. Survivin mRNA expression in SCLC cell lines, xenografts, and resected patient tumors compared with normal tissue.
In addition, an adenovirus-based gene therapy approach
targeting survivin is under development.37
ABERRANT ANTI-GROWTH SIGNALING
A review of key tumor suppressors, frequently
mutated in lung cancer is presented below and summarized in Table 3.2, followed by an update within the
field of tumor suppressor reactivation in experimental
lung cancer therapy.
Apart from upregulation of growth stimulatory signaling, cancer cells often lack expression of a number of
tumor suppressors. In contrast to oncogenes, tumor
suppressor genes act to prevent and control cell growth,
often via tight control of cell cycle progression. Full
inhibition of tumor suppressor activity often requires
inactivation of both alleles of a tumor suppressor gene
in the cancer cell. This dual inactivation is frequently
accomplished by a two-step process, involving a chromosomal translocation or deletion resulting in loss of
heterozygosity (LOH), followed by an inactivating point
mutation of the remaining allele. In lung cancer cells,
LOH of distinct chromosomal regions is frequently
detected and many of these regions harbor genes encoding central tumor suppressors, known or speculated to
be involved in cancer pathogenesis. Tumor suppressor
activity may also be inhibited by dominant negative
mutations, which actively inhibit the activity of wildtype protein binding partners within the cell. Finally,
epigenetic alterations (i.e. mutation-independent mechanisms) have in recent years gained increased attention
in the regulation of tumor suppressor knock-down.
Tp53 mutations
The transcription factor p53 is one of the most intensely
studied tumor suppressors. The Tp53 gene is located
within a region of chromosome 17 (17p13), which is
mutated or altered in the majority of lung cancers with
a specifically high prevalence in SCLC and squamous
cell carcinoma.38,39 The types of Tp53 alterations observed
in lung cancer range from gross chromosomal changes
such as LOH, homozygous deletions, and DNA rearrangements, to local point mutations,40 all of which
contribute to Tp53 malfunction or inactivation.
The p53 protein is a key player in the cellular
response to stress, acting as a gatekeeper of the cell
cycle. Activation of p53 signaling in normal cells generally occurs in response to different types of cellular
stress including DNA damage, aberrant oncogenic
growth factor signaling, and exposure to extracellular
factors such as chemotherapeutics and UV light. The
level of p53 protein and activity within the cell is regulated at the level of degradation rather than the level of
synthesis and, under normal conditions, the protein is
rapidly degraded within the cell. The cellular enzyme
Molecular biology of lung cancer 27
Table 3.2 Aberrant anti-growth signaling
Tumor suppressor gene mutations/inactivations and LOH in lung cancer
Mutation/inactivation frequency
Tumor suppressor gene
Chromosome location
NSCLC (%)
SCLC (%)
References
Tp53
RB
p16INK4a
TGFbRII
LOH 3p
17p13
13q14
9p21
3p22
3p regions
∼50
∼30
∼70
∼44
70–100
∼80
∼90
∼10
<75
>90
43
44, 61
45, 61
48, 62
51, 52
MDM2 plays an important role in the downregulation
of p53. MDM2 serves as a p53 binding partner, which
facilitates the attachment of ubiquitin tags to p53,
thereby targeting it for degradation. Furthermore,
MDM2-bound p53 activates transcription of the MDM2
gene, resulting in increased MDM2 levels, p53 ubiquitinylation, and degradation. Upon lowering of the p53
concentration, fewer MDM2–p53 complexes are
formed, resulting in reduced MDM2 transcription and
decreased p53 degradation. As such, the MDM2–p53
interaction generates an oscillating feedback loop of
p53 and MDM2 degradation and synthesis within the
cell (Figure 3.4).
Activation of p53 requires post-translational modifications (such as acetylation, glycosylation, and addition
of phosphate groups), some of which may inhibit p53
degradation by inhibiting its binding to MDM2. This is
the case upon DNA damage, where activation of different proteins such as ATM-kinase and DNA-dependent
kinase facilitates the phosphorylation of p53 at sites
involved in the interaction with MDM2, resulting in
p53 activation (Figure 3.4).
Active p53 regulates transcription of a number of
genes involved in cell cycle control (such as cyclindependent kinase inhibitors), resulting in cell cycle
arrest, thus allowing for repair of damaged DNA by the
cellular repair machinery. Activation of p53 also induces
apoptosis via activation of a number of apoptotic mediators (including Bax) and inhibits blood vessel formation by activation of genes encoding anti-angiogenic
factors.
A frequent observation in lung cancer cells with
mutated p53 is accumulation of p53 within the
cell, due to increased stability of the mutated protein.41
A number of studies have investigated the prognostic
role of p53 mutations in lung cancer patients, and
although the results are somewhat conflicting, accumulating evidence suggests that p53 mutations result in a
poorer prognosis in NSCLC. Given the high abundance
of p53 mutations in SCLC patients, the limited number
of patients with intact p53 signaling limits prognostic
studies in this malignancy. For a detailed review of p53
mutations in lung cancer, and the clinical impact of
these aberrations, see reference 42.
Mutated RB and p16INK4a
A central tumor-suppressing signaling cascade, frequently altered in human lung cancer, is the p16INK4a/
CDK-cyclin-D/Rb pathway. The retinoblastoma (RB)
tumor suppressor gene located at 13q14 encodes a
transcription factor involved in the regulation of G1
to S-phase transition in the cell cycle. The tumorsuppressing activity of Rb depends on its level of phosphorylation. In its hypophosphorylated state, Rb binds
to and inhibits the activity of different binding partners,
including members of the E2F family of transcription
factors. Upon phosphorylation of Rb, E2F is released
and activated, resulting in transcription of genes responsible for G1 to S-phase cell cycle progression (Figure 3.5). Consequently, Rb in its hypophosphorylated
state serves as a tumor suppressor. Phosphorylation of
Rb is mediated by different complexes of cell cycle proteins such as cyclin D and CDK4 and 6. The formation
of these complexes is inhibited by p16INK4a, which
thereby serves as a tumor suppressor upstream of Rb by
indirectly inhibiting its phosphorylation and thereby
promoting Rb association with its binding partners
(Figure 3.5).
Inactivation of the RB gene by LOH and/or mutation
is observed in 90% of SCLC tumors,43 whereas the
p16INK4a gene is frequently inactivated in NSCLC,44
resulting in lack of activity of the Rb tumor suppressor
pathway in virtually all lung cancers. These findings
indicate that inactivation of this pathway is a mandatory step in the pathogenesis of pleural malignancies.
The p16INK4a gene locus is located at chromosome 9p21,
28 Textbook of Lung Cancer
DNA damage
p14ARF
Decreased
p53 activity
MDM2 p53
ATM-kinase/DNA
dependent kinase
INCREASED
MDM2-SYNTHESIS
MDM2
p14ARF MDM2
ACTIVE
p53
Altered gene expression
- Cell cycle arrest
- Apoptosis
- Anti-angiogenesis`
Figure 3.4
p53 signaling. In normal cells p53 plays a key role in regulation of
the cellular response to a number of stress factors, but the p53
protein is frequently mutated in lung cancer and other malignancies. Under normal conditions p53 activity is inhibited by the
binding of MDM2 to the protein. Upon cellular exposure to
stress, cellular proteins such as p14ARF and specific kinases (i.e.
ATM-kinase and DNA-dependent kinase) release p53 from MDM2
inhibition, resulting in activation of p53. This again may result in
cell cycle arrest, apoptosis, and anti-angiogenic signaling.
which is a region frequently subjected to LOH in NSCLC.45
Apart from p16INK4a, the same locus also encodes the
tumor suppressor p14ARF through an alternative reading
frame. The p14ARF protein is known to bind to MDM2,
thereby inhibiting ubiquitinylation and degradation of
p53 (Figure 3.4). Furthermore, E2Fs are known to activate p14ARF transcription, providing a functional link
between the Rb and p53 tumor suppressor pathways.
Aberrant TGFβ signaling
The transforming growth factor β (TGFβ) receptor
system is also commonly altered in lung cancer. In
contrast to the growth factor receptor systems described
in previous sections, the effects of signaling by TGFβ
are mostly associated with inhibited cellular proliferation in many cell types. TGFβ signaling is mediated via
serine-threonine-kinase receptors that can be divided
into two subgroups termed TGFβRI and II. Lack of
response to TGFβ (termed TGFβ resistance) in SCLC
has been correlated with lack of TGFβRII,46,47 and this
association was recently confirmed by the introduction
of functional TGFβRII into receptor-negative lung cancer cells, resulting in restored sensitivity to TGFβ.48
TGFβ signaling is associated with a number of cellular
functions, the best described of which relate to inhibition of the cell cycle. Growth inhibitory effects of TGFβ
signaling have been associated with inhibition of expression and assembly of some of the cyclin/CDK components responsible for Rb activation.49
Loss of chromosome 3p and related genes
Probably the most frequent chromosomal abnormality
in lung cancer is loss of regions within chromosome
3p. LOH at chromosome 3p has been reported in
70–100% of all NSCLC and more than 90% of SCLC.50,51
A number of genes within this region have been suggested as putative tumor suppressors.
The loss of the fragile histidine triad (FHIT) gene
located at position 3p14.2 is frequent in lung cancer,
with more extensive genetic lesions occurring in highergrade tumors compared with low-grade and premalignant
lesions.52 Accumulating evidence points to a role of
FHIT as a tumor suppressor. Expression of FHIT protein in NSCLC cell lines and mouse xenograft models
has been shown to suppress tumor growth and induce
apoptosis,53 and recently FHIT has been found to stabilize p53 presumably by interaction with MDM2, which
thereby becomes incapable of binding and ubiquitinylating p53.54 This points to a functional role of FHIT in
apoptotic signaling, although the exact function of
FHIT remains to be fully elucidated.
RASSF1A is a different candidate tumor suppressor
gene residing at chromosome 3p (position 3p21). This
gene is inactivated in virtually all SCLC and more than
60% of NSCLC.55,56 Apart from allelic loss, the RASSF1A
gene has been found to be inactivated by epigenetic
mechanisms and hypermethylation of distinct regions
(so called CpG islands) within the promoter of the
RASSF1A gene, which inhibits gene transcription.
Reintroduction of RASSF1A has been found to reduce
colony formation, suppress anchorage-independent
growth, and inhibit tumorigenicity of NSCLC cells in
vitro and in nude mice.55 Furthermore, RASSF1A has
been shown to associate with microtubules, and recently
overexpression of RASSF1A has been reported to inhibit
motility of NSCLC cells and increase cell adhesion, suggesting a role for RASSF1A in cell migration and metastasis.57 Several other genes reside at the frequently
deleted regions of chromosome 3p but much remains
to be learned about the role of these genes in tumor
suppression. For a review of candidate tumor suppressor
Molecular biology of lung cancer 29
CDK4/6
CYCLIN D
p16INK4a
Rb
E2F
Rb
CDK4/6 CYCLIN D
P
ACTIVE
E2F
Altered gene expression
- Cell cycle progression
- Cell proliferation
- Anti-apoptosis
Figure 3.5
Rb signaling. The Rb–p16INK4a–tumor suppressor pathway, which is
frequently mutated in lung cancer, acts by inhibiting the
activation of the E2F family of transcription factors responsible for
growth promoting and anti-apoptotic signaling within the cell.
p16INK4a, which is frequently mutated in NSCLC, acts by inhibition
of the cyclin-CDK4/6 complex responsible for release of E2F from
Rb inhibition. In SCLC, Rb itself is frequently mutated, rendering
the protein incapable of inhibiting E2F signaling. The high
frequency of Rb and p16INK4a mutations in SCLC and NSCLC,
respectively, suggests that inhibition of this pathway is
0mandatory in the development of pleural malignancies.
genes residing at chromosome 3p which may play a
role in lung cancer pathogenesis see reference 58.
Experimental treatments: reintroduction of tumor
suppressors
Since the loss of activity of certain tumor suppressor
pathways is a distinctive characteristic of human lung
cancer, reintroduction of tumor suppressor activity is
an attractive strategy for therapeutic intervention. For
this purpose, replacement gene therapy by
delivery of lost tumor suppressor genes to cancer cells
has become increasingly attractive. Most reports of
tumor suppressor replacement gene therapy of lung
cancer involve reintroduction of TP53 in NSCLC, where
a number of clinical trials have been published. In general, the treatment has been found to be well tolerated
and responses have been observed in terms of tumor
regression and disease stabilization in some of the
enrolled patients. However, the limiting factor of gene
therapy today remains poor delivery of the therapeutic
gene to the cancer cells. The clinical studies performed
to date have all used modified viruses for gene delivery.
Although the delivery rates using viral systems have
been improved, a major drawback of using viruses for
gene delivery is the induction of immune responses
against the virus in the patients. This results in the production of antibodies which target the virus for degradation and limit the efficiency of repeated treatments.
Novel non-viral delivery vehicles are being developed,
which may in the future provide a potent alternative to
viral gene therapy. The status within the field of replacement gene therapy for lung cancer and delivery vector
development has recently been reviewed.59
Reintroduction of other tumor suppressor genes in
lung cancer has been evaluated in preclinical studies.
Co-delivery and expression of FHIT and TP53 have
been reported to provide a synergistic tumor-suppressing
effect in NSCLC in vitro and in vivo.54 Future studies
will be necessary to assess the potential of these strategies for treatment of lung cancer patients.
REPLICATIVE POTENTIAL AND TELOMERASES
When cultures of differentiated somatic cells are established in vitro they have a well-defined potential for cell
division. After a number of divisions, the cells are predetermined to enter crisis, a state characterized by
extensive cell death and chromosomal aberrations. This
phenomenon has been termed the mitotic clock and is
part of the tight regulation of normal cell growth. In
contrast, cancer cells propagated in culture have an
unlimited potential for continuous cell division and are
said to be immortalized.
The molecular explanation for the mitotic clock
resides in the chromosomal structure and mechanism
of DNA replication. Upon cell division, the cell initiates
DNA replication which proceeds to produce new leading and lagging strands from the DNA double helix.
Since DNA replication can only proceed in one direction (3′–5′), only the leading strand of the double helix
is continuously synthesized, whereas the new lagging
strand is assembled by ligation of smaller DNA fragments. The discontinuous replication of the lagging
strand results in a gap at the 5′ end of the newly synthesized DNA strand, resulting in loss of chromosomal
material during each mitotic cycle.
The chromosomal ends are termed telomeres
and are composed of six nucleotide repeats. The telomeres are involved in the correct orientation of the chromosomes during cell division. Due to the continuous
shortening of telomeric DNA following cell division,
30 Textbook of Lung Cancer
lack of telomere maintenance ultimately results in chromosomal degradation and end-to-end chromosome
fusion, exemplified by the massive cell death observed
during the crisis state of untransformed cells cultured
in vitro. In order to overcome the limitation of telomere
shortening, cancer cells activate a program for telomere
maintenance, which is normally shut down in fully differentiated normal cells. Most frequently, this is accomplished by activation of an enzyme complex known as
telomerase, but a subset of cancer cells lacks telomerase
activity and are immortalized by a process known as
alternative lengthening of telomeres (ALT). The implications of the telomere-activating machinery in lung
cancer and the development of therapeutic strategies
targeting telomere maintenance are discussed below.
Telomere maintenance in lung cancer
The core telomerase enzyme comprises an RNA
subunit (hTERC) which provides the template for synthesis of new telomeric DNA facilitated by the catalytic
subunit human telomerase reverse transcriptase
(hTERT). The RNA component hTERC is ubiquitously
expressed in many cells, whereas hTERT expression is
normally confined to undifferentiated cells such as
germ line cells and bone marrow stem cells, identifying
the enzyme moiety as the limiting factor for telomere
maintenance. Indeed, the great majority of SCLC and
NSCLC expresses the enzyme hTERT,60 whereas hTERT
expression and telomerase activity has been found to be
repressed in the majority of lung carcinoids, a malignancy which is also associated with a longer-term survival.61 A number of studies have shown that increased
telomerase activity and increased levels of hTERT
mRNA are mainly found in patients with poorly differentiated tumors (such as SCLC) and advanced disease
and correlate with poor survival, suggesting telomerase
activity as an important prognostic marker for patients
with lung cancer.62,63
A number of alternative splice variants of hTERT mRNA,
many of which lack enzymatic activity, have been identified, but the prognostic value and molecular role of these
mutations in lung malignancies remain to be clarified.
As previously mentioned, a small subset of cancer
cells acquires telomere maintenance without activation
of telomerase by a process termed ALT. Although this
phenomenon remains to be fully elucidated, ALT appears
to involve recombination of chromosome ends in a
mechanism associated with DNA replication.64 No studies reporting ALT in lung cancer have been published
to date, and whether ALT plays a role in lung cancer
cell immortalization therefore remains to be elucidated.
Experimental therapeutic targeting of telomerase
in lung cancer
Due to the central role of telomerase in the transformation of lung cancer cells, and the lack of telomere maintenance in normal tissues, blocking the activity of this
enzyme appears an intriguing target for therapeutic
intervention.
A number of small molecular inhibitors of telomerase
activity have been developed and some of these agents
have been reported to inhibit the growth of NSCLC
cells in vitro, albeit with a delay in growth inhibition of
several months after the initiation of treatment.65
The compound GRN136L is a lipid-modified oligonucleotide, which binds to the hTERC subunit of telomerase with high affinity, thereby inhibiting reverse
transcription by blocking access of hTERT to its RNA
template. GRN136L has recently been reported to successfully inhibit telomerase activity, leading to telomere
shortening and resulting in decreased growth of adenocarcinoma cells in vitro and effective prevention of
tumor metastasis in a xenograft mouse model.66
Another strategy involves activation of an immune
response towards telomerase by administration of a vaccine composed of hTERT-derived peptides. Recently a
clinical phase I/II study investigating the effect of treatment with two hTERT peptides in patients with
advanced NSCLC was published,67 reporting the treatment to be well tolerated and detecting immune responses
towards telomerase in 11 and tumor response to treatment in 2 of 24 patients. A new clinical trial is being
planned, aiming to investigate the effect of telomerase
immunogenic peptides in combination with chemo- and
radiotherapy.
ANGIOGENESIS
The vasculature is crucial for cell function and survival
in all tissues, since oxygen and nutrients are supplied
by the vessels. The growth of new blood vessels, called
the process of angiogenesis, is a normal physiologic
process taking place under organogenesis, which under
these conditions is transitory and carefully regulated.2
In a similar way tumors must develop angiogenic ability
to progress. This ability appears by activating the angiogenic switch. The activation is probably a result of the
change in the balance of angiogenesis inducers and
countervailing inhibitors, e.g. by altered gene transcription. Angiogenesis can be described as a result of a
dynamic balance between pro-angiogenic factors and
anti-angiogenic factors.68 Once a tumor has activated its
Molecular biology of lung cancer 31
angiogenic switch it becomes able to grow; in the
absence of this activation the tumor remains in a dormant state and is unable to grow in size beyond a few
millimeters. Angiogenesis, however, involves more
components than pro- and anti-angiogenic factors only.
For succesfull angiogenesis, interactions between tumor
cells, activation of the endothelial cells and mature vessels, degradation of the surrounding basement membrane, and invasion and migration of endothelial cells
into the surrounding connective tissue are needed.
Hereby tumor-associated neovascularization can take
place by establishing continuity with the systemic circulation, allowing tumor survival and growth and, more
seriously, facilitating further metastatic spreading.
Many different pro- and anti-angiogenic factors have
been identified. The angiogenesis-initiating signals
are exemplified by vascular endothelial growth factor/
vascular permeability factor (VEGF/VPF) and acidic
and basic fibroblast growth factors (FGF1/FGF2), which
all bind to transmembrane tyrosine kinase receptors
displayed by endothelial cells.69 The typical angiogenesis inhibitor is thrombospondin-1, which binds to
CD36, a transmembrane receptor on endothelial cells
coupled to intracellular Src-like tyrosine kinases.70 In
total there are up to nearly one hundred different proand anti-angiogenic factors. These include platelet-derived endothelial cell growth factor (PE-ECGF),
platelet-derived growth factor (PDGF), EGF, angiogenin, angiotensin II, platelet-activating factor (PAF),
and the inhibitor angiostatin. Most of the molecules
involved in angiogenesis are not specific to vascular
endothelial cells, but have a broad spectrum of target
cells, except from VEGF, which activates only endothelial cells. VEGF is a heparin-binding glycoprotein, which
binds selectively to two high-affinity tyrosine kinase
cell surface receptors: VEGFR1 and VEGFR2. These
receptors are found in blood vessels within or near
tumors, and the expression is found to be upregulated
in most cancers including lung cancer. VEGF has been
demonstrated to be an important predictor of poorprognosis in NSCLC.71
Targeting angiogenic factors
Inhibiting angiogenesis through anti-angiogenic and/or
vascular targeting agents seems logical, as new anti-cancer
treatment strategies. In particular, much attention has
focused on targeting VEGF and VEGFR. Compounds
currently under investigation in cancer therapy include
anti-VEGF/VEGFR antibodies, small molecule VEGFR
tyrosine kinase inhibitors, antisense suppression of
VEGF, immunotherapy, viral-directed targeting of
VEGFR signaling, ribozymes, and various toxin conjugates.72 Furthermore, blocking angiogenesis may
enhance conventional anti-cancer treatments such as
radiation therapy in situations where tumors are unresponsive to current anti-growth factor efforts, and the
benefits of combining angiogenic inhibitors with radiation are being explored. Recent clinical trials have
shown that the anti-VEGF antibody bevacizumab, combined with standard first-line chemotherapy in NSCLC,
provided a statistically and clinically significant survival
advantage with tolerable toxicity.73 In addition, more
recently tested compounds characterized as antivasculature agents have been shown to be effective
against mutiple targets; the efficiency of such compounds is currently being investigated in clinical trials
for NSCLC.
TISSUE INVASION AND METASTASIS
As mentioned above, cancer cells and tissues often have
dysregulation of crucial processes and factors, such as
apoptosis, growth factors, angiogenesis, replication
potential, sensitivity to anti-growth signaling, and
invasion and metastasis. Many of these processes are
dependent on proteases, making proteases an interesting target for new anti-cancer treatments. Proteases
(proteolytic enzymes) are highly involved in invasion
and metastasis by degradation of the extracellular
matrix, e.g. basement membranes. Proteases are involved
in both extra- and intracellular protein degradation.
Under normal conditions proteolysis is a physiologic
process leading to, for example, wound healing, but in
the malignant tumor proteolysis becomes a harmfull
factor enabling tumor cells to move out, invade adjacent tissues, and thence travel to distant sites where
they may succeed in founding new colonies, metastases
(Figure 3.6), which are the cause of 90% of human
cancer deaths.74 Thus, based on the degradation of
extracellular proteins and basement membranes by
proteolytic enzymes, increased invasion and metastasis
can take place in malignant diseases. The major components of the basement membrane and the extracellular
matrix are type IV collagen, laminin, fibronectin, vitronectin, and proteoglycans. Tumor cells can produce
a number of proteolytic enzymes which can degrade
these protein structures, including matrix metalloproteinases (MMPs), collagenases, urokinase plasminogen
activator (uPA), plasmin, cathepsins, and others. MMPs
are known to play a functional role in the metastatic
spread of lung cancer.75 Different MMPs are active in
32 Textbook of Lung Cancer
Extravasation
Intravasation
Regional lymph
node metastasis
Survival in
circulation
Growth in new
environment
Figure 3.6
Metastasis. This diagram illustrates the importance of proteolysis in cancer, leading to tissue degradation, invasion, and metastasis.
different steps of the invasive and metastatic process,
and a better understanding of the involvement of MMPs
in the invasion and regulation of growth of both primary and metastatic tumors may help to implement
these as anti-cancer therapy targets. Cathepsins have
been demonstrated to have a prognostic value in NSCLC
and levels of the receptors for uPA (uPAR) and other
components of the plasminogen activation system are
associated with survival in NSCLC.76
Targeting proteases and the metastatic process
It is expected that inhibition of the metastatic potential
of a tumor by interaction with extracellular protein degradation could be an important target, especially during
early tumor development. Drugs targeting MMPs have
been in clinical trials, but have shown little or no activity in lung cancer. Inhibition of MMPs has especially
been focused on targeting MMP-2 and -9. In studies on
cell lines and xenografts, the MMP inhibitor batimastat
has shown an ability to decrease the invasion of cancer
cells and to prolong survival in the treated animals.
However, these finding have been most consistent in
pancreatic cancer. The efficacies of batimastat and
another MMP inhibitor marimastat have been tested in
different solid tumor types, but the studies have been
limited by toxicity. In the clinical phase I and II studies
performed to date, little or no activity has been reported
in lung cancer. At the moment new MMP inhibitors
such as CP-471,358 are being evaluated in phase I and
II studies in a number of malignancies including lung
cancer.77
CONCLUSION
As is evident from the preceding sections, major advances
in molecular biologic research during recent decades
have resulted in a substantial insight into important
signaling pathways and mediators contributing to lung
cancer pathology. Recently, the first novel therapeutic,
which directly targets growth-promoting pathways, was
approved for treatment of lung cancer and many other
drugs are presently under clinical investigation. However, although some patients respond well to the new
treatments, it has become evident that further insight
into the mechanism of action of many of these novel
agents must be gained, in order to better individualize
the targeted treatments to the patients who will benefit.
Gaining further knowledge into the complexity of
molecular lung cancer biology, correctly applying this
knowledge in the development of novel therapeutics,
and optimization of presently available agents therefore
represent important challenges in lung cancer research
and clinics for the years to come.
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70. Bull HA, Brickell PM, Dowd PM. Src-related protein tyrosine
kinases are physically associated with the surface antigen CD36
in human dermal microvascular endothelial cells. FEBS Lett
1994; 351: 41–4.
71. Imoto H, Osaki T, Taga S et al. Vascular endothelial growth
factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc
Surg 1998; 115: 1007–14.
72. Raben D, Helfrich B. Angiogenesis inhibitors: a rational strategy
for radiosensitization in the treatment of non-small-cell lung
cancer? Clin Lung Cancer 2004; 6: 48–57.
73. Yano S, Matsumori Y, Ikuta K et al. Current status and
perspective of angiogenesis and antivascular therapeutic strategy: non-small cell lung cancer. Int J Clin Oncol 2006; 11:
73–81.
74. Sporn MB. The war on cancer. Lancet 1996; 347: 1377–81.
75. Brown PD, Bloxidge RE, Stuart NS et al. Association between
expression of activated 72-kilodalton gelatinase and tumor
spread in non-small-cell lung carcinoma. J Natl Cancer Inst
1993; 85: 574–8.
76. Pedersen H, Brunner N, Francis D et al. Prognostic impact of
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77. Planting A, van der GA, Schoffski P et al. A phase I and pharmacologic study of the matrix metalloproteinase inhibitor
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Chemother Pharmacol 2005; 55:136–42.
4
Tobacco policy
Nigel Gray
Contents Introduction • Basic policy • Developing countries • The future
INTRODUCTION
The single global public health objective in this field is
to reduce consumption of tobacco by all possible means
as quickly as possible. Major successes such as the
decline in British consumption and mortality are currently matched by the steep ascent of these two indices
in developing countries, particularly China,1 which
illustrates the urgency of policy action.
It is reasonable to assert that implementation of
policy lags, sometimes decades, behind policy development, which lags similarly behind the development of
knowledge. In a number of sophisticated countries,
among which are the UK, Norway, Sweden, Australia,
Canada, and the USA, the proportion of the population
which continues to smoke has fallen from over a half to
about a quarter. Mortality declines have usually followed, but at very different rates. So it is wrong to be
pessimistic but important to be impatient. Pressing for
activist policies, on the grounds that outcomes take a
long time, seems to be an integral part of the duty of the
health professions.
Comprehensive tobacco policy has been well established and understood since the mid-1970s.2 The recommendations in this chapter are informed by long
experience of successful and unsuccessful policies in
many diverse countries. Many of the important policy
issues and outcomes have never been the subject of refereed articles in the technical press, so the reader must
be satisfied with basic references and must be willing to
search newspaper archives for historic detail.
Tobacco use has been, and is, perhaps the most difficult issue faced by public health workers in the 20th
century. Historic diseases such as smallpox, polio, measles, diphtheria, tetanus, whooping cough, rubella, and
scarlet fever were conquered in developed countries
within a decade or so of the arrival of effective control
systems. When vaccines and antibiotics worked, they
were used. Failures in developing countries relate to the
failure of national and international social organization
and rarely to organized opposition. The reappearance
of malaria and tuberculosis, depressing though it is, is
partly due to these factors and partly due to the lack of
really effective means of control.
The singular feature of the tobacco problem is that
someone is selling it. No one is selling tuberculosis. To
this can be attributed the fact that, five decades after
discovering its carcinogenicity, tobacco consumption
worldwide is falling very slowly. Comparisons with the
other industries selling toxic products are unsatisfactory. There is no pretence that asbestos does not cause
asbestosis, nor that drunken driving is merely a pleasurable habit. The international tobacco industry is
unique in its stubborn refusal to concede the sideeffects of its product, despite revelations3 which make
it clear that the industry knew of the carcinogenic and
addictive properties of tobacco some decades ago. Once
having retreated into its legal bunker it is now in the
difficult position of facing enormous legal and financial
consequences if it makes concessions or tells the truth.
Thus the forces of public health and the global tobacco
industry are locked in continuous warfare and prospects for peace are slight.
While no form of tobacco use has been discovered to
be safe, the cigarette is the most ubiquitous, widely
used, and best-studied product. The myriad forms of
tobacco use seen in India and other parts of Asia are
carcinogenic in many different ways and, being personally grown or based on cottage industry production,
each poses specific individual problems. Certainly it is
easier to develop policies to control cigarette smoking
than tobacco/betel chewing as the product is factory
made, taxed, exported and imported, and often the
subject of retail licensing.
The unrepentant nature of the global tobacco industry, which is controlled by relatively few major manufacturers, is reflected in the sales statistics. Sales are in
decline in the most developed countries and the
expected indices follow. Lung cancer in males, especially younger ones, is declining, as is heart disease.1
By contrast, tobacco exports from the USA are climbing
and the antique tobacco monopolies of the previously
36 Textbook of Lung Cancer
communist world are being replaced by modern mass
production systems owned by the same people. Marketing measures forbidden in the USA, UK, and Europe
are rampant in many developing countries.
Consideration of tobacco policy may conveniently
focus first on the cigarette. Such consideration should
take note that smoking is a learned habit which is initiated by social forces but sustained by the development
of addiction in persistent users.
•
BASIC POLICY
This is theoretically simple:
•
•
•
•
change the cultural background;
change the smoker;
change the cigarette;
protect the children.
Changing the cultural background
The cultural background against which tobacco smoking must be considered is a mixture of community law
and community norms. Laws usually arise as a result of
public opinion at a point in time and are an important
reflection of community norms, although they do not
always mirror public opinion in those countries where
the tobacco industry is strongest. The failed battle to
introduce strong tobacco legislation in the USA in 1998
shows the difficulties in the path of lawmakers that are
posed by the organized and well-funded opposition of
tobacco manufacturers. This situation, while obvious in
the USA, arises in most countries when tobacco policy
requires lawmaking, although the opposition may be
less obvious and behind the scenes.
An important element in the interaction between
government, parliaments, and popular opinion may be
non-government organizations. Policy frequently arises
in the non-government sector, as may the drive for legislation. Thus the interactive process of introducing legislation may be an important part of providing a driving
force for implementation. Popular laws are more likely
to be implemented. Opposition to standard comprehensive laws is to be expected and is routinely led by
those with vested interests, supported by the industry,
using arguments now outdated and often ugly when
exposed to public gaze.
•
•
•
Model legislation
•
•
Health warnings These should state government
policy and the facts. Rotating, explanatory warnings
are the first step. Warnings researched for understandability and offering a telephone number to an
information service are better. Warnings with
graphic pictures are even better.
Packet labeling There is a powerful case for generic
packaging as a way of interfering with global brand
advertising. Packaging should declare yields of
known major carcinogens and other substances,
which may be specified as knowledge develops.
Packet inserts are a way of providing the sort of
comprehensive information that is given with such
substances as aspirin. Tobacco industry claims for
the right to compete for adult markets are specious
as adults and children co-exist in society and measures to protect or attract children often impinge
on adults and vice versa.
Abolition of promotion – in every form Tobacco brand
names need to be forbidden in advertisements for
any other product. Direct and indirect advertising
needs to be specifically addressed. This issue
remains difficult because of the cross-border abilities of satellite media. It should be understood that
there is no case which can be made in favor of
tobacco promotion as the product is seriously and
chronically toxic when used as the manufacturers
intend. Evasion of promotional restrictions is the
profession of a large number of people, all of whose
arguments should be ignored. Even at point of sale,
advertisement should be forbidden.
Availability Sales to children, defined as 16–18 in
most countries, need to be prohibited and the prohibition policed. Such legislation is widespread,
but policing is not. Vending machine sales need to
be supervised in places inaccessible to children, or
forbidden. This policy measure is widely adopted
but almost nowhere has policing been tried. Until
that experiment is done and shown to fail this
issue remains high on the agenda for developing
countries.
Smoke-free environments These need encouragement for exemplary as well as risk-avoidance reasons. Schools, hospitals, workplaces, and public
transport should be smoke-free, as a minimum.
Smokers in many countries have been remarkably
accepting of this policy. It is an important downward pressure on smoking rates in all age groups,
and probably reduces daily dose as well as encouraging quitting.
Tax This should be high in the context of individual
income and should be regularly increased; a set
proportion should be allocated to health purposes
Tobacco policy 37
•
including tobacco education.4 Tobacco tax is among
the only taxes demonstrated to be popular. There is
good reason why the price of a packet of cigarettes
should be several times that of a hamburger.
Regulation of the product It is unacceptable that a
product as dangerous as tobacco should be unregulated. Additives need to be demonstrated to be
non-toxic in both burnt and unburnt form; and
upper limits should be set, and continuously
reviewed, for major carcinogens and toxins. Public
health advisors and departments have been slow to
act in this field, possibly because of perceived
complexities. However, the establishment of upper
limits for cigarette emissions is relatively straightforward and is in need of urgent implementation.
The importance of legislation is underlined by the
experience of Norway, the pioneer, in 1975, of comprehensive tobacco legislation. Tobacco consumption
peaked in the mid-1970s, having risen by about 25%
between the mid-1950s and mid-1970s. Since then it
has declined by approximately the same amount. The
original legislation in Norway was from a unanimous
parliament, but was surrounded by much discussion
and public interaction. This early legislation did not
include severe workplace and public place restrictions,
and Norwegian prices have risen only slightly, in real
terms, since the 1980s.5 While it is possible to argue
over the potential benefits of more aggressive pricing,
public education, and smoking opportunity restrictions, the Norwegian experience is a testimony to the
efficacy of good legislation as the basis for a comprehensive anti-tobacco program.
Community norms are usually well reflected in public opinion. A comprehensive tobacco policy would
include regular surveys of tobacco consumption, public
opinion, relevant attitudes among smokers and nonsmokers, and evaluation of education programs. Opinion may move slowly, but it does move with time and
in the presence of well-directed education programs. It
is both logical and true that parental attitudes and
example flow through to youth behavior, so changing
the cultural background implies measuring beliefs and
recruiting all the potential role models of society as well
as removing the tobacco industry’s ability to promote
its product. It is also logical to believe that education
programs work better without opposition, further
underlining the importance of complete eradication of
promotion.
In summary, changing the cultural background
requires an activist and persistent approach to legislation
and community involvement. This means that a wellorganized and co-ordinated anti-smoking movement is
a necessary basis. Such movements are not always large;
efficiency and co-ordination are the keys.
Changing the smoker
Changing the smoker to become a non-smoker
is a complex multifaceted process requiring analysis of
individual society’s smoking patterns. It is accepted
that addiction to tobacco is the major force in maintaining smoking status. Progress towards becoming a nonsmoker may be generally and simply summarized:
Rational information → dissonance → attempts to quit →
success → maintenance
Dissonance may be defined as dissatisfaction with
one’s own smoking behavior, and affects a majority of
smokers in the USA, for example, but probably a minority in less well-informed societies. Clearly dissonance is
more likely to occur if the victim/person is well
informed, so the place of varied education programs,
targeted to the subgroups as well as the totality of smokers, cannot be doubted, but is country-specific, at least
to a degree. Other factors can be expected to stimulate
dissonance: the smoke-free workplace and public
places; peer group and family pressure; negative peer
group experiences such as deaths or disease; societal
attitudes and levels of information. Such factors reflect
the cultural background and vary from country to
country.
Attempts to quit occur frequently in sophisticated
countries and policy should encourage and provide
support for smokers who make them.
The role of nicotine replacement therapy (NRT) is
crucial and in need of considerable development. Its
value is well established although results are generally
disappointing by comparison to expectations. Better
products are needed as is greater availability and more
support services. It is bizarre that cigarette content is
virtually unregulated while bureaucratic restrictions on
alternative sources of clean nicotine are widespread.
The general global failure of health professionals,
especially physicians, in support of patients and provision of therapy is a disturbing reflection of health priorities, which at least means there is hope for potential
improvement.
The debate over nicotine addiction6 per se ought not
to hold back development of better products and services. Tobacco is a uniquely toxic way of delivering the
desired dose of nicotine while NRT appears to be safe
or relatively so. Up to this time there is no evidence of
38 Textbook of Lung Cancer
mass addiction to nicotine chewing gum, although the
lack of competitive products which will deliver the
quick, efficient, ‘fix’ of the cigarette might well explain
this. Nevertheless, policy should be aimed at providing
support, NRT, and whatever other pharmaceutical aids
may be developed, since the status quo is an ongoing
disaster which justifies greater effort than it receives.
Continuing use of NRT in smokers who cut down but
do not abstain is a sensible form of harm reduction,
although the obvious goal is abstinence.
Policy makers should note that the costs of helping
smokers are infinitely less than those of treating them
and that, while the most immediate mortality, morbidity, and cost benefits are achieved by attention to longduration heavy smokers, every smoker is at risk sooner
or later, and early intervention is always best.
learned in reducing vehicle emissions to the cigarette,
and to base regulations upon it.
It is known8,9 there is great diversity in the levels
of major carcinogens in mainstream smoke yields on
the world market, so the evidence that cigarettes
with lower carcinogen levels can be made and sold is
indisputable – cigarettes low in nitrates and nitrosamines are made and sold.
The policy issues then become the following:
•
•
•
Changing the cigarette
The cigarette is a uniquely efficient nicotine delivery
device which has so far escaped significant production
controls worldwide. This is in contrast to motor vehicles, pharmaceuticals, food, houses, and even sewage
systems. While the reasons for this disparity are interesting, as they include corruption on a global scale,
there can be no excuse for continuing to allow the
tobacco industry alone to decide what will go into the
product, and therefore what is present in mainstream
smoke.
First it is necessary to state that the policy of
the 1960s, which favored reduction of tar and nicotine
levels over time, has not produced the benefits anticipated. Changes in cigarette design7 have brought about
reductions in some carcinogens and increases in others.
Mortality benefit, if present, is small, and adenocarcinoma has increased in the USA and elsewhere. Since tar
measurement takes no account of the qualitative changes
which have occurred in smoke it is misleading. Over the
same time, bioavailability of nicotine has been increased
and, together with compensatory smoking, means
the machine-measured levels of nicotine are also misleading.
It can therefore be unequivocally stated that tar and
nicotine measures as currently used should be abolished – the policy question is what they should be
replaced with?
It must be recognized that cigarette design is best
understood by the tobacco industry and is clouded by
commercial secrecy, and that no governments have
applied the necessary research resources to know enough
to tell manufacturers how to make their product. However, it is certainly possible to apply the principles
•
•
•
•
Governments must claim power to regulate the
content of cigarette smoke – this power exists in
some countries.
Health authorities require suitable advisory systems involving independent scientists and with
mandatory access to industry information.
Initially, major carcinogens such as benzo(a)pyrene,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK), and N-nitrosonornicotine (NNN) should
be targeted. Market analysis would show the range
of yields. Those cigarettes yielding above the median
should be removed from the market, or modified,
within a standard period such as 12 months.
Over time this process would allow progressive
reduction in carcinogens and other toxins, since
the starting point is a level found to exist on the
market and already achieved by at least some
manufacturers.
Nicotine needs special treatment. The first essential
is a new measurement system. However, a measure
which measures smoke content will not accurately
reflect what gets into the smoker’s bloodstream, as
it cannot control for compensatory smoking practices. Therefore, while control of smoke yield can
be exerted by a measure such as nicotine content
per liter of smoke, the decision-making process
which sets the yield levels needs to be informed by
behavioral experiment and analysis.
The ultimate policy decision – whether mass weaning of nicotine-dependent populations should be
attempted by regulatory reduction of dose per cigarette – cannot be made in the light of knowledge
in 2007. However the goal of reduction in the
addictiveness of the cigarette is a proper one and
should be pursued as a matter of policy.
In facing the decision to control nicotine yields,
policy makers must understand that the rise of
cigarette smoking was a vast unplanned experiment performed by the tobacco industry, initially
ignorant of its product’s toxicity. Long-term decisions on nicotine policy will require similarly large
Tobacco policy 39
•
experiments based on sensibly considered probabilities. The decision to reduce tar and nicotine
was sensible when conceived but subverted by
industry manipulation. This mistake should not be
made again but should not prevent innovative regulatory policies.
New products containing tobacco ought also to be
regulated and only tested in situations similar to
those which are used for the testing of new pharmaceuticals. So far the tobacco industry has not
produced a successful alternative to the standard
cigarette. They should not be discouraged from
doing so but should not receive marketing advantages over NRT and other nicotine alternatives.
ongoing smokers need to be related to those of children
to a smoke-free and promotion-free environment.
Policy is not only about prohibitions and restraints.
There is a clear need for experimentally based, expensive, education programs aimed at children. The fact
that few of these have been developed outside a few
richer countries, and even fewer adequately funded, is
not an excuse for failure to change. Every society which
spends money on treating sick smokers would be well
advised to spend funds of the sort spent on promotion
of cola drinks on campaigns aimed at discouraging
smoking.
DEVELOPING COUNTRIES
Protecting the children
As social norms and fashions have changed over time,
so have the specific stimuli which trigger or contribute
to initiation of the smoking habit. Age of onset of initiation varies around the world, beginning earlier in
developed countries. Cultural differences play an important role, as exemplified by the great diversity in smoking rates between men and women in countries such as
China. Whereas the factors which contribute to initiation in particular societies differ, the policy question is
what can be done to interfere with the pressures toward
initiation – or in simple terms, what can be done to
protect the children?
The first policy approach is to remove or reduce all
the pro-smoking pressures which can be controlled.
Formal and informal promotion of tobacco has been
dealt with above. Nevertheless, it must be re-emphasized that children are extremely sensitive to promotional pressures and that any presentation of a tobacco
brand name needs to disappear from the social environment. This has been substantially achieved in a number
of countries, but has been subverted to a variable degree
by cross-border advertising of events such as motor
races and cricket matches sponsored by tobacco interests. Global control of this phenomenon will not be
achieved easily, but the battle, slowly being won in
developed countries, needs to be fought in developing
countries as the industry seeks to source such events
from them.
Local social pressures need policy attention. The role
of parents, siblings, peer groups, and local and international role models should be the subject of education
programs and local campaigns, with the specific objective of reducing initiating pressures wherever they exist.
What happens in schools, homes, workplaces, and public places needs detailed consideration. The rights of
Tobacco use is already built in to many developing
countries and takes many forms. No form of tobacco
use has been shown to be free of risk and the fact that
snuff use in Sweden is less hazardous than tobacco/
betel chewing in India is not sufficient to allow fantasies
of safe tobacco products to intrude on public policy.
The principles set out above are applicable to some
degree with most forms of tobacco use. However, local
cultures in which the many and strange variants of
tobacco smoking and chewing persist need to be considered individually. The broad-brush weapons of education, warning labels, taxation, and restriction where
relevant can be considered by policy makers, and locally
suitable policies developed and tried. The after-effects
of tobacco use as known are such that no variant of use
can be neglected.
The reappearance of the cigar as a social status
symbol in the USA should warn against complacency.
THE FUTURE
The basic principles of tobacco policy discussed here
have been tested and appraised in real societies and
shown to work to a greater or lesser degree. The degree
usually depends on the enthusiasm with which policies
are implemented. The force of the vested interests of
the tobacco industry has been able to slow policy implementation, but the fact remains that tobacco use in
developed countries had declined substantially and the
tobacco industry is now seeking to replace its lost,
dying, and dead smokers in developed countries with
new users in the poor and developing world.
The political battle over the proposed tobacco settlement in the USA in 1998, although seemingly lost at
40 Textbook of Lung Cancer
that time, is a serious and important indication of the
degree to which the international tobacco industry has
declined in power and influence. It is to be expected
that the public health principles espoused here will be
applied progressively and more rapidly over the next
decade. The result can only minimize the tobacco mortality epidemic already set in train by past events, but
while tobacco remains one of the largest causes of
avoidable death and disease, it remains one of the major
global public health targets for all countries.
REFERENCES
1.
2.
Peto R, Lopez AD, Boreham J et al. Mortality from smoking
world-wide. Br Med Bull 1996; 52: 12–21.
Gray N (ed). Lung Cancer Prevention; Guidelines for Smoking
Control. Geneva: Union Internationale Contre le Cancer,
1977.
3.
4.
5.
6.
7.
8.
9.
Glantz SA, Slade J, Bero LA et al. The Cigarette Papers. Berkeley: University of California Press, 1996.
Manley M, Glynn TJ, Shopland D. The Impact of Cigarette
Excise Taxes on Smoking Among Children and Adults: Summary Report of a National Cancer Institute Expert Panel.
Bethesda MD: National Cancer Institute, 1993.
Bjartveit K, Lund KE. The Norwegian Ban on Advertising of
Tobacco Products. Has it Worked? Oslo: Norwegian Cancer
Society, 1996.
Benowitz NL, Henningfield JE. Establishing a nicotine threshold for addiction. N Engl J Med 1994; 331: 123–4.
Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995.
J Toxicol Environ Health 1997; 50: 307–64.
Fischer S, Speigelhalder B, Preussmann R. Tobacco specific
nitrosamines in commercial cigarettes; possibilities for
reducing exposure. Relevance to Human Cancer of NNitroso Compounds, Tobacco Smoke and Mycotoxins.
International Agency for Research on Cancer. Monograph 105.
Lyon: 1991 489–93.
Gray N, Boyle P, Zatonzki W. Tar concentrations in cigarettes
and carcinogen content. Lancet 1998; 352: 787–8.
5
Smoking cessation programs
Philip Tønnesen
Contents Introduction • Clinical approach • Stages of motivation • Carbon monoxide in expired air
• Nicotine replacement therapy • Varenicline • BupropionSR • Other drugs • New drugs • Alternative
therapies • Smoking reduction • Special considerations for lung cancer patients who smoke
• Weight gain • Conclusions
INTRODUCTION
This chapter focuses on the proper use of nicotine
replacement therapy (NRT), varenicline, and bupropionSR, golden rules in smoking cessation, predictors of
success, and the concept of smoking reduction. It should
be remembered that cigarette smoking is an addiction,
and for that reason smoking cessation cannot be compared with treatment of other medical conditions. NRT
will produce low success rates when used without
adjunctive behavioral support; however, since most
smokers quit on their own and using over-the-counter
(OTC) NRT, even these low success rates will have an
important influence on public health. The degree of
supportive adjunctive behavioral therapy parallels the
actual success rate, while the relative success rate (i.e.
the odds ratio between NRT and placebo) remains more
or less unchanged at around a factor of two.1
As a preventive tool, smoking cessation is very costeffective. Smoking cessation with NRT or bupropionSR
is approximately eight times more cost-effective per
saved year compared with 300 medical treatments.2
Also, smoking is the most important etiologic factor in
the development of lung cancer, accounting for almost
85% of all lung cancer cases, and has been strongly correlated with other cancers, including oral, laryngeal,
and bladder cancer. Around one-third of all cancer
deaths are attributed to tobacco.3 Also, tobacco use is a
major contributor to chronic obstructive pulmonary
disease (COPD) and coronary arteriosclerosis – diseases
that often prevent lung cancer patients from undergoing curative surgery.
CLINICAL APPROACH
When a health care provider, i.e. a physician, nurse,
dentist, or pharmacist, meets with a smoking patient,
he or she has a responsibility to interfere and discourage
tobacco use.4,5 The first thing is to ask whether or not
the patient is a smoker. Already, by asking, one shows
to the patient that one cares about smoking and that
smoking might be of importance in relation to health.
It is important that the patient’s smoking be handled in
a neutral way without anger or condemnation. The
smoker should be informed about the risks of smoking,
and the information should be individualized for the
particular patient.
STAGES OF MOTIVATION
Some smokers are contented smokers: they do not consider quitting and do not think about the dangers of
smoking. But many smokers would like to quit. Motivation to do so can be regarded as a cyclic process of
changes, as described by Prochaska and Goldstein.6
However, these stages do not correlate well with success in quitting. It is much more important for patients
with smoking-related diseases such as lung cancer to
quit compared with ‘healthy smokers’. Continued smoking in lung cancer patients has a negative effect on the
outcome of surgery, chemotherapy, and radiation therapy, and increases the risk of secondary primary lung
cancers in long-term survivors.
The therapist’s approach to the smoker depends on
the motivation to quit. Use of the questions in Table 5.1
is an easy and quick way to classify the motivational
stage of the individual smoker and then to apply the
right treatment approach. If the smoker wants to quit
you should support with advice about NRT and the
golden rules of smoking cessation, use NRT, varenicline, or bupropionSR, clinician-provided assistance
and skills training, and follow-up visits.7 If the smoker
is only interested in cutting down, the smoking reduction concept should be applied. Patients who declare
42 Textbook of Lung Cancer
Table 5.1 Assessment of motivation to quit smoking or to
reduce
1.
Will you participate in a smoking cessation
course now?
Answer ‘Yes’: Start smoking cessation
‘No’: Continue to 2
2. Will you try to cut down your daily number of
cigarettes now?
Answer ‘Yes’: Start smoking reduction
‘No’: Recommend cessation and give
brochures
3. How motivated are you to quit on a scale from
0 to 10?
(0 = not at all motivated;
10 = extremely motivated)
Answer _______ score (0–10)
4. How motivated are you to reduce on a scale
from 0 to 10?
(0 = not at all motivated;
10 = extremely motivated)
Answer _______ score (0–10)
no interest in smoking cessation or reduction should
receive brochures and other self-help material about
smoking or smoking cessation. More detailed guidelines for smoking cessation have been published by the
Agency for Health Care Policy and Research in the USA
and by NICE in the UK.8,9
However, there are some basic principles related to
successfull smoking cessation that are important for the
therapist to consider: smokers must stop smoking completely at quit day (even one or two cigarettes per day
during the first one or two weeks of cessation are usually followed by relapse):
•
•
•
•
•
the use of NRT, varenicline and bupropionSR
lessens withdrawal symptoms and improves cessation outcome;
for lung cancer patients aggressive use of NRT,
varenicline, or bupropionSR should be used;
follow-up should be arranged to prevent relapse
(which is highest during the first three to six
weeks, then gradually declines, similarly to other
addictions);
smoking reduction might be a gateway to smoking
cessation in smokers low in motivation to quit;
if the patient relapses, he or she should be encouraged to make another attempt to quit later on and
then receive retreatment (‘recycling’).
CARBON MONOXIDE IN EXPIRED AIR
In most smoking cessation studies, sustained abstinence
is used as the outcome measure. It consists of the
smoker’s statement of not smoking now and not having
smoked since the last visit, together with biochemical
verification by carbon monoxide (CO) in expired air.
CO measurement is an easy and inexpensive way to
verify abstinence biochemically. The half-life of CO
varies between four and six hours, and the cut-off value
between non-smokers and smokers is usually 10 parts
per million (ppm). Most non-smokers attain CO values
of 1–4 ppm, and some use a cut-off value of 6 ppm.
Subjects exposed to passive smoking might attain values
of 6–9 ppm.
CO levels are most often measured with a portable
CO monitor (Bedfont Monitor, Sittingbourne, UK) in
expired air after a 15 s breathhold, with a CO value of
less than 6–10 ppm verifying abstinence.10 The result is
displayed immediately. Calibrations have to be performed at least every six months using a 50 ppm CO
test gas. False-positive values might be observed in subjects with lactose malabsorption. Although an ethanol
filter is present, high ethanol concentrations in the
breath might interfere with measurements. Drifting of
the zero-point might be observed if many smokers
are tested consecutively. Without CO monitoring, up
to 10% of failures might state that they do not smoke.
Plasma, saliva, or urinary cotinine levels are another
biochemical way to verify smoking abstinence.
NICOTINE REPLACEMENT THERAPY
The rationale for nicotine substitution is as follows.
When quitting smoking, the administration of nicotine
decreases withdrawal symptoms in the first months,
thus allowing the subject to cope with the behavioral
and psychologic aspects of smoking (Table 5.2).
Table 5.2 The principle of nicotine replacement
therapy (NRT)
•
•
•
•
•
Principle: quit cigarettes
Use NRT to reduce withdrawal
Break the psychologic addiction
After two to four months, stop NRT
Some might need NRT for longer periods
Smoking cessation programs 43
Withdrawal symptoms (craving for cigarettes, irritability, anxiety, depression, drowsiness, difficulty in
concentrating, restlessness, headache, hunger, sleep
disturbances) are usually assessed on a four-point scale
(0 = not at all; 1 = mild; 2 = moderate; 3 = severe).11,12
Withdrawal symptoms often appear four to eight hours
after quitting, peak during the first week (days 3–5),
and then gradually decline over the next two to four
weeks. Nicotine dependence is measured by the Fagerström test of nicotine dependence (FTND), with a possible scoring of 0–10 (most dependent)13 (Table 5.3).
With the nicotine replacement products used today,
lower nicotine levels are attained compared with smoking
(i.e. the high peak plasma levels of nicotine reached
during smoking are not achieved) (Figure 5.1). Patients
are weaned off nicotine replacement products (usually
over two to six weeks) when withdrawal symptoms are
lessened owing to decreased dependence. The average
12-month success rate reported in most studies is about
15–25%.8,9 Predictors that correlate with a lower success rate are higher nicotine addiction, lower age, no
previous quit attempts, previous depression, suffering
from COPD and cardiovascular disease, a smoking
spouse, and low motivation to quit.
Nicotine is the drug of choice to assist smoking
cessation. Results reported in a Cochrane meta-analysis
Table 5.3 Fagerström test for nicotine dependence (FTND)
Item
1.
How soon after you wake up do
you smoke your first cigarette?
2.
Do you find it difficult to refrain from
smoking in places where it is forbidden, i.e.
in church, at the library, in the cinema, etc.?
3. Which cigarette would you most hate most
to give up?
4. How many cigarettes per day do you smoke?
Do you smoke more frequently during the first
hours after waking than during the rest of the day?
6. Do you smoke if you are so ill that you are in bed
most of the day (or absent from work)?
Plasma nicotine concentrations (ng/ml)
5.
35
Answer
Score
Within 5 min
6–30 min
31–60 min
61 min or more
Yes
No
3
2
1
0
1
0
The first one in the morning
Any others
1–10
11–20
21–30
31 or more
Yes
No
Yes
No
Total score
1
0
0
1
2
3
1
0
1
0
0–10
Figure 5.1
Plasma nicotine levels during cigarette smoking, nicotine nasal
spray (NNS) use, and 4-mg nicotine chewing gum use.
30
25
20
Cigarettes
15
NNS
4-mg gum
10
5
0
8
9
12
16
20
Time (hours)
24
4
8
44 Textbook of Lung Cancer
of 105 trials with 39 503 subjects, who received various
forms of NRT (gum, patch, spray, inhaler, and sublingual/lozenge), indicated that NRT almost doubled
long-term (6–12 months) quit rates.14 The odds ratio
for success of NRT compared with controls was 1.8
(95% confidence interval, CI, 1.7–1.9). The odds ratios
for the different nicotine replacement products were
1.6 for gum, 1.8 for patch, 2.4 for nasal spray, 2.1 for
inhaler, and 2.1 for sublingual/lozenge (Table 5.4).
Overall, there was no statistical difference between the
different forms of NRT and this has also been found in
comparative studies.
The nicotine products described above are self-dosing systems to be used ad libitum, in contrast to the
patch, which ‘infuses’ about 1 mg of nicotine per hour
at a constant rate.
There are six different formulations of nicotine
replacement products (Table 5.5) and the determination of the most appropriate product should be according to patient preference, cost, nicotine dependence,
and number of daily cigarettes (Tables 5.6–5.9).
Nicotine chewing gum
Gum users should only chew a piece five to ten times
until they can taste the nicotine, then let the gum rest
in the cheek for a few minutes, and then chew again
to expose a new surface of the gum. Free nicotine can
then be absorbed and reduce side-effects due to
swallowed nicotine. The gum can be chewed for about
20–30 minutes. About 0.8–1.2 mg of nicotine is absorbed
from a piece of 2-mg nicotine gum, and 1.2–1.5 mg
of nicotine from a 4-mg piece15 (Table 5.5). With use
of nicotine gum throughout the day, blood levels of
one-third (for 2-mg gum) and two-thirds (for 4-mg
gum) of the nicotine obtained through smoking are
achieved.16,17
A basic advantage of gum is the possibility of
self-titrating the dose, in contrast to the patch, which
delivers a fixed dose. Thus it is possible to use a piece of
gum whenever it is wanted or needed during the day.
The principal disadvantage of gum use is potential
underdosing, which might explain the lack of effect in
several trials. The approximate dose equivalent for most
nicotine patches is approximately 20 pieces of the 2-mg
Table 5.5 NRT formulations
Gum
2 and 4 mg content: 0.8–1.2 mg and 1.2–1.5 mg
absorbed, respectively
Patch
15 mg/16 h; 21 mg/24 h
Inhaler
10 mg in one container: 4–5 mg released (2–3 mg
in clinical use)
Nasal spray
0.5 mg/dose in each nostril
Sublingual tablet
2 mg content: 0.8–1.2 mg absorbed
Lozenge
1 mg and 2 mg content: 0.5 and 0.8–1.2 mg
absorbed
Table 5.6 NRT use: 1
1–9 cigarettes/day (not-evidence based)
• 2-mg gum
• Inhaler
• 1-mg lozenge
7–9 cigarettes/day
• As above, or
• Patch 10-mg/16 h or 7-mg/24 h
Table 5.4 Efficacy of NRT
Table 5.7 NRT use: 2
•
•
•
10–20 cigarettes/day
• Patch: 15-mg/16 h or 14-mg/24 h
• Gum 2- or 4-mg
• Inhaler
• 2-mg lozenge or 2-mg sublingual
•
•
•
•
•
Meta-analysis controlled trials
Success rates sustained for one year
Odds ratio
1.77 (95%
CI 1.67–1.89)
Gum:
1.66
Patch:
1.81
Nasal spray:
2.35
Inhaler:
2.14
Sublingual/lozenge:
2.05
15–20 cigarettes
• As above, or
• NNS
Smoking cessation programs 45
Table 5.8 NRT use: 3
21+ cigarettes/day
• Patch: 25-mg/16 h or 21-mg/24 h
• Gum: 4-mg
• NNS
• Inhaler
• Sublingual 2-mg or lozenge 2-mg
• Gum as rescue in relapse situations
• NRT as long-term use if needed
• Combination of patch and one of the other
NRTs
• NRT in combination with bupropionSR
Table 5.9 NRT use: 4
•
•
•
•
•
Use of NRT in smokers as withdrawal
suppressor
Meetings, workplaces, travel
Few hours: gum, inhaler
6 or more hours: gum, inhaler, patch
Instruct smoker to try a piece of
gum/inhaler before travel starts
Table 5.10 Varenicline use
10+ cigarettes/day
• Varenicline 0.5 mg in morning days 1–3; then
0.5 mg b.i.d. days 4–7
• Quit smoking after 1 (–2) week
• Varenicline 1 mg b.i.d.
• Duration: 12 weeks
• In quitters after 12 weeks eventually continue
with varenicline up to 6 months
• Side-effects: mild nausea (30%), vomiting (2%)
• Contraindications: severe renal failure
gum, whereas the mean number of pieces of gum consumed daily is only around five to six in most studies.
Thus underdosing is a plausible explanation for lack of
efficacy in several studies.18,19
From these observations, it would be logical to
attempt to raise the consumed dose either by increasing
the number of pieces of gum chewed or by using the
higher-dose (4-mg) gum. In four studies comparing
the 4- and 2-mg gums, the 4-mg gum was superior to
the 2-mg gum for short-term outcome. Another way to
increase the amount of consumed gum might be to
administer it in fixed-dosage schedules as shown by
Killen et al.20
Side-effects of gum consist mainly of mild, transient,
local symptoms in the mouth, throat, and stomach due
to swallowed nicotine (i.e. nausea, vomiting, indigestion,
and hiccups). After adequate instruction, most smokers
can learn to use the gum properly. However, without
instruction many will discontinue use or underdose
themselves.
In the Lung Health Study, among 3094 smokers who
were followed for five years, the use of the 2-mg gum
appeared safe and did not produce cardiovascular
problems or other adverse events, even in subjects who
continued to smoke and still used nicotine gum.21
It is suggested that smokers be instructed to stop
smoking completely, use the nicotine gum on a fixed
schedule (i.e. every hour, from early morning, for at
least 8–10 hours), and to use extra pieces of gum whenever needed.
The optimal duration of treatment is not known;
however, in most studies, the gum has been used for at
least 6–12 weeks and up to one year. Individualization
of treatment duration is recommended.
Nicotine transdermal patch
The nicotine patch is a fixed nicotine delivery system
that releases about 1 mg of nicotine per hour for 16
hours (daytime patch) or for 24 hours (24-hour patch).
Nicotine substitution is about 50% of the smoking level
(21-mg patch/24 h and 15-mg patch/16 h) (Table 5.5).
The nicotine curve attained in plasma with patches is
flat, without the high peaks attained by cigarette
smoking. It is much easier to administer the patch and
to use it compared with gum, but it is not possible to
self-titrate.22 The recommended treatment duration is
8–12 weeks.
In a multicenter smoking cessation trial from the
USA, examining the effect of 0, 7-mg, 14-mg, and
21-mg nicotine patches, a dose–response effect of
increasing nicotine dosages was reported.23 Two large
placebo-controlled trials with 600 and 1686 smokers
have been published.24,25 The one-year success rate was
9.3% in the active patch group versus 5.0% in the placebo patch group in the first study,24 and 9.0% versus
6.3% in the other study.25 Among 19 studies examining
long-term (i.e. 6–12 months) smoking cessation success, 10 showed a significant outcome in favor of the
nicotine patch.22 The pooled success rate was 15.8% for
active patches versus 8.8% for placebos (odds ratio
1.98; 95% CI 1.70–2.30).
46 Textbook of Lung Cancer
Side-effects are mainly mild local skin irritation,
occurring in 10–20% of subjects. In only 1.5–2.0% of
subjects was the patch terminated owing to more persistent and severe skin irritation at the patch location.22
Because of its ease of use, the patch may be the first
choice of nicotine delivery system today. Transdermal
nicotine replacement does increase success in smoking
cessation with minimal adjunctive support.
Nicotine inhaler
An inhaler consists of a mouthpiece and a plastic tube
with a porous plug impregnated with nicotine, which
releases nicotine vapor when air is drawn through the
plug. Most of the nicotine is absorbed through the
mouth and throat. Each inhaler contains 10 mg of nicotine (Table 5.5). In clinical use, each inhaler releases
approximately 2–3 mg of nicotine, and the number of
inhalers used daily averages five or six. Thus, nicotine
levels comparable to those found during use of the
2-mg nicotine gum are attainable (i.e. relatively low
concentrations).
Few controlled trials have been conducted with nicotine inhalers. The efficacy and safety of the nicotine
inhaler were examined in a double-blind, clinical,
smoking cessation trial.26 The first published study was
a one-year, randomized, double-blind, placebo-controlled trial that enrolled 286 smokers. The success rates
for smoking cessation were 15% and 5% at 12 months
(p < 0.001) for active and placebo, respectively. The
mean nicotine substitution based on determinations
after one to two weeks of therapy was 38–43% of smoking levels. The treatment was well accepted, and no
serious adverse events were reported. Three other studies have confirmed the above finding, with odds ratios
in favor of active treatment of 1.6, 2.2, and 1.6.27 The
inhaler may replace some of the habit patterns associated with smoking (e.g. oral and handling reinforcement), along with providing nicotine replacement. At
least four inhalers should be used per day, the optimal
number being 4–10 per day and the duration of use
three months, with another 3–9 months of use and
downtitration if needed. With rapid and frequent puffing, it is possible to increase the dose.
Nicotine nasal spray
The nicotine nasal spray (NNS) consists of a multidose,
hand-driven, pump spray with nicotine solution. Each
puff contains 0.5 mg nicotine; thus a 1-mg dose is delivered if both nostrils are sprayed as recommended
(Table 5.5). The NNS is a strong and rapid means of
delivering nicotine into the body with a pharmacokinetic
profile closer to cigarettes. After a single dose of 1 mg
nicotine, the peak level is reached within 5–10 minutes,
with average plasma trough levels of 16 ng/ml. Three
published studies with the NNS indicate that the
one-year success rates for active NNS versus placebo,
respectively, were 26% and 10%, 27% and 15%, and
27% and 17%.28,29
This strong spray induces localized side-effects, such
as sneezing, nasal secretion and irritation, and congestion, watery eyes, and coughing. Up to 5% of subjects
rate these side-effects as unacceptable; however, most
symptoms decrease within a few days after the spray is
initiated. Highly nicotine-dependent smokers might be
the target group for this delivery mode of nicotine.
The NNS should be used for three months, but has
been used for up to one year in some studies. The dose
is from 10 to 40 puffs in each nostril per day.
Nicotine sublingual tablet/lozenge
The 2-mg sublingual tablet should be placed under the
tongue, where it will disintegrate within 20 minutes.
The 1-mg and 2-mg lozenges should be sucked at until
a strong taste appears, they should then rest in the
cheek for a few minutes and then the cycle is repeated
for 15–20 minutes. The nicotine released from the tablet will be absorbed through the oral mucous membrane and the dose delivered is comparable with the
2-mg nicotine chewing gum.30 Side-effects are similar
to those from the nicotine gum. Many subjects with
dentures who cannot use nicotine gum can use tablets
or lozenges.
The tablet/lozenge should be used for three months,
but duration of treatment should be individualized
for up to one year or longer. One tablet per hour is
the recommended dosage up to 20/day, with a maximum dose up to 40 tablets/day in highly dependent
smokers.
Combination of two different NRTs
Relatively few studies have been published about the
combination of two NRT products. A short-term
increase in success has been observed in some, and a
trend towards a statistically significant 12-month
increase has been found in meta-analysis.14
A dose–response effect has been observed with both
the nicotine gum and patch. Even 22- and 44-mg
patches have been tested with promising results after
four weeks of treatment, i.e. success rates of 45% and
68%. In two studies the degree of nicotine substitution
was compared to outcome and in both higher success
rates were found with increasing degree of substitution.
Smoking cessation programs 47
In the CEASE study comprising 3575 subjects, a higher
success rate was achieved with 25-mg 16-hour patches
compared with 15-mg nicotine patches.31
Overall, in clinical use the combinations of different
NRT administration forms seem safe with few sideeffects. Also, concomitant use of NRT and cigarette
smoking seems safe, with nicotine concentrations similar
to those found during normal cigarette smoking.
VARENICLINE
Varenicline affects the central nicotine receptors by
binding to the nicotine receptor as an agonist with some
antagonist action. This means that varenicline mimicks
the effect of nicotine, but also prevents the pleasure
from cigarette smoking by preventing nicotine from
binding to the receptor. In two studies with 1025 and
1027 smokers with similar design, varenicline 1 mg bid
was compared with bupropionSR 150 mg bid versus
placebo for three months.32,33 The quit rate after 1 year
was 22% and 23% for varenicline, 16.4% and 15% for
bupropionSR, and 8.4% and 10.3% for placebo, i.e.
there were significantly higher quit rates for varenicline
versus placebo and bupropionSR.
A relapse prevention study reported that, in subjects
who had quit after 3 months, prolongation of varenicline use for another three months resulted in a higher
quit rate after one year.34 The major side-effect was
nausea in approximately 30% of cases, with 2–3% discontinuing the drug due to nausea and vomiting. However, in most subjects the nausea was not a major
problem. No drug interactions have been found, and
no significant contraindications have been reported,
except severe renal failure. Varenicline has no effect on
post-cessation weight gain.
Overall, varenicline is a new, effective, and safe agent
for smoking cessation. Also, varenicline tends to be more
effective than bupropionSR. Varenicline should be considered a first-line drug in lung cancer patients.
The dosing should be varenicline 0.5 mg a.m. for
3 days, 0.5 mg bid for another 3 days, then quit cigarettes from day 7 and continue with 1 mg varenicline
bid for 12 weeks and, if needed, up to six months.
of 19 placebo-controlled studies reported a doubling of
quit rates with an odds ratio of 2.06 (95% CI 1.8–2.4)
in favor of bupropionSR.35
The recommended dosing for bupropionSR is
150 mg a.m. for one week prior to the quit date, in order
to establish adequate blood levels. Therapy should then
continue with 150 mg bid for 7–12 weeks.
Common adverse events from bupropionSR are
insomnia (up to 40%) and dry mouth. These sideeffects usually decline during the first week of therapy.
In clinical trials the treatment was stopped due to
adverse events in 10–12% of subjects. The most serious
adverse event was epileptic seizures, which were
reported in 0.1% of patients, and allergic reactions
(1–2%), with 0.1% cases of serious hypersensitivity.35,36
The formulation is slow release to prevent high peak
concentrations as seizures are concentration-dependent.
BupropionSR is contraindicated in individuals with an
increased risk of seizures (e.g. epilepsy, earlier head
trauma, anorexia nervosa). A reduced dose – that is,
one tablet daily – is recommended in patients with
severe liver impairment. As bupropionSR is metabolized in the liver, interactions occur with several drugs.
Similarly, it is important not to increase the dose above
300 mg, and to administer the daily dose in divided
form, with an interval of at least eight hours. The last
dose should not be taken later than 6 p.m. if insomnia
is a problem. Post-cessation weight gain is reduced by
2–3 kg during the drug treatment period.
There are few studies comparing bupropionSR
with NRT or looking at the combination effect; however,
the combination seems safe and is recommended for
hard-core smokers such as lung cancer patients.
BupropionSR is of similar efficacy to NRT and is
generally well tolerated in smoking cessation. As bupropionSR has a more severe side-effect profile, more contraindications, and is only available on prescription,
I regard NRT as first-line medication and bupropionSR
as a second-line drug, but this is a matter of personal
judgment and in most guidelines bupropionSR is a
first-line medication. The dosing should be bupropionSR 150 mg a.m. for 6 days, then quit cigarettes from
day 7 and continue with 150 mg bid for 7–12 weeks
and, if needed, up to six months (see Table 5.11).
BUPROPIONSR
OTHER DRUGS
BupropionSR, an amino-ketone, is an antidepressant that
differs from tricyclic antidepressants and serotonin reuptake inhibitors, and the effect on smoking is not coupled to the antidepressive effect per se. A meta-analysis
Nortriptyline, a tricyclic antidepressant, has been shown
to be as effective as NRT and bupropionSR in smoking
cessation. A meta-analysis of four trials found an odds
48 Textbook of Lung Cancer
Table 5.11 BupropionSR use
10+ cigarettes/day
• BupropionSR 150 mg in the morning
for 7 days
• Quit smoking after 7 days
• Increase dose: bupropionSR 150 mg b.i.d.
• Duration: 7–12 weeks
• Side-effects: sleep disturbances, seizures in
1:2000
• Contraindications: epilepsy, increased risk of
seizures, impaired liver function
It might be used as a secondary drug, especially in
smokers afraid of or not accepting weight gain. Rimonabant has been marketed as a weight-reducing agent due
to the low efficacy in smoking cessation.
Several nicotine vaccines are under development.
The principle is to produce antibodies in the blood that
prevent most of the inhaled nicotine from cigarettes
from reaching the brain. Phase II studies have found
that it is possible to induce a long-term antibody level
in humans with a safe vaccine and that high antibody
response is associated with smoking cessation.40
ALTERNATIVE THERAPIES
ratio of 2.8 (1.7–4.6) for one-year quit rates for nortriptyline versus placebo at a dose of 50–75 mg daily.37
There are contraindications, common anticholinergic
side-effects, and particularly cardiac conduction disturbances and a decrease in orthostatic blood pressure.
However, at the relatively low dose used for smoking
cessation, nortriptyline seems to be relatively well tolerated and is a second-line agent or even first-line agent,
especially in countries that cannot afford the more
expensive first-line drugs or where they are not marketed. Several other antidepressants including selective
serotonin re-uptake inhibitors have not been found to
be effective in smoking cessation, e.g. doxepin, fluoxetine, sertraline, moclobemide, and venlafaxine.
Clonidine, an α2-noradrenergic agonist, has been
used as a smoking cessation agent. Six studies were
included in a meta-analysis comprising 722 subjects,
and the odds ratio of success with clonidine versus placebo was 1.89 (95% CI 1.30–2.74).38 However, a high
incidence of adverse effects (median 71%) occurred
(e.g. dry mouth, sedation, dizziness, and symptomatic
postural hypotension). In my opinion – due to the high
incidence of adverse events – clonidine is an obsolete
drug in this area.
NEW DRUGS
Rimonabant is a cannabinoid type 1 receptor antagonist
with a central action and has been tested in smoking
cessation trials. Preliminary results showed an increased
three month quit rate with rimonabant, with relatively
low absolute abstinence rates.39 Rimonabant more or
less prevents post-cessation weight gain; however,
when the drug is ceased weight increases. The role
of rimonabant in smoking cessation has to be defined.
Other ‘popular’ interventions often used are acupuncture and hypnosis. However, there is no evidence to
support an effect from hypnosis or other alternative
therapies. A meta-analysis comparing active versus
control acupuncture found that acupuncture was no
more effective than placebo.41 One study reported no
effect for laser therapy in 320 adolescents.42
SMOKING REDUCTION
Many smokers would prefer to reduce the number of
cigarettes smoked daily instead of quitting completely.
The aim of smoking reduction is to widen access to cessation by including smokers not currently able or willing to stop abruptly, wanting to reduce smoking, or
unable or unwilling to quit. As shown below, by the
concept of smoking reduction it is possible to recruit a
new segment of smokers who are not interested in
abrupt cessation. The reduction process should be
looked at as a gateway to complete cessation.
The definition of smoking reduction is a decrease in
the number of cigarettes (or tobacco) smoked daily. A
50% reduction or more in daily cigarettes has been
chosen arbitrarily in most studies.43,44
Several randomized controlled trials have been published. In eight studies, two using nicotine inhalers
and six using nicotine chewing gum for half to one
year, comprising 2424 smokers, a reduction (>50%)
was reported in 15.9% of smokers using nicotine products compared with a reduction in 6.7% of placebo
users.45 Surprisingly, after one year a smoking cessation
rate of 8.4% was found among nicotine users versus
4.1% in placebo users. A reduction of more than 50%
after 3–4 months had a strong predictive value for
quitting at one year. Also, participation in reduction
Smoking cessation programs 49
trials increased the motivation to quit smoking,
thus not undermining the motivation to stop smoking
completely.
Another way to attain smoking reduction and reduce
the harm of smoking could be through tobacco product
modification.46 For the group of smokers not motivated
to quit smoking a less hazardous cigarette might be an
advantage. Also, smokeless tobacco (chewing tobacco
and snuff) might be an alternative with tobacco smoking,
with fewer health risks compared with smoking.47 Epidemiologic studies in Sweden have found much less
harm in snuff users compared with cigarette smokers.48
The smoking reduction concept should be offered to
smokers who are not motivated to quit. They should be
prescribed NRT – nicotine gum or inhaler – for three
months and recommended to reduce the number of
cigarettes by at least 50% during the first 1–2 weeks
and then to try to reduce further. If the smoker has not
reduced by more than 50% after three months, NRT
should be stopped as the chance of quitting then is low.
In smokers who have reduced by more than 50%, NRT
should be continued for up to one year, and after six
months they should be recommended to try to stop
smoking completely.
In summary, smoking reduction seems to have a role
for smokers not motivated or able to quit, as a gateway
to complete cessation. There is limited evidence that
smoking reduction is followed by an improvement in
health, in contrast to the use of smokeless tobacco
products.
SPECIAL CONSIDERATIONS FOR LUNG
CANCER PATIENTS WHO SMOKE
In this group of patients as many as 80% quit smoking
during the time of diagnosis.49 However, up to 50% of
patients undergoing curative surgery for lung cancer
relapse and smoke after five years, thus increasing the
risk of a secondary primary lung cancer.50,51 In healthy
smokers a high relapse rate is observed during the first
month after quit day, in contrast to cancer patients
where most relapses occur between one and six months
after quit day.52,53
An increasing proportion of lung cancer patients
undergo chemotherapy and this proportion will probably further increase during the next decade due to
increased public focus on this disease. Thus, in the
future most patients will undergo treatment with surgery and/or chemotherapy. The importance of smoking
cessation is due to a decreased complication rate after
surgery and during chemotherapy and radiation therapy if the patient has stopped smoking.
The period of diagnosis and therapy might elicit
depressive reactions and put a heavy strain on the
patient’s and family’s mental and social situations. Many
family members of lung cancer patients are often smokers and do not quit spontaneously during this period.54
It might also be that lung cancer patients are more
nicotine dependent.55 Overall, this calls for a more
intensive and aggressive effort to get these patients to
successfully quit smoking. A nurse-managed program
reported an abstinence rate of 40% after six weeks.54 A
combination of nicotine patch with another NRT product should be the rule, and also a longer duration of
treatment with the possibility to continue long term
with NRT. A combination of NRT and bupropionSR
might also be an option. However, as many of these
smokers have tried NRT previously, varenicline might
be the right option for these dependent smokers. Scheduled visits with smoking cessation counseling and
support are important, to be combined eventually with
telephone calls.
In healthy smokers higher quit rates have been
obtained if spouses are also enrolled in the same program and quit smoking, and this might also prove to be
the case for lung cancer patients. For the small fraction
of lung cancer patients with the lowest performance
status, where only supportive therapy is prescribed and
who have an expected short survival time, I would not
actively suggest smoking cessation.
The clinics involved with the diagnostics and therapy
of lung cancer should be able to cover smoking
cessation, and the health-care workers should have an
adequate knowledge about smoking cessation.52 It is
important that a specific budget is allocated to each
clinic for a smoking cessation service.
WEIGHT GAIN
A weight gain of 3 to 6 kg for abstainers after one year
is found in most studies.56,57 In 10% of males and 13%
of females the weight increase is more than 14 kg, i.e.
they are ‘supergainers’. About half of the participants
are afraid of gaining weight and it may be a more
significant problem for females. Weight gain can be
regarded as a withdrawal symptom due to increased
hunger and increased caloric intake. NRT products are
only partially able to reduce the post-cessation weight
gain while bupropionSR has a slightly greater effect, i.e.
a reduction in post-cessation weight gain of 2–3 kg.57
50 Textbook of Lung Cancer
For lung cancer patients the increase in weight might
be an advantage if they are underweight. The increase
in appetite might also be an advantage for patients with
decreased appetite.
CONCLUSIONS
In summary, NRT, varenicline, and bupropionSR
almost double the one-year cessation outcome, and,
combined with counseling and behavioral strategies,
are important adjuncts for maintaining long-term smoking cessation. Nicotine gum, patch, and inhaler are first
line drugs, while NNS nasal spray is for the more heavily dependent smokers. The patch might not be the first
choice for heavily dependent smokers. The duration of
NRT treatment is approximately three months, with
individual variations.
NRT is a very cost-effective treatment compared with
several other medical treatments, and should be much
more widely implemented in the future. If the smoker
has failed using NRT, varenicline or bupropionSR is the
choice.
As lung cancer patients might be more nicotinedependent and have more difficulty in stopping smoking, a more aggressive therapeutic approach should be
used, i.e. higher doses of NRT, a combination of two
NRT formulations, varenicline, bupropionSR plus NRT,
a longer duration of therapy (6–12 months), and more
support visits. Family members who smoke should also
be enrolled in a cessation program.
Most lung cancer patients have used NRT previously,
varenicline seems to be the drug of choice as it seems
more effective than bupropionSR, with fewer adverse
effects and almost no contraindications or interactions.
Also, varenicline tends to be more effective when compared with bupropionSR.
Physicians and other health-care providers have
an obligation to discourage tobacco use in their
patients and to deliver up-to-date assistance in smoking cessation.
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33. Jorgenby DE, Hays T, Rigotti NA et al. Efficacy of varenicline,
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bupropionSR for smoking cessation. J Intern Med 2003; 254:
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52 Textbook of Lung Cancer
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6
Current status of lung cancer screening
James L Mulshine
Contents Introduction • Current evidence • Technical innovations with CT imaging • Recommendations
from professional societies • Recent developments • Conclusion
INTRODUCTION
Lung cancer screening is the crucible where providing
an expensive new service with the potential for harm in
vast numbers of variably at-risk individuals collides
with the consequences of the world’s most lethal cancer. With over 160 000 annual deaths, lung cancer
accounts for 30% of cancer deaths in the USA.1 Regional
or distant metastatic spread is evident in at least threequarters of lung cancer cases at time of initial diagnosis
resulting in a 5-year survival rate of 15%. For surgically
resected cancer, the 5-year survival rate exceeds 60%.
By comparison, localized breast and prostate cancer are
detected at rates of 63 and 82%, so correspondingly
their 5-year survival rates are much better at 87 and
98%, respectively. For women, there has been a 600%
increase in the frequency in lung cancer over the last
eighty years, and lung cancer death rates in United
States women are the least favorable in the world.2 Unlike
cardiovascular disease, the risk of developing lung
cancer remains elevated after smoking cessation.3–5
Lung cancers are being diagnosed at least as frequently
in the over 45 million former smokers as in current
smokers,3 and smoking cessation strategies are of no
utility in the growing cohort of former smokers. The
progress in cardiovascular disease has not been matched
in lung cancer outcomes, so this cancer has recently
emerged as the dominant cause of death in tobaccoexposed individuals.6 Tobacco-related diseases are the
leading cause of premature death and account for half
of health-care costs in our society, so better approaches
to lung cancer management are critical.7
Promising reports with high-resolution computed
tomography (CT) detection have renewed interest in
early lung cancer screening.4,8–11 No major lung cancer
screening trial has been completed here in decades and
the recent United States Preventive Services Task Force
(USPSTF) analysis acknowledges the methodologic limitations of the previous chest X-ray screening trials.12–14
Lingering debate about those earlier trials has fostered
concern about CT-based lung cancer detection being not
only prohibitively expensive but possibly dangerous.15–17
Against this charged back drop, it is timely to review the
status of early lung cancer detection.
CURRENT EVIDENCE
A number of CT screening pilot studies have been
reported over the last few years (Table 6.1). While there
are different eligibility criteria and case work-up
approaches, these single-arm studies have been consistent for several critical parameters. Frequency of stage I
detection with CT screening is about 80%, which is
considerably higher than the national experience of
17%.1 This published experience is too recent to have
long-term clinical outcomes except for a recently presented Japanese series. From 1975–1993, the Anti-lung
Cancer Association performed 26 338 screening chest
X-rays,18 and in the detected cases 42% were stage I
lung cancer with an average primary size of 3 cm and
33% were stage III/IV. During 1993, this group began
using CT and, by 2002, 15 342 scans had been performed. With CT screening, 78% of the detected cases
were stage I with a mean diameter of 1.5 cm and the
rate of detection for stage III/VI disease had decreased
to 14%. With this transition, the overall 5-year survival
improved from 49% with chest X-ray-detected cases to
84% with CT-detected cases. This experience is consistent with the early reports from the International-Early
Lung Cancer Action Project (I-ELCAP), whose screening experience with current and former smokers was
presented with prevalence evaluation of over 26 000
subjects and follow-up incidence data from 19 700
subjects.19,20
The critical endpoint of a randomized trial is significant cancer-related mortality reduction in the
screened population compared to a control population.
The randomized trial design addresses the potentially
confounding influence of overdiagnosis. The term
54 Textbook of Lung Cancer
Table 6.1 Distillation of the pilot CT screening results for non-small cell lung cancer
No of subjects
Prevalence
cohorts8,37,38,67,71
Incidence
cohorts33,37,38,67,71
Number of CT-detected
lung cancers tumors
Mean size of
primary (mm)
Percent stage I
cancers
13 122
112
16.5
79
9 401
54
14.8
81
‘overdiagnosis’ refers to clinical outcome events not
adjusted for disease that would remain clinically covert
until death from other causes. If there is considerable
overdiagnosis, an apparently favorable screening result
in regard to stage or 5-year survival would not lead to
a significant lung cancer mortality reduction in the
screened arm. With current information it is not possible to establish a reliable estimate of the magnitude of
overdiagnosis, but emerging clinical and biologic information suggests that these small screen-detected lung
cancers may behave like symptom-detected lung
cancers.21,22
Furthermore, the term ‘overdiagnosis’ is used loosely
and may be construed to include the situation where a
clinically aggressive lung cancer is detected by CT
screening. However, in certain situations overdiagnosis
also refers to the patient who expires first of a co-morbid
condition related to tobacco yeast. In the decades since
the last major NCI-sponsored lung cancer screening trials, the influence of competing risks has diminished
related to both improved coronary artery disease outcomes and the increasing number of former smokers
perhaps mitigating the influence of overdiagnosis.6,23–25
Finally, overdiagnosis could also be construed as cases
where lethal iatrogenic complications occur in the course
of clinical management of screen-detected lesions.26
Overtreatment refers to the use of an intervention that
may entail greater morbidity than benefit of screening
that may be accrued to an individual choosing to undergo
lung cancer screening.
The best clinical management for small CT-detected
primary cancers is emerging to be different from the
standard management recommended for a chest X-raydetected lung cancer.27,28 For example, an anatomic
lobectomy with mediastinal dissection is the appropriate operation to manage a chest X-ray-detected lung
cancer, but is it the best way to remove a 7 mm peripheral primary lung cancer? Since even with subcentimeter screen-detected primary cancers, the frequency of
regional nodal involvement remains around 10%, the
optimal size range for finding lung cancers before lymphatic dissemination must be even smaller. Nevertheless, the evidence for more favorable outcomes in
managing smaller primary lung cancers is growing.29–36
From the experience in Tokyo, Rochester (MN), New
York City, and Milan, it is evident that centers of excellence can deliver high-quality lung cancer screening
care and measures reducing the number of invasive
diagnostic procedures improve cost efficiencies.8,33,37–40
Professional groups such as the Society for Thoracic
Surgery have developed national registries as a tool
for improving quality outcomes in thoracic surgery
(http://www.sts.org/doc/8406), and these measures may
allow favorable management outcomes to become more
generalized.4,41 Currently, the best approach to reducing
overtreatment, and with it the morbidity and mortality
of screening case management, is an area of uncertainty,
but clear research opportunities exist and preliminary
studies in this regard are being undertaken.42–45
An important finding at both Mayo Clinic and Cornell is that smoking cessation counseling in the setting
of lung cancer screening is associated with favorable
quit rates.46,47 Tobacco control has been the dominant
public health response for improving lung cancer outcomes.48 Linking smoking cessation with early detection research efforts may improve the cost economy of
lung cancer screening.
In light of the reports suggesting spiral CT can detect
small, early lung cancer, the NCI rapidly initiated the
National Lung Cancer Screening Trial (NLST) to evaluate whether CT screening leads to a significant improvement in lung cancer-related mortality. This urgency
was heightened by the concern that widespread ad hoc
CT screening, despite being a non-reimbursed service,
could preempt the opportunity for conducting a formal
randomized trial. Based on favorable initial data, many
people believe that lung cancer screening will be a
sensitive test for early disease. While this may be true
for many individuals, from a public health policy perspective it is also necessary to place emphasis on the
Current status of lung cancer screening 55
specificity of a screening test. The specificity of the
screening test will affect the resultant costs to society, in
terms of morbidity and dollars, in regard to overdiagnosis, overtreatment, false positives, and adverse events
associated with appropriate treatment. Conventional
wisdom is that these factors can only be assessed in a
prospective, randomized trial with a control group and
a lung cancer mortality endpoint.
The NLST, which has already completed full accrual,
uses multi-detector-row scanners (at least four rows)
for the 25 000 volunteers on the CT arm of that trial.
The control group of 25 000 receives annual chest X-ray
screening. The NLST subjects will receive annual
screening for three years, and follow-up will continue
for a few years until a mortality endpoint is reached.
The Dutch national randomized CT screening trial will
use 16-detector scanners and computer-assisted-detection (CAD) tools for their entire study population and
compare outcomes with a standard care control arm.
Other European trials including studies in France and
Italy are coming online. Investigators from the American and European trials will have periodic meetings to
standardize elements of data acquisition so that comparison of results from the various trials may be more
productive.
While breast cancer screening trials were conducted
over several decades with relative stability of the imaging detection tool,49 the dynamic pace of innovation
with spiral CT and its consequences have imposed an
unprecedented challenge to the randomized trial design
concept.50,51 Thoughtful analysis of the relative utility of
different trial designs, large databases, and other
resources in permitting adaptive public health progress
is a profound strategic challenge, but one that merits
more serious attention.19,41
TECHNICAL INNOVATIONS WITH CT IMAGING
Over the last decade, there have been substantial
improvements in the speed and quality of CT imaging.
Ten years ago, a typical single-detector CT scanner
acquiring one centimeter thick views (slices) along the
entire axial length of the thorax took several minutes
and consequently the respiratory motion of chest structures seriously compromised image resolution. Since
then there have been several generations of multi-detector CT scanners; the latest 64-detector-row scanners
will image the entire thorax using 0.625 mm slice thicknesses in several seconds. This thinner slice thickness
may allow for markedly better image resolution, but the
amount of data generated in this process is daunting.
Currently, the average size of incident primary cancers
detected at one center is under 1.0 cm.27,52,53 The gap
between the technical capabilities of the hardware in
acquiring vast amounts of imaging data and the availability of validated software to harness this improved
imaging capability highlights the importance of research
into CAD for early cancers. A potential benefit of higher-resolution imaging is that the evaluation may be
more sensitive in finding smaller primary cancers. This
size reduction may further decrease the frequency of
metastatic disease as well as interval-detected cancer.27–
32
A particular problem in this regard is the reliable
detection of curable small cell lung cancer cases.
CAD has not had a major clinical impact on breast
cancer imaging,54 but this is a two-dimensional data situation. With the anatomically more precise, three-dimensional spiral CT, this situation could be different for lung
cancer. The additional information provided by the third
dimension greatly improves the precision of measurement and of volume comparisons across time.55–57
If CT screening is validated to be effective, many
more lung CT scans will be performed. Even with
screening high-risk cohorts, the frequency of cancer in
a high-risk population will typically be about 1% or
less, so software to allow efficient work flow is essential
to leveraging the productivity of thoracic radiologists.
However, to reliably establish clinically relevant features such as the irregular boundary of small pulmonary lesions abutting normal adjacent structures, the
amount of imaging information required by a CAD system may exceed the amount of imaging information
that it is reasonable to expect a radiologist to review.
This disconnection will be most evident when CAD is
being applied to evaluate very small lesions, where
human vision has limited capabilities and determining
the ‘ground truth’ will be problematic. Therefore, developing and validating CAD applications for cancer
screening are great challenges, but standardized image
evaluation tools may prove essential in moving population-based lung cancer screening into routine care
settings.54,58–60 For this reason, the NCI developed the
Lung Image Database Consortium (LIDC) to accelerate
the maturation of image-processing tools for CAD. The
key aspect of this cooperative group is to create a large,
well-characterized database of images and clinical outcomes data for CAD algorithm research and validation.
This resource could expedite such projects as the utility
of volumetrically determined growth rates for identifying potential cancerous pulmonary nodules53,61 or
studies on the natural history of newly reported
56 Textbook of Lung Cancer
ground-glass opacities (or non-solid nodules).39,42,62
Rapid progress with CT-based imaging is expected to
continue. To extract clinically significant information
from such a detail-rich image, computer-assisted tools
will be crucial. The further pragmatic issues encountered in the breast cancer screening efforts in regard to
radiologists’ workload, reimbursement, and professional liability may also be ameliorated if validated
computer-aided diagnosis methods are developed.63,64
A major concern about widespread CT screening
relates to its cost, especially in light of one study which
projected enormous costs from models assembled using
assumptions based on early screening reports.15 More
extensive use of non-invasive imaging techniques in the
work-up of screen-detected lesions may explain why
the cost features of some screening management
approaches are less expensive.65 Only 13% of the
screened cases require further follow-up, with most of
those cases evaluated by serial CT imaging for nodule
growth rate.52,53,61 Further potential for cost savings and
morbidity reductions can be achieved by carefully
defining the risk features of the screened cohort,66
by reducing the screening intensity in following up
screen-negative populations,67 as well as from further
innovation with the imaging technology.
RECOMMENDATIONS FROM PROFESSIONAL
SOCIETIES
The American Cancer Society (ACS) updated its statement on testing for early lung cancer and recommended
against testing for early lung cancer in the asymptomatic population of at-risk individuals.68 However, this
revised statement recommends that individuals at high
risk for lung cancer, due to significant exposure to
tobacco smoke or occupational exposure, should discuss with their physician the potential benefits and
harm to inform their testing decision. ACS further recommends that such testing be done only in experienced
centers linked to multidisciplinary specialty groups for
diagnosis and follow-up.69
Table 6.2 Points to consider for clinicians in discussing lung cancer screening and its implications with individuals considering
spiral CT screening
•
•
•
•
•
•
•
•
•
•
•
The risk and benefits of lung cancer screening should be discussed, including potential morbidity,
mortality, and associated medical costs
No data are available from the two randomized trials evaluating for improvement in lung cancer-related
mortality and results are expected in several years
Results from observational studies of CT screening among high-risk patients (i.e. those with a history of
heavy smoking) indicate a high rate of diagnosis of lung cancer in stage I (a relatively curable stage)
The risk:benefit issues around lung cancer screening may be different for current smokers compared to
former smokers.
• For current smokers, smoking cessation remains the single most important measure to improve one’s
overall but especially cardiovascular health prospects
• For former smokers, the elevated risk of developing lung cancers persists for the rest of their lives
CT screening reveals many non-calcified nodules, only a fraction of which will be found to be lung cancer
The approach to diagnostic evaluation of suspicious nodules should be refined to maximize information
yield from non-invasive procedures while minimizing iatrogenic risk
Referral to a facility that is experienced and committed to providing high-quality integrated screening care
is essential. At such a facility there would be experienced and credentialed clinicians from
multidisciplinary fields (including thoracic surgeon, pathologist, pulmonologist)
The surgeon selected to perform the lung cancer operation should not only be specifically trained to
provide such care but should also perform lung cancer operations frequently
Facilities providing lung cancer screening care should provide objective information about the quality of
their outcomes
There is a persistent increased risk of subsequent lung cancers after curative resection of lung cancer, so
ongoing surveillance is essential
Participation in research to optimize CT screening management should be strongly encouraged
Current status of lung cancer screening 57
The conclusions from the USPSTF analysis, based on
a review of the literature published as of January 2003,
(http://www.ahrq.gov/clinic/uspstf/uspslung.htm) are as
follows:
The USPSTF recommends neither for nor against
using chest x-ray, computed tomography (CT scan),
or sputum cytological examination to look for lung
cancer in people who have no symptoms to suggest
the disease. If screening is being considered, doctors
and patients should discuss the pros and cons of
screening before going ahead with x-ray, CT scan, or
sputum cytologic examination to screen for lung
cancer. Patients should be aware that there are no
studies showing that screening helps people live longer. They should also know that false-positive test
results are common and can lead to unnecessary
worry, testing, and surgery.12
This statement represents a change from their previous
recommendation against screening and this reflects the
accumulation of more persuasive though not yet definitive data regarding the utility of lung cancer screening.
As a reflection of the extraordinary pace of this field, a
number of relevant reports have been published since
the completion of the USPSTF literature review on new
cohorts,18,38,39 efficiency of the diagnostic work-up,27,53,70
outcomes,72,73 and cost-effectiveness.45,65
In this dynamic setting, clinicians have a major challenge in staying abreast to provide current information
to their patients. Issues to consider in discussion with a
patient who may be considering lung cancer screening
are complex. In light of recent reports about health literacy there is a major communications challenge in responsibly educating about lung cancer screening (see
http://www.iom.edu/report.asp?id=19723 and http://
www.ahrq.gov/clinic/epcsums/litsum.htm).
Since the clinical management for lung cancer screening has a higher probability of morbid and mortal complications than cancer screening for other organs, a
mortality reduction benefit found by the NLST may not
result in improved national outcomes with lung cancer
if screening care delivery systems for early lung cancer
are not in place.41 The choice is between organized
screenings, where screening services are provided in
centers committed to excellence in early cancer management, or ad hoc screening, where the specifics of
screening care are left to be refined by market forces.
We recently tried to organize a series of issues that
should help physicians organize their dialog with
subjects considering lung cancer screening.72
RECENT DEVELOPMENTS
The New England Journal of Medicine recently published
a landmark experience in using spiral CT in over 31 000
individuals at risk for lung cancers from 38 institutions
across three continents.73 Over the last 15 years, the
group at Cornell, together with their collaborators, has
systematically explored the best approach to finding
and operating on early lung cancer. In a series of peerreviewed publications they have defined innovative
uses of spiral CT, image processing techniques, and
internet-based clinical trial co-ordination, driving progress in the detection and management of early lung
cancer. There is controversy about the benefit of CTbased screening for lung cancer, but there should be no
argument about the core strategy of attempting to
improve our ability to routinely find early, localized
lung cancer.
In community-based populations, finding early lung
cancer is a daunting process since disease prevalence is
relatively low. Finding economic approaches to detect
and confirm the occurrence of lung cancer in this setting is a critical public health challenge. The Cornell
group has described a successful approach to this and
has integrated minimally invasive diagnostic and surgical techniques as feasible for early lung cancer management. In addition, they have worked with a number of
the most respected thoracic pathologists in the world
(mostly from IASLC) to review these cases and, in their
recent publication, reported that the cases found by CT
screening fulfill standard criteria for fully fledged aggressive lung cancers.74 This supports recent tumor biology
information suggesting that these screen-detected
tumors behave like routinely detected lung cancers.22
Of the more than 400 cancers recently reported in the
Cornell study, 85% of the detected cases were stage I.
The 10-year survival analysis, after three years of median
follow-up, shows that over 90% of the people undergoing operations were projected to be alive and lung cancer free. All eight individuals who for personal reasons
declined surgery died of lung cancer.
A key enabler of this large study consortium was the
use of a web-based early lung cancer management system developed by the Cornell group which allowed
research to go on in the setting of clinical care. The current I-ELCAP results convincingly demonstrate that
systematic efforts to find early lung cancer can be associated with very favorable outcomes and their organizational process accelerates early lung cancer research. A
challenging debate is proceeding about the sufficiency
58 Textbook of Lung Cancer
of the I-ELCAP data to change national health-care
policy on lung cancer screening. This is a profoundly
important scientific, medical, and political process.
However, the IASLC could play a pivotal role in generating the research data to inform the process. There are
many steps in moving to responsible management of
early lung cancer and we need better information about
all of them. How do we identify the optimal cohort,
how do we do the diagnostic work-up, how do we do
the most appropriate removal of the primary cancer,
how frequently do we do follow-up CT scans to find
synchronous primaries, etc. These and many more
issues need to be addressed with research using stateof-the-art imaging tools. Since the progress in improving imaging tools is moving so fast, it is a major challenge
for our research processes. This is a part of the discussion about early detection research that merits much
more serious and urgent research attention. The contentious discussion surrounding screening trial design
has distracted us from a profound emerging opportunity to much more successfully manage lung cancer.
CONCLUSION
CT screening for lung cancer detection has considerable promise. Yet many individuals seeking lung cancer
screening services, such as the lower-risk subject outlined in the introductory vignette, may have a greater
chance of iatrogenic harm that screening benefit. While
definitive trials are in progress, the opportunity should
not be lost to conduct further essential research to generalize a potential mortality reduction benefit evident in
a lung cancer screening trial to routine care settings.
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60 Textbook of Lung Cancer
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7
Histopathology of lung tumors
Elisabeth Brambilla, Sylvie Lantuejoul
Contents Introduction • Squamous cell carcinoma • Adenocarcinoma • Small cell carcinoma
• Large cell carcinoma • Adenosquamous carcinoma • Sarcomatoid carcinoma
• Typical and atypical carcinoid • Conclusions
INTRODUCTION
With 169 500 new cases per year in the United States
and 182 000 new cases per year in Europe, lung cancer
is the most common worldwide diagnosed cancer and
the major cause of mortality,1 with157 400 cancer
deaths2 in the USA and 190 000 cancer deaths in the
European Union in 2001. Although cancer incidence
began to decline in men in the USA from 1980,3 its rate
is increasing in women,2 as a consequence of the
increasing proportion of women who smoke.
The international standard for histologic classification of lung tumors is that proposed by the World
Health Organization (WHO) and the International
Association for the Study of Lung Cancer (IASLC;
Table 7.1).4 The four major histologic types of lung
cancer are squamous cell carcinoma, adenocarcinoma,
the incidence of which is increasing at the expense of
squamous cell carcinoma, small cell carcinoma (SCLC),
and large cell carcinoma. These major types have been
subclassified into subtypes, the clinical significance of
which might be extremely important, such as the bronchioloalveolar carcinoma (BAC) as a variant of adenocarcinoma.4
Although lung cancer can be divided into many subtypes, the most important distinction is between SCLC
and non-small cell lung carcinoma (NSCLC). Clinical
importance has been given to this distinction because
of the major clinical differences in presentation, metastatic spread, and response to therapy of SCLC. However, this is an extremely simplistic means of distinction
between these subtypes which is not recommended
because it may override the clinical significance of specific subtypes like BAC. Histologic heterogeneity is an
important feature of the pathology of lung cancer,
which consists of a mixture of histologic types that represent a derivation of lung cancer from a pluripotent
stem cell.5–10 This histologic heterogeneity is apparent
on light microscopic examination in at least 30% of
lung cancers, and is even more frequently seen by
electron microscopy.
SQUAMOUS CELL CARCINOMA
A malignant epithelial tumor showing keratinization
and/or intercellular bridges that arises from bronchial
epithelium.11
Squamous cell carcinoma (SCC) accounts for approximately 30% of all lung cancers in the United States12
and 45% in Europe. Twenty years ago it was the most
frequent histologic type of lung cancer in Europe, and
it has progressively decreased, while adenocarcinoma
has increased in incidence. Over 90% of SCC occurs in
cigarette smokers. Two-thirds of SCCs present as central tumors, whereas one-third present as peripheral
tumors, although the primary bronchial site may be
easily detected at histology.13,14 The morphologic features that characterize squamous differentiation include
intercellular bridging and keratinization (or individual
cell keratinization or squamous pearl formation). These
differentiated features are readily apparent in well-differentiated tumors, and are difficult to detect in poorly
differentiated ones.15 However, this spectrum of differentiation has not been demonstrated to correlate with
prognosis in lung SCC. Segmental bronchi more often
than lobar and mainstem bronchi are the primary site
of SCC.16
Variants described in the WHO classification include
papillary, clear cell, small cell,17 and basaloid subtypes.4
This last variant has a dismal prognosis as compared to
poorly differentiated SCC.18,19 In a recent evaluation of
a large series of cases where basaloid carcinoma appeared
to have a shorter survival than other types of NSCLC
(p = 0.005) the basaloid variant of SCC did not differ
from pure basaloid cases with regard to survival.20
Papillary SCC often shows a pattern of exophytic endobronchial growth.21,22
62 Textbook of Lung Cancer
Table 7.1 WHO histologic classification of tumors
of the lung
Table 7.1 Continued
Malignant epithelial tumors
Squamous cell carcinoma
Papillary
Clear cell
Small cell
Basaloid
8070/3
8052/3
8084/3
8073/3
8083/3
Small cell carcinoma
Combined small cell carcinoma
8041/3
8045/3
Adenocarcinoma
Adenocarcinoma, mixed subtype
Acinar adenocarcinoma
Papillary adenocarcinoma
Bronchioloalveolar carcinoma
Non-mucinous
Mucinous
Mixed non-mucinous and
mucinous or indeterminate
Solid adenocarcinoma with mucin
production
Fetal adenocarcinoma
Mucinous (‘colloid’) carcinoma
Mucinous cystadenocarcinoma
Signet ring adenocarcinoma
Clear cell adenocarcinoma
8140/3
8255/3
8550/3
8260/3
8250/3
8252/3
8253/3
8254/3
Large cell carcinoma
Large cell neuroendocrine carcinoma
Combined large cell
neuroendocrine carcinoma
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Large cell carcinoma with
rhabdoid phenotype
8012/3
8013/3
8013/3
Adenosquamous carcinoma
8560/3
Sarcomatoid carcinoma
Pleomorphic carcinoma
Spindle cell carcinoma
Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
8033/3
8022/3
8032/3
8031/3
8980/3
8972/3
Carcinoid tumor
Typical carcinoid
Atypical carcinoid
8240/3
8240/3
8249/3
8230/3
8333/3
8480/3
8470/3
8490/3
8310/3
8123/3
8082/3
8310/3
8014/3
(Continued)
Salivary gland tumors
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma
Preinvasive lesions
Squamous carcinoma in situ
Atypical adenomatous hyperplasia
Diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia
Mesenchymal tumors
Epithelioid hemangioendothelioma
Angiosarcoma
Pleuropulmonary blastoma
Chondroma
Congenial peribronchial
myofibroblastic tumor
Diffuse pulmonary lymphangiomatosis
Inflammatory myofibroblastic tumor
Lymphangioleiomyomatosis
Synovial sarcoma
Monophasic
Biphasic
Pulmonary artery sarcoma
Pulmonary vein sarcoma
Benign epithelial tumors
Papillomas
Squamous cell papilloma
Exophytic
Inverted
Glandular papilloma
Mixed squamous cell and glandular
papilloma
Adenomas
Alveolar adenoma
Papillary adenoma
Adenomas of the salivary gland type
Ta
Mucous gland adenoma
Pleomorphic adenoma
Others
Mucinous cystadenoma
Lymphoproliferative tumors
Marginal zone B-cell lymphoma
of the MALT type
Diffuse large B-cell lymphoma
8430/3
8200/3
8562/3
8070/2
9133/1
9120/3
8973/3
9220/0
8827/1
8825/1
9174/1
9040/3
9041/3
9043/3
8800/3
8800/3
8052/0
8052/0
8053/0
8260/0
8560/0
8251/0
8260/0
8140/0
8940/0
8470/0
9699/3
9680/3
(Continued)
Histopathology of lung tumors 63
Table 7.1 Continued
Lymphomatoid granulomatosis
Langerhans cell histiocytosis
Miscellaneous tumors
Harmatoma
Sclerosing hemangioma
Clear cell tumor
Germ cell tumors
Teratoma, mature
Immature
Other germ cell tumors
Intrapulmonary thymoma
Melanoma
Metastatic tumors
9766/1
9751/1
8832/0
8005/0
9080/0
9080/3
8580/1
8720/3
From WHO Classification of Tumors, 2004.
Behavior is coded /0 for benign tumors, /3 for malignant tumors, and /1
for borderline or uncertain behavior.
ADENOCARCINOMA
A malignant epithelial tumor with glandular differentiation
or mucin production, showing acinar, papillary, bronchioloalveolar, or solid with mucin growth patterns, or a mixture
of these patterns.
Adenocarcinoma can be classified into:
•
•
•
•
•
•
•
•
•
adenocarcinoma mixed subtype;
acinar adenocarcinoma;
papillary adenocarcinoma;
bronchioloalveolar carcinoma;
– non-mucinous
– mucinous
– mixed non-mucinous and mucinous
– solid adenocarcinoma with mucin production.
Variants are:
fetal adenocarcinoma;
mucinous (‘colloid’) carcinoma;
mucinous cystadenocarcinoma;
signet ring adenocarcinoma;
clear cell adenocarcinoma.
Adenocarcinomas account for about 30% of lung
cancers in Europe and the USA.12 Most primary pulmonary adenocarcinomas, in contrast with metastases, are
highly heterogeneous and consist of a mixture of histologic subtypes. Most adenocarcinomas are histologically heterogeneous, consisting of two or more of the
histologic subtypes and whilst a majority of the lung
adenocarcinomas diagnosed are classified today into
the mixed subtype. For this reason the adenocarcinoma
mixed subtype was moved to the top of the list of adenocarcinoma subtypes in the 2004 WHO classification,
although it was not recognized in the 1981 WHO
classification.23 The acinar and papillary subtypes are
recognized by their architectural pattern of tumor cell
growth and invasion. A substantially different definition has been given to bronchioloalveolar carcinoma
(BAC subtype), which should be restricted to tumors
that grow in a purely lepidic fashion without invasion
of stroma, blood vessels, or pleura. The solid type is a
poorly differentiated carcinoma presenting intracytoplasmic mucins that should be of at least five mucin
droplets in two different high-power fields. Mucin
stains recommended are PAS (periodic acid–Schiff)
with diastase digestion and Kreyberg staining with
alcian blue.
Several additional unusual variants have also been
recognized, such as well-differentiated fetal adenocarcinoma,24 mucinous (‘colloid’) adenocarcinoma,25 mucinous cystadenocarcinoma,26–28 signet ring carcinoma,29
and clear cell adenocarcinoma.4 Two unusual gross
patterns of adenocarcinoma include the endobronchial
polypoid adenocarcinoma30 and pseudomesotheliomatous adenocarcinoma.31–33
Bronchioloalveolar carcinoma is uncommon, and
probably restricted to fewer than 5% of all lung malignancies.12 In the new 1999 WHO/IASLC classification,
BAC is defined as a tumor showing lepidic growth
along pre-existing alveolar septa with intact elastic and
basal lamina frames, without invasive growth. It should
be noticed that some increased fibrotic collagen deposit
of alveolar walls is accepted, as long as no myofibroblastic proliferation is visible. The lack of invasive
growth is added as an essential criterion4 based on clinico-pathologic data indicating that in patients with less
than a 2 cm tumor, BAC may be curable by economic
surgical resection.34 As a result of the narrow criteria for
BAC, the term ‘adenocarcinoma, mixed subtype’ is used
for tumors that have BAC and an invasive component.
In such cases the invasive patterns present (acinar, papillary, or solid) should be mentioned. It is common to
observe central scars in pulmonary adenocarcinoma
that contain invasive components and a focal BAC-like
pattern at the periphery of the tumor.
As a consequence of this revised definition of BAC,
the literature dealing with these tumors need complete
re-evaluation. Indeed, previous to the last classification,
BAC included tumors with obvious invasive growth.23,35,36
More than 50% of tumors previously classified as BACs
presented focal central desmoplastic scarring tissue or
64 Textbook of Lung Cancer
intra-alveolar complex papillary growth while the lepidic
growth started around the edge of the scar.37 For tumors
showing malignant tumor cell nests in a desmoplastic
stromal reaction, the diagnosis is adenocarcinoma mixed
subtype and the various subtypes present should be
mentioned (such as acinar, papillary, or BAC). These are
no longer considered as pure BAC.13,37 In addition, filling of alveolar lumens by papillary or micropapillary
structures is considered to be papillary adenocarcinoma,
but not bronchioloalveolar carcinoma.
BAC has two major cytologic subtypes, non-mucinous
and mucinous,4 and are rarely mixed, consisting of an
association of mucinous and non-mucinous cells.4 The
majority of BACs are mucin-producing, followed by the
non-mucinous type, while about 12% are a mixture of
both.37,38
Non-mucinous BACs consist of Clara cells and type
II pneumocytes; the latter cell type is a common stem
cell for distal bronchioles and alveoli identified in fetal
lung and is nowadays considered as the lung adenocarcinoma stem cell.39 The non-mucinous BACs are more
likely to be solitary38 than the mucinous type. These
tumors are composed of cuboidal cells proliferating
along alveolar septa and showing a hobnail appearance.
Specific nuclear inclusions are patent in half of the nonmucinous tumor cells that are stained with diastasedigested PAS and immunohistochemically for surfactant
apoprotein. On electron microscopy, these inclusions
form a network of 40-nm diameter microtubules.40,41
The mucin-producing BACs tend to be more multicentric and characteristically have mucin production.38
They may cause lobar consolidation resembling pneumonia on gross examination. Histologically, these
tumors consist of tall columnar cells with abundant apical cytoplasmic mucin and small, basally oriented, regular bland nuclei lining thin alveolar septa. Alveolar and
bronchiolar spaces are filled with abundant mucin.
According to the 1999 WHO/IASLC classification, a
final diagnosis of BAC can only be achieved on examination of a surgical resection specimen. Small biopsies
obtained by bronchoscopy or fine needle sampling may
show a lepidic growth pattern suggesting the possibility
of BAC, but are not sufficient to exclude the presence of
an invasive growth.
Pathoradiologic correlations
There are several growth presentations for the most
common adenocarcinoma mixed subtype with BAC:
•
•
a solitary nodule;
multiple nodules;
•
•
lobar consolidation;
diffuse (pseudopneumonic) consolidation pattern.
The typical radiologic appearance of BAC (pure BAC
or BAC component) is the ground glass pattern by CT
and an ill-defined, aerated, spongy density on gross
examination. In contrast, a grossly circumscribed nodule at growth examination and a pure solid appearance
on CT is typical of purely invasive adenocarcinoma
(acinar, papillary, solid). In between, a mixture of
these growths and CT appearances is seen in mixed
subtype adenocarcinoma with both invasive (often centrally located) components and BAC component (often
peripheral). When BAC and other adenocarcinomas
present with multiple nodules they can be unilateral or
bilateral. Unilateral nodules are classified as T4 by the
TNM classification and multiple nodules in another
lobe are classified as M1. Lobar consolidation and diffuse pseudopneumonic condensation patterns are difficult to distinguish grossly or radiologically from
infective pneumonia. All cases of adenocarcinoma
presenting with a diffuse or pseudopneumonic consolidation pattern have been shown to correspond to
mixed subtype adenocarcinoma with BAC component.
They are more frequently of the mucinous cell type,
with varying amounts of acinar, papillary, and solid
components.
Prognostic correlations with solitary small
peripheral lung nodules
Several important clinico-pathologic studies have
shown the clinical significance of BAC.34,42,43 Noguchi
et al34 reported that, in a large series of 236 peripheral
lung adenocarcinomas less than 2 cm in size, the
patients achieved 100% 5-year survival. These were
pure BACs, in contrast to patients with ‘invasive BAC’
who experienced higher mortality and a 5-year survival
of 75%, while the purely invasive form had a 5-year
survival of 52%. Suzuki et al42 demonstrated that the
size of the fibrotic scar was correlated with survival in
a series of 100 peripheral adenocarcinomas less that
3 cm in size: a 5-year survival of 100% was recorded
for patients with a scar size of 5 mm or less, in contrast
to 70% for patients with scars 5 to 15 mm in size
and 40% for patients with a central scar greater than
15 mm. In this study, the size of central fibrosis was
an independent prognostic factor on multivariate analysis (p = 0.01), as significant as vascular invasion
(p = 0.024) and lymph node metastasis (p = 0.024).
Yokose et al43 studied multiple pathologic factors for
prognostic assessment in 200 patients: 100% 5-year
Histopathology of lung tumors 65
survival was associated with at least one of the following
features:
•
•
•
a pattern of lepidic growth of more than 75%;
a central scar measuring 5 mm or less;
lack of destruction of the elastic fiber framework
by tumor cells.43
The most significant determinants of shorter survival
in the multivariate analysis were vascular invasion
(p < 0.001) and more than 25% papillary or invasive
growth (p = 0.043). Size and grade/pattern of stromal
invasion44,45 also influence survival. This has practical
consequences: all small (≤3 cm) tumors with a predominant BAC component should be entirely sampled serially, and included so that potential foci of invasion are
detected.
BAC is not a unique feature for lung adenocarcinoma
since about 15% of digestive mucinous carcinoma
metastases might mimic the histologic appearance of
BAC. Thyroid transcription factor-1 (TTF-1) immunostaining restricted to primary lung adenocarcinoma is
of great help in this distinction.
SMALL CELL CARCINOMA
A malignant epithelial tumor consisting of small cells with
scant cytoplasm, ill-defined cell borders, finely granular
nuclear chromatin, and absent or inconspicuous nucleoli.
The cells are round, oval, and spindle-shaped.
SCLC accounts for 25% of all lung cancers in
the USA as well as in Europe.12 Two-thirds of SCLCs
are proximal and present as a perihilar tumor. They
occur in a bronchial location, infiltrating the bronchial
submucosa and subsequently leading to bronchial
obstruction by circumferential compression. SCLCs are
not commonly observed on a surgical specimen since
extensive lymph node metastasis is common and the
tumor is not surgically curable. Macroscopically the
tumor is soft, friable, white-tan, and extensively necrotic.
Extensive lymph node metastasis is very frequent and
less than 5% of cases present as a solitary coin
lesion.46,47
The 1999 WHO/IASLC classification presents only
two types of SCLC: SCLC (with pure SCLC histology)
and combined SCLC (combined with any non-small cell
type) (see Table 7.1).4 The two subtypes oat cell carcinoma and intermediate cell type, that were proposed
in the 1981 WHO classification, as well as the category
of mixed small cell, large cell, proposed in 1988 by
the IASLC, were discarded from the new classification
because of difficulties in reproducibility of these subtypes and lack of confirmation that these patients have a
different prognosis.48,49
SCLC has a distinctive histologic appearance. The
tumor cells have a small size, not exceeding that of
three lymphocytes. They have a round or fusiform
shape, scant cytoplasm with a nuclear to cytoplasmic
ratio of 9 to 10, a finely granular nuclear chromatin
(‘salt and pepper’ appearance), and absent or inconspicuous nucleoli.4 Owing to the scarcity of cytoplasm,
nuclear molding and smearing of nuclear chromatin is
frequent, caused by crush artifacts. There is usually
extensive necrosis and a mitotic rate exceeding 20 and
reaching 100 mitoses per 2 mm2 area. Most often, the
growth pattern consists of diffuse sheets, although
endocrine differentiations with rosettes, palisading, ribbons, and organoid nesting might be seen.50 Basophilic
encrustation of vessel walls is known as the Azzopardi
effect in necrotic areas.50
Depending on the biopsy specimens, the tumor cell
size of SCLC might appear larger, which is often the
case in well-fixed open biopsies.
Fine needle aspiration (FNA) biopsy and core biopsy
may provide excellent material for assessment of the
diagnosis of SCLC, essentially because cytologic features of SCLC have a high diagnostic value and the
architecture is not critical for the diagnosis. The small
cell proliferation, with nuclear moulding, the very high
nuclear to cytoplasmic ratio, and the ‘salt and pepper’
quality of chromatin are extremely useful for this diagnosis on FNA. The diagnostic markers (NE markers,
TTF-1, absence of CK34βE12 expression) are of primary help in the diagnosis of SCLC. There is an excellent yield of these markers on FNA and/or biopsy.
Combined small cell lung cancer
The frequency of combined SCLC depends on the
extent of histologic sampling, and the extent of the
associated component. Combined SCLC represents
about 10%49 of SCLC if small biopsies are considered.
However, in a recent study on surgically treated SCLC,
using a conservative estimate of 10% of tumors showing associated NSCLC for subclassifying a tumor as a
combined variant of SCLC, 28% of the cases of SCLC
showed a combination with NSCLC, more commonly
with large cell lung carcinoma followed by adenocarcinoma and squamous cell carcinoma.48,49,51–53 SCLC can
also be associated, although rarely, with spindle cell
carcinoma,54,55 giant cell carcinoma,54 and carcinosarcoma.56 Immunohistochemistry might help to differentiate associated components, such as cytokeratin antibody
66 Textbook of Lung Cancer
cocktails, which tend to stain NSCLC components, a
good example of which is cytokeratin 1, 5, 10, 14 recognized by 34βE12.57 However, evidence is lacking
that pure and combined SCLC behaves differently with
regard to prognosis and response to therapy.51 Following chemotherapy, a mixture of large cells, squamous
cells, adenocarcinoma or giant cells with SCLC may be
seen in 15 to 45% of the cases.52,58–60
Differential diagnosis
Because SCLC has distinctive clinical properties with
an aggressive clinical course, frequent widespread
metastasis of presentation, common paraneoplastic
syndrome, and responsiveness to chemotherapy, histologic classification of lung cancer often is simplified
into SCLC versus NSCLC. A constellation of criteria is
applied for the distinction between SCLC and large
cell neuroendocrine carcinoma (LCNEC) including cell
size, nucleoli, nuclear-to-cytoplasmic ratio, nuclear
chromatin pattern, nuclear molding, cell shape (fusiform versus polygonal), and Azzopardi phenomenon
(Table 7.2).4,23,61,62
Disagreement among expert lung cancer pathologists
over this distinction occurs in up to 10% of cases,10,63
owing to the fact that sometimes LCNEC may adopt the
nuclear features of SCLC. With the new description of
LCNEC, the main differential resides in the distinction
of SCLC from LCNEC (Table 7.2). Crush artifact is
common in small biopsy specimens owing to scarcity of
stromal protection; this can also be seen in carcinoid
tumors, lymphocytic infiltrates, or poorly differentiated
NSCLC. In these cases, cytology specimens might be
helpful because the morphology may be more diagnostic than on a small biopsy specimen. Immunohistochemistry for neuroendocrine differentiation, keratins,
and common leukocyte antigen (lymphoid marker) can
be useful in marking SCLC versus lymphoid cells,
respectively.64 TTF-1 has been shown to be of great
help in distinguishing between SCLCs, which are 85%
positive for TTF-1 nuclear staining, and other proliferating small cells such as the small cell variant of
squamous cell carcinoma and basaloid carcinoma, both
of which are always TTF-1 negative.57,65 The most useful and specific neuroendocrine markers for distinction
of SCLC in formalin-fixed, paraffin-embedded tissue
sections are chromogranin A, synaptophysin, and neural cell adhesion molecule, especially the 123C3 clone
and CD56.61,66–70 Keratin (AE1/AE3) and epithelial
membrane antigen (EMA) as well as TTF-1 stain virtually all SCLCs in open lung biopsy and transbronchial
biopsy specimens.57,61,65,66 In contrast, a specific set of
cytokeratins never expressed in neuroendocrine proliferations (CK 1, 5, 10, 14) called 34βE12 is always absent
in pure SCLC. In the cases where common cytokeratins
Table 7.2 Light microscopic features for distinguishing small cell carcinoma and large cell neuroendocrine carcinomaa
Histologic feature
Small cell carcinoma
Large cell neuroendocrine
carcinoma
Cell size
Larger
Nuclear/cytoplasmic ratio
Nuclear chromatin
Smaller (less than diameter
of 3 lymphocytes)
Higher
Finely granular, uniform
Nucleoli
Absent or faint
Nuclear molding
Fusiform shape
Polygonal shape with
ample pink cytoplasm
Nuclear smear
Basophilic staining of
vessels and stroma
Characteristic
Common
Uncharacteristic
Lower
Coarsely granular or vesicular,
less uniform
Often (not always) present,
may be prominent or faint
Less prominent
Uncommon
Characteristic
Frequent
Occasional
Uncommon
Rare
a
From Travis WD, Linnoila RI, Tsokos MG, et al.61 Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma.
An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15: 529–533, 1991; with permission.
Histopathology of lung tumors 67
Table 7.3 Histochemical differential diagnosis between
small cell lung carcinoma (SCLC), basaloid carcinoma, and
large cell neuroendocrine carcinoma (LCNEC)
SCLC
Basaloid
carcinoma
LCNEC
NE markers
TTF-1
Cytokeratins
1, 5, 10, 14
+
−
+
−
−
+
+
+/−
−
are negative in a suspected SCLC, the pathologist
should exclude other possibilities such as chronic
inflammation, lymphoma (CD45 positive), primitive
neuroectodermal tumor, or small cell round sarcoma.
One difficulty resides in the fact that about 25% of
SCLCs express the antigen CD99/MIC-2, as do primitive neuroectodermal tumors and small round cell sarcoma. It is important to recognize that this distinction
is based primarily on light microscopy (Table 7.2).4
Since no single monoclonal antibody can reliably
distinguish SCLC from NSCLC,70,71 a set of reliable
markers should be considered (Table 7.3).
LARGE CELL CARCINOMA
Large cell carcinoma is a tumor that shows no differentiation pattern to allow classification into squamous cell
carcinoma, adenocarcinoma, or small cell carcinoma.
These poorly differentiated tumors most often arise in
the lung periphery, although they may be located centrally. They frequently appear at gross examination as
large, necrotic tumors. Histologically, these consist of
sheets or nests of large polygonal cells with vesicular
nuclei and prominent nucleoli.23 Although they are
undifferentiated by light microscopy, features of
squamous cell or adenocarcinoma might be found on
electron microscopy examination.6,7,72
There are several variants of large cell carcinoma, some
of which have high clinical significance, recognized in
the new WHO/IASLC histologic classification of lung
cancer (Table 7.1).4 These include LCNEC,4,61,73 basaloid
carcinoma,18,19,74 lymphoepithelial-like carcinoma,75–77
clear cell carcinoma,78 and large cell carcinoma with
rhabdoid phenotype.79 Lymphoepithelial-like carcinoma is described as an EBV (Epstein–Barr virus)
dependent epithelial proliferation more commonly seen
in the upper respiratory tract.
Because lung cancers are classified according to the
best differentiated component, areas of large cell carcinoma are frequently observed in poorly differentiated
adenocarcinoma or squamous cell carcinoma, and due
to the common heterogeneity of these cancers it is difficult to specifically and appropriately classify many
lung cancers in which only small pieces of tissue are
available. In such cases, the best diagnosis might be
‘non-small cell carcinoma’ and specification of the most
obvious component.5,80,81
Large cell neuroendocrine carcinoma
LCNEC is a variant of large cell carcinoma. It is a highgrade non-small cell neuroendocrine carcinoma that
differs from atypical carcinoid and small cell carcinoma.
Histologic criteria include:
(1) neuroendocrine morphology (organoid, palisading,
trabecular, or rosette-like growth patterns;
(2) non-small cell cytologic features (large size, polygonal shape, low nuclear to cytoplasmic (N/C) ratio,
coarse or vesicular nuclear chromatin, and obvious
nucleoli);
(3) high mitotic rate (≥11 per 2 mm2) with a mean of
60 mitoses per 2 mm2;
(4) frequent necrosis; and
(5) at least one positive neuroendocrine immunohistochemical specific marker or neuroendocrine
granules by electron microscopy.4,61
It is difficult to diagnose LCNEC based on small
biopsy specimens because of frequent lack of neuroendocrine morphology without a substantial sampling of
the tumors. Some criteria have been proposed based on
cytology.82
The term combined LCNEC is used for tumors associated with other histologic types of NSCLC, such as
adenocarcinoma or squamous cell carcinoma (Table 7.1).4
Any combination of LCNEC with SCLC is diagnosed as
SCLC combined.4 A variety of criteria must be used to
separate SCLC from LCNEC (Table 7.2).
Differential diagnosis
In 10% of the cases of NSCLC lacking neuroendocrine
morphology, immunohistochemical neuroendocrine
markers or neuroendocrine granules by electron microscopy can be demonstrated. Such tumors are called nonsmall cell carcinomas (adenocarcinoma, squamous cell
carcinoma, or large cell carcinoma) with neuroendocrine
differentiation (NSCLC-NED).4,61 Although Iyoda et al83
found that the tumor size of large cell carcinoma with
68 Textbook of Lung Cancer
neuroendocrine differentiation was significantly larger
than that for LCNEC, the survival was not different
in this series from patients with LCNEC. At the present
time, the clinical significance of the diagnosis of NSCLCNED is not known. Whether these tumors are responsive
to SCLC chemotherapy regimens84–86 or whether expression of neuroendocrine markers may be an unfavorable
prognostic factor87–94 remains to be determined.
show no staining in small cell, large cell and LNEC
whereas it stains quite all basaloid carcinoma. TTF-1 is
never present in basaloid carcinoma, but is present in
the majority of SCLC and LCNEC (Table 7.3).57,95 p63
is expressed in most cells of all basaloid carcinomas.
Basaloid carcinoma
Basaloid carcinoma is the most prominent variant of
large cell carcinoma after LCNEC.4,18,74 Basaloid carcinoma represents 3 to 4% of NSCLCs in Europe, almost
always occurs in males, and most of these tumors
develop in proximal bronchi where they frequently
have an endobronchial component. Two-thirds of these
tumors arise from long areas on the bronchial mucosa
and show prolonged and laterally extended in situ carcinoma. About half of the tumors present with a pure
basaloid pattern that belongs to a variant of large cell
carcinoma. The remaining cases have minor (less than
50%) components of squamous cell carcinoma or, more
rarely, adenocarcinoma and are thus classified as
squamous cell carcinoma (basaloid variant) or adenocarcinoma, respectively. These tumors consist of a lobular, trabecular, or palisading gross pattern of relatively
small monomorphic cuboidal to fusiform cells with
moderately hyperchromatic nuclei, finely granular
chromatin, absent or only focally conspicuous nucleoli,
scant cytoplasm but a nuclear to cytoplasmic ratio lower
than that of SCLC, and a high mitotic rate from 20 to
100 mitoses per 2 mm2. Neither intercellular bridges
nor individual cell keratinization are present which
allows them to be distinguished from poorly differentiated squamous cell carcinoma. Patients with basaloid
carcinoma have a significantly shorter survival than
those with poorly differentiated squamous cell carcinoma which deserves this differential diagnosis.18,19,74
Adenosquamous carcinoma accounts for 0.6 to 2.3% of
all lung cancers96–100 and is defined as a lung carcinoma
having at least 10% of squamous cell or adenocarcinoma components.4 Adenosquamous carcinoma should
not be confused with mucoepidermoid carcinoma, a
malignant epithelial tumor characterized by the presence of squamoid cells, mucin-secreting cells, and cells
having intermediate type, identical to the same tumors
encountered in the salivary glands. Mucoepidermoid
carcinoma of high-grade malignancy is differentiated
from adenocarcinoma by a variety of features including
a mixture of mucin-containing cells and squamoid cells,
transition areas from classic low-grade mucoepidermoid carcinoma, and lack of keratinization.
Differential diagnosis
Since comedo type necrosis is common, palisading is a
characteristic feature of basaloid carcinoma, and rosettes
can be identified in about one-third of cases, the main
differential diagnosis resides in separation from LCNEC.
Immunohistochemical stains for neuroendocrine markers are negative in basaloid carcinoma and positive in
LCNEC. No secretory granules have been seen by electron microscopy in basaloid carcinoma. Two antibodies
are helpful to make the distinction on small biopsies
between basaloid carcinoma, SCLC, and LCNEC. The
specific cytokeratins 1, 5, 10, 14 recognized by 34βE12
ADENOSQUAMOUS CARCINOMA
SARCOMATOID CARCINOMA
This group of lung carcinomas is poorly differentiated
and expresses a spectrum of pleomorphic, sarcomatoid,
and sarcomatous elements. They express the features and
the biological behavior of epithelial cells that adopt an
epithelial to mesenchymal transition in certain conditions of culture in vitro. Pleomorphic carcinomas tend
to be large peripheral tumors invading bronchial
lumens, forming endobronchial growth. They often
invade the chest wall and are associated with a poor
prognosis.54 Because of the characteristic histologic heterogeneity of this tumor, adequate sampling is required
and should consist of at least one section per centimeter of the tumor diameter. To enter in this category a
pleomorphic carcinoma should have at least a 10%
component of spindle or giant cells associated with, but
distinctly identifiable from, other histologic types
such as adenocarcinoma or squamous cell carcinoma.4
A few giant cells disseminated in an otherwise recognizable squamous cell adenocarcinoma or SCLC have no
value for classification in the category of sarcomatoid
carcinoma.
Rarely carcinomas present with a pure giant cell or
spindle cell pattern and deserve the terms giant cell or
spindle cell carcinoma. Giant cell carcinoma consists of
Histopathology of lung tumors 69
huge, bizarre, pleomorphic and multinucleated tumor
cells that engulf numerous inflammatory cells, particularly polymorphonuclear leukocytes, in their cytoplasm.101–
103
They are discohesive and separated by significant
infiltration of inflammatory cells. This tumor is defined
as a carcinoma by light microscopy, but immunohistochemical and epithelial markers such as keratins
are also quite helpful in confirming their epithelial
nature.4
Carcinosarcoma
Carcinosarcoma is a tumor composed of a mixture of
carcinoma and sarcoma. A heterologous component
should be demonstrated such as cartilage, bone, or
skeletal muscle – heterologous elements which do not
display cytokeratin staining.4 Experience proves that
these cases are extremely rare while observations of
pseudochondromatous or pseudo-osseous patterns in
sarcomatoid carcinoma are frequent: in these cases the
pseudosarcomatous components also express keratins.
Pulmonary blastoma
Pulmonary blastomas are defined as biphasic tumors
consisting of an association of a glandular component
that resembles well-differentiated fetal adenocarcinoma
and a primitive sarcomatous or mesenchymal component.4 Well-differentiated fetal adenocarcinoma is no
longer regarded as the epithelial pattern of monophasic
pulmonary blastoma but, rather, as a variant of adenocarcinoma.4
TYPICAL AND ATYPICAL CARCINOID
Carcinoid tumors accounts for 1 to 2% of all invasive
lung malignancies.12 The majority of patients are
asymptomatic at presentation.104 Symptoms include
hemoptysis, postobstructive pneumonitis, dyspnea, paraneoplastic syndromes including carcinoid, Cushing’s
syndrome,104–106 and acromegaly.107 There is no gender
predilection.104,108 There is no association with smoking
since 40% of patients with carcinoid are non-smokers,
which is the proportion within the normal population.
The mean age is 55 years, with a range up to 82 years.104
This is the most common lung tumor in childhood.109
The treatment of choice of pulmonary carcinoids is
surgical resection.104,110 Patients with typical carcinoid
(TC) have an excellent prognosis and rarely die from
their tumors.104,111 However, metastases do not disqualify the diagnosis of typical carcinoid. Five to ten percent
of TCs have regional lymph node involvement that does
not affect their clinical outcome.13 Compared with TC,
atypical carcinoid (AC) presents with a larger tumor
size, higher rate of metastases, and a significantly
reduced survival. Most series where the diagnosis was
based on actual accepted criteria reported a mortality of
27 to 47%.104,112–114
Carcinoid tumors are most often centrally located
with a polypoid endobronchial obstructive component.
When peripheral carcinoids occur they are more often
of the spindle cell type. Both TC and AC are characterized histologically by an endocrinoid, organoid growth
pattern and uniform cytologic features, consisting of
moderate eosinophilic, finely granular cytoplasm, a
nucleus with a finely granular chromatin (Table 7.4),
and inconspicuous nucleoli that can be discretely more
prominent in AC. A variety of histologic patterns may
occur in AC and TC, including trabecular, palisading,
rosette-like, papillary, sclerosing papillary, glandular,
paragangliomatous, spindle cell, and follicular patterns.61 More rarely, the tumor cells of pulmonary carcinoid tumors may have oncocytic, acinic cell-like, signet
ring, mucin-producing, or melanocytic features.61
The most distinguishing feature between typical carcinoid and atypical carcinoid is the rate of mitosis and
the presence or absence of necrosis. Typical carcinoids
show less than 2 mitoses per 2 mm2 area of viable tumor
(per 10 high power field) and no necrosis. The presence of between 2 and 10 mitoses per 2 mm2 or necrosis73 defines the diagnosis of atypical carcinoids. The
presence of features such as cell pleomorphism, vascular invasion, and increased cellularity are of no help in
separating TC from AC and in allowing stratification of
patients for prediction of survival.73 TC may well show
focal cytologic pleomorphism, as do paragangliomas in
the head and neck area.61,112 The necrosis in AC usually
consists of small foci centrally located within organoid
nests of tumor cells.
Immunohistochemistry
Nearly 80% of TC and AC stain for pancytokeratins and, as other pulmonary neuroendocrine
tumors, they always express cytokeratins 8, 18, and
19.115 From a more practical standpoint, expression of
cytokeratins 1, 5, 10, and 14 has never been observed
along the whole spectrum of neuroendocrine tumors of
the lung.116
Neuroendocrine markers are present in all carcinoids. Chromogranin A is present in neurosecretory granules and synaptophysin is contained in synaptic
vesicles.68 They all express CD 56/NCAM, which belong
to the immunoglobulin superfamily of transmembrane
70 Textbook of Lung Cancer
Table 7.4 Typical and atypical carcinoid: distinguishing features
Histologic or clinical feature
Typical carcinoid
Atypical carcinoid
Histologic patterns: organoid,
trabecular, palisading, and
spindle cell
Mitoses
Characteristic
Characteristic
Absent or <2 per 2 mm2 area
of viable tumor (10 high power
fields on some microscopes)
Absent
2–10 per 2 mm2 or area of viable
tumor (10 high power fields
on some microscopes)
Characteristic, usually focal or
punctate
Often present
Necrosis
Nuclear pleomorphism,
hyperchromatism
Regional lymph node
metastases at presentation
Distant metastases at
presentation
Survival at 5 years
Usually absent, not sufficient
by itself for diagnosis of AC
5–15%
Disease-free survival
at 10 years
40–48%
Rare
20%
90–95%
58%
90–95%
35%
adhesion molecules, and to date, as for other neuroendocrine tumors of the lung, NCAM remains the most
useful immunohistochemical marker, even on crushed
biopsies or small specimens, in the differential diagnosis with papillary adenocarcinoma and sclerosing
hemangioma. In contrast, as widely reported, NSE
immunostaining is of little help in the diagnosis of
neuroendocrine tumors in general because of its lack of
specificity.69,117
TTF-1 expression was demonstrated to be negative
in the spectrum of neuroendocrine hyperplasia, tumorlets, and typical and carcinoid tumors.118 However,
other authors have reported some TTF-1 expression in
nearly one-third of TC and AC,119,120 predominantly in
a peripheral location.121 This discrepancy could be
related to differences in immunohistochemical techniques or in assessing the threshold of positivity. TTF-1
expression has not been demonstrated in cDNA expression profiling, whereas it is in high-grade NE tumors of
poor prognosis.122
Concerning the proliferation antigen Ki 67 in carcinoids, staining is observed in less than 10%, and an index
higher than 4%, more frequently observed in AC, seems
to be related to a shorter survival.123,124
Differential diagnosis
Carcinoids differ from tumorlets by the size of the latter,
which do not exceed 5 mm in diameter. Sclerosing
hemangiomas may resemble carcinoids, especially with
a papillary or pseudoglandular pattern. The demonstration of neuroendocrine markers and absence of TTF-1
expression distinguish carcinoids from sclerosing
hemangiomas.124 Carcinoids may be confused with
paragangliomas, but this lesion remains very rare in the
lung, and the lack of cytokeratin expression in the latter
has a discriminative feature. Glomus tumors and other
smooth muscle tumors may mimic carcinoids, from
which they are distinguished by the presence of smooth
muscle actin and the absence of neuroendocrine markers. Adenocarcinoma enters the differential diagnosis
because a gland-like pattern occurs in carcinoids. Mucin
production is not a definitive distinguishing feature
since carcinoids may disclose mucin formation. TTF-1
expression and the absence of neuroendocrine markers
in adenocarcinoma are of great help. The solid type
adenoid cystic carcinoma may be mistaken for carcinoid, but is negative for neuroendocrine markers.
CONCLUSIONS
Histologic subclassification of lung tumors is essentially
based on light microscopy in order to achieve the widest application through the world and assume comparability and consistency of data. However, techniques
including immunohistochemistry, electron microscopy,
Histopathology of lung tumors 71
tissue culture, and molecular biology might provide
valuable information on carcinogenesis, histogenesis,
and differentiation. It is well recognized that immunohistochemistry and electron microscopy may detect
differentiation, specifically regarding the histologic
heterogeneity of lung cancer, that cannot be seen by
routine light microscopy. However, these techniques
are occasionally required for precise classification.
An example of this is LCNEC and malignant mesothelioma, which require appropriate immunohistochemical and/or electron microscopic findings to confirm the
diagnosis.
15.
16.
17.
18.
19.
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8
Clinical diagnosis and basic evaluation
John J Mullon, Eric J Olson
Contents Introduction • History • Physical examination • Imaging • Diagnostic techniques
• Overview of basic evaluation • Future developments
INTRODUCTION
HISTORY
Lung cancer is the most lethal of all malignant diseases
worldwide and remains the leading cause of cancerrelated death in the United States.1 Lung cancer is
responsible for the overall increase in cancer mortality
noted over the second half of the 20th century in
the USA, which since 1999 has exceeded heart disease
as the leading cause of death in those less than 85 years
of age.1 Although the overall death rates due to lung
cancer have decreased in the USA and western Europe
since 1991, largely due to reductions in tobacco
smoking,2,3 global lung cancer incidence and mortality
rates are expected to continue to rise as a result of
the ongoing tobacco use in countries with developing
or transitional economies.4 Three- to five-year diseasefree rates for resected stage I lung cancer as high as
60 to 90% are reported, but less than 20% of all
lung cancers are stage I at the time of diagnosis and
five-year survival rates for all stages of lung cancer
remain approximately 15%.1 It is imperative that
clinicians be familiar with the evaluation of lung
cancer given its tremendous worldwide public health
impact and the prognostic importance of early cancer
detection.
Lung cancer outcome depends on the cell type
and stage of disease at presentation based on the
TNM classification. Accordingly, the essential aspects
of lung cancer evaluation are the histologic distinction
of small cell (SCLC) and non-small cell (NSCLC) types
and accurate determination of the extent of disease so
that appropriate treatment can be initiated. The evaluation of lung cancer begins with a careful history and
physical exam, followed by testing to obtain a tissue
diagnosis and stage the extent of disease. This chapter
will review aspects of clinical presentation, imaging,
and diagnostic testing for bronchogenic carcinoma.
Details regarding staging are discussed elsewhere in
this text.
Lung cancers are clinically silent for the majority of
time as they theoretically grow from a single malignant
cell to a potentially detectable lesion. The vast majority
of patients diagnosed with lung cancer are symptomatic
at the time of diagnosis. In only about 10% of cases is
lung cancer discovered incidentally in an asymptomatic
patient, for instance as a solitary pulmonary nodule on
a routine chest radiograph. Smoking history,5 concurrent chronic obstructive pulmonary disease (COPD),6
and previous exposures to certain environmental and
occupational carcinogens,7 including environmental
tobacco smoke,8 predict a higher risk for bronchogenic
carcinoma. Ethnic and racial differences also contribute
to the smoking-related risk of lung cancer, with African
Americans and native Hawaiians within the USA at
higher risk.9 Local tumor growth, regional extension,
metastases, paraneoplastic phenomenon, or a combination of mechanisms may cause tumor-associated symptoms (Table 8.1). There are no characteristics of clinical
presentation which absolutely distinguish NSCLC and
SCLC.
Local effects
The most common initial symptom of lung cancer is
cough, which occurs in 45–75% of patients,10 and may
be productive in up to 27%.11 Bronchorrhea, the expectoration of large-volume, thin, mucoid secretions, may
be seen with advanced bronchioloalveolar carcinoma
(BAC), but is rare. Due to the location of vagal afferent
cough receptors, which principally line the airway
mucosa, cancer types with a predilection for central airway involvement (notably SCLC or NSCLC in the form
of squamous cell carcinoma) may cause cough earlier in
their course, whereas peripherally located tumors such
as adenocarcinoma or large cell carcinoma may only
cause cough as a late symptom. In addition to bronchial
mucosa tumor invasion, causes of cough may include
76 Textbook of Lung Cancer
Table 8.1 Aspects of lung cancer presentation
Asymptomatic
Symptomatic
Effects of local tumor growth
Cough
Bronchorrhea
Fever, chills, purulent sputum
production (postobstructive pneumonitis)
Dyspnea
Hemoptysis
Chest pain
Wheeze
Stridor
Effects of regional tumor extension
Hemidiaphragm paralysis
Hoarseness
Dysphagia
Bronchoesophageal fistula
Pericardial effusion/tamponade/
tachyarrhythmias
Lymphangitic carcinomatosis
Pulmonary nodules
Tumor microembolism
Pleural effusion
Superior vena cava syndrome
Pancoast syndrome
Metastatic effects
Adrenal
Liver
Central nervous system
Bone
Paraneoplastic effects
See Table 8.2
postobstructive pneumonitis/atelectasis, tumor cavitation, or pleural effusion. Although cough is a nonspecific symptom frequently present in patients with
co-existent smoking-related airways disease, a change
in the character of a chronic cough, such as new hemoptysis or co-existent fever and chills, should raise suspicion of an additional process such as lung cancer. Lung
cancer is overall an unusual cause of chronic cough,
occurring in less than 2% of patients,12 and is even less
likely in the setting of a normal chest radiograph.13
One-third to one-half of patients initially report dyspnea that may arise from large airway obstruction,
postobstructive pneumonitis/atelectasis, pleural effusion, lymphangitic metastases, pericardial effusion, or
concurrent illnesses such as COPD. Dyspnea in a lung
cancer patient with a normal chest X-ray may be due to
pulmonary thromboembolism or, less commonly,
tumor microembolism. Lung cancer presents with
hemoptysis in many patients as a result of tumor necrosis, mucosal ulceration, tumor erosion into pulmonary
vasculature, postobstructive pneumonia, and pulmonary thromboembolism. Retrospective studies reveal
that bronchogenic carcinoma accounts for 19–29% of
cases of hemoptysis.14,15 In patients with a normal chest
radiograph and hemoptysis, only 2–9% are subsequently found to have lung cancer.16 Hemoptysis is
commonly blood-streaked sputum, although large central tumors may lead to massive hemoptysis that can
result in death by asphyxiation. Tumor involvement of
the parietal pleura, chest wall, and mediastinum leads
to chest pain as an initial complaint in 25–50% of
patients.17 Other causes of pain include rib cage metastases, pulmonary embolism, and postobstructive pneumonitis. Pneumothorax is a rare cause of chest pain and
dyspnea in lung cancer patients.
Regional extension effects
Direct mediastinal extension by lung cancer or metastases to mediastinal lymph nodes can lead to a variety of
presentations due to the diversity of adjacent structures.
Phrenic nerve involvement by tumor may cause ipsilateral diaphragmatic paralysis demonstrated on chest
X-ray by hemidiaphragm elevation often in the setting
of a centrally located mass. If lung cancer is not initially
identified as the etiology of diaphragm paralysis, it is
unlikely to become the explanation over time.18 Hoarseness, a finding at presentation in 5–18% of lung cancer
patients,17 is usually attributable to unilateral left vocal
paralysis resulting from damage to the left recurrent
laryngeal nerve anywhere along its intrathoracic course.
Extrinsic esophageal compression by tumor or metastatic lymph nodes may cause dysphagia. Postprandial
coughing raises the possibility of bronchoesophageal
fistula. Pericardial involvement, which may be present
in 20% of patients,17 occurs by hematogenous, lymphatic, or direct extension routes, and may cause
asymptomatic pericardial fluid/thickening detected
radiographically, tachyarrhythmias, or pericardial tamponade.
In addition to its characteristic tendency to spread to
hilar and mediastinal lymph nodes, lung cancer may
metastasize within the lung in several patterns. One
type is lymphangitic carcinomatosis, which usually
appears on chest radiography as focal or diffuse reticular or reticulonodular interstitial infiltrates and Kerley B
lines, possibly combined with central adenopathy and
Clinical diagnosis and basic evaluation 77
pleural effusions. By high-resolution chest computed
tomography (CT), this process characteristically appears
as irregular nodular thickening along bronchovascular
bundles and interlobular septa, consistent with the role
of lymphatics in this form of dissemination.19 Intrapulmonary metastases may also appear as single or multiple nodules/masses in one or both hemithoraces. A
management dilemma occurs in patients with otherwise resectable lung cancer who have one or more
radiographically indeterminate lung nodules. The differential diagnosis is broad, but includes synchronous
lung cancers, granulomatous processes, silicotic nodules, metastatic extrapulmonary malignancies, Wegener’s granulomatosis, and others. An individualized
approach to these situations is generally recommended.
Lung cancer microembolism to the pulmonary arterial
system, a rare form of intrathoracic metastasis, produces dyspnea and is very difficult to diagnose antemortem. Diagnosis has been occasionally accomplished
by cytologic examination of blood drawn through a
wedged pulmonary artery catheter.
Pleural effusion
Ten percent of all lung cancers metastasize to the pleura,
with adenocarcinoma being the most common.17,20
Malignant pleural effusions due to lung cancer are generally on the same side as the main tumor. They may be
moderate to large in size, bloody, and recurrent following thoracentesis. Pleural effusions develop in the setting of malignancy from local effects of the tumor
(pleural metastases, lymphatic obstruction, bronchial
obstruction with pneumonia or atelectasis, chylothorax), systemic effects (pulmonary thromboembolism,
hypoalbuminemia), or as complications of therapy. The
main mechanism for malignant pleural effusion formation is altered lymphatic drainage. Metastatic tumor
implants on the pleural surface may alter capillary
permeability and further increase pleural fluid formation. In most cases, metastatic involvement of the pleura
is thought to begin with hematogenous seeding of the
visceral pleura followed by subsequent movement
and attachment of tumor cells to the parietal pleural
surface.
Malignant effusions are usually exudative (effusion
meets at least one of the following criteria: pleural fluid/
serum total protein ratio >0.5, pleural fluid/serum lactate dehydrogenase [LDH] ratio >0.6, or pleural fluid
LDH > two-thirds of the upper limits of normal of the
serum). The fluid may appear serous, serosanguinous,
or frankly bloody. The initial thoracentesis of a malignant effusion reveals malignant cells 50% of the time.
The cytologic yield increases to 65% and 70% on the
second and third attempts, respectively. Pleural fluid
cytology is more sensitive than closed pleural biopsy,
primarily because pleural metastases tend to be focal
and percutaneous biopysy is performed blindly. Pleural
biopsy adds very little to the overall diagnostic yield
when combined with cytology.21 Therefore, a second
thoracentesis is usually performed rather than closed
pleural biopsy if malignant effusion is suspected. Low
pleural fluid pH (<7.30) and glucose (<60 mg/dl) values predict higher pleural fluid cytology yields, but also
predict poor response to pleurodesis and short survival
time.22
Malignant cells in pleural fluid indicate T4 or stage
IIIB disease in NSCLC and this eliminates further consideration of surgical resection. It is important to
remember, however, that the mere presence of a pleural
effusion does not categorically preclude surgery for
NSCLC. Other conditions that can cause pleural fluid
without direct tumor involvement of the pleura include
postobstructive pneumonitis/atelectasis, pulmonary
embolism, or illnesses unrelated to the tumor, such as
congestive heart failure, non-obstructive pneumonia,
and cirrhosis. Therefore, the physician must thoroughly
evaluate pleural effusion in NSCLC patients with otherwise potentially resectable disease. Unfortunately, series
have demonstrated that only 5–10% of lung cancer
patients with cytologically negative pleural effusions are
ultimately found to have operable disease.23
Superior vena cava syndrome
Several well-known syndromes result from regional
growth of lung cancer. Obstructed venous flow due to
extrinsic compression of the superior vena cava (SVC)
by adjacent bronchogenic carcinoma causes the SVC
syndrome.24 Overall, approximately 2–4% of patients
suffering from bronchogenic carcinoma will develop
the SVC syndrome;25 however occurrence is as high as
20% in those with SCLC due to its propensity to develop
in the central airways.26 Clinical manifestations result
from venous hypertension above the level of the obstruction. Symptoms and signs typically include headache
and facial fullness (which may be worse in the recumbent position), swelling and ruddiness of the face, neck,
and upper extremities, distended neck veins, and
prominent/tortuous collateral venous drainage over the
upper torso (Figure 8.1). Chest radiography may reveal
mediastinal widening or a right perihilar mass. The differential diagnosis also includes lymphoma, metastatic
extrathoracic malignancies, granulomatous mediastinal
inflammation/fibrosis, postirradiation fibrosis, and aortic
78 Textbook of Lung Cancer
Figure 8.1
Tortuous, prominent, collateral venous drainage over the upper
torso in superior vena cava syndrome. (Courtesy of JH Ryu MD,
Mayo Clinic, Rochester, MN.)
imaging (MRI) in staging is recommended and is superior to CT in determining the extent of local invasion.33
A magnetic resonance angiogram (MRA) is likewise
superior to both MRI and CT in assessing vascular
involvement.34 The majority of cases of Pancoast’s syndrome are due to NSCLC, but SCLC, metastatic extrapulmonary cancer, and infectious conditions (bacterial,
mycobacterial, and fungal) have also been implicated.
Tissue diagnosis is recommended and transthoracic
needle aspiration is frequently and successfully employed
in this regard. Pancoast’s tumors are generally found to
be stage IIB, IIIA, or IIIB lesions.
aneurysms. Although the treatment goal remains
prompt initiation of palliative chemotherapy or radiation, SVC syndrome is no longer regarded as a medical
emergency.27 Diagnostic studies can be safely executed
and a tissue diagnosis should be obtained before starting therapy. Overall treatment with radiation and/or
chemotherapy is effective in approximately 60% of
cases of SVC syndrome due to NSCLC; however recurrence occurs in almost 20%.28 The presence of SVC
syndrome is a poor Prognostic indicator for patients
with NSCLC, with a median survival of five months.29
Metastatic effects
Approximately 40–50% of NSCLC patients present with
metastatic disease that precludes surgical resection. SCLC
has an even greater propensity to metastasize earlier in
its course. Consequently, SCLC is considered a systemic
disease at time of diagnosis, even if it appears limited to
the chest. Lung cancer dissemination may occur via lymphatic, hematogenous, or interalveolar routes. Metastases to nearly every organ have been described, but the
most common sites of involvement are the lung, adrenals,
liver, central nervous system, and bone. Clinical manifestations depend upon the extent of specific organ dysfunction induced by metastases. Quoted frequencies of
metastases differ depending upon whether initial presentation or autopsy series are cited.
Pancoast’s syndrome
Pancoast’s syndrome is characterized by a tumor situated in the extreme apical region of the hemithorax
called the superior sulcus, in conjunction with ipsilateral shoulder and medial scapular discomfort. Pancoast
initially described the syndrome of shoulder and arm
pain in the distribution of the eighth cervical and first
and second thoracic nerve trunks, Horner’s syndrome,
and ipsilateral hand atrophy and weakness associated
with superior pulmonary sulcus tumors.30 Most patients
do not have all of these signs and symptoms until late
in the course of the disease. Tumor invasion of the
adjacent chest wall, brachial plexus, and sympathetic
ganglion is the cause for the clinical manifestations.
The clinical findings vary depending on the extent to
which the adjacent structures are involved. Shoulder
pain is the most common symptom, occurring in up to
88% of patients, with arm weakness noted in 40% and
Horner’s syndrome in 30%.31 Superior sulcus tumors
may manifest on chest radiography as unilateral apical
thickening (>5 mm), an apical mass (Figure 8.2), or
bony destruction.32 The use of magnetic resonance
Adrenal
Adrenal metastases are common in lung cancer. They
are usually asymptomatic and initially detected as unilateral adrenal gland enlargement on staging chest CT
extended to the upper abdomen. In two series totaling
576 NSCLC patients, 4–7.5% were found to have an isolated unilateral adrenal mass, and approximately 30–40%
of the adrenal lesions were found to be malignant.35,36
Adrenal adenomas occur in 2–10% of the general population and typically appear on CT as homogeneous,
low attenuation (due to fat content), well-circumscribed
lesions <3 cm in diameter.37 The differential diagnosis
for benign adrenal enlargement includes adrenal adenomas, nodular hyperplasia, and hemorrhagic cyst.
Chemical shift MRI has been shown to be 96% sensitive
and 100% specific for distinguishing adenomas,38 and
more recently 18F-fluoro-2-deoxy-D-glucose positron
emission tomography (18F-FDG-PET) has been shown
to be 93% sensitive and 90% specific for detecting adrenal metastases in patients with known lung cancer.39
A positive result on 18F-FDG-PET, although highly
suspicious, does not confirm the presence of adrenal
Clinical diagnosis and basic evaluation 79
(a)
(b)
Figure 8.2
(a) Posteroanterior and (b) lateral chest radiographs, and (c) CT appearance of a large right
superior sulcus tumor in a 52-year-old smoker
who presented with right shoulder pain.
Transthoracic needle aspiration revealed
squamous cell carcinoma.
(c)
metastasis, which must be further proven by CT or
endoscopic ultrasound-guided needle biopsy before
withholding potentially curative resection.
Liver
Metastatic involvement of the liver is common and
usually clinically silent early in the course of disease.
Liver metastases are particularly common with SCLC.
History and physical exam do not dependably detect
liver metastases. Liver involvement may be suggested
by abnormalities on the initial staging CT or by elevated
liver test values. Advanced liver involvement may be
associated with systemic symptoms, such as anorexia,
weight loss, and jaundice.
Central nervous system
Lung cancer is the most common cause for brain metastases, accounting for approximately 70% of cases.40 Clinical and autopsy data indicate that approximately 40% of
lung cancer patients will develop brain metastases.17 Small
cell and adenocarcinoma are the most common histologic
types of lung cancer to cause brain metastases. Although
occasionally asymptomatic, brain metastases usually cause
either non-focal symptoms, such as headache (most common), nausea, and vomiting, or focal abnormalities,
including seizures, hemi-sensorimotor changes, and cranial nerve deficits. Neurologic symptoms precede lung
cancer symptoms in most patients with concurrent disease. Metastases develop more commonly in the cerebral
hemispheres, particularly in the parietal and frontal lobes,
than in the cerebellum.41 Metastatic lesions are detected
by CT or MRI. Central nervous system metastases signal
stage IV disease and generally herald an ominous prognosis, but neuro- and radiosurgical advances have resulted
in successful treatment of brain metastases leading to
improvements in neurologic status and survival.41,42 In
SCLC the brain is a common site of relapse and prophylactic cranial irradiation is shown to confer a significant
3-year survival benefit to those patients who experience a
complete initial response.43
Other forms of central nervous involvement by metastatic lung cancer include spinal cord metastases and
80 Textbook of Lung Cancer
leptomeningeal carcinomatosis. Intraspinal lesions
usually cause back pain that is worsened by movement,
straining, and supine positioning. Neurologic deficits
from spinal cord compression, such as sensory defects
at or below the level of the lesion, paraparesis or paraplegia, and bowel/bladder incontinence tend to develop
quickly, progress rapidly, and be irreversible. In this
event, spinal metastases become a medical emergency
for which steroids should be starting pending definitive
therapy. Leptomeningeal carcinomatosis is uncommon
and uniformly predicts a short survival time. Neurologic symptoms may also result from a number of paraneoplastic syndromes, which are discussed below.
Bone
Skeletal metastases occur in approximately 25–30% of
lung cancer patients and are typically found as osteolytic lesions in the vertebral bodies, ribs, and long
bones of the arms and legs.17 These lesions usually produce pain or elevations of calcium or alkaline phosphatase.37 Twenty percent of SCLC patients may also
have bone marrow involvement, which may not initially
be accompanied by clinical or laboratory abnormalities.
Bony metastases may be detectable on plain radiographs.
If these are negative or non-diagnostic, a planar bone scan,
single photon emission computed tomogram (SPECT),
or 18F-FDG-PET scan should be obtained. Of these
three, 18F-FDG-PET is the most sensitive, but is associated with greatest expense and is not universally
available.44,45 Directed MRI of the culprit region remains
an alternative as MRI is highly sensitive and specific for
bony metastasis, although it has not yet been systematically compared to 18F-FDG-PET in this regard.
Paraneoplastic effects
Bronchogenic carcinomas are associated with paraneoplastic syndromes more than any other tumor. Ten to
twenty percent of lung cancer patients will develop
paraneoplastic syndromes.46 These diverse phenomena,
most of which are more common with SCLC, result
from effects of lung cancer on other organ systems
beyond those related to the physical presence of the
primary or metastatic lesions. The clinical manifestations are frequently non-specific and are mediated by
the ectopic production of biologically active peptides,
cytokines, and antibodies. An awareness of the paraneoplastic syndromes is important since they may be
the presenting feature of an otherwise difficult to detect
lung cancer in its earlier or recurrent stages. With the
clinically frustrating exception of the neurologic syn-
dromes, the course of most paraneoplastic syndromes
is analogous to that of the underlying lung cancer.
Table 8.2 lists the paraneoplastic syndromes associated
with lung cancer. The most common paraneoplastic
syndromes are discussed below.
Hypercalcemia
Hypercalcemia is the most frequently encountered paraneoplastic syndrome, occurring in up to 12.5% of patients
with lung cancer.47 Lung cancer is the most commonly
responsible malignancy, with squamous cell the usual
histologic type. Hypercalcemia generally results from
tumor production of parathyroid hormone-related peptide (PTHrP).48 Rarely, hypercalcemia is due to osteolytic
bony metastases or aberrant elaboration of other cytokines. PTHrP mimics the actions of endogenous parathyroid hormone (PTH), so hypercalcemia results from
heightened osteoclastic bone breakdown, decreased bone
formation, and decreased renal calcium excretion. The
manifestations of hypercalcemia are malaise, weakness,
fatigue, abdominal pain, constipation, anorexia, polydipsia, polyuria, confusion, hyporeflexia, and shortened QT
interval on electrocardiogram. Coma and death are late
manifestations. Diagnosis is made by demonstrating a
combination of increased serum ionized calcium level
(or disproportionate increase in total serum calcium
relative to the serum albumin), normal or low PTH level
by immunoassay (to rule out primary hyperparathyroidism), and exclusion of other causes of hypercalcemia
(granulomatous disorders such as sarcoidosis, hyperthyroidism, adrenal insufficiency, acute renal failure,
Paget’s disease, and medications such as thiazide diuretics and vitamin D). It is also very important to rule out
bony metastases. PTHrP is detectable by radioimmunoassay. Treatment strategies are volume repletion with normal saline, increased urinary calcium excretion with a
loop diuretic such as furosemide, decreased bony resorption with bisphosphanates, calcitonin, or gallium, and
treatment of the underlying malignancy. A novel therapeutic approach inhibiting osteoclast activity through
the use of an immunologically mediated tumor necrosis
factor receptor blockade has effectively inhibited hypercalcemia in a murine model.49 This therapeutic approach
has yet to be fully investigated. Hypercalcemia in the setting of lung cancer is generally a late complication occurring in the setting of advanced disease. The median survival
after onset of hypercalcemia is two to three months.
Syndrome of inappropriate antidiuretic hormone
The cardinal manifestation of the syndrome of inappropriate antidiuretic hormone (SIADH) is hyponatremia
Clinical diagnosis and basic evaluation 81
Table 8.2 Paraneoplastic syndromes associated with lung
cancer
Endocrine/metabolic
Hypercalcemia
Syndrome of inappropriate antidiuretic hormone
Cushing’s syndrome
Gynecomastia
Galactorrhea
Acromegaly
Carcinoid syndrome
Hyperthyroidism
Hypercalcitoninemia
Hyperglycemia
Hypoglycemia
Hypouricemia
Cachexia/anorexia
Cutaneous
Clubbing/hypertrophic osteoarthropathy
Dermatomyositis
Acanthosis nigricans
Erythema gyratum repens
Hyperpigmentation
Urticaria
Vasculitis
Pruritis
Basex’s syndrome (acrokeratosis)
Tylosis
Erythroderma
Acquired ichthyosis
Erythema annulare centrifugum
Sign of Leser–Trelat
Musculoskeletal
Polymyositis
Myopathy
Neurologic
Lambert–Eaton myasthenic syndrome
Peripheral neuropathy
Cerebellar degeneration
Limbic encephalitis
Polyradiculopathy
Myelopathy
Opsoclonus/myoclonus
Dysautonomia
Retinopathy
(Continued)
Table 8.2 Continued
Hematologic
Anemia
Polycythemia
Hypercoagulable state
Migratory thrombophlebitis
Disseminated intravascular coagulation
Non-bacterial thrombotic endocarditis
Leukocytosis/leukemoid reaction
Dysproteinemia
Eosinophilia
Thrombocytopenia purpura
Renal
Glomerulonephritis
Tubulointerstitial disorders
Nephrotic syndrome
Modified from references 37 and 46.
due to the inappropriately sustained ectopic production of arginine vasopressin (AVP; antidiuretic hormone), which acts on the distal renal tubule to promote
free-water conservation. Small cell is almost always the
underlying lung cancer histologic type.50 SIADH can
occur with equal frequency in limited and extensive
SCLC and may produce symptoms in 5% of patients.46
What, if any, prognostic significance SIADH may have
is unclear, although a recent study suggested a slightly
worse survival in those patients with limited stage SCLC
and SIADH when compared with those without SIADH.51
This is in contrast to earlier studies that found no difference in responsiveness to chemotherapy or survival
in patients with SCLC and SIADH in comparison to
those without SIADH.50,52 Clinical manifestations of
hyponatremia are due to cerebral edema and occur
more in relation to the rate of fall of the serum sodium
rather than to the absolute serum sodium level. Because
the hyponatremia usually develops slowly in SIADH,
many patients are asymptomatic at presentation. Early
symptoms include fatigue, weakness, nausea, and
anorexia. The diagnostic criteria for SIADH are hyponatremia, serum hypoosmolality (<275 mosm/kg), inappropriately increased urine osmolality (>200 mosm/kg),
natriuresis (urine sodium >20 mEq/l), clinical euvolemia,
and the absence of renal, adrenal, and thyroid dysfunction. Central nervous system disorders, other pulmonary lesions (notably pneumonia), and drugs (including
cyclophosphamide, tricyclic antidepressants, thiazide
diuretics, morphine, and vincristine) can also cause
SIADH.
82 Textbook of Lung Cancer
Asymptomatic or mildly symptomatic patients may
be treated with restriction of water intake to less than 1
liter per day (although sustained compliance is difficult) and demeclocycline (which gradually blocks the
action of AVP on the kidney). More serious symptoms,
such as seizures, cognitive decline, and mental status
changes, or more profound hyponatremia (serum
sodium <120 mEq/l), should be treated with normal
(0.9%) saline and a loop diuretic. Use of normal saline
alone may actually decrease the serum sodium concentration so a loop diuretic must be added. The use of
hypertonic (3%) saline is rarely indicated. The goal
should be to raise the serum sodium at a maximum rate
of 2 mEq/l/hour (maximum 20 mEq/l/day) to a target of
120–125 mEq/l. More aggressive sodium correction
may theoretically result in central pontine myelinolysis,
a devastating central neurologic insult usually resulting
in death.
Ectopic adrenocorticotropic hormone syndrome
Cushing’s syndrome describes a constellation of
findings due to excess glucocorticoid production.
Approximately 80% of adrenocorticotropic hormone
(ACTH)-dependent cases of Cushing’s syndrome are
due to Cushing’s disease – an ACTH-secreting tumor of
pituitary origin. The remaining cases are due primarily
to ectopic ACTH or corticotropin-releasing hormone
(CRH) production, usually by bronchial carcinoid
tumors, but also occurring as a result of thymic carcinoid, gastrinoma, pheochromocytoma, and small cell
carcinoma.53 Ectopically produced ACTH directly stimulates adrenal glucocorticoid release, while CRH triggers ACTH release from the pituitary. Slowly growing
carcinoid tumors may be accompanied by the classic
features of Cushing’s syndrome, including truncal
weight gain, moon facies, hypertension, purplish cutaneous striae, hirsutism, glucose intolerance, and proximal muscle weakness. Cushing’s manifestations in more
rapidly growing SCLC are usually limited to weight
loss, hypertension, edema, weakness, poor skin integrity, hypokalemic alkalosis, and glucose intolerance.
Overall, less than 5% of SCLC patients develop Cushing’s syndrome46 and its occurrence predicts a shorter
survival time, perhaps due to the co-morbidities induced
by glucocorticoid excess. An elevated 24-hour urinary
free cortisol level (four or more times the upper limit of
normal) and failure to suppress cortisol during lowdose dexamethasone challenge generally confirm the
presence of Cushing’s syndrome. Late-night salivary
cortisol levels have been shown to have high diagnostic
sensitivity and specificity for Cushing’s syndrome and
may in the future replace urinary free cortisol or lowdose dexamethasone suppression as a first-line screening test.54 The diagnosis is at times problematic as
tumors responsible for Cushing’s syndrome may have
variable secretory activity and, especially pulmonary
carcinoids, may be suppressible with low-dose dexamethasone. Treatment options include resection (carcinoidtumors),chemotherapy(SCLC),bilateraladrenalectomy,
or medical suppression of adrenal glucocorticoid production with ketoconazole, aminoglutethimide, etomidate, or metyrapone.
Neurologic syndromes
There are several stereotypic neurodegenerative syndromes that occur primarily in SCLC patients. These
paraneoplastic syndromes are distinct from the nonfocal neurologic dysfunction induced by systemic effects
of cancer. They are felt to be sequelae of autoimmune
phenomena that can involve any level(s) of the nervous
sytem (brain, cranial nerves, spinal cord, peripheral
nerves, neuromuscular junction, and muscle). The proposed pathogenetic sequence begins with the ectopic
expression by tumor cells of antigens similar to those
normally expressed in the nervous system. The shared
antigen is sensed as foreign and an immune response
ensues, causing nervous system injury and clinical
deficits.55,56 In support of this mechanism are the observations that these syndromes are associated with specific detectable antibodies, nervous system injuries are
strikingly limited to specific cell types, deposits of
immunoglobulin have been demonstrated in areas of
neuronal cell loss, and the characteristic antibodies are
made in the central nervous system by autoreactive
lymphocytes. The prototypic process of the autoantibody pathogenetic mechanism is the Lambert–Eaton
myasthenic syndrome (LEMS). However, not all patients
with clinically similar syndromes have detectable
autoantibodies, attempts to induce similar syndromes
in animals with passive immunoglobulin transfer or
immunization with the culprit antigen have been largely
unsuccessful, and immunosuppressants are not usually
effective treatments. Our understanding of these syndromes continues to evolve.
Lambert–Eaton myasthenic syndrome
Proximal muscle weakness, hyporeflexia, and autonomic dysfunction (dry mouth, erectile dysfunction,
constipation, blurred vision) characterize LEMS. The
pathognomonic electromyographic finding is a marked
increase of the compound muscle action potential following high rates of nerve stimulation. Similarly, augmented strength and reflexes can be demonstrated on
Clinical diagnosis and basic evaluation 83
physical exam after maximal contraction of the involved
muscle groups. Clinical manifestations are due to antibodies to P/Q type voltage-gated calcium channels
expressed on the presynaptic cholinergic synapses of
peripheral nerves that interfere with the release of acetylcholine.57 These voltage-gated calcium channels
also appear on SCLC cells. Treatments of potential
benefit include 3,4-diaminopyridine (increases presynaptic calcium influx), pyridostigmine (inhibits acetylcholinesterase), oral immunosuppressive agents such as
corticosteroids, plasma exchange, intravenous immunoglobulin, and treatment of the underlying tumor.
Approximately one-third to one-half of LEMS patients
will improve with treatment of the underlying SCLC.
However, not all patients with LEMS have an identifiable underlying malignancy.
Antineuronal nuclear autoantibodies-1-associated
(ANNA-1) syndromes
ANNA-1, also known as anti-Hu antibodies, are IgG
antibodies that recognize a family of nuclear mRNA
binding proteins expressed in SCLC cells and neurons
of the central and peripheral nervous systems. These
antibodies are distinct from the autoantibodies of systemic lupus erythematosis, and whether ANNA-1 antibodies have a pathogenetic role in the neurologic
manifestations remains unclear. Seropositivity for
ANNA-1 is associated with a diverse set of neurologic
disorders that can occur in varying combinations.58
Lucchinetti and colleagues59 reported on the wide spectrum of neurologic and oncologic findings in 162
ANNA-1 seropositive patients. Twice as many women
were afflicted as men. By the end of follow-up, a malignancy had been detected in 142 patients (88%), with
81% having SCLC. Of the patients with SCLC, 17
developed at least one other malignancy. Neurologic
signs associated with ANNA-1, in decreasing frequency,
were neuropathy (sensory > mixed somatic > autonomic
> motor), cerebellar ataxia, limbic encephalitis (neurocognitive and neurobehavioral deficits), polyradiculopathy, LEMS, myopathy, myelopathy, opsoclonus/
myoclonus, motor neuronopathy, brachial plexopathy,
and aphasia. Gastrointestinal dysmotility occurred
in 38 (28%) patients, as manifested primarily by gastroparesis and intestinal pseudoobstruction due to
involvement of the myenteric plexus. The neurologic
manifestations preceded the cancer diagnosis in 96% of
patients, and usually progressed in a subacute manner.
None of the 49 patients who received immunosuppressant therapy (steroids, plasma exchange, intravenous
immunoglobulin, or cyclophosphamide) experienced
neurologic improvement. Somewhat ironically, ANNA-1
seropositivity is associated with more limited stage
SCLC at presentation, higher complete tumor response
to chemotherapy, and longer survival.60 Patients with
unexplained neurologic findings, ANNA-I positivity,
and a history of smoking should undergo a thorough
search for SCLC, including a chest CT with contrast. If
evidence of SCLC is not clearly identified by CT the
addition of an 18F-FDG-PET scan should be considered as the combination of CT and 18F-FDG-PET has
been shown in one small series to be 100% sensitive for
tumor detection.61 Five to fifteen percent of SCLC patients
may be ANNA-1 seropositive without neurologic
findings.
Other neurologic paraneoplastic syndromes
Type 2 antineuronal nuclear autoantibodies (ANNA-2),
also known as anti-Ri antibodies, are linked with
opsoclonus/myoclonus (opsoclonus are involuntary,
conjugate, arrhythmic high-amplitude, saccadic eye
movements) in breast cancer. Paraneoplastic cerebellar
degeneration is associated with a specific anti-Purkinje
cell antibody called anti-Yo (PCA 1) in females with
breast and gynecologic malignancies. Similar syndromes
can occur in SCLC and NSCLC, but lung cancer patients
are typically, although not always, ANNA-2 or anti-Yo
seronegative. Cancer-associated retinopathy is a rare
complication of SCLC, felt to be due to detectable antibodies directed at the retinal photoreceptor layer or
ganglion cells. SCLC is also strongly associated with
other antineuronal autoantibodies such as collapsing
response-mediating protein-5 (CRMP-5), which has yet
to be directly associated with a discrete clinical syndrome. It has been suggested that abnormalities identified on autoantibody paraneoplastic panels may serve
best to predict the underlying neoplasm rather than a
specific neurologic syndrome.62
Other paraneoplastic syndromes
Clubbing of the fingers and toes is characterized by loss
of the angle between the base of the nail bed and cuticle, rounded nails, and enlargement of the digit tips.
Hypertrophic osteoarthropathy (HPO) is a painful, proliferative periostitis that classically involves long bones
of the arms and legs. The affected bones reveal periosteal
new bone formation on plain radiographs and increased,
symmetric uptake on radionuclide studies. Clubbing
and HPO are rare entities that can occur together or as
isolated findings. The cause(s) remains unknown; however recent data suggest that platelet microthrombi with
subsequent release of platelet-derived and vascular
84 Textbook of Lung Cancer
endothelial growth factors may play a role in the development of clubbing.63 Clubbing and HPO can occur in
conjunction with bronchogenic carcinoma, as well as a
variety of cardiopulmonary suppurative processes
(bronchiectasis, cystic fibrosis, empyema, subacute
bacterial endocarditis), usual interstitial pneumonitis/
idiopathic pulmonary fibrosis, pulmonary arteriovenous
malformations, congential cyanotic heart disease,
inflammatory bowel disease, and cirrhosis. The potential association between the inflammatory myopathies
and lung cancer remains to be fully defined.64 Similarly,
it is unclear how thoroughly the physician should
search for malignancy in patients with unexplained
venous thromboembolism. A prospective randomized
trial of 201 patients with idiopathic venous thromboembolism65 identified a 10% incidence of occult
malignancy in the extensively screened cohort. Over a
two-year follow-up, 9.8% of patients in the control
group subsequently developed symptomatic malignancy. Overall malignancies were detected earlier and at
an earlier stage in the extensively screened group,
although a significant survival benefit could not be
demonstrated. Currently no professional organization
recommends extensive screening for malignancy in the
setting of idiopathic venous thromboembolism. A prudent strategy may be to maintain a low threshold of
suspicion for malignancy when venous thromboembolism develops without conventional risk factors, and to
proceed with additional testing as directed by history,
physical exam, and routine initial investigation.
PHYSICAL EXAMINATION
A careful physical exam is a vital component of the lung
cancer evaluation as it may provide important diagnostic, prognostic, and staging clues. General appearance
may be normal or may reveal debilitation, cachexia,
lethargy, pallor, jaundice, fever, or significant comorbidities. Blood pressure irregularities can be seen in
conjunction with neurologic or adrenal paraneoplastic
phenomena. Hoarseness suggests recurrent laryngeal
nerve compromise.
Respiratory system examination should be conducted
in an orderly manner. On inspection, tachypnea may
signal painful rib metastases, pleural effusions, or postobstructive pneumonia, while expiratory prolongation
is consistent with underlying COPD. Signs of venous
hypertension limited to the head, neck, and arms are
seen with SVC syndrome, while jugular venous hypertension and pulsus paradoxus are signs of pericardial
tamponade from metastatic disease. Pain may cause the
patient to favor the upper extremity ipsilateral to a
superior sulcus tumor. Neck palpation may yield evidence of spread to supraclavicular lymph nodes. Focal
rib tenderness implies metastases. Direct extension of
lung cancer to the chest wall is rarely palpable. The
combination of percussible dullness, diminished breath
sounds, and reduced fremitus suggests pleural effusion,
hemidiaphragm dysfunction due to phrenic nerve
entrapment, or postobstructive pneumonitis/atelectasis.
Bronchial breath sounds and increased fremitus indicate consolidation with patent proximal airways. Focal
wheezing is detected with central airway compromise
by an endobronchial tumor or extrinsic compression,
generalized wheezing with COPD. Concurrent interstitial lung diseases, such as asbestosis, may be heralded
by characteristic Velcro-type inspiratory crackles.
Depending on their distribution, rubs may be due to
venous thromboembolic events or metastatic pericardial or pleural involvement.
The remainder of the exam is equally important. Pertinent skin findings include cutaneous metastases, typically over the torso and scalp, and Basex’s syndrome,
which is hyperkeratosis of the acral regions. Acanthosis
nigricans, brown velvety plaques of the groin, back of
neck and axillae, may be paraneoplastic phenomena,
but are more commonly seen with obesity and diabetes.
The differential diagnosis for bony pain in the cancer
setting includes skeletal metastases and HPO. Liver
metastases may be palpable. A thorough nervous system examination is crucial, especially in patients with
headache, sensorimotor complaints, and back pain.
Unilateral lower extremity swelling, tenderness, and
erythema may accompany deep venous thromboses.
The history and physical exam findings can be combined to estimate general health status, such as by the
Karnofsky (Table 8.3) or Eastern Cooperative Oncology
Group (ECOG, Table 8.4) performance scores.66,67
These clinical indices provide a convenient framework
to rate the impact of the lung cancer and comorbidities on the patient. Performance status has been
reproducibly shown to be an important prognostic variable in NSCLC and SCLC, and usually influences treatment decision-making.
IMAGING
Standard chest radiograph
The standard posteroanterior and lateral chest radiograph is usually the first test to suggest bronchogenic
Clinical diagnosis and basic evaluation 85
Table 8.3 Karnofsky Performance Scale (modified from Mor et al66)
Definition
Percent
Able to carry on normal activity
and to work; no special care
needed
100
90
80
Unable to work; able to live at
home; cares for most personal
needs; a varying amount of
assistance is needed
70
60
50
Unable to care for self; requires
equivalent of institutional or
hospital care; disease may be
progressing rapidly
40
30
20
10
Criteria
Normal; no complaints; no evidence of disease
Able to carry on normal activity; minor signs or symptoms of
disease
Normal activity with effort; some signs or symptoms of disease
Cares for self; unable to carry on normal activity
or to do active work
Requires occasional assistance but is able to care for most of
needs
Requires considerable assistance and frequent medical care
Disabled; requires special care and assistance
Severely disabled; hospitalization is indicated, although death
may not be imminent
Very sick; hospitalization necessary; active supportive
treatment necessary
Moribund; fatal processes progressing rapidly
Table 8.4 Eastern Cooperative Oncology Group Performance Scale (from Oken et al67)
Performance status
Definition
0
1
Fully active; no performance restrictions
Strenuous physical activity restricted; fully ambulatory and able to carry out light
work
Capable of all selfcare but unable to carry out any work activities.
Up and about >50% of waking hours
Capable of only limited selfcare; confined to bed or chair >50% of waking hours
Completely disabled; cannot carry out any selfcare; totally confined to bed or chair
2
3
4
carcinoma, and it helps to assess the intrathoracic extent
of cancer, guides subsequent work-up, and identifies
simultaneous thoracic disease.68 The spectrum of possible findings is broad, but the most common are a
localized opacity (nodule or mass), pleural effusion,
infiltrate, atelectasis, and adenopathy. Certain radiographic appearances may suggest histologic types of
lung cancer, but these generalizations are not absolute.
Squamous cell carcinoma usually presents as a large
mass centered at or near the hilum, that may cavitate.
Due to the central airway origin, up to 50% of patients
with squamous cell carcinoma will present with endobronchial obstruction with postobstructive pneumonia
or atelectasis.69 SCLC may also present as a rapidly
enlarging central mass with contiguous hilar and mediastinal involvement. Only 5–10% of SCLCs present as
peripheral lung lesions. Adenocarcinoma typically arises
peripherally as a solitary nodule or mass. Large cell carcinoma is characteristically a large peripheral mass. BAC
may appear as a nodule or an alveolar infiltrate that can
be diffuse. The drawbacks of plain chest radiography
include lack of specificity and resolution limitations.
Lesions smaller than 2–3 mm are not reliably detectable
and the miss rate for lesions less than 2 cm may exceed
50%.70 Regions obscured by the heart, clavicles, and
diaphragm may be particularly difficult to interpret.
Estimates are that chest radiography is 70–80% accurate in the overall detection of lung cancer, 50–60%
sensitive in the detection of hilar adenopathy, and less
than 50% sensitive in the detection of mediastinal adenopathy.71 Studies using commercially available computer-aided diagnostic software to improve the sensitivity of
digital chest radiographs show modest improvements
in nodule detection.72
86 Textbook of Lung Cancer
Computed tomography
CT greatly enhances the imaging of bronchogenic carcinoma by providing further definition of the primary
lesion’s appearance, detecting concurrent parenchymal
or pleural disease missed by plain chest radiography,
demonstrating lymphangitic spread of malignancy,
guiding diagnostic maneuvers, and evaluating hilar and
mediastinal lymph node metastases. CT also helps in
the evaluation of distant metastases by the routine practice of extending the examination to include the liver
and adrenals. The delineation by CT of the relation of
bronchogenic carcinoma to surrounding structures is
particularly important since these findings significantly
influence prognosis and, in the case of NSCLC, surgical
options. However, the resolution limitations of CT in
this regard must be acknowledged. Consensus calls for
intrathoracic lymph nodes larger than 1 cm in the short
axis dimension to be considered abnormal by CT; however, using this criterion CT is only 57% sensitive and
82% specific in identifying hilar and mediastinal lymph
metastases.73 The sensitivity of CT suffers from microscopic lymph node metastases, while the specificity is
influenced by benign causes for lymphadenopathy,
such as reactive hyperplasia, granulomatous inflammation, and anthracosis. CT also has difficulties in accurately diagnosing chest wall or mediastinal structure
invasion, detecting endobronchial lesions, and differentiating tumor from adjacent atelectasis or pneumonia. Hence, CT is not a substitute for histologic
information and patients must not be denied surgery
for NSCLC simply on CT findings without tissue confirmation.
Solitary pulmonary nodule
Solitary pulmonary nodule (SPN) is a common clinical
radiologic dilemma. Defined as a singular rounded
lesion entirely surrounded by normal lung parenchyma
and without associated lymphadenopathy, an SPN may
be caused by malignant and benign processes
(Table 8.5).74 The majority of SPNs are benign. Most
malignant SPNs are clinical stage I bronchogenic carcinomas. SPNs are usually incidental findings on plain
chest radiographs or CTs obtained for other purposes.
The questions become whether the SPN is benign or
malignant, and whether it should be observed, biopsied, or removed. The evaluation begins, if possible,
with review of previous chest radiographs. A nodule
that has been radiographically stable for at least two
years is by definition benign, and no further maneuvers
are necessary. A steadily growing nodule is considered
malignant and should be immediately resected. When
Table 8.5 Causes of solitary pulmonary nodules (from
Midthun et al74)
Infectious granuloma
Tuberculosis
Histoplasmosis
Coccidiomycosis
Bronchogenic carcinoma
Metastatic cancer
Breast
Head and neck
Colon
Renal cell
Sarcoma
Germ cell
Bronchial carcinoid
Hamartoma
Organizing pneumonia/abscess
Wegener’s granulomatosis
Rheumatoid nodule
Arteriovenous malformation
Pulmonary infarction
Bronchogenic cyst
Lipoma
Amyloidoma
comparison studies are insufficient, the next step is to
assess for calcification in the nodule with CT. Central,
concentric, or popcorn calcification patterns are reliable indicators of their benign nature. Eccentric calcification does not rule out malignancy. Thin-section CT
images may also detect fat within the nodule, indicative
of a hamartoma, which is always benign. Taking advantage of the differences in vascular supply between
benign and malignant nodules, Swensen and colleagues75 demonstrated that the level of nodule enhancement detected by thin-section CT after injection of
intravenous contrast reliably differentiated benign versus malignant lesions (Figure 8.3). Using 15 Hounsfield
units as the threshold for enhancement, sensitivity of
this technique for malignancy was 98%. Specificity was
just 58%, since some inflammatory and infectious
lesions may enhance. The negative predictive value was
96% – if a nodule does not enhance, it is almost always
benign. Recently 18F-FDG-PET was compared to nodule enhancement CT and found to have similar sensitivity and superior specificity in differentiating malignant
from benign pulmonary nodules, although noduleenhancement demonstrated a negative predictive value
Clinical diagnosis and basic evaluation 87
(a)
Figure 8.3
CT images demonstrating enhancement
of 87 Hounsfield units (HU) of a left lung
nodule after injection of iodinated
contrast (31 HU on the precontrast image
versus 118 HU on the postcontrast
image). The circle within the nodule
circumscribes the region used to
measure enhancement.
(b)
HU= 31
of 100%.76 The authors concluded that 18F-FDG-PET
is preferable to nodule-enhancement CT in evaluating
indeterminate pulmonary nodules; however noduleenhancement CT remains a useful tool due to its very
high negative predictive value, convenience, and lower
cost. If radiologic studies are inconclusive, clinical factors which predict a higher risk of malignancy include
advanced age of the patient, smoking history, prior
malignancies, and larger nodule size. The patient’s
wishes must be considered in the decision-making process. Lesions ≥3 cm in size are malignant in over 90%
of cases and should not be observed. If a lesion is not
removed and is indeterminate, then it must be observed.
Observation typically involves obtaining serial chest CT
scans every three months for the first six months, and
then every six months for the remainder of two years.77
Serial plain chest radiographs do not reliably detect
enlargement of small nodules. If the nodule grows, it
must be resected. If the nodule is stable for two years,
it is safe to assume that it is benign.
With the introduction of helical and multi-detector
row CTs the detection of nodules as small as 1–2 mm
is becoming common. The Mayo Clinic CT Screening
Trial demonstrated that less than 1% of nodules <5 mm
in size in patients without a history of cancer proved to
be malignant.78 Henschke and colleagues79 further demonstrated that the follow-up interval for nodules <5
mm in size at initial detection could safely be extended
to 12 months. The likelihood that an incidentally
detected nodule is malignant also depends on known
risk factors such as cigarette smoking, as well as radiographic characteristics such as density. With this in
mind the Fleischner Society80 has endorsed a statement
recommending variable follow-up of small nodules
(<8 mm) identified incidentally based on patient risk
factors and nodule size at the time of detection. Included
in this is a provision for no follow-up of incidentally
detected nodules less than or equal to 4 mm in size in
low-risk patients.
HU= 118
Ground-glass opacities
Recent advances in CT screening for lung cancer (discussed below) have led to increased detection of focal
ground-glass opacities (GGOs). A GGO is defined as a
hazy area of increased lung attenuation with preserved
bronchial and vascular margins (Figure 8.4).81 These
features may be the result of interstitial thickening, air
space filling or partial collapse, or increased capillary
blood flow; alternatively they may be seen as a feature
of normal exhalation. As such, GGO is a non-specific
finding which may be caused by a variety of infectious,
inflammatory, and neoplastic processes.82,83 A recent
series84 demonstrated that GGOs with no concomitant
solid component will represent malignancy approximately 20% of the time; however with serial follow-up
almost 40% will regress or disappear spontaneously. In
the same series, GGOs with a concomitant solid component represented malignancy approximately 30% of the
time; however up to 50% regressed or disappeared spontaneously. Regression, when present, occurred within
the first 90 days of follow-up in the vast majority of cases.
Malignant and premalignant lesions are most commonly
BAC, adenocarcinoma, and atypical adenomatous hyperplasia.85 Female gender, spiculated border, a concomitant solid component, and size greater than 1 cm appear
to be risk factors for malignancy, whereas an elevated
serum eosinophil count may predict a benign etiology.
When malignant, tumor doubling times vary widely and
may be as long as 1486 days for some BACs.86 Frequent
spontaneous regression, relatively high malignancy rates,
and long doubling times all make management decisions
for GGOs problematic, and currently no specific guidelines exist for the follow-up or management of GGOs.
Based on available data it may be reasonable to biopsy
GGOs that persist beyond 90 days and are greater than
1 cm in size or have other concerning characteristics.
Serial follow-up, if elected, should continue beyond five
years before determining that an identified GGO does
not represent malignancy.
88 Textbook of Lung Cancer
18
Figure 8.4
Chest CT demonstrating a ground-glass opacity measuring
12 × 7 mm (circled). Note the preservation of underlying vascular
and interstitial structures.
CT lung cancer screening
Five-year survival for stage I lung cancer approaches
70%; however <20% of lung cancers are detected at
this early stage. That the vast majority of these early
stage lung cancers are asymptomatic and identified
incidentally on a radiograph or CT obtained for other
purposes has raised tremendous interest in devising a
rational method to screen for lung cancer radiographically, similar to the way a mammogram is used to screen
for breast cancer. Early screening trials conducted in
the 1970s using chest radiography and sputum cytology demonstrated a higher incidence rate, resectability,
and survivorship among the intensively screened group,
but failed to show a mortality benefit (summarized in
reference 87). A number of more recent studies investigating the use of low-dose CT have shown an ability
to detect earlier stage cancers; however, they have also
shown high false-positive rates with indeterminate nodules identified in up to 70% of participants.88,89 Recent
five-year prospective data collected on over 1500 highrisk participants suggest that overdiagnosis rather than
earlier diagnosis may be playing a role in the use of CT
screening, and did not demonstrate a mortality benefit.90 Conversely, a recently reported multicenter study91
enrolling over 31 000 patients over ten years identified
484 lung cancers, 85% of which were stage I. For those
patients diagnosed at stage I, the estimated ten-year
survival rate was 88%, and 92% for those who underwent surgical resection within one month of diagnosis.
At this time no professional organization recommends
screening for lung cancer.
F-fluoro-2-deoxy-D-glucose positron emission
tomography
Accurate staging of NSCLC is essential to determine
appropriate therapy and estimate prognosis. Evaluation
of mediastinal nodal disease and extrathoracic metastasis is crucial in this regard due to their impact on operative candidacy and potential surgical cure. As discussed
above, the accuracy of CT for predicting mediastinal
nodal metastasis is not ideal. 18F-FDG-PET is a radionuclide test that involves injection of the radioisotope
18
F-fluorodeoxyglucose (18F-FDG). Tissues with high
metabolic activity, such as high-grade neoplasms,
demonstrate increased glucose uptake relative to normal tissues and will show increased isotope deposition.
A meta-analysis of 18 studies found 18F-FDG-PET
to have a sensitivity of 84% and specificity of 89%
when investigating the mediastinum for metastases
(Figure 8.5).73 In lymph nodes smaller than 1 cm specificity may be as high as 95%, although sensitivity is
lower.92 18F-FDG-PET also increases detection of extrathoracic metastases (Figure 8.6), identifying unsuspected distant metastases in as many as 28% of patients
with stage III disease in one series,93 and reducing by
20% non-therapeutic thoracotomies in a series enrolling
patients with stages IA–IIIA NSCLC.94 18F-FDG-PET
imaging has been shown to be superior to conventional
imaging for identifying tumor recurrence.95 False-positive results may be seen with various inflammatory and
infectious processes such as sarcoidosis, pulmonary
Langerhans cell histiocytosis, and mycobacterial and
fungal diseases. False-negative results may occur
with low-grade neoplastic processes such as BAC and
bronchial carcinoid tumors. Because of the occasional
false-positive findings potentially metastatic sites should
be proven by biopsy when clinically and technically
feasible.96
Magnetic resonance imaging
MRI does not have a routine role in the evaluation of
lung cancer. However, its superiority over CT in distinguishing tumor abutment versus invasion of chest wall,
vertebral, and mediastinal structures makes MRI a useful adjunct in situations such as superior sulcus tumors
and possible neuroforaminal encroachment. The magnetic resonance angiogram (MRA) is the study of choice
to investigate vascular invasion.
Other nuclear medicine studies
In NSCLC patients with marginal pulmonary function,
quantitative ventilation-perfusion (V/Q) lung scans
can be used to assess candidacy for lung resection.
Clinical diagnosis and basic evaluation 89
(a)
(c)
Figure 8.5
18F-FDG-PET scan with CT fusion
demonstrating a primary adenocarcinoma in the left upper lobe (a), with
contralateral hilar metastasis (b).
(c) Coronal 18F-FDG-PET without CT
fusion, demonstrating no extrathoracic
involvement. Transbronchial needle
aspirate of the right hilar lymph node
confirmed metastatic adenocarcinoma
with stage IIIB NSCLC assigned. (See color
plate section, page xiii)
(b)
The fraction of total ventilation or perfusion from the
contralateral lung is multiplied by the preoperative
forced expiratory volume in 1 second (FEV1) to predict
postoperative FEV1 for patients undergoing pneumonectomy. A postoperative FEV1 of 40% of predicted
suggests the patient should tolerate resection from a
pulmonary perspective.97 Bone scan and 18F-FDG-PET
are useful in investigating bony metastases in patients
with bone pain, hypercalcemia, increased alkaline
phosphatase, and/or pathologic fractures. Of these three
techniques, 18F-FDG-PET is the most sensitive and
has the additional advantage of identifying other areas
of intra- and extrathoracic metastases. Abnormalities
identified with these techniques will require further
evaluation by plain radiography or MRI, and, under
appropriate clinical circumstances, biopsy.
DIAGNOSTIC TECHNIQUES
An accurate tissue diagnosis is an essential early step in
the management of lung cancer because of its therapeutic
and prognostic import. Biopsy procedures are not always
required before surgical therapy, but are conducted in
most patients suspected of lung cancer since clinical and
radiographic findings are not uniquely assigned to SCLC
or NSCLC. Various techniques are available to obtain
tissue for cytologic and histopathologic analysis.
90 Textbook of Lung Cancer
(a)
(c)
Figure 8.6
18F-FDG-PET scan with CT fusion
demonstrating a primary adenocarcinoma involving the left upper lobe with
ipsilateral mediastinal lymph node
metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without
CT fusion demonstrating mediastinal and
extrathoracic (left adrenal) involvement.
CT-guided biopsy of the left adrenal
confirmed metastatic adenocarcinoma
with stage IV NSCLC assigned. (See color
plate section, page xiv)
(b)
Sputum examination
Sputum cytology
Sputum cytology is a non-invasive method to obtain a
diagnosis in appropriate situations.98 The yield depends
on the ability of the patient to produce acceptable sputum, tumor size, location of the tumor in relation to
major central airways, and the skills of the cytopathologist. The average sensitivity is approximately 65%, with
sensitivities ranging from 22 to 98% reported.99 Most
studies, although not all, show decreased sensitivity for
the diagnosis of peripherally based nodules and masses,
with an overall sensitivity of 71% for central and 49%
for peripheral lesions.99 The appropriate number of
specimens to collect remains unclear, but one to three
consecutive early morning samples or a three-day pooled
sputum specimen are generally recommended.100 A sputum sample can be obtained spontaneously or induced,
and is considered representative if bronchial epithelial
cells or alveolar macrophages are present. Overall diagnostic yield appears highest with specimens collected
spontaneously, except in the setting of peripherally
based cancers where induced specimens appear more
informative.101,102 Abnormal findings may also result
from concurrent pulmonary infections (false-positives)
or unsuspected head and neck cancers.
Sputum cytometry
Recent data suggest that the yield of sputum cytology
may be improved through the use of molecular, genetic,
Clinical diagnosis and basic evaluation 91
and immunocytochemical markers of malignancy.
Studies evaluating archived sputum specimens collected
as part of lung cancer screening programs have shown
that abnormal cells may be identified as early as twenty
months prior to the diagnosis of lung cancer using these
techniques. Xing and colleagues103 further demonstrated a twenty-fold improvement in sensitivity over
sputum cytology alone using automated cytometric
techniques. They were able as well to detect severe dysplasia/carcinoma in situ lesions and correctly identified
over 70% of peripherally based cancers. A sensitivity of
75% and specificity of 98% has been shown for semiautomated sputum cytometry in the diagnosis of lung
cancer in a multinational study.104 These results have
sparked interest in the implementation of this technique as part of a co-ordinated lung cancer screening
process.
specimens. TBNA should be obtained before sampling
other endoscopically visible lesions to avoid false-positive
results. Bleeding is a very infrequent complication of
TBNA. Autofluorescence bronchoscopy exploits the
difference in fluorescence properties between normal
bronchial mucosa and that of invasive and pre-invasive
disease. The best-known device uses a helium-cadmium
laser (442-nm wavelength) and an optical multichannel
analyzer in place of the standard white light source,
with normal mucosal surfaces having a green coloration
whereas premalignant and malignant lesions appear
reddish in color. A prospective, multicenter trial demonstrated an increase in the detection of preinvasive
disease with the use of autofluorescence by a factor of
2.1 when compared to white light bronchoscopy
alone.110 Bronchoscopy in COPD patients confers only
a slightly increased risk if obstruction is severe.
Flexible fiberoptic bronchoscopy
Flexible fiberoptic bronchoscopy is commonly used for
diagnostic and staging purposes. Endoscopically visible
abnormalities are approached with traditional biopsy
forceps, brushings, and washings. Transbronchial needle aspirations (TBNAs) may also be performed on submucosal tumors or those causing extrinsic bronchial
compression. The yield from an endoscopically visible
lesion should be in excess of 80%. Peripheral lesions
are sampled with fluoroscopically guided transbronchial biopsies, brushings, and washings. Lesion size is
the primary determinant of outcome, with yields of
25% reported for malignant lesions under 2 cm, 60–70%
for lesions >2cm, and 80% for lesions >4 cm.105
Yield, particularly for lesions <2 cm, may be increased
with the use of electromagnetic navigation bronchoscopy, with a recent study demonstrating 74% diagnostic yield for peripheral lesions in this size range.106
Transbronchial lung biopsies should detect lymphangitic spread of malignancy. For staging purposes, bronchoscopy may occasionally detect synchronous lesions,
assess proximal extent of tumor, and facilitate sampling
of paratracheal, subcarinal, and hilar lymph nodes by
TBNA.
Traditional TBNA sensitivity is 50%, with a specificity
of 90% for mediastinal staging.107 However, guidance
using endobronchial ultrasound (EBUS) increased the
sensitivity to 94% in one study of 500 patients.108 EBUS
also appears superior to CT in differentiating airway
tumor infiltration from extrinsic compression.109 Chest
CT should be obtained before TBNA to help guide the
attempts. Use of 19-gauge needles improves sensitivity
by allowing procurement of cytologic and histologic
Transthoracic needle aspiration
Peripheral lesions or those with extension to the mediastinum, chest wall, or pleura may also be sampled by
fluoroscopically or CT-guided transthoracic needle
aspiration (TTNA). Suspicious peripheral lesions are
sometimes directly resected for diagnosis and treatment
if surgery would be the anticipated maneuver regardless of TTNA results. However, TTNA may be applied
when a tissue diagnosis is needed but the patient cannot or will not undergo surgery, the patient is
undecided about surgery pending tissue confirmation
of cancer, or fiberoptic bronchoscopy was non-diagnostic.
Yields above 90% have been reported.111,112 Pneumothorax is the main complication, occurring in up to 30% of
cases, yet less than 15% typically require a chest tube.
Tumor seeding of the biopsy tract is a very rare complication. Increased risk situations for TTNA include
bullous emphysema in the region to be biopsied, lesions
located away from the pleural surface, a poorly cooperative patient, and underlying lung disease whose
impact would significantly increase if pneumothorax
developed. There is a substantial false-negative rate
(20–30% of patients with a negative TTNA may have a
malignant lesion)37 so indeterminate or negative TTNA
results must not be interpreted as a diagnostic endpoint. A repeat TTNA is diagnostic in 35–65% of cases.37 Percutaneous radiologic-guided needle aspiration
is used to confirm metastases to liver, bone, and
adrenals.
Endoscopic ultrasound
The linear array echoendoscope was introduced in the
mid-1990s and is gaining popularity due to its ability to
92 Textbook of Lung Cancer
permit fine-needle aspiration of mediastinal abnormalities from a transesophageal approach that are not easily
accessed by bronchoscopy or mediastinoscopy. Endoscopic ultrasound (EUS) easily identifies vascular structures and is useful in sampling tissue from inferior and
posterior mediastinal (station 8, 9), aortopulmonary
window (station 5, 6), and subcarinal (station 7) lymph
nodes. Lobar (station 12), interlobar (station 11), and
anterior tracheal nodes (station 3) are not well evaluated by EUS. In a study of 26 patients undergoing
transesophageal biopsy performed with EUS and fineneedle aspiration the overall sensitivity for the diagnosis of malignancy was 89% and the specificity was 83%,
with a positive predictive value of 100% and a negative
predictive value of 75%.113 Recent studies further suggest that EUS may be superior to CT and PET in establishing mediastinal staging of NSCLC,114,115 and may be
superior to mediastinoscopy in sampling paratracheal
and subcarinal nodes.116
Thoracic surgery techniques
Cervical mediastinoscopy and anterior mediastinotomy have been the traditional routes by which histologic verification of mediastinal metastases has been
obtained. These are safe procedures whose findings
may obviate the need for further surgery in NSCLC
patients. Cervical mediastinoscopy allows sampling of
the right paratracheal and subcarinal nodes, while
anterior mediastinotomy accesses the left paratracheal,
supra-aortic, and aortopulmonary window nodes.37 It
remains controversial whether mediastinal sampling
should be routinely performed before all surgery for
NSCLC. Many surgeons may forego mediastinoscopy
in patients with radiographic T1N0 disease due the
relatively low prevalence (5–15%) of nodal metastases
in this group. 18F-FDG-PET may have a role in these
patients, allowing those without evidence of mediastinal involvement to avoid mediastinal lymph node
sampling, although PET combined with CT may still
miss up to 5% of mediastinal micrometastases.117 Video-assisted thoracoscopic surgery (VATS) is a more
recent, less invasive technique for sampling of indeterminate peripheral nodules, pleural thickening and
effusions, and mediastinal/hilar lymph nodes. Scalene
or supraclavicular lymph node biopsy is an appropriate diagnostic and staging procedure in the setting of
clinically significant enlargement. The patient with a
suspicious lesion (enlarging or spiculated nodule)
without evidence of metastatic disease may go
directly to thoracotomy for definitive diagnosis and
treatment.
OVERVIEW OF BASIC EVALUATION
The purpose of the basic evaluation is to efficiently and
accurately establish the diagnosis and initial extent of
lung cancer. Aspects of this process are influenced by
local practice biases. The core elements include a careful
history and physical exam, posteroanterior and lateral
chest radiographs, and basic blood tests, including complete blood count and chemistry profile (especially electrolytes, serum calcium, alkaline phosphatase,
glutamic-oxaloacetic transaminase, albumin, total bilirubin, and creatinine).36 While the cost-effectiveness of the
blood tests can be debated, they may suggest metastatic
disease, paraneoplastic phenomena, or co-morbidities.
Chest CT with extension to upper abdominal CT is routinely obtained to define the primary lesion and locoregional extent of disease. 18F-FDG-PET scanning plays an
additive role in addressing the solitary pulmonary nodule and should be included when investigating mediastinal and extrathoracic metastases from a known NSCLC.
Testing for extrathoracic metastases is pursued as directed
by the initial information. Biopsy of suspected metastases
may allow simultaneous diagnosis and staging. For
peripheral chest lesions the diagnostic options are TTNA,
bronchoscopy, VATS, or thoracotomy. It is unclear
whether TTNA or bronchoscopy is the better initial
choice. TTNA may enjoy a higher yield for smaller
lesions, but also a higher complication rate. Bronchoscopy allows for endobronchial visualization and would
still be performed at the time of thoracotomy if TTNA
were positive. For central lesions or hemoptysis with
negative chest film, sputum cytology is also an option,
and bronchoscopy is usually favored over TTNA.
Additional pulmonary testing may be necessary if
surgical resection is considered. Given the common
etiologic thread of smoking, it is not surprising that
80–90% of lung cancer patients also have COPD,
20–30% with severe disease.118 Lung resection, incisional pain, medical appliances, and postoperative use
of sedatives and analgesics impact negatively on lung
function and defense. Preoperative spirometry and diffusing capacity (DLCO) should be obtained. Patients with
FEV1 >1.5–2 l, maximal voluntary ventilation (MVV)
>50% predicted, and DLCO >60% predicted can proceed
to thoracotomy. Patients below these values may need
to undergo a more thorough examination that includes
quantitative V/Q lung scanning and/or exercise testing
with evaluation of maximum oxygen uptake. Although
no value categorically precludes surgery, predicted
postoperative FEV1 <40% of predicted, hypercapnia
(PCO2 >45), or maximal oxygen consumption <10 ml/
Clinical diagnosis and basic evaluation 93
kg/min during exercise testing predicts significant postoperative problems.119 The use of VATS and limited
resections have dramatically changed the definition of
inoperability due to pulmonary limitations.
FUTURE DEVELOPMENTS
Given the dramatic differences in overall lung cancer
survival versus those enjoyed with resectable stage I
disease, interest will continue to focus on methods of
earlier lung cancer detection and more accurate staging.
The recent use of spiral CT scanners allows for extremely
rapid thoracic imaging at a reduced radiation dose,
thereby imparting the benefits of CT sensitivity with the
speed and radiation levels of more traditional radiographic imaging. Whether CT screening, alone or in
concert with other screening modalities, results in earlier detection and decreased mortality from lung cancer
remains to be demonstrated and the results of the
National Lung Screening Trial will determine to a great
extent whether CT screening is adopted as a viable
standard screening modality. Sputum cytometry and
autofluorescence bronchoscopy additionally show
promise as methods to identify cancerous and precancerous lesions within the central airways early, when
directed therapy or resection is most successful. Their
role in standardized screening warrants further investigation. In 2007 a five-year randomized surveillance
study funded by Cancer Research UK incorporating
combined techniques of sputum cytology/cytometry,
CT scanning, and autofluorescence bronchoscopy
began enrollment and have helped define the role of
these techniques in screening for lung cancer. Early
reports of serum proteomic patterns being able to distinguish patients with ovarian and prostate cancer from
normal controls are exciting, although preliminary.
What, if any, role proteomic patterns may play in the
detection and diagnosis of lung cancer is one of the
most intriguing new areas of investigation in early
detection. It is hoped that these new techniques combined with greater participation of patients in prospective clinical trials (currently only 1% of lung cancer
patients in the USA are enrolled) will result in improved
lung cancer survival rates.
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9
Staging, classification, and prognosis
Michael Dusmet, Peter Goldstraw
Contents Introduction • The staging system • The staging process • The staging tests • Restaging after
induction chemotherapy • Other prognostic indicators • Prognosis
INTRODUCTION
It is logical that this chapter should fall between the
preceding one on diagnosis and evaluation and those
that follow on the treatment modalities for non-small
cell lung cancer (NSCLC) and small cell lung cancer
(SCLC). At its most simplistic, ‘staging’ is the process by
which the clinician examines and describes the local,
regional, and distant extent of the cancer. This precise
information is then used to determine the appropriate
therapy for a patient diagnosed to have lung cancer.
However, staging should not be thought of as a set of
investigations that are performed between diagnosis
and treatment. Many of the tests that are undertaken to
establish the diagnosis, such as chest radiography,
bronchoscopy, and pleural aspiration cytology, provide
valuable information as to stage. Often the choice of
test by which to establish the diagnosis will be made on
the basis of the clinician’s assessment of the probable
stage of the disease. In this context, obviously taking
into account the financial cost and the potential morbidity of every procedure, it is desirable to undertake
first the test that will prove the highest stage. For example, if a patient has a lung lesion and a probable adrenal
metastasis, biopsy of the adrenal will, if positive, provide both a tissue diagnosis of cancer and the stage
(M1).Tests undertaken to decide stage proceed in parallel with those required to establish the diagnosis and
others to assess patient fitness for possible treatment
options, often interweaving and providing information
across these categories. Tests may have to be repeated
if undertaken without sufficient foresight to look
beyond the diagnosis and consider the consequential
issues of treatment. Sometimes treatment may be recommended after staging and before a firm diagnosis. A
surgeon may ‘stage’ a patient and recommend thoracotomy with only the strong clinical–radiographic suspicion of lung cancer and without pursuing the diagnosis
to a cytologic or histologic conclusion. In such circumstances the surgeon will establish the diagnosis as the
first step at thoracotomy using rapid, ‘frozen section’
histology prior to proceeding with treatment by pulmonary resection.
Thus staging has several objectives, some patient
orientated and some disease centered. Precise staging
will allow the clinician to offer the individual patient
the best treatment, on the basis of the understanding
of prognosis that derives from the stage. Staging
allows clinicians to evaluate the results of different
treatment regimens and to exchange and compare them
between different centers. This also allows new treatment strategies to be assessed. Finally it allows us to
evaluate in an on-going manner the results of staging
modalities.
We will consider the separate aspects of staging: the
‘staging system’, the ‘staging process’, and the ‘staging
tests’.
THE STAGING SYSTEM
The International Staging System (ISS) for lung cancer
is the TNM Classification of Malignant Tumors, administered by the International Union Against Cancer
(UICC).1 This provides a recognized shorthand to
describe the extent of the disease, in which the
T descriptor indicates the extent of the primary tumor,
the N descriptor the extent of lymph node involvement,
and the M descriptor the presence or absence of distant
metastases. For each descriptor, advancing numeric
subscripts are allocated for progressively advancing
disease. The latest revision of the ISS was published in
1997,2,3 and integrated into the sixth edition of the
UICC TNM Classification of Malignant Tumors manual
in 2002.4 The next revision of the staging system is
due to be published early in 2009. The descriptors as
presently defined are listed in Table 9.1. A more precise
definition of the boundaries and definitions can be found
in another article by Dr Mountain.5 The definition
of the great vessels includes the aorta, the vena cava,
98 Textbook of Lung Cancer
Table 9.1 TNM descriptorsa
Primary tumor (T)
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or
bronchial washings but not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence
of invasion more proximal than the lobar bronchusb (i.e. not in the main bronchus)
T2 Tumor with any of the following features of size or extent:
• >3 cm in greatest dimension
• involves main bronchus, ≥2 cm distal to the carina
• invades the visceral pleura
• associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve
the entire lung.
T3 Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors),
diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus <2 cm distal to the
carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the
entire lung
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus,
vertebral body, carina; or tumor with a malignant pleural or pericardial effusion,c or with satellite tumor
nodule(s) within the ipsilateral primary-tumor lobe of the lung
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes
involved by direct extension of the primary tumor
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular
lymph node(s)
Distant metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis presentd
a
Reproduced with kind permission of Dr CF Mountain and the Editor of Chest.2
The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also
classified T1.
c
Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural
fluid show no tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not
related to the tumor, the effusion should be excluded as a staging element and the patient’s disease should be staged T1, T2, or T3. Pericardial effusion is classified
according to the same rules.
d
Separate metastatic tumor nodule(s) in the ipsilateral non-primary-tumor lobe(s) of the lung are also classified M1.
b
and their main intrathoracic branches and tributaries.
The point at which the pulmonary vessels become great
vessels (a T4 descriptor) is the pericardium: the intrapericardial portions of these vessels are considered to
be great vessels. As an example, a tumor of 5 cm in diameter, involving the ipsilateral mediastinal lymph glands
and with an additional pulmonary nodule, believed to
be malignant, in the contralateral lung would be
described as T2N2M1.
For convenience, TNM subsets with similar survival
prospects and for which treatment options would be
similar are combined into stage groups (Table 9.2)
and the example given above would be assigned to
stage IV.
Staging is done at various time points during the
patient’s journey through preliminary investigations
and then treatment. It is important to know when
staging is done so as to compare like with like when
Staging, classification, and prognosis 99
Table 9.2
Stage
0
IA
IB
IIA
IIB
IIIA
IIIB
IV
Stage grouping: TNM subsetsa,b
TNM subset
Carcinoma in situ
T1N0M0
T2N0M0
T1N1M0
T2N1M0
T3N0M0
T3N1M0
T1N2M0
T2N2M0
T3N2M0
T4N0M0
T4N1M0
T4N2M0
T1N3M0
T2N3M0
T3N3M0
T4N3M0
Any T Any N M1
a
Staging is not relevant for occult carcinoma, designated TXN0M0.
Reproduced with the kind permission of Dr CF Mountain and the Editor
of Chest.2
b
evaluating different treatment regimens. The initial, pretreatment, stage is the clinical/evaluative stage, or
cTNM. This may integrate the information obtained
from imaging and bronchoscopy as well as, for example, the histopathology from a fine needle aspiration
biopsy (FNAB) of a distant metastasis. Obviously, with
the addition of information obtained at surgery and the
pathologic examination of the resection specimen, the
postsurgical/pathologic stage known as the pTNM will
be more accurate. (See comments later on ‘stage migration’.) The ‘y’ prefix is used when the patient is restaged
after induction or neo-adjuvant therapy (induction
therapy being a treatment modality aimed at rendering
an inoperable stage tumor operable; the goal of neoadjuvant therapy is to improve the survival rate of an
operable tumor). This can be used in conjunction with
the ‘c’ and ‘p’ prefixes. Thus ycTNM would reflect the
clinical restaging after induction or neo-adjuvant therapy and ypTNM the pathologic (i.e. postsurgical) stage
after similar presurgical chemo- and/or radiotherapy.
The ‘r’ prefix is used for the staging of recurrent tumors
and the ‘a’ prefix for autopsy findings.4
It is important to understand the principle differences the fifth edition of the TNM Classification of
Malignant Tumors brought to the staging system for
lung cancer in 1997 as many studies on induction/
neo-adjuvant therapy were designed and/or implemented before that year. The four main differences are:
(1) that stages I and II were subdivided, respectively,
into stages IA, IB and IIA, IIB; these reflect the
increase in size of the tumor from T1 to T2 (i.e. ≤
or >3cm in diameter);
(2) stage T3N0M0 was moved from stage IIIA to IIB as
the five-year survival is more akin to this latter
stage;
(3) separate nodules within the same lobe were assigned
to the T4 category; and
(4) separate nodules in other, ipsilateral lobes and the
contralateral lung were included in M1 disease.
Many clinicians feel that such detailed staging is
irrelevant for SCLC, and consider that a cruder division
into ‘limited’ and ‘extensive’ disease allows clinical decisions to be made on treatment.6 There are two definitions: from the Veterans Administration Lung Study
Group (VALG) and from the International Association
for the Study of Lung Cancer (IASLC). In the former,
limited disease (LD) is defined as tumor which is
restricted to one hemithorax, often including the ipsilateral supraclavicular fossa, basically a single radiotherapy field, whilst any wider-spread disease, including
distant metastases, is considered as extensive disease.
In the IASLC staging system all patients without distant
metastases are considered to have LD, including those
with a malignant pleural effusion and all patients
with contralateral mediastinal and/or supraclavicular
lymph node metastases to be included in the LD category. It has been shown that the IASLC staging system
is a better discriminator of survival.7 Whilst this distinction is certainly sufficient for the vast majority of
sufferers with this cell type the TNM stage remains relevant for the fortunate patient with unusually localized
disease (stage I essentially, possibly stage IIA) for whom
surgical therapy or multimodality therapy should be
considered.5,8
THE STAGING PROCESS
The clinician is confronted with a bewildering array of
tests which may, when used appropriately, provide
information as to the extent of disease and therefore
permit one to stage the patient and advise on therapy.
The value and place of each test will be discussed in the
100 Textbook of Lung Cancer
next section. The clinician may utilize any and all such
tests to construct a clinical/evaluative TNM stage
(cTNM). Such tests may include surgical exploration
such as mediastinoscopy and video-assisted thoracoscopy (VATS) undertaken prior to a decision to recommend treatment. It is as well to remember that as one
proceeds with this information-gathering exercise, the
tests become increasingly costly and more invasive.
Once sufficient information has been collected as to
permit a decision regarding treatment, then further
tests become obtrusive and unwarranted. The difficulty
for the clinician is to know where to draw the line and
to decide that the evidence is sufficiently reliable as to
make the case for a particular treatment.
There can be no rigid protocol for staging and the
clinician will decide the next step based upon the overall picture as it emerges as each step provides additional
information. For most clinicians the critical point in the
staging process is reached once the patient’s disease has
been shown to be too extensive to permit surgical treatment. The oncologist or radiotherapist might still consider other staging tests to be important in defining the
most appropriate regimen. If the patient comes through
the assessment of the clinician and is still considered
operable, the surgeon may wish to define the stage
more precisely before making a final decision to operate. As this frequently involves a decision as to the
probable extent of resection, and the use of surgical
investigations such as mediastinoscopy, this step should
be left to the surgeon.
The issue as to which tests are considered the minimum necessary to establish cTNM has been considered
by the IASLC, and is one that is regularly updated at
their workshops.9,10 The American Thoracic Society and
the European Respiratory Society have accepted similar
recommendations.11 More recent guidelines have been
published by the American College of Chest Physicians
(ACCP) in 2003,12 and by the National Institute for
Health and Clinical Excellence (NICE) in the UK in
2005.13 A summary of these recommendations is shown
in Table 9.3.
Once a decision has been made as to treatment, the
cTNM assigned to that patient should not be changed
in the records. As alluded to above, additional information will accumulate if the patient proceeds to thoracotomy and pulmonary resection. This will allow the
pTNM to be established. This should be recorded separately, and does not replace the cTNM.
The UICC4 allows and recommends that a record
be made of the assessment of residual disease after
treatment. This is also the recommendation in the
Manual for Staging of Cancer, produced by the American
Joint Committee on Cancer Staging and End Results
Reporting.15 This is most usually done after surgical
resection. The designation R is used to define this. RX
indicates that it is not possible to evaluate the presence
of residual disease. R0 indicates that no residual disease
remains, i.e. that there was a complete resection with all
resection margins through normal, non-tumoral tissues. R1 indicates that microscopic residual tumor
remains and R2 signifies that there is macroscopic
residual tumor after what must be considered an incomplete resection. Most workers interpret the R1 status as
applying to the case where the resection margins are
unexpectedly positive on subsequent histologic examination of the resection specimen. Honest surgeons will
also use this descriptor when tumor tissue has been
cleaved off remaining structures. This classification is
not part of the staging system but represents good practice. The 2005 IASLC guidelines define the requirements
of complete resection.16 These require histologically
proven free resection margins, complete lymph node
clearance (vide infra) with no extracapsular spread in
the nodes, and disease-free highest mediastinal node.
We believe that at least six lymph node stations (three
N1 and three N2) need to be completely resected (as
opposed to sampled) to qualify as lymph node clearance, as specified in the European Society of Thoracic
Surgeons (ESTS) guidelines for intraoperative staging.17
When the resection margins are free but all of these
criteria are not met, or if there is carcinoma in situ at
the bronchial resection margin, or if the pleural lavage
cytology is positive, then the term ‘uncertain resection’
should be used.
As time passes the disease may recur or progress and
additional tests may be indicated to establish a retreatment or rTNM. Some would consider that our ultimate
insight into the extent of disease is realized at autopsy,
when a TNM can be created. However, time is the ultimate test and our understanding of disease progression
is curtailed by death, preventing the development of
clinically relevant disease that could be overlooked at
autopsy.
In summary, the first step in the evaluation of a
patient with suspected lung cancer is to take a very
careful history and perform a thorough physical examination. Chest radiographs and computerized tomographic (CT) scans (chest and abdomen to include the
entire liver and both adrenals) are then obtained. Bronchoscopy will usually be performed at this time, especially if the tumor is centrally located. If there is a
suspicion of brain metastases appropriate imaging will
Staging, classification, and prognosis 101
Table 9.3 Pretreatment minimal staging6,9,11,12
Step 1
Investigation
Clinical history
Weight loss and
performance status
Patient group
All patients
Clinical examination
Chest radiographs
All patients
PA
All patients
Lateral
Blood tests
Hb
All patients
Alk phosphatase
Transaminase
Lactate dehydrogenase
If still thought suitable for curative therapy proceed to Step II
Step II
Investigation
Bronchoscopy
Patient group
All patients with central
tumors or those in whom
central extension is
suspected
All patients if available
Confirmatory tests
As appropriate
As appropriate
Aspiration of any effusion
(considered positive if cytology malignant)
As for high-risk patients in
Step II
Confirmatory tests
The features of proximal, extrinsic
compression are unreliable and require
further evaluation of the mediastinum by
CT and/or mediastinal exploration
Dubious findings confirmed (not
necessarily histologic)
CT chest and upper
abdomen (to lower
pole of kidneys with
iv contrast enhancement
of mediastinal vessels)
Liver ultrasound
High risk groupa if CT
of abdomen not available
Brain assessment by
Advisable in high risk groupa
MRI (or CT if MRI not
available)
a
High risk patients are those having non-specific features identified by Hooper et al.14
• Unexplained anaemia (Hb <11%)
• Unexplained weight loss (>8 lb (3 kg) in 6 months)
• Abnormal alk phosphatase, or transaminase
• Where any clinical suspicion of metastatic disease exists
• Patients with stage III disease
If still thought suitable for curative treatment proceed to Step III
Step III
Investigation
(a) PET-CT
(b) Bone scan only if PET not available
(c) Bronchoscopy if not previously
undertaken
(d) Thoracoscopy (video-assisted)
Patient group
All patients
Skeletal X-rays ± CT/MRI of bone if dubious positive result
All patients
If pleural effusion present and cytology negative but clinical
suspicion remains, do a pleural biopsy
(Continued)
102 Textbook of Lung Cancer
Table 9.3 Continued
(e) Mediastinal exploration
• It is recommended that this
is performed pre-operatively by:
• Transtracheal or transesophageal
aspiration
Patients in whom CT suggests mediastinal
invasion or if CT shows aspiration nodes >1.0 cm in Short
axis diameter
• Cervical mediastinoscopy
Same
• Additional evaluation of the
The above groups with tumors of the left upper
subaortic fossa by left anterior
lobe or left main bronchus if suspicion of station
mediastinotomy or VATS
5 or 6 metastases on CT or PET
• This must be performed
All patients – including those whose
intra-operatively
mediastinum has been assessed preoperatively
• Palpation insufficient
• Careful and extensive mediastinal
dissection (‘systematic nodal
dissection’)
• Separate labeling as per Naruke
or ATS of excised nodes for
subsequent histologic examination
(only N1 nodes on resection
specimen)
• Re-evaluation of T stage:
completion of intra-operative
staging of tumor and pleural
space
Proceed with definitive therapy, which will be surgical resection in all but the most unusual
circumstances
be obtained (preferably magnetic resonance imaging
(MRI) – vide infra). If the patient is a candidate for radical (i.e. ‘curative’) therapy then a positron emission
tomography (PET)-CT should be obtained.13 While this
staging process is being undertaken the functional evaluation of the patient can be carried out so that at the
end of this process a treatment decision can be made. If
the treatment decision is to give the patient induction
therapy this process will need to be repeated at the term
of the induction therapy so as to determine the logical
next step.
THE STAGING TESTS
Lung cancer is dealt with nowadays by teams which
comprise pulmonary physicians, surgeons, oncologists,
radiotherapists, palliative care physicians, radiologists,
pathologists, and numerous support staff. In the UK
this is known as the multidisciplinary team (MDT). In
an age of technologic progress it is often necessary to
remind ourselves of the importance of good clinical
acumen. All of our elaborate scans have to be directed
by clinical assessment and interpreted in the light of
this.
Clinical history and examination
These remain the most basic and most cost-effective
assessments of disease extent. The clinician, whilst
enquiring as to symptoms of the primary tumor, will be
looking to assess performance status and co-morbid
conditions. Watching the patient come into the consultation room and careful enquiry into his/her functional
status and exercise tolerance will determine the patient’s
ability to undergo aggressive treatment, be it surgery,
chemotherapy, or radiotherapy. Investigations may be
curtailed in a very unfit patient because their results
will not influence treatment choices. The performance
status (Table 9.4) of every patient should be recorded
at the first clinical visit.
A few questions are critical to assess stage. The presence of chest wall pain is more accurate at determining
Staging, classification, and prognosis 103
Table 9.4 ECOG performance status142
Grade
ECOG performance status
0
Fully active, able to carry on all predisease
performance without restriction
Restricted in physically strenuous activity
but ambulatory and able to carry out work
of a light or sedentary nature, e.g. light
house work, office work
Ambulatory and capable of all self-care but
unable to carry out any work activities; up
and about more than 50% of waking hours
Capable of only limited self-care, confined
to bed or chair more than 50% of waking
hours
Completely disabled; cannot carry out any
self-care; totally confined to bed or chair
Dead
1
2
3
4
5
chest wall invasion than a CT scan. The presence of
unexplained weight loss should alert the clinician to
the increased possibility of disseminated disease in such
patients. A patient may well dismiss weight loss as
attributable to changes in diet and a deliberate attempt
at weight reduction. Further enquiry may show that
repeated previous attempts at weight reduction have
failed without the assistance of disseminated malignancy! The patient coming to see a chest specialist will
not volunteer the recent onset of bone pain, assuming
it to be degenerative or traumatic in nature, and may
assume that hoarseness is due to the trauma of coughing. Similarly, patients and their relatives may rationalize the change in personality as due to anxiety after
hearing the diagnosis and dismiss neurologic symptoms
as due to minor nerve damage.
A careful examination should focus upon any questions raised in the history and also routinely examine
for cervical lymphadenopathy and hepatomegaly. One’s
ability to detect enlarged neck nodes improves with
practice and this important examination should not be
designated to the most junior member of the team.
Examination of the supra-clavicular fossa with ultrasound (US)-guided FNAB is becoming increasingly
popular and does detect a number of otherwise unsuspected lymph node metastases, which are very important as they are an N3 determinant (stage IIIB). When
reading the literature on routine US screening of the
supra-clavicular fossa it is important to determine
the prevalence of nodal disease, which will be related to
the inclusion criteria for the study (patients with ‘operable’ NSCLC vs all patients with suspected or proven
NSCLC vs patients with suspected N2 disease) as this
has an obvious impact on the incidence of N3 disease
detected by this investigation. Thus in one study of
‘operable’ patients with NSCLC this technique proved
N3 disease by virtue of supra-clavicular lymph node
metastases in 8% of patients, but this led to upstaging
of only 4%.19 In a study of patients with lung cancer at
any stage, 31% were found to have supra-clavicular
lymph node metastases in non-palpable nodes.20 This
was the same frequency as probable or proven adrenal
metastases and the supra-clavicular lymph node metastases were often associated with mediastinal lymphadenopathy and/or other distant metastatic disease. This
study also showed that US was superior to CT in detecting non-palpable supra-clavicular lymph node metastases. Finally, the yield was again very low in otherwise
apparently operable patients with NSCLC. In one study
of patients with NSCLC and probable stage N2 disease,
46% of patients were found to have supra-clavicular
lymph node metastases, and this obviated the need for
other staging procedures in 42%.21 These results have
two implications. First it means that US-guided FNAB
of supra-clavicular lymph nodes will obviate the need
for more invasive staging procedures in a significant
number of patients, sparing them the risks of the procedure and making considerable cost savings for the
health-care economy. Second, it will upstage a significant number of patients, and this can have considerable
therapeutic consequences as in many cases this will
mean a shift from so-called curative treatment modalities to a more palliative approach. However, the yield
and benefit are greatest in patients who are already suspected of having at least stage IIIA disease, and the
yield in patients with stage I and II disease is much more
limited, making its routine application for this subset of
patients much more debatable. This finding was confirmed in another study in which only 3/117 patients
were upstaged by supra-clavicular US-guided biopsy of
non-palpable lymph nodes.22
Chest radiography
This is usually the starting point in further evaluation.
Whilst it usually provides clues as to the diagnosis, it
also gives valuable staging information as to tumor size
and possible local invasion.23 It is as well to check the
radiograph for rib erosion, elevation of the hemidiaphragm, the presence of other lung nodules, or evidence of an effusion (Figure 9.1). The presence of such
features may allow one to cut short the process of
104 Textbook of Lung Cancer
the surgeon will wish to examine the airway with respiration suspended under general anesthesia, often using
the rigid bronchoscope with its wider field of view and
facility for larger biopsies. Bronchoscopy also allows
the clinician to rule out other small endobronchial
tumors and demonstrates anatomic variants of bronchial anatomy to the surgeon.
Figure 9.1
The chest radiograph of a patient with a mass in the right upper
lobe (arrow). The film also shows gross widening of the superior
mediastinum (arrow head), strongly suggestive of mediastinal
nodal disease, but there is also a right pleural effusion. Aspiration
cytology of the effusion gave the diagnosis of adenocarcinoma,
allowed staging of the disease as T4 (stage IIIB), and also showed
the patient to be inoperable.
assessment by establishing the diagnosis and staging
the patient with a single investigation, such as pleural
aspiration cytology. The posteroanterior and lateral
films can also be useful for tumor localization in relation to the fissures.
Hematologic parameters
Parameters such as anemia, disturbance of liver enzymes,
or elevation of serum alkaline phosphatase are reliable
indicators, suggesting a greater probability of distant disease.24 Such tests are inexpensive and widely available,
and should be a routine part of the staging process.
Bronchoscopy
For the patient who remains operable at this point a
wide vista of additional tests may be appropriate. The
diagnosis may be established by sputum cytology, an
underutilized investigation, but for all patients except
those with extensive disease, bronchoscopy will be
undertaken. This provides an opportunity for more
accurate determination of cell type by histologic examination and allows one to assess the proximal extent of
the disease within the tracheobronchial tree. The
fiberoptic bronchoscope is an excellent screening tool
for the respiratory physician, but in borderline cases
Computerized tomography
CT has greatly aided the staging of lung cancer and the
proliferation of CT scanning facilities attests to the
enormous value of this investigation. However, much
depends upon technical aspects of the scanner, the protocol used for the study, and the experience of the radiologist.25 CT scans of the chest provide an enormous
amount of three-dimensional information as to disease
extent. One can analyze the individual components of
the scan, assessing the accuracy with which CT can
detect mediastinal gland involvement, mediastinal invasion, chest wall invasion, the presence of additional
pulmonary nodules, or deposits in the abdominal
organs or brain. However, in reality the value of the
information provided by CT scanning is far greater than
the sum of its component parts. The three-dimensional
construct helps the surgeon anticipate the possible
extent of resection, the technical problems that may be
encountered, and the areas to inspect for possible tumor
extension. The surgeon can use such information in
evaluating the patient’s fitness for such extended surgery, to guide intraoperative assessment, and to plan
the operative strategy to deal with likely areas of extension or concern. It does not matter to the surgeon that
such areas of concern may prove to be fallacious, it is
better to be prepared, but for the clinician the lack of
specificity must be an ever-present concern in evaluating the true extent of disease. One would not want to
deny the patient potentially curative surgery on the
basis of a radiographic feature that lacks accuracy. Confirmatory tests are often necessary, particularly if the
decision hinges upon a single, adverse CT feature.
The significance of additional pulmonary nodules will
depend upon geographic factors such as the local prevalence of benign granulomatous disease. In one study,
two-thirds of such nodules were shown to be definitely
benign, and only 11% were definitely malignant.26 Mediastinal lymph nodes can be seen more easily on CT than
with conventional radiology.27 As the size of such nodes
increases, so does the probability that they contain
metastases. However, there is no size criterion below
which deposits are excluded with certainty, nor above
which deposits are certain to be present (Figure 9.2).
Staging, classification, and prognosis 105
Figure 9.2
A CT scan of the chest with contrast enhancement of the mediastinal vessels. An enlarged node is visible in the right paratracheal
area (arrow). Although this node was larger than 1 cm, it was
shown at mediastinoscopy to be benign, and this was confirmed
at subsequent thoracotomy.
Figure 9.3
A CT scan of a patient with a left upper lobe tumor.
The CT shows unequivocal evidence of irresectable involvement of
the mediastinum with tumor encircling the main pulmonary
artery to its origin. A left anterior mediastinotomy would be
unnecessary unless tissue diagnosis was required.
As one increases the size limit permitted for normality,
those nodes deemed ‘abnormal’ are more likely to contain metastases, and the evaluation gains greater specificity, but at the cost of declining sensitivity. If one
applies a lower cut-off the reverse applies, sensitivity
rises at the expense of falling specificity, and one is
more likely to designate nodes as ‘abnormal’ when they
do not contain metastases.28 This is the dilemma for the
radiologist. The commonest compromise is to report
nodes as abnormal if their short-axis diameter is greater
than 1.0 cm.29 The accuracy of this assessment depends
upon many factors: the speed of the scanner, the use of
contrast to enhance the mediastinal vessels, and the
rigor with which lymph node deposits are sought at
thoracotomy. The reported sensitivity and specificity
fall from 70–80% to 60% when the CT assessment is
subjected to detailed intrathoracic staging.30–32 Abnormal nodes, larger than this, should be examined by
mediastinal exploration to gain histologic confirmation
of their involvement. Such enlarged nodes within the
superior mediastinum are accessible to cervical mediastinoscopy and anterior mediastinotomy (see later).
Enlarged nodes beyond the reach of these techniques
can be accessible to video-assisted thoracoscopy (VATS),33
but such nodes have less impact on the results of surgical treatment and their accurate designation can usually
be left until thoracotomy.
If the CT scan of the chest shows the mediastinal
nodes are within this size limit the surgeon may proceed to thoracotomy without mediastinal exploration.34
However, there are four classic risk factors for false negative mediastinal imaging studies (including position
emission tomography (PET) scanning, which will be
discussed below). These are: large tumors, central
tumors, PET-positive hilar nodes, and cell type of adenocarcinoma or large cell poorly differentiated carcinoma.35 This should be taken into account when deciding
whether invasive mediastinal staging is indicated. Also,
many surgeons will be more cautious (i.e. more extensive in their preoperative staging) when faced with a
higher risk resection (right pneumonectomy, for example) or a high-risk patient, or both together.
Mediastinal invasion may be suggested on CT, but this
assessment is unreliable36 unless there is gross involvement (Figure 9.3). More frequently the CT scan of the
chest will show that the tumor, and the associated
atelectasis or consolidation, is contiguous with the mediastinal outline (Figure 9.4). If CT does not demonstrate
a fat line separating these two opacities the radiologist
will warn that invasion may be present.37 This judgement carries a sensitivity and specificity of around
60%,38 but is imperfect and dependent upon the experience of the radiologist. Such a worry can often be
resolved by mediastinoscopy (Figure 9.5), with the
addition of mediastinotomy in appropriate cases. A
suggestion of mediastinal invasion beyond the reach of
these techniques can be inspected using VATS, but is
usually deferred until thoracotomy when a more determined assessment of resectability can be made without
the danger of massive bleeding. The CT evaluation of
chest wall invasion is similarly imperfect unless rib erosion or extension outside the chest wall can be demonstrated.39 Fortunately, such invasion does not preclude
successful resection with good survival results.40,41
Most clinicians when requesting a CT scan will ask
for the chest study to extend into the abdomen to the
106 Textbook of Lung Cancer
Figure 9.4
A chest radiograph (a) and CT scan (b) of
a patient with a tumor in the right
middle lobe. This was initially deemed
inoperable by another clinician based
on his interpretation of the CT scan. The
appearances are not unequivocal and at
thoracotomy resection of a T2N0 tumor
was possible by bilobectomy. The chest
radiograph (c) was taken 3 years later
and the patient is still well and diseasefree 12 years later.
Figure 9.5
The CT scan of a patient with a tumor in the right upper lobe
encroaching upon the mediastinum and the right main bronchus.
This was evaluated by mediastinoscopy and found to be resectable. The patient underwent right upper lobectomy and sleeve
resection for a T2N1 tumor.
Figure 9.6
The CT of the abdomen suggested a liver metastasis. The
appearances were not clarified by ultrasound and a needle biopsy
showed a benign hemangioma.
lower pole of the kidneys in a search for distant metastases in the liver, abdominal nodes, adrenals, and kidneys. Whilst this is a useful addition to the CT protocol,
an isolated abnormality should not be taken as proof
unless there is confirmatory evidence that such an
abnormality is metastatic (Figure 9.6).42 This may
require CT-guided needle biopsy (Figure 9.7). We have
found this to be a useful role for PET, if this is available
(see later). The addition of CT of the brain is debated.
Undoubtedly the number of unsuspected metastases
discovered is small, around 5%,12,43 but as this has a
profound effect on the advisability of thoracotomy we
routinely undertake CT of the brain, chest, and
abdomen prior to surgery.44 If there is any suspicion of
Staging, classification, and prognosis 107
Figure 9.7
A CT-guided needle biopsy of an indeterminate mass in the right
adrenal gland. It showed the presence of an adenoma.
brain metastases, and indeed for screening purposes,
MRI should always be the preferred brain imaging
modality unless local availability is an issue.45,46
Scintigraphic scans
These are largely obsolete, with the possible exception
of bone scintigraphy.47 This has retained a place in staging if and only if PET is not available. Most clinicians
use bone scans selectively in ‘high-risk’ individuals in
whom distant metastases have been suggested clinically
by symptoms, or the presence of non-specific features
such as weight loss or disturbed blood parameters.48,49
As false-positive bone scans can occur with trauma and
degenerative conditions it is as well to follow up any
abnormality with skeletal radiology, and in doubtful
cases a local CT or MRI of the area.50 However, if a
whole body PET scan is obtained then the bone scan is
redundant. PET has both higher sensitivity and higher
specificity than scintigraphic bone scans.51–53 However,
despite this higher accuracy confirmatory studies
should be performed if there is any doubt about the
diagnosis of metastatic disease.12
Abdominal ultrasound
This is widely available and, in experienced hands, is as
good as CT at detecting metastases in the liver54 or
adrenals.55 If CT is not available, US should be performed in high-risk cases. US is helpful to obtain
additional information to characterize any abdominal
abnormality on CT, and may obviate the need for needle biopsy. It is also a useful guiding technique for the
biopsy, if required.
Mediastinal exploration
This is a fundamental tool to select patients for surgery
because of the strong negative prognostic implication
of N2 and N3 disease. The ESTS has recently published
guidelines on both the pre-operative and the intra-operative lymph node staging.17,35 If it is felt that the
patient would be a candidate for induction (also called
neo-adjuvant) therapy, then it may be desirable to avoid
surgical staging of the mediastinum so that the most
definitive procedure can be carried out in an unoperated and unscarred mediastinum at the end of the
induction therapy (see section below on restaging of
the mediastinum after induction therapy). It can also be
desirable to avoid surgical staging in more frail patients.
Unfortunately, the reliability (the combined sensitivity
and specificity) of all techniques increases with invasiveness. The true gold standard of mediastinal staging
is the systematic nodal dissection done at the time of
thoracotomy. Mediastinoscopy has a false-negative rate
of less than 10%,56 whereas all endoscopic techniques
with FNAB have a false-negative rate of around 15% in
the best of hands. So the decision as to how to proceed
will depend on the clinical indices of suspicion for
mediastinal lymph node involvement as well as the
patient and the planned resection, as it is clearly
desirable to avoid the discovery of false-negative staging at thoracotomy in a high-risk situation. So in most
centers mediastinoscopy is now used selectively to
evaluate the mediastinum when CT has suggested the
presence of enlarged mediastinal nodes or mediastinal
invasion,57 if there are PET-positive nodes in the
mediastinum, or if there are other clinical indices leading to heightened suspicion of mediastinal lymph node
involvement.
Cervical mediastinoscopy58 is undertaken under general anesthesia through a short cervical incision. It
allows inspection and biopsy of lymph nodes in the
paratracheal region to both sides of the trachea, in the
pretracheal area, and below the carina, excluding gross,
often irresectable, nodal metastases. When the nodes
are of a normal size and metastases are small and intranodal there is obviously a risk of sampling error, and
this is the most common cause of false-negative mediastinoscopy. The one area where more overt mediastinal nodal deposits can be missed is classically the
inferior part of station 7 (the subcarinal nodes) as well
as its most posterior aspect. This risk can be minimized
by dissecting station 7 off both left and right main
bronchi, as well as off the pericardium posteriorly prior
to taking biopsies. There are several reports of falsenegative rates of well over 10%. We feel that using a
108 Textbook of Lung Cancer
video mediastinoscope, with its greatly enhanced vision,
this is unacceptable and, if this is the case, the surgeon
should consider taking more care to identify all possible nodes, to dissect them out more so that larger biopsies can be taken safely, and to prepare the subcarinal
fossa as described above so that it can be extensively
biopsied. When the tumor is a left-sided tumor it is the
practice of the authors to do this part of the mediastinoscopy quite aggressively because it then becomes
part of the systematic nodal dissection. Likewise, as it
is extremely difficult to reach L4 and L2 effectively
through a left thoracotomy, it is the practice of the
authors to resect as many nodes as possible at mediastinoscopy, again with the view that mediastinoscopy, if
negative, will then become a seamless part of the operative management of the tumor, fulfilling the philosophy of intraoperative staging as described in the ESTS
guidelines.17
Two more radical methods of mediastinal staging have
been described. These are VAMLA (video-assisted mediastinoscopic lymphadenectomy) and TEMLA (transcervical extended mediastinal lymphadenectomy).59–61 As
the names imply, both techniques aim to perform
a radical mediastinal lymphadenectomy removing all the
para-tracheal nodes as well as emptying out in a radical
manner the subcarinal fossa (and therefore more than
just station 7). TEMLA also aims to remove stations 5,
6, and 8. In experienced hands these techniques can be
performed safely with entirely acceptable morbidity.
However, at the moment experience is limited and they
are only performed in a few centers. Furthermore their
exact place in mediastinal staging remains to be established. First, do we truly want a perfect method to stage
the mediastinum? Patients with true minimal N2 disease (single-station, intracapsular involvement) have a
25–40% five-year survival with surgery alone. It is
uncertain whether it is in these patients’ best interest to
be denied surgery because they are found to have N2
disease. Second, at the end of this chapter we shall
explore the issue of restaging the mediastinum after
induction chemotherapy. It is when the N2 disease has
been eradicated that there is an indication for surgery.
This would be impossible after VAMLA or TEMLA,
making the decision whether to proceed with surgery
more difficult because all that would be left would be
to assess the decrease in the maximal standardized
uptake value (SUV max) of the primary tumor as a
measure of the response to induction chemotherapy.
The major advantage for such techniques at present
would appear to be in allowing the mediastinal component of systematic nodal dissection (see later) to be
performed prior to surgery when video-assisted resection is planned.
Mediastinoscopy can also be very useful to assess
direct mediastinal invasion by right upper lobe tumors,
so in some cases it can also be useful to assess T stage
and thus resectability. When wishing to inspect the
area around the aortic arch and subaortic fossa, as in
patients with tumors arising in the left upper lobe or
reaching the left main bronchus, cervical mediastinoscopy should be supplemented by left anterior mediastinotomy.58 This allows digital examination and, if necessary,
cautious biopsy of disease in this area (Figure 9.8). It is
applied selectively depending upon the CT appearances
in this area of the mediastinum.62 Some surgeons prefer
to use VATS to biopsy stations 5 and 6. Such techniques do not exclude more subtle mediastinal disease
but, with experience, ensure that complete resection is
possible in 95% of negative cases.63,64 The surgeon will
often be encouraged to proceed with thoracotomy and
resection when other, less accurate techniques such as
CT have raised doubts. When the lung cancer is in the
left upper lobe and the CT shows only small-volume
nodes, completely surrounded by fat, in the para- or
subaortic area on CT, some surgeons do not routinely
explore this area preoperatively because the five-year
survival in patients with this pattern of nodal disease
may be equivalent to that of patients with N1 (i.e. stage
II) disease, and not that of patients with N2 (i.e. stage
IIIA disease).65,66
Mediastinal needle biopsy
This can be undertaken through the bronchoscope.67
Suitable target nodes should be identified in the main
Figure 9.8
This patient has a tumor in the left upper lobe and the surgeon is
undertaking evaluation by cervical mediastinoscopy and left
anterior mediastinotomy. After all biopsies have been taken,
bi-digital palpation of the subaortic fossa will exclude invasion or
gross mediastinal gland enlargement in this critical area.
Staging, classification, and prognosis 109
carina or the paratracheal area, usually on CT. This
technique may obtain tissue diagnosis and confirm
irresectability, but there is a small risk of false-positive
samples.68,69 It cannot be considered to be a reliable
alternative to staging the mediastinum by surgical exploration prior to thoracotomy, even with US-guided biopsies. Overall, bronchoscopic FNAB techniques have a
false-negative rate of around 15%, so the main value of
these techniques is when this minimally invasive technique proves mediastinal lymph node involvement.
Transesophageal fine needle aspiration (with
ultrasound guidence)
EUS-FNA has been used to assess the presence of
mediastinal node enlargement, but is limited by the
same size criteria as CT.70 The transesophageal route is
attractive as a conduit to examine the mediastinum
below the carina, beyond the reach of the mediastinoscope, as well as the left para-tracheal area, checking
areas where CT has suggested mediastinal lymph node
involvement or tumor invasion. The results have proven
unreliable,71 being of a similar order of magnitude as
with trans-tracheal biopsies. The same caveats therefore
apply to this technique, even with US guidance. However, it has been shown that EUS-FNA can be used to
improve the yield of mediastinoscopy.69 In this study
there were 36/100 patients who were ultimately proven
to have N2/N3 disease. These were located within reach
of EUS-FNA in 29 patients, and were positive at EUSFNA in 22. Mediastinoscopy detected N2 (17%) or N3
(2%) lymph node metastases in 19 of the 100 patients.
These were located within reach of mediastinoscopy in
29 patients and were confirmed in 19 of these patients.
Lymph node metastases were confirmed in 31 (86%) of
36 patients by either EUS-FNA or mediastinoscopy.
The five lymph node metastases that were missed by
both techniques were located at station 4L in one
patient, 5 in one patient, 7 in two patients, and 8 in one
patient. This study also showed that T4 status can be
correctly assessed by this technique in a number of
cases. Similar results with this combined technique
have been reported by others.72
Positron emission tomography
PET using the 18F-labeled glucose analog fluoro-2-deoxy-D-glucose (FDG-PET) has emerged as an exciting
addition to the staging tests. It is expensive, and in
many areas is still not widely available, and we are still
assessing its cost-effectiveness. It provides an alternative, metabolic search for malignant disease that is independent of the anatomic features of the deposits and is
thus a useful tool to detect and characterize the primary
tumor as well as loco-regional and distant metastases.73
It can characterize the lung lesion reliably in many
cases,74 failing only to detect very small deposits and
more indolent tumors such as broncho-alveolar carcinoma.75 False-positive cases can occur with chronic
inflammatory conditions, most notably tuberculosis
and histoplasmosis. PET may thus have a role in diagnosis and its place relative to bronchoscopy or needle
aspiration is under discussion.76 PET is reliable for
lesions that are over 8–10 mm in diameter, and should
probably not be performed for smaller lesions.12 Interest, however, has focused on the possibility that PET
could aid the non-invasive search for metastatic disease
in the mediastinum and at distant sites.77 Initially it was
said that PET is more accurate in the detection of mediastinal nodal disease than CT and even mediastinal
exploration, with a reported sensitivity of 80–100%
and specificity of 70–100%.78 However, the images
produced by FDG-PET scanners are indistinct and lack
anatomic precision (Figure 9.9). It is difficult to accurately define the margins of hilum and mediastinum. In
many centers this problem has been addressed by concomitant PET and CT scanning in a dedicated PET-CT
scanner. Two studies have shown the superiority of
integrated PET-CT as compared to the combination of
a PET study and a CT with correlation of the images by
the examining physician.79,80 This superiority was found
to be significant for the determination of T stage,
N stage, and M stage. A final caveat regarding PET is that
one study has shown it to be significantly less reliable
in smokers (or recent quitters) than in non-smokers.81
The maximal SUV was also higher in never-smokers,
both in the primary tumor and in mediastinal metastases. This could be due to the fact that the background
FDG uptake is higher in smokers than in never-smokers. Most centers having access to PET continue to rely
upon CT and confirm positive PET findings by mediastinal exploration, thus adding to the expense of staging.82 There is also the philosophical problem as to
whether one wishes to detect all mediastinal nodal
deposits. There are many reports of five-year survival of
20–30% after complete resection in the presence of
truly minimal N2 disease.64,83–85 Mediastinal exploration will miss such subtle N2 disease, perhaps to the
patient’s benefit, encouraging one to proceed with surgery with complete resection in 85% of cases.64 It is
unknown to what extent detection of this minimal N2
burden and induction chemotherapy would alter the
natural history of this entire very small subset of
patients (because induction therapy does not eradicate
110 Textbook of Lung Cancer
Figure 9.9
The chest radiograph (a) of a patient who
presented with a tumor in the left lower
lobe; there is an additional lesion at the
right apex (arrow). The CT scan (b) did
not suggest this additional lesion was a
tumor. An FDG-PET study (c) showed high
uptake in both lesions, and the rightsided lesion was confirmed histologically
to be malignant.
N2 disease in the majority of patients with more bulky
N2 disease). Furthermore, we do not know if the results
of induction chemotherapy would be better, worse, or
the same as adjuvant chemotherapy, which would now
be offered to these patients unless contraindicated.
PET will detect otherwise unsuspected distant metastases in 11–29% of patients otherwise thought suitable
for thoracotomy.86–88 However, the specificity of this
evaluation is not 100%. With regard to distant staging,
the initial enthusiasm for PET needs to be tempered. A
recent study with much larger numbers (350 patients)
demonstrated solitary extrathoracic lesions in 72 patients
(21%). A diagnosis was obtained in 69: 37 were true
metastases, 32 were not. These 32 lesions proved to be
unrelated malignancies in 6 and benign tumors or
inflammatory lesions in 26.89 Similarly, in the study by
Reed et al otherwise unsuspected metastatic disease was
identified in 15/287 (5.2%), as well as three second
primary tumors. However, PET also identified 19
potential areas of M1 disease that were proven not to be
metastases (6.6%). Thus the sensitivity of PET for M1
disease was 83%, the specificity was 90%, the negative
predictive value was 99%, and the positive predictive
value was 36%.90 This underscores the value of the recommendation in the current ACCP12 and NICE13 guidelines for histologic verification of apparent solitary
metastases detected by PET.
Similarly our experience with PET as a staging tool
for the mediastinum has grown and some of the initial
enthusiasm has been tempered by this experience.
There have been many recent studies and all essentially
show similar results to the three published reports.90–92
These studies included between 202 and 400 patients.
The sensitivity of PET ranged from 64 to 71%, the specificity from 77 to 84%, the positive predictive value
from 44 to 56%, and the negative predictive value from
87 to 91% (Table 9.5). An editorial by Kernstine
explains why these values are the best one can expect
with the current technology.93 What these results mean
is that, if one relies exclusively on PET to rule out N2/
N3 disease, between 9 and 13% of patients will be found
at thoracotomy to have unexpected N2 disease which
might have precluded surgery. Putting together what we
know from the CT era and this knowledge it seems reasonable to proceed with thoracotomy for small, peripheral tumors (unless known to be an adenocarcinoma or
Staging, classification, and prognosis 111
Table 9.5 Accuracy of PET-CT for mediastinal staging
Reference
Number of
patients
Sensitivity (%)
Specificity (%)
Positive predictive
value (%)
Negative predictive
value (%)
Reed et al90
Gonzalez-Stawinski
et al91
Cerfolio et al92
303
202
61
64
84
77
56
45
87
88
400
71
67
44
91
poorly differentiated large cell carcinoma) on the basis
of the PET scan alone, provided that the surgeon is prepared to resect unexpected minimal N2 disease if found,
on the basis that surgery alone offers a 20–35% chance
of cure in this situation.35 This might be improved with
adjuvant chemotherapy if the patient is fit for this treatment modality. Otherwise, invasive staging of the mediastinum should be carried out. This does not make PET
useless. First, in the apparent stage I (and possibly II)
patients with peripheral lesions it can allow lung resection to be carried out without surgical staging of the
mediastinum. Second, because it is precisely the patients
with the highest risk of unsuspected mediastinal disease who are also at highest risk of distant metastatic
disease that PET has the highest chance of detecting
otherwise occult stage IV disease.
Integrated PET-CT has been shown to be more accurate than PET alone with correlation to a previously
performed CT;79,80 however not to a degree that fundamentally changes this discussion about the indications
for surgical staging of the mediastinum.
Despite all our improvements in non-invasive staging,
invasive staging remains the closest we have to a prethoracotomy gold standard for the detection of N2 disease. The risk factors for unsuspected N2 disease that
we knew from the CT era of staging are still pertinent
in the PET age. They are tumor size, location, and histology and PET-positive hilar nodes.35 Large tumors,
central tumors and adenocarcinoma/poorly differentiated large cell carcinomas present the greatest risk of
false-negative non-invasive staging. The true gold standard for the precise diagnosis and assessment of N2
disease remains the intra-operative systematic nodal
dissection.17 This is not only a staging tool but could
also have a beneficial effect on outcome.94–97
Magnetic resonance imaging
MRI is little or no more accurate than CT in routine
staging. Some authorities consider that the ability to visualize in planes other than axial gives MRI an advantage
Figure 9.10
An MRI scan of a patient with a right-sided Pancoast tumor. The
scan gives coronal reconstruction of this difficult area, but also
suggested nodes at the main carina, which were confirmed to
contain metastatic disease at mediastinoscopy.
in difficult areas such as the lung apex and lower mediastinum.98 Most would recommend MRI when evaluating Pancoast tumor (Figure 9.10).99 With modern, fast,
multislice CT scanners and the software to do multiplanar reconstructions many of the advantages of MRI
have been obviated. If appropriately thin cuts are
obtained, modern CT scanners have higher spatial resolution than MRI. However, MRI remains of value as a
problem-solving tool looking at the central nervous
system. MRI is more accurate than CT at detecting and
characterizing brain lesions.45,46,100 If there is a clinical
suspicion of brain metastases then MRI should be
obtained unless there are local availability issues. We
would also recommend its use if CT of the brain shows
an abnormality (to rule out multifocal disease) or when
clinical suspicion remains after a negative CT. The routine use of MRI as a screening tool for asymptomatic
brain metastases has not been shown to be of value.
Similarly, if the CT raises doubts as to tumor extension
around the spine and into the spinal canal, MRI will
give clearer definition and valuable information. Whenever a neurosurgical opinion is to be sought, MRI
should be obtained beforehand.
112 Textbook of Lung Cancer
The tests described above should allow one to determine cTNM and, in appropriate cases, recommend thoracotomy. For the surgeon, however, the staging process
does not end there. We have come to appreciate that a
detailed re-evaluation at thoracotomy is a valuable step
prior to proceeding with resection. Intrathoracic staging
will evaluate areas of concern remaining after CT and
subsequent mediastinal evaluation, search for additional pulmonary nodules and pleural deposits not seen
on CT,101 and permit a thorough evaluation of nodal
extent by systematic nodal dissection.102
There is debate as to the value of pleural lavage
cytology as a routine step immediately after opening
the chest. Kondo and his colleagues found positive
pleural cytology in 9% of cases and showed it to be a
strong indicator of poor prognosis.103 Other workers
have confirmed the incidence of positive cytology but
did not find a statistically significant influence on prognosis after resection.104 We have reviewed our experience with pleural lavage cytology. We found malignant
cells in the lavage in 4.5% of the 292 patients studied.
Positive pleural lavage had a statistically highly significant and independent impact on survival: patients with
positive pleural lavage had a median survival of only 13
months, as compared to 49 months for those with a
negative lavage.105
Despite rigorous preoperative staging with CT and,
where appropriate, mediastinal exploration, cTNM has
been shown to be inaccurate in over half of the patients
coming to thoracotomy.106 Whilst occasionally cTNM
will overestimate the extent of disease, in most cases the
disease will be shown to be more extensive. As yet we
do not know precisely how the integration of newer
(a)
STEP 1
(b)
tools such as PET-CT will improve this. It is clearly
important that the surgeon obtains such valuable insight
into the extent of disease before making a decision
whether to proceed with resection, and when judging
the extent of pulmonary resection necessary to achieve
complete resection.
Systematic nodal dissection (SND) begins with the
excision of all mediastinal fat and the lymph nodes contained therein (Figure 9.11). It is recommended that
the nodes be labeled in accordance with an internationally recognized chart such as that proposed by Naruke
(Figure 9.12)107 or that of Mountain and Dressler
(Figure 9.13).3 It is our routine to slice these nodes at
the operating table and examine the internal architecture before deciding whether rapid histologic confirmation is necessary by frozen section analysis. If resection
is deemed possible we proceed to examine the N1
nodes similarly, in a centrifugal fashion, until the extent
of resection has been determined. The only nodes
remaining in the resection specimen can be assumed to
be N1. In such a way the surgeon will ensure complete
resection with the minimum resection of lung parenchyma.
We have shown that SND will disclose N2 disease in
18% of patients coming to thoracotomy without histologic evidence preoperatively, and only 60% of patients
will be shown to be node negative.108 This study confirmed that SND could not be omitted on the basis of
cell type, tumor size, tumor origin, lobe of origin, or by
preoperative mediastinal exploration. As ‘skip’ lesions
to the mediastinal nodes without hilar node involvement were found in 6% of cases, the assessment of the
mediastinum is important irrespective of the findings in
STEP 2
Figure 9.11
An operative specimen showing fat and
lymph node stations removed during the
first step in SND (a). These can be
correlated with the Naruke chart to show
that a complete circumnavigation of the
right side of the mediastinum has been
accomplished. Step 2 of the nodal
dissection (b) removes the nodes from the
fissure and the hila of the individual
lobes.
Staging, classification, and prognosis 113
1
2
1
4
5
10
10
7
13 12
14
2
3 6
10
14
2
3
2
4
1
10
10
10
10
10
11
11
12
11
8
14
13
12
8
13
14
14
14
13
12 13
13 14
13
8
13
13
14
14
9
1
3p
8
9
2 3
4
3a
9
1 Superior mediastinal or highest mediastinal
2 Paratracheal
3 Pretracheal
1
3a anterior mediastinal
3p retrotracheal or
2
3a
3
posterior mediastinal
6
4 Tracheobronchial
5 4
5 Subaoratic or Botallo’s
6 Paraaortic (ascending aorta)
7 Subcarinal
8
8 Paraesophageal
(below carina)
9 Pulmonary ligament
9
10 Hilar
11 Interlobar
12 Lobar … upper lobe
middle lobe and
lower lobe
13 Segmental
14 Subsegmental
Figure 9.12
The nodal chart devised by Naruke. The lymph node stations are
numbered: 1–9 indicate mediastinal nodal stations. (Reproduced
with permission of Dr T Naruke and Mosby Inc from J Thorac
Cardiovasc Surg 1978; 76: 832–9.107)
the hilum. If mediastinal node deposits are discovered
at thoracotomy and yet complete resection has been
confirmed to be feasible, the surgeon must decide
whether to proceed with resection, balancing the
reduced prospects of survival after complete resection
and the added morbidity and mortality of pulmonary
resection. The surgeon will be aware that the patient
has already necessarily incurred the morbidity and
mortality of thoracotomy (annual returns, The Society
of Cardiothoracic Surgeons of Great Britain and Ireland), and will base the decision to resect upon the
patient’s fitness, the extent of resection necessary, the
cell type, and the number and position of positive
nodes. Complete resection will be deemed appropriate
in 85% of cases, although the perioperative mortality is
higher and the five-year survival reduced to around
20–30%.64,83–85
Subsequent histologic examination of lymph node
stations removed at surgery will show metastases that
the surgeon had not appreciated in up to 9% of cases.109
The pathologist will also study the specimen and
attached lymph nodes, looking for the presence of
pleural invasion and satellite lesions that may have
eluded the surgeon. Some authors have suggested that
the use of monoclonal antibody stains will detect nodal
deposits not seen with conventional stains in up to 6%
of lymph nodes in 22% of patients.110 Others have suggested that this is the result of taking additional slices
of the nodes and that the majority of such micrometastases will be found with conventional stains by more
thorough histologic examination.111
To establish the pTNM the clinician will thus have to
scrutinize the operative findings and study the detailed
pathology report. The accuracy of pTNM will depend
heavily on the detailed nature of such reports.
RESTAGING AFTER INDUCTION CHEMOTHERAPY
A full discussion of the place of induction chemotherapy in the management of NSCLC is outside the remit
of this chapter. However, if multimodality therapy is
considered, restaging of the patient prior to surgery is
of paramount importance.
Recently there have been studies that have challenged
the role of surgery in all but true minimal N2 disease
(i.e. intracapsular, single node N2 disease found at
the time of thoracotomy), showing apparently similar
results with radical radiotherapy after induction
chemotherapy.112–114 However, in one of these studies114
there was a significantly improved progression-free survival with surgery and a trend towards increased overall
survival, and the authors concluded that surgery can be
considered in fit patients, especially if a pneumonectomy will not be required. In another,112 the number of
complete responses (only 4% overall) was far less than
usually found and the pneumonectomy rate (50%) was
unusually high, so it does seem fair to consider the
results of the experience to date as inconclusive. The
authors of this European trial112 themselves point out
that we do not know what the outcome would be in the
patients who are now considered to be the appropriate
candidates for surgery, i.e. those who have been downstaged from N2 to N1 or N0. It is interesting to note
that in this same study the locoregional recurrence rate
was much lower in the surgery arm (55% vs 32% in the
radiotherapy arm). Finally, RTOG 89-01 was closed
prematurely to give priority to another trial, which will
114 Textbook of Lung Cancer
Figure 9.13
The nodal chart established by the American
Joint Committee on Cancer (AJCC) and the Union
Internationale Contre le Cancer (UICC) in 1997.3
(See color plate section, page xv)
weaken the conclusions that can be drawn from this
trial.113
With induction chemotherapy, typically 30–50% of
patients will have the N2 nodes cleared of cancer by the
induction therapy. It is interesting to note that, when
there was sequential induction therapy comprising chemotherapy followed by chemoradiation therapy, and
when PET was performed at the outset, after the
chemotherapy and at the end of the induction process
it was the postchemotherapy PET (and not the PET
post-total induction therapy) that was the better predictor of survival.115
If the N2 nodes have been cleared of cancer, the fiveyear survival ranges from 29 to 44%,35,116,117 and if a
pathologic complete response is observed the five-year
survival is estimated to be 54% (median survival not
reached).118 If, on the other hand, this is not the case
then the five-year survival is 7–24%, usually below the
10–15% range in most studies. This is why it is considered essential to restage the mediastinum after induction therapy to avoid futile and potentially dangerous
thoracotomies and resections if there is persistent N2
disease. Unfortunately there is no perfect tool to restage
the mediastinum.35
Repeat mediastinoscopy has been used to restage the
mediastinum. The best results have been published
(and recently updated) by the Antwerp group.119 Over
10 years they had 32 patients who underwent repeat
mediastinoscopy after induction therapy. They were
able to perform the procedure in all patients and had
only five false-negative repeat mediastinoscopies, yielding a sensitivity of 71%, a specificity of 100% and an
accuracy of 84%. De Leyn et al reported the Leuven
experience of 30 prospectively studied patients and, in
their hands, there were only five positive repeat mediastinoscopies. In 18 cases the node which had been
positive at the first mediastinoscopy could not be adequately assessed because of extensive scarring and
fibrosis. All patients underwent thoracotomy and the
systematic nodal dissection revealed persistent N2 disease in 17. Therefore the sensitivity of repeat mediastinoscopy was 29%, its specificity was 100%, and its
accuracy only 60%.120 A Dutch group reported their
experience with repeat mediastinoscopy in 15 patients.
In 6 patients the procedure was considered to be inadequate; there were 9 adequate procedures – 2 were true
positives and 2 were false negatives.121 The conclusion
must be that in the real world repeat mediastinoscopy
Staging, classification, and prognosis 115
is a challenging operation with insufficiently robust
results to recommend its routine use for restaging of the
mediastinum after induction therapy.
CT scanning is even more inaccurate for restaging
than it is for primary staging.35 PET, when used for
restaging the mediastinum after induction therapy, is
less accurate than when used for primary staging, with
a sensitivity of 50–60% and a specificity of 85–90%.35
Fused PET-CT is better that PET alone in this situation
and in one study (with by far the best results) the sensitivity was 77%, the specificity was 92%, and the accuracy was 83%.120 However the results of fused PET-CT
are not usually as good as this.35 Again, a variety of
FNAB techniques have been described, with essentially
the same sensitivity and specificity as when used in the
chemo-naïve setting. Thus restaging of the mediastinum
after induction therapy in N2 disease remains a fraught
subject, often requiring a complex step-wise approach
with CT, PET-CT, trans-tracheal or esophageal FNAB,
and repeat mediastinoscopy, and still with a risk of
false-negative assessment of the mediastinum.35
As we have seen, tissue diagnosis is the ideal restaging
tool, but it is difficult and, even in the best hands, it will
always have a finite false-negative rate; it also requires
heavy use of time and resources, and can submit the
patient to multiple procedures. PET has been shown to
be an alternative, or surrogate way to restage the mediastinum after induction therapy. Cerfolio et al have
published two papers on an overlapping patient population, looking at the change in the SUV max on PET
before and after induction chemotherapy.122,123 In the
first study122 they demonstrated that a drop in SUV max
of 80% in the primary tumor predicted a pathologic
complete response with a sensitivity of 90%, a specificity of 100%, and an accuracy of 96%. These results are
roughly as accurate as the best combined invasive
restaging strategies. In the second study123 they showed
that a drop in SUV max of 75% predicted complete
response. If the SUV max in the mediastinal nodes
decreased by 55% there was a very high chance of being
a partial responder. The median decrease in SUV max
was 100% (range 75–100%) in complete responders,
58% (range 2–100%) in patients who had a complete
response in the N2 nodes but residual viable tumor in
the primary tumor, and 32% (range ⫺5–82%) in patients
with residual N2 disease. In terms of N2 disease,
PET-CT was less reliable. A decrease of SUV max of
>55% had a likelihood ratio of 9.1 in predicting clearance of the N2 nodes, but in reality residual N2 disease
was missed by PET-CT in 13/65 patients (20%). One
group studied the SUV max before and after induction
chemotherapy.124 These patients underwent induction
chemotherapy followed by chemo-radiation therapy
then surgery. A PET-CT was performed at time 0, after
the chemotherapy (t1), and at the end of the induction
process (t2). Patients with either a complete response
or less than 10% viable tumor cells in the tumor had a
drop in SUV max of 67% at t1 and 73% at t2. Follow-up
was short so the survival data are difficult to interpret.
Another group used PET to study the metabolic rate of
glucose.125 The multivariate analysis showed that the
absence of N2/N3 disease at PET had a survival hazard
ratio of 2.33 (95% CI 1.04–5.22; p <0.04). Reading
from the graphs, this translates into a three-year survival of a little under 0.6 for N2/N3 negative patients vs
around 0.25 for those with N2/N3 disease. The hazard
ratio for each 10% drop in the metabolic rate of glucose
was 0.99 (95% CI 0.98–0.99; p <0.01). A residual metabolic rate of glucose after induction of ≤0.13 had a
hazard ratio of 1.95 (95% CI 1.28–2.97; p <0.002).
Again, looking at the graphs this translates into a threeyear survival of around 0.6 vs 0 for a value >0.013.
Restaging with PET may also reveal previously undetected metastases after induction chemotherapy. This
was seen in 9/47 patients in one study,126 and in 10/56
in another.127
The only alternative would be to try to stage the
mediastinum with any of the variety of FNAB techniques, and, if that fails but there is a high index of
clinical suspicion of N2 disease, administer induction
chemotherapy to the patient. This would allow mediastinoscopy to be performed in an unscarred mediastinum, hopefully with a much higher sensitivity. However
this approach is unvalidated at present.
There is one important pitfall with the whole concept
of offering patients induction chemotherapy. The harsh
reality is that only 30–50% of patients will be downstaged and offered surgery, the rest going on to radical
radiotherapy. This means that their chemo-radiation
therapy will be sequential instead of concurrent, and
there is a consensus now that concurrent chemoradiotherapy is the standard of care in stage IIIA and
IIIB disease. The patient needs to be aware of this when
consent is sought for induction therapy.
OTHER PROGNOSTIC INDICATORS
Table 9.6 summarizes known or supposed prognostic
factors in surgically resected NSCLC. Cell type is not per
se a prognostic indicator,128 but as we have discussed
previously certain cell types (adenocarcinoma and large
116 Textbook of Lung Cancer
Table 9.6 Prognostic factors in surgically resected NSCLC
Prognostic factors
Tumor related
Host related
Environment related
Essential
T category
N category
Extracapsular nodal
extension
Superior sulcus location
Intrapulmonary
metastases
Histologic type
Grade
Vessel invasion
Tumor size
Molecular/biologic
markers
Weight loss
Performance status
Resection margins
Adequacy of mediastinal
dissection
Gender
Age
Radiotherapy dose
Adjuvant radiotherapy
Additional
New and
promising
Quality of life
Marital status
Published with kind permission of the editors and the UICC.129
cell poorly differentiated carcinoma) represent a risk
factor for presenting at a higher stage of disease. The
failure of screening to improve survival in a screened
population129 is in part due to so so-called overdiagnosis of indolent disease, proving that the term indolent
adenocarcinoma is not an oxymoron. Only performance
status equals stage in its impact on survival after all
treatment modalities. Others factors such as weight loss
and the presence of systemic symptoms are accepted as
important. Cell type, degree of differentiation, and vascular invasion may be significant, but reports vary depending upon stage and whether surgery was possible.130 Sex
is a prognostic indicator – females have better survival
independently of TNM stage and histology.131–133 Age
has an impact on treatment but is not an independent
variable. Certainly information on these factors should
be recorded and data presented in any report of results.
There is great interest in biologic markers in lung cancer,
and the hope that a panel of markers, including oncogenes and tumor suppresser genes, can provide an
independent, biologic method of anticipating outcome.
At present our knowledge of these markers is imperfect,
and there are still no markers that have translated into
the clinical setting because they do not discriminate in
a sufficiently robust way to allow therapeutic decisions
to be made.130 It is recommended that, where possible,
cryopreserved tissue from well-staged, surgical specimens should be stored for future studies.
On-going smoking is increasingly found to have an
effect on prognosis. All textbooks cite that the risk of
developing a second primary lung cancer following
successful management of NSCLC is 1% per patientyear, and this is doubled if the patient continues to
smoke. It is now starting to emerge that smoking can
interfere with the effectiveness of radiotherapy.134 Similarly, smoking can reduce the effectiveness of chemotherapy upregulation of the pathways targeted by
chemotherapy, thus inhibiting chemotherapy-induced
apoptosis.135 Smoking has a particularly strong inhibitory effect on tyrosine-kinase inhibitors (TKIs). The
BR.21 study on erlotinib in NSCLC showed that plasma
concentrations of the drug were around twice as high in
non-smokers and ex-smokers compared to current
smokers. This is attributed to a lack of induction of cytochrome P450 1 A isoforms by cigarette smoke as well as
a higher incidence of K-ras mutations in smokers resulting in faster plasma clearance of erlotinib in smokers.136
Genomics are starting to show promise in identifying
patients at high risk of recurrence.137 It remains to be
proven whether these patients will benefit from more
aggressive postoperative chemotherapy. Similarly,
ERCC1 is an enzyme that can repair the DNA damage
induced by cisplatin. When cisplatin-based adjuvant
chemotherapy was given to patients, those with tumors
that were ERCC1-negative had a significantly longer
survival than those with ERCC1-positive tumors.138
The SUV max also seems to indicate prognosis.139
When the SUV max is higher than 10, tumors tend to
be more likely to be poorly differentiated and to present
at a higher stage. For each stage, if the SUV max is
greater than the median value seen for that stage this
also tends to indicate a poorer prognosis – for example
Staging, classification, and prognosis 117
in stage IB NSCLC the four-year survival was 80% for a
SUV max lower than median, and only 66% when it
was higher than the median (p = 0.048). These values
were, respectively, 64% vs 32% (p = 0.028) for stage II
and 64% vs 16% (p = 0.012) for stage IIIA.
PROGNOSIS
The survival of patients with each stage of disease is
discussed in detail in the chapters on treatment in this
book, but a few comments are pertinent when considering staging. When reading the literature on the results
of treatment of lung cancer, especially surgical series,
the reader is reminded of two phenomena: what Shields
has termed ‘the diminishing denominator’,140 and the
impact of ‘stage migration’ or the Will Rogers effect.141
The diminishing denominator can give a false impression of the value of surgery in an advanced stage of lung
cancer by reporting only the results on patients found
to be within this stage at thoracotomy and surviving
complete resection. Other patients are ‘censored’ from
the analysis if found at thoracotomy not to fall into the
study population, if resection is not possible, if incomplete resection has been performed, and even if dying
after operation. The reported survival of patients in this
stage who survive complete resection gives little guidance to the clinician armed only with cTNM, and results
are further inflated by the use of actuarial survival statistics. Thus 300 patients with a presumptive advanced
stage (IIIA for example) may proceed to thoracotomy.
Eighty will be found to be in a lesser stage at thoracotomy, 60 will be technically irresectable (so-called open
and close thoracotomy), 95 will undergo an incomplete
resection (R1 or R2, as described in a previous section),
and 15 will die after surgery. The analysis is thus
restricted to the 50 patients who survived a complete
resection for the designated advanced stage. Therefore
the actuarial survival of the 10 who survive to five years
after complete resection is computed to be 20%. Whilst
this may impress the unwary, closer study reveals that
more patients (15) will die of such unwarranted surgery
than those in whom the prognosis is improved, at a cost
of 220 major operations and much morbidity.
Stage migration is an inevitable consequence of more
detailed staging. As one refines the group under study,
those eliminated usually cascade into the more advanced
stages, swelling their numbers, although a few will
prove to have less advanced stage disease. These new
recruits to the higher stages have a better prognosis
than the original patients do in that group, defined by
cruder staging techniques, and the prognosis of the
group is thus improved. The shifting populations are
evident in any study giving details of the results of
surgery based upon cTNM and pTNM. In one study,142
the number of patients who fell into the T1N0 category
fell from 349 to 264 when shifting from cTNM to pTNM
and, conversely, the number of patients with T3N0
disease rose from 109 to 147. This demonstrates the
improved staging achieved by thoracotomy. The fiveyear survival of patients based upon pTNM will always
be superior to that based upon cTNM, and this effect is
more pronounced in higher stage groups. In another
study,2 the five-year survival of T1N0 patients rose from
61% to 67%, a 10% improvement, when moving from
cTNM to pTNM, whilst survival of T3N0 patients rose
from 22% to 38%, an improvement of 87% in the survival of this group. These statistical realities are legitimate, but one must resist the temptation to attribute
the improved survival to the staging evaluation itself.
The prognosis of NSCLC is very variable in different
series. This is often a reflection of the rigor of both
the pre- and intra-operative staging of the cancer. If
pre-operative staging is not completely thorough there
will be 10–20% undetected N2 disease at thoracotomy,
provided that intra-operative staging has been done as
it should. However, there are still many centers that
do not routinely perform systematic nodal dissection
(which in itself is a term which is often abused). A telltale sign is the five-year survival of stage I NSCLC.
In properly staged patients this will be around 80%,
down to around 65% when staging is less rigorous.
Stage migration will then deploy its effects as stage
progresses.
When evaluating the benefits of any treatment for
lung cancer it is important to study each paper carefully, to determine the true denominator, and to note
all the tests used to define the population under study.
Thus the reader may be better able to place into context
the results reported in the following chapters.
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J Clin Oncol 1993; 11: 1757–62.
119. De Waele M, Hendriuks J, Lauwers P et al. Nodal status
at repeat mediastinoscopy determines survival in non-small
cell lung cancer with mediastinal nodal involvement, treated
by induction therapy. Eur J Cardiothorac Surg 2006; 29:
240–3.
120. De Leyn P, Stroobants S, De Wever W et al. Prospective comparative study of integrated positron emission tomographycomputed tomography scan compared with remediastinoscopy
in the assessment of residual mediastinal lymph node disease
after induction chemotherapy for mediastinoscopy – proven
stage IIIA – N2 non-small-cell lung cancer: a Leuven Lung
Cancer Group Study. J Clin Oncol 2006; 24: 3333–9.
121. Maas KW, Schramel FMNH. Repeat mediastinoscopy after
neoadjuvant therapy for non-small cell lung cancer. Lung
Cancer 2003; 39: 347.
122. Cerfolio RJ, Bryant AS, Winokur TS et al. Repeat FDG-PET
after neoadjuvant therapy is a predictor of pathologic response
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in patients with non-small cell lung cancer. Ann Thorac Surg
2004; 78: 1903–9.
Cerfolio RJ, Bryant AS, Ohja B. Restaging patients with N2
(stage IIIA) non-small cell lung cancer after neoadjuvant
chemoradiotherapy: a prospective study. J Thorac Cardiovasc
Surg 2006; 131: 1229–35.
Pöttgen C, Levegrün S, Theegarten D et al. Value Of 18F-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in non-small-cell lung cancer for prediction
of pathological response and times to relapse after neoadjuvant chemoradiotherapy. Clin Cancer Res 2006; 12: 97–106.
Hoekstra CJ, Stroobants SG, Smit EF et al. Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy
D-glucose positron emission tomography in patients with
locally advanced non-small-cell lung cancer. J Clin Oncol
2005; 23: 8362–70.
Hellwig D, Graeter TP, Ukena D et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction
therapy of locally advanced bronchogenic carcinoma. J Thorac Cardivasc Surg 2004; 128: 892–9.
Akhurst T, Downey RJ, Ginsgerg MS et al. An initial experience with FDG-PET in the imaging of residual disease after
induction therapy for lung cancer. Ann Thorac Surg 2002; 73:
259–66.
Brundage MD, Mackillop WJ. Lung cancer. In: Gospodarowicz MK, O’Sullivan B, Sobin LH, eds. Prognostic Factors in
Cancer, 3rd edn. Hoboken, New Jersey: John Wiley & Sons,
2006: Chapter 19.
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new biological predictors. Lung Cancer 1997; 17 (Suppl 1):
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presentation, management, and prognosis of patients with
non-small cell lung carcinoma. J Thorac Cardiovasc Surg
2000; 119: 21–6.
Cerfolio RJ, Bryant AS, Scott E et al. Women with pathological
stage I, II and III non-small cell lung cancer have a better
survival than men. Chest 2006; 130: 1796–802.
Browman GP, Wong G, Hodson I et al. Influence of cigarette
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cancer. N Engl J Med 1993; 328: 159–63.
Dasgupta P, Kinkade R, Joshi B et al. Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating
XIAP and survivin. PNAS 2006; 103: 6332–7.
Comis RL. The current situation: erlotinib (tarceva) and gefitinib (iressa) in non-small cell lung cancer. Oncologist 2005;
10: 467–70.
Potti A, Mukherjee S, Petersen R et al. A genomic strategy
to refine prognosis in early-stage non-small cell lung cancer.
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in non-small-cell lung cancer and cisplatin-based adjuvant
chemotherapy. N Engl J Med 2006; 355: 983–91.
122 Textbook of Lung Cancer
139. Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum
standardized uptake values on positron emission tomography
of a non-small cell lung cancer predict stage, recurrence and
survival. J Thorac Cardiovasc Surg 2005; 130: 151–9.
140. Shields TW. The significance of ipsilateral mediastinal lymph
node metastasis (N2 disease) in non-small cell carcinoma of
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141. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon: stage migration and new diagnostic techniques as a
source of misleading statistics for survival in cancer. N Engl
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142. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and
survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988; 96:
440–7.
FURTHER READING
Rami-Porta R, Ball D, Crowley J et al. on behalf of the International
Staging Committee. The IASLC Lung Cancer Staging Project:
proposals for the revision of the T Descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer.
J Thorac Oncol 2007; 2: 593–602.
Rusch VW, Crowley J, Giroux DJ et al. on behalf of the International
Staging Committee on Cancer Research and Biostatistics. The
IASLC Lung Cancer Staging Project: proposals for the revision
of the N Descriptors in the forthcoming (seventh) edition of the
TNM classification for lung cancer. J Thorac Oncol 2007; 2:
603–12.
Postmus PE, Brambilla E, Chansky K et al. on behalf of the International Staging Committee. The IASLC Lung Cancer Staging
Project: proposals for revision of the M Descriptors in the
forthcoming (seventh) edition of the TNM classification for
lung cancer. J Thorac Oncol 2007; 2: 686–93.
Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International
Staging Committee, Cancer Research and Biostatistics. The IASLC
Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M Descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification
of malignant tumors. J Thorac Oncol 2007; 2: 694–705.
Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International Staging Committee, Cancer Research and Biostatistics.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh)
edition of the TNM classification of malignant tumors. J Thorac
Oncol 2007; 2: 706–14.
10 Treatment of non-small cell lung cancer
10.1 Treatment of NSCLC: surgery
Robert J Korst
Contents Introduction • Historical summary • Stage I disease (T1–2N0) • Stage II disease (T1–2N1 and T3N0)
• Stage III disease • Stage IV disease • Special considerations • Palliative surgery • Summary
INTRODUCTION
Lung cancer is one of the leading causes of cancer death
worldwide. Approximately 80% of cases of newly diagnosed lung cancer are of the non-small cell type (NSCLC).
Unfortunately, a large percentage of these patients will
have inoperable disease on the basis of distant metastases (stage IV) or locally advanced disease (stage IIIB).
For the remaining patients with early stage disease (stage
I and II), as well as selected patients with locally advanced
disease (stage IIIA), complete surgical resection remains
the best hope for cure, provided that the operative risk
is tolerable.
Over the past four decades, several points regarding
the conduct of resection have become accepted as the
surgical management of NSCLC has evolved. First,
incomplete resections leaving either gross or microscopic disease behind will fail to cure the disease and
are rarely indicated in a palliative setting. Intraoperative
frozen section analysis should be employed frequently
to ensure negative margins. Second, general oncologic
principles should be followed, including the resection
of the tumor and surrounding normal lung (lobectomy
or pneumonectomy) with draining lymphatics and lymph
nodes. Third, the mediastinal lymph nodes should be
dissected to accurately stage the patient, and fourth, en
bloc resection of the tumor and surrounding structures
is desirable whenever technically possible.
Survival following surgical resection for NSCLC is
stage-dependent (Table 10.1.1). Despite the development of the principles mentioned above, less than 15%
of all patients can presently be expected to be cured of
their disease. This dismal figure underscores the need
for prevention as well as continued investigation into
better treatment options for patients with NSCLC.
HISTORICAL SUMMARY
Although non-anatomic pulmonary resection for lung
cancer had been reported in 1895, the first anatomic
lobectomy was performed by Davies in 1912. It was not
until the advent of an effective underwater drainage
system, however, that pulmonary resection could safely
be performed on more of a routine basis. Following a
report by Graham of the first pneumonectomy in 1933,
surgical resection became the treatment of choice for
lung cancer. Over the next several decades, various types
of anatomic lung resections continued to be described,
including segmentectomy, sleeve lobectomy, and pneumonectomy, as well as resection for superior sulcus
tumors.
Through the 1970s and 1980s, it became recognized
that despite radical resection with negative margins,
many patients with resected NSCLC ultimately died of
their disease, with the majority of recurrences being distant metastases. This fact was especially true for patients
found to have disease metastatic to the lymph nodes
(locally advanced disease) at the time of resection. As a
result of this observation, strategies which combine
treatment modalities (surgery, chemotherapy, and radiation) are becoming more popular and are the subject
of active investigation for nearly all stages of NSCLC. In
addition, recent breakthroughs in the use of adjuvant
chemotherapy following complete resection of NSCLC
are changing the postoperative management of patients
with this deadly disease.
STAGE I DISEASE (T1–2N0)
Patients with this early stage of NSCLC typically present
without symptoms and most are cured with primary
surgical excision. These tumors are usually peripheral in
location and are discovered on a routine chest radiograph.
These peripheral ‘coin lesions’ are mainly adenocarcinomas, or bronchioloalveolar carcinomas. Uncommonly,
a radiographically ‘occult’ tumor may be discovered.
Unlike the peripheral lesions, occult tumors are mainly
squamous in histology and patients may present with
hemoptysis. Not infrequently, occult tumors are detected
during screening bronchoscopy after a previous lung
124 Textbook of Lung Cancer
Table 10.1.1 Survival following resection for NSCLC by stage
(see text for references)
Stage
Stage I
Overall
T1N0M0
T2N0M0
Stage II
T1–2N1M0
T3N0M0
Chest wall invasion
Mediastinal invasion
Proximal bronchus
Stage III
N2
Clinically negative
mediastinum
Clinically positive
mediastinum
Five-year survival (%)
76
84
68
47
56
29
36
34
9
cancer resection,1 or in patients who have undergone
bronchoscopy as part of the work-up for another process, such as head and neck or esophageal cancer.
Complete surgical excision is the treatment of choice
for stage I NSCLC, provided the operative risk is acceptable. Patients should undergo preoperative pulmonary
function testing to assess lung reserve, as well as cardiac
evaluation if indicated from the patient’s history. The
operation of choice is anatomic lobectomy. Occasionally, a more extensive resection needs to be performed
when the location of the tumor is such that removal of
a single lobe is not adequate. When the tumor protrudes into the mainstem bronchus, sleeve lobectomy is
the procedure of choice to obtain negative bronchial
margins; however, a tumor involving the bronchus
intermedius usually requires a bilobectomy, while a
lesion more extensively involving the mainstem bronchus requires pneumonectomy. Pneumonectomy may
also be indicated in the rare circumstance when the
tumor is closely associated with the proximal, extrapericardial pulmonary artery. For upper lobe lesions that
invade the pulmonary artery to the lower lobe a vascular
sleeve resection can be performed, sparing the lower
lobe. Multiple series now suggest that sleeve resection for
central tumors produces results similar to that seen with
pneumonectomy from an oncologic standpoint.2,3
Although limited resections (wedge resection or segmentectomy) remain an option for patients with poor
pulmonary reserve, this practice should be avoided
whenever possible due to the higher rate of local recurrence and trend toward decreased long-term survival
when these lesser resections are performed, a standard
set by the results of The Lung Cancer Study Group
(LCSG) trial 821.4 In this study, patients with T1N0
NSCLC were randomized to undergo either lobectomy or
limited resection (wedge resection or segmentectomy).
Patients who underwent limited resection had a significantly higher rate of local recurrence than those in the
lobectomy group, with a survival difference approaching statistical significance. However, in the modern era
of lung cancer screening using computed tomography
(CT), many tumors are detected while still very small
(<1–2 cm). This observation, combined with the emergence of retrospective studies reporting excellent survival rates following limited resection for small, T1 lung
cancers,5,6 suggests that a trial similar to LCSG 821
should be initiated to reset the standard for these very
small, screen-detected tumors.
Most anatomic pulmonary resections for stage I NSCLC
have traditionally been performed using a posterolateral thoracotomy, during which a rib-spreading retractor is utilized. However, many surgeons now undertake
these resections using a complete, videothoracoscopic
(VATS) approach. The most commonly performed type
of VATS resection involves the creation of two thoracoscopy ports as well as a 6–8 cm ‘utility’ incision, the
latter used for dissection of the hilum as well as specimen
retrieval. Multiple published reports have suggested that
anatomic pulmonary resections can be performed safely,
and are oncologically sound when performed via VATS
for early-stage lung cancer.7,8 Additional benefits include
less postoperative discomfort as well as decreased length
of hospital stay with the VATS approach compared to
open thoracotomy. As a result, VATS lobectomy has
replaced its open counterpart for the management of
stage I lung cancer in many centers.
Although it has been suggested that mediastinal
lymph node dissection is unnecessary in patients with
very small T1 tumors, the vast majority of patients
undergoing resection for NSCLC should have this procedure routinely performed. Although this approach
has never definitively been shown to improve survival,
it is the only way to accurately stage a patient’s disease,
and adds very little time and morbidity to the operation.
In addition, approximately 16% of patients with peripheral T1N0 tumors where the primary tumor is less than
3 cm in size will have mediastinal node metastases.9
When resecting a right-sided tumor, the right paratracheal, pretracheal, subcarinal, and inferior pulmonary
Treatment of NSCLC: surgery 125
ligament nodes should be dissected. On the left, the
preaortic, aortopulmonary window, subcarinal and
inferior pulmonary ligament nodes are accessible. Given
the uncertain survival benefit of complete mediastinal
lymph node dissection for early-stage NSCLC, a randomized trial conducted by The American College of
Surgeons Oncology Group is currently underway to
investigate this question.
Operative mortality following pulmonary lobectomy
for all stages of disease should not surpass 2%, but should
be considerably less for patients with stage I disease.
Morbidity and mortality increase with higher stages of
disease and extended resections. Operative mortality
following pneumonectomy is near 6% in most series,
with some being even lower.10 The five-year survival for
patients with completely resected T1N0 lesions surpasses 80% in some reports, while this figure is reduced
to approximately 65% for T2N0 tumors. The overall
five-year survival for patients with completely resected
stage I NSCLC is approximately 75%.11 Recurrences
following complete resection for stage I NSCLC are
mainly in the form of distant metastases, as displayed
in Table 10.1.2.
No form of adjuvant therapy has traditionally been
recommended for patients undergoing resection of
stage I NSCLC. Recent randomized trials, however,
have suggested a small survival benefit for patients with
completely resected stage IB-III NSCLC. One of these,
the National Cancer Institute of Canada Clinical Trials
Group (NCIC) trial JBR.10, randomized 482 patients
with stage IB or II NSCLC to either surgery alone or
platinum-based adjuvant chemotherapy.13 Patients in
the adjuvant therapy arm enjoyed significantly longer
overall survival (69% vs 54% at five years) compared to
those who underwent surgery alone. Despite this, mature
results of the Cancer and Leukemia Group B (CALGB)
9633 trial, performed exclusively in stage IB patients, did
not support these findings. CALGB 9633 randomized
Table 10.1.2 Sites of first distant recurrence following
resection in 159 patients with stage I NSCLC lung cancer12
Site
Brain
Lung
Liver
Bone
Other
Disseminated
Number
51
20
14
11
8
5
344 patients with stage IB NSCLC to either surgery
alone or surgery followed by four cycles of paclitaxel/
carboplatin chemotherapy.14 No statistically significant
difference in survival was noted between groups. As a
result, the role of adjuvant chemotherapy in the management of patients with completely resected stage IB
NSCLC remains controversial. Many clinicians will recommend adjuvant chemotherapy to these patients if their
tumors appear to possess characteristics associated with
a poor prognosis (e.g. tumors greater than 5 centimeters,
vascular/lymphatic invasion). Adjuvant radiotherapy is
currently not recommended for patients with completely resected stage I NSCLC, in light of the results of
a meta-analysis showing that postoperative radiotherapy may increase mortality in these patients.15
Most clinicians would agree that patients require follow-up after resection for NSCLC; however, the nature
of the follow-up regimen remains controversial. Given
the poor prognosis associated with recurrent metastatic
disease in patients who have undergone resection of
NSCLC, follow-up regimens should probably be geared
toward the detection of second primary lung cancer
(SPLC), which occurs with an annual cumulative incidence of 2% per patient/year of follow-up.16 Recent published data suggest that serial computed tomography
(CT) of the chest has the ability to detect SPLC while still
in its early stages;17 however, the cost-effectiveness of
this approach has not yet been substantiated.
STAGE II DISEASE (T1–2N1 AND T3N0)
N1 disease
Patients with T1–2N1 NSCLC represent a small subset
in the spectrum of this disease, usually comprising less
than 10% of patients coming to surgery. As with stage
I, the majority of patients can be effectively treated with
lobectomy, although about a third will require pneumonectomy, mainly due to involved hilar lymph nodes
adherent to the pulmonary artery or major bronchi.
Similar to stage I disease, it is important to perform
a thorough mediastinal lymph node dissection in this
group of patients, especially since there is a higher incidence of occult N2 disease. Recurrence following complete resection for T1–2N1 NSCLC is common, with
five-year survival rates approaching only 45%.18 As
with stage I, the most common form of recurrence is
distant metastatic disease, especially if the tumor is an
adenocarcinoma. Patients enjoying a better prognosis
tend to be those with small primary tumors, squamous
histology, and only one involved lymph node.
126 Textbook of Lung Cancer
T3N0 disease
Chest wall involvement
T3 tumors invading the chest wall are readily amenable
to surgical resection. As a general guideline, one rib
above and one below the gross margin of the tumor
should be taken to ensure negative margins. Although
en bloc resection is desirable and should be achieved
whenever possible, discontinuous resection can be done
when absolutely necessary as long as meticulous attention is paid toward documenting margins. It currently
remains controversial whether a complete chest wall
resection, including ribs, is necessary for tumors invading only the parietal pleura. A parietal pleurectomy with
negative deep margins may be sufficient, but should be
used with extreme caution.
Following resection, the issue of chest wall reconstruction needs to be addressed. The first question regarding
this is whether the chest wall reconstruction is really
necessary, and this usually depends on the assessment
of chest wall stability. After resection of short segments
of one or two ribs, or up to three posterior segments
under the paraspinous muscles or scapula, reconstruction is not usually necessary. When reconstruction is
undertaken, the marlex/methylmethacrylate sandwich
technique readily restores stability and prevents the flail
chest phenomenon during breathing (Figure 10.1.1). A
Gore-Tex patch, stretched tightly, has also been used
with acceptable results. Mortality following chest wall
resection is low, but is related to the size and location
of the defect in the chest wall, the amount of lung
resected, and the technique of reconstruction.
Factors which affect long-term survival following resection of these tumors are the extent of chest wall involvement, the ability to completely resect the tumor, and
the presence or absence of lymph node involvement.
The overall five-year survival of patients with T3N0M0
tumors invading the chest wall undergoing complete en
bloc surgical resection is approximately 50–60%.19
Patients with a T3N0M0 tumor that involves only the
parietal pleura have a better prognosis than those where
the tumor invades into muscle and ribs.
Tumors invading the mediastinum
Tumors invading the mediastinal pleura, fat, nerves,
and pericardium, but not the major mediastinal vessels
or organs, represent another subset of the T3 classification. These patients have a notoriously poor five-year
survival following surgical resection alone. In part, this
poor survival is due to the high likelihood of mediastinal
node metastases and the low rate of complete resection
Figure 10.1.1
Stage IIB NSCLC (T3N0M0) invading the chest wall. (a) Chest CT
revealing a large lung mass invading the chest wall. Cervical
mediastinoscopy was negative, while transthoracic needle
aspiration revealed large cell carcinoma.(b) Chest radiograph
following right upper lobectomy, mediastinal lymph node
dissection, and resection of the involved chest wall. Stable
reconstruction was achieved using a marlex mesh and methylmethacrylate prosthesis.
attained when the mediastinum is invaded. Additionally, even when these tumors are completely resected and
the mediastinal nodes are negative, patients with T3
disease invading the mediastinum have a worse prognosis when compared to other types of T3 tumors.20
Due to the high frequency of N2 disease, patients
with evidence of mediastinal invasion on CT scan should
undergo cervical mediastinoscopy to rule out nodal
involvement or T4 disease. If N2 disease is detected,
induction (neo-adjuvant) therapy may offer these
patients a better chance at long-term survival, if surgical resection is being considered. If there is no N2, N3,
or T4 disease found at mediastinoscopy, these patients
can undergo primary surgical resection with five-year
survival rates of 30% if complete resection can be
performed.20
Treatment of NSCLC: surgery 127
Tumors in proximity to the carina
Tumors within 2 cm but not involving the main carina
comprise another subset of T3 tumors. As with the
other T3 tumors, patients with these proximal bronchial lesions are candidates for surgical resection. Technical considerations when resecting tumors involving
the main bronchi pertain to the extent of resection,
intraoperative airway management, and techniques of
sleeve resection. Small, solitary squamous cell lesions
confined to the left main bronchus with no invasion
through the bronchial wall can very occasionally be
handled with excision of the main bronchus alone, with
total lung preservation and primary anastomosis. However, frequently these lesions are multiple and are best
treated with endobronchial laser or radiation (brachytherapy). If resection is being considered for a solitary,
proximal lesion on the right, however, usually a pneumonectomy or right upper lobe sleeve resection is
required due to the close proximity of the right upper
lobe orifice to the main bronchus. Sleeve lobectomy (vs
pneumonectomy) is the preferred resection when possible for tumors extending into the orifice of the lobar
or mainstem bronchus.
When invasion into peribronchial tissues or N1 disease
is present, sleeve lobectomy can be attempted if the disease is limited, but pneumonectomy is usually required
for extranodal spread. If the tumor extends very close
to the carina, resection of the main bronchus flush with
the trachea may be required to encompass the tumor
with negative margins. In this case, stapling of the bronchial stump may not be possible and a hand-sewn closure
may be required. If not, tracheal sleeve pneumonectomy
is the procedure of choice.
Airway management and ventilation are of paramount
importance when the proximal bronchi are resected.
Standard double lumen endobronchial tubes or endobronchial blockers with single lung ventilation can be
utilized for sleeve resections of the main bronchi. Tracheal sleeve pneumonectomy requires ventilation of the
distal remaining lung. This problem can be handled in
several ways, including passage of a thin, single lumen
endotracheal tube past the anastomotic site, jet ventilation into the distal lung, or in-field ventilation through
the open bronchus using sterile ventilator tubing.
Factors which adversely affect long-term survival following resection include peribronchial extension of the
tumor and the presence of N2 nodal metastases. Overall five-year survival following complete resection for
tumors within 2 cm of the carina is currently reported
to be 36%;21 however, patients with tumor confined to
the main bronchi with no invasion of peribronchial tis-
sues or associated N2 disease have been reported to have
a five-year survival of 80% in one series.22 Patients with
T3 tumors approaching the carina associated with N2
nodal metastases separate from the primary tumor (‘true’
N2) have a negligible five-year survival. Patients with
N2 disease which is present by virtue of direct spread
from the primary tumor, however, remain surgical candidates. Therefore, it is mandatory to perform cervical
mediastinoscopy prior to an attempted resection to identify those patients with ‘true’ mediastinal nodal disease
who would receive no benefit from primary surgical
resection. If N2 nodes are identified at cervical mediastinoscopy, induction therapy may be of value, but this
awaits clinical trials.
The role of adjuvant therapy for stage II NSCLC has
evolved similar to that for stage I disease. The previously mentioned Canadian trial13 demonstrated a small,
but significant survival benefit of adjuvant, platinumbased chemotherapy for patients with stage II NSCLC
who have undergone complete surgical resection.
Although no clear survival benefit has been noted,
patients with incompletely resected tumors or those
with mediastinal nodal metastases should receive postoperative radiation therapy to decrease the incidence of
local recurrence.15 Intraoperative implantation of radioisotopes may potentially be of some benefit for those
patients who undergo an incomplete resection. The role
of induction chemoradiotherapy in poor prognostic T3
tumors (N2 disease, full thickness chest wall invasion)
is now being investigated.
STAGE III DISEASE
Stage IIIA (T3N1) disease
T3 tumors with associated ipsilateral bronchopulmonary or hilar lymph node involvement comprise the first
category of stage IIIA disease. The preferred treatment
is, again, complete resection via lobectomy with mediastinal lymph node dissection. The previously mentioned issues concerning N1 disease apply in this setting
as well.
Stage IIIA (N2) disease
The decision to perform primary surgical resection for
patients with N2 disease requires careful preoperative
selection, since the overall five-year survival for patients
with N2 disease undergoing surgical resection alone is
a mere 5–15%. Those with only single station, intracapsular nodal disease, T1 primary tumors, and ‘clinically’
negative mediastinums by mediastinoscopy or CT
128 Textbook of Lung Cancer
scanning are reported to enjoy a five-year survival of
approximately 30% following complete surgical resection, compared to less than 10% for those with ‘bulky’
N2 disease identified preoperatively and those with
associated T3 primary tumors.23 Patients with left upper
lobe tumors and N2 disease confined to level 5 or 6
have the best prognosis of all, with five-year survival
rates as high as 42% when completely resected.24 Unfortunately, patients with ‘minimal’ N2 involvement for
whom primary surgery is beneficial represent a small
fraction of all patients with N2 disease, and clearly further therapeutic advances need to be made for those
patients with bulky, ‘clinical’ N2 disease.
Although adjuvant radiotherapy provides no survival
benefit compared to surgery alone, a reduction in local
recurrence is seen.15 Unfortunately, 80% of patients
undergoing surgical resection for NSCLC with N2 nodal
disease recur at distant metastatic sites (especially brain),
suggesting that further systemic therapy is needed to
improve survival.
Postoperative, adjuvant chemotherapy has been used
in an attempt to improve survival for patients with
resected stage IIIA (N2) NSCLC. Until recently, however, this strategy has not been shown to be of significant benefit in the adjuvant setting. In this regard, a
meta-analysis of 52 previously conducted randomized
trials of adjuvant chemotherapy for completely resected
NSCLC suggested only a small advantage (5% at five
years) of cisplatin-based chemotherapeutic regimens
given in the adjuvant setting.25 As a result of the metaanalysis, the International Adjuvant Lung Cancer Trial
(IALT) randomized 1867 patients with completely
resected NSCLC to either observation or cisplatin-based
chemotherapy.26 Of these, nearly 40% had stage III disease. The overall survival rate across all stages was
significantly higher in the chemotherapy group (44.5%
at five years) versus the surgery alone group (40.4%),
representing a small, but significant advantage. Subgroup analysis, however, revealed that the patients
which received the most benefit were those with stage
III disease.
Data from Japan has suggested a significant survival
advantage for patients receiving oral tegafur plus uracil
(UFT) following complete surgical resection of NSCLC
compared with surgery alone. Although these results
have not been reproduced in all studies using this strategy, and no data exist outside of Japan, a recent metaanalysis including data from 2003 patients demonstrated
that adjuvant therapy with UFT does indeed provide a
survival advantage.27 However, this agent is not available for use in the USA.
Multimodality therapy
Induction chemotherapy emerged as an option for
patients with N2 disease after it became clear that only
a minority of these patients benefit from surgical resection alone and that preoperative radiation therapy has
no effect on survival. To date, many phase II trials of
induction chemotherapy or chemoradiation therapy
both with and without postoperative adjuvant therapy
have been reported. Preoperative chemotherapy, such
as the MVP regimen utilized at The Memorial Sloan
Kettering Cancer Center and The University of Toronto,
has shown survival benefit in this group of patients
when compared to historical controls.28,29 The majority
of reports, however, deal with preoperative chemoradiation and essentially mirror the results of the previously mentioned induction chemotherapy trials.
Although hundreds of patients have been enrolled in
such phase II studies, no real effect of the treatment can
be assessed for two reasons. First, the chemotherapy and
radiotherapy protocols have varied widely from one trial
to the next, as did the extent of preoperative staging,
making the results difficult to interpret. Second, patients
in these phase II trials are not randomized, and therefore no control groups exist other than historical data.
Three small phase III trials do exist comparing induction chemotherapy and surgical resection to surgical
resection alone in the treatment of patients with N2 disease (Table 10.1.3). Although different chemotherapy
protocols were utilized and the numbers were small,
the survival rates were significantly higher in two of
these studies30,31 in the chemotherapy groups compared
to the control arms, with the third showing a similar
trend.32 Surprisingly, in all three studies, the rate of
complete resection was no different in the treatment
arms compared to the control arms. These three small
phase III trials and the phase II trials that have been
matched to historical controls seem to suggest an improvement in survival for these patients, at least with induction chemotherapy, but the results of current, larger
phase III trials for N2 disease will be important, especially since a French trial suggested no benefit of induction chemotherapy for patients with N2 disease.33
Treatment-related mortality in the induction trials
has resulted from the chemotherapy, radiation therapy,
and surgery, or a combination of these modalities. Most
trials report a treatment-related death rate in the range
of 5–15%. Chemotherapy-related deaths are dependent
on the specific agent and dose, as well as the immunosuppressive effects of these drugs. Morbidity following
induction chemotherapy can be manifested in several
organ systems. Pulmonary function studies should be
Treatment of NSCLC: surgery 129
Table 10.1.3 Three phase III trials of induction chemotherapy for NSCLC with ipsilateral mediastinal lymph node metastases
Author
Number of patientsa
Chemotherapy agents
Percent resectablea
Median survivala,b
Pass32
13/14
85/86
29/16
Roth30
26/32
61/66
64/11
Rosell31
30/30
Cisplatin
Etoposide
Cisplatin
Etoposide
Cyclophosphamide
Mitomycin
Ifosfamide
Cisplatin
85/90
26/8
a
Induction chemotherapy followed by surgery group/surgery alone group.
Overall median survival in months.
b
repeated after induction chemotherapy to assess the
pulmonary effects of such drugs as mitomycin and cyclophosphamide, which appear to be toxic to both the pulmonary endothelium and epithelium, resulting in impaired
diffusion of gases. Cardiac toxicity of doxorubicin should
be assessed with a myocardial imaging study following
the administration of this drug, and creatinine clearance should be measured following treatment with cisplatin and the vinca alkaloids if the serum creatinine
level has become elevated. These chemotherapyspecific toxicities demand that the induction chemotherapy patient be monitored more closely in the
perioperative period to prevent failure of an already
compromised organ system.
Bronchial obstruction needs to be relieved prior to
the administration of cytotoxic drugs to avoid postobstructive pneumonia and death during leukopenic
events. This can be handled either with radiation therapy or endobronchial resection techniques/stents. Radiation therapy is also associated with toxicity that, when
given in combination with chemotherapy and surgery,
can result in the patient’s demise. Examples include the
enhanced pulmonary toxicity when radiation therapy is
used with mitomycin, the myocardial damage when
used with doxorubicin, and the higher incidence of
bronchopleural fistula in irradiated patients following
pulmonary resection.
Morbidity and mortality from the surgical procedure
itself can be minimized by careful anesthetic management,
close perioperative monitoring of cardiac, pulmonary,
and fluid status, as well as some specific interventions
to treat certain toxicities. For example, mitomycin pulmonary toxicity appears to be exacerbated by high inspired
oxygen fractions. Therefore, the lowest possible oxygen
concentration in the inspired gases should be used,
while maintaining adequate oxygenation of the blood.
Perioperative corticosteroids can effectively treat both
mitomycin and radiation-induced pulmonary toxicity
as well. Tight control over fluid administration should
be realized, thereby avoiding pulmonary edema as a
result of impaired cardiac and renal function, but still
maintaining enough volume for adequate end organ
perfusion.
Finally, the role of surgical resection itself for patients
with N2 disease was addressed by the results of the
North American Intergroup 0139 Trial.34 In this study,
patients who received induction chemoradiotherapy were
randomized to either surgical resection or continued
radiotherapy without an attempt at resection. Although
the initial survival analysis revealed no difference in
overall survival, progression-free survival was significantly prolonged in the patients undergoing resection.
This observation, combined with the higher treatmentrelated mortality in the surgical arm (mainly in pneumonectomy patients), suggests that if perioperative care
can be optimized, especially for patients undergoing
pneumonectomy, surgical resection may offer these
patients the best chance for long-term survival.
Stage IIIB (T4 or N3) disease
Patients with this stage of locally advanced NSCLC are
considered inoperable. Exceptions do exist, however,
and generally apply to selected patients with T4 disease. Tracheal sleeve pneumonectomy can be considered
for the occasional patient with endobronchial tumor
involving the main carina; however, involvement of
peribronchial tissue or lymph nodes should preclude
this procedure. The five-year survival for patients with
T4 (carina) N0 tumors undergoing tracheal sleeve
pneumonectomy has been reported to approach 20%;
however, the operative mortality from this procedure
can be as high as 15–30%.35,36
130 Textbook of Lung Cancer
It is presently debated whether subclavian artery
invasion represents T3 or T4 disease, but apical tumors
invading this vessel should be resected if a complete
resection can be performed. This vessel can be reconstructed either primarily or with a synthetic graft. Again,
for patients to benefit from such an extended resection,
node-negative status should be confirmed prior to
resection using cervical mediastinoscopy.
Sporadic reports exist concerning aortic resection for
T4 tumors with an occasional long-term survivor,37 but
no significant survival benefit has been demonstrated in
these patients. Similarly, although technically possible,
resection of tumors involving the vertebral body has
not been shown to provide a survival advantage.38 These
last two scenarios should be considered for clinical protocols involving induction chemo(radio)therapy, followed by reassessment. If a significant response is seen,
resection can be considered in the protocol setting.
If, at thoracotomy for presumed T3 disease, an incomplete resection is all that can be done due to involvement
of mediastinal organs or vessels (T4), partial resection
with implantation of radioisotopes combined with postoperative external beam radiation may provide some
benefit with up to a 10% salvage rate, but has never been
compared to primary (external) radiotherapy as an alternative approach.
Although technically considered to be T4 disease, patients
with multiple lesions in the same lobe (‘satellite’ lesions)
constitute a unique subgroup of stage IIIB NSCLC. Following anatomic resection, patients with T4 disease due
to the presence of satellite lesions enjoy appreciably
longer survival than other subgroups of stage IIIB lung
cancer.39 As a result, when satellite lesions are detected
preoperatively, patients should undergo lobectomy and
mediastinal lymph node dissection whenever possible.
STAGE IV DISEASE
Surgery for stage IV disease is limited to young, healthy
patients with a solitary site of metastatic disease, and an
easily resectable primary tumor contained within the
chest. An exhaustive search should be carried out prior
to consideration of resection of stage IV disease, looking
for other sites of metastatic disease not clearly evident
by history and physical examination. Positron emission
tomography (PET) may emerge as a useful test for this
purpose, and all suspicious lesions should be biopsied
to obtain a histologic diagnosis. Solitary bone, liver, and
skin metastases are rare, but the following sites warrant
mentioning due to their more frequent occurrence.
Brain metastases
Approximately one-third of patients with NSCLC and
brain metastases present initially with neurologic symptoms, with the lung cancer being found only after a
search for the primary tumor has been carried out. In
addition to the patients with stage IV disease at presentation, recurrences following resection of NSCLC are
most commonly distant metastases, and of these, nearly
30% are located in the brain. It is now accepted that
patients with solitary brain metastases from NSCLC are
best treated by resection of the brain lesion followed by
postoperative whole-brain radiation therapy. Using this
strategy, five-year survival in these patients should
approach 20%. Even if a cure is not obtained, survival
is prolonged and quality of life improved when compared to a non-surgical approach.40
When patients present with NSCLC and a single, synchronous brain metastasis, and both lesions are resectable, the brain tumor should be resected prior to the
primary tumor, provided that no urgent intrathoracic
process is occurring (i.e. massive hemoptysis). This strategy is based on the observation that recovery from
intracranial surgery is less intensive than that from thoracotomy. If the resectability of either lesion is in question
prior to surgery, one should approach the questionable
lesion first to ensure that both lesions can be completely
resected prior to undertaking a potentially unnecessary
operation. If a brain metastasis is found but a search for
the primary tumor is negative, one should proceed with
resection of the intracranial tumor.
Adrenal metastases
Solitary metastases to the adrenal glands are being diagnosed with greater frequency due to routine scanning of
the upper abdomen with newer generation, spiral CT
scanners. The utility of adrenalectomy for a solitary NSCLC
metastasis has been reported in small case series and individual reports. In a relatively large series of patients with
solitary adrenal metastases (23 patients), an overall survival of 23.3% was obtained after resection of the lung and
adrenal lesions.41 Patients with metachronous lesions and
a disease-free interval of more than six months received
the greatest benefit from this aggressive approach.
SPECIAL CONSIDERATIONS
Superior sulcus tumors
Superior sulcus tumors are apical lung cancers that are
at least T3 by definition, since they invade the chest
wall. In addition to chest wall invasion, these tumors
Treatment of NSCLC: surgery 131
also invade neighboring vital structures including the
brachial plexus, vertebral body, and subclavian vessels.42 Presenting symptoms almost always include pain
in the shoulder radiating down the upper, inner aspect
of the arm (T1 nerve root) as well as into the ulnar distribution in the hand (C8 nerve root). Patients may also
have Horner’s syndrome, resulting from invasion of the
stellate ganglion in the sympathetic chain, a condition
which implies advanced local invasion.
Treatment of these lesions is by surgical resection. Prior
to resection, mediastinal node metastases must be ruled
out using cervical medastinoscopy owing to the poor
prognosis of these patients after resection when N2 disease is present. Several different operative approaches
have been described, depending on whether the tumor
invades the anterior or posterior aspect of the first rib.
It is agreed that posterior lesions should be approached
through a posterolateral thoracotomy extending up to
the neck, as described by Shaw et al.42 This enables the
scapula to be lifted off the chest wall and access to the
apex of the hemithorax from outside the chest wall.
Tumors that appear to invade more anteriorly can be
approached through any number of anterior approaches,
the most common being an L-shaped transcervical incision43 and the hemiclamshell approach.44 The advantage of the hemiclamshell incision is easy access to the
pulmonary hilum for the performance of lobectomy
with mediastinal lymph node dissection. In addition to
lobectomy, the standard operation for superior sulcus
tumors includes the resection of at least the first rib, the
transverse processes of the vertebral bodies associated
with each resected rib, and the T1 nerve root.
Following complete resection, the five-year survival
of patients with superior sulcus tumors approximates
30%. Unfortunately, many patients do not have a complete resection due to invasion of the previously mentioned vital structures. To address this issue, the
Southwest Oncology Group Trial 9416 administered
induction chemoradiotherapy in a phase II design to
111 patients with superior sulcus tumors.45 Of the 83
patients who underwent subsequent thoracotomy, 92%
had a complete resection. The five-year survival was
44% for all patients and 54% for those who underwent
a complete resection. Given these encouraging results,
induction chemoradiotherapy followed by surgical
resection has become the standard for patients with
superior sulcus tumors in most centers.
Multiple primary tumors
It is not uncommon for patients to present with more than
one lung malignancy. Either these tumors represent
synchronous primaries or one lesion is a metastasis
from the other. When the tumors are of different histologies, the diagnosis of synchronous primary lung
cancers is made. If the lesions are of the same histology,
cervical mediastinoscopy should be routinely performed
because if positive mediastinal nodes are discovered,
the chance of one lesion being metastatic rises. Pathologic evidence of two separate primary tumors is the
presence of carcinoma in situ in both lesions; however,
this information is rarely present at the time of surgery.46 In many equivocal instances, the ‘benefit of the
doubt’ is given to the patient and the tumors are labeled
as synchronous primaries.
Optimal oncologic treatment for patients with synchronous primary NSCLC is two staged lobectomies for
contralateral tumors, and bilobectomy or pneumonectomy for ipsilateral tumors. In cases where the resectability of one lesion is questioned, the questionable tumor
should be resected first. If the patient’s lung function
permits only one lobectomy, a decision must be made
as to which lesion will be resected via lobectomy and
which will be approached with a limited resection.
Generally, the limited resection should be reserved for
the smaller, squamous cell cancers, since these are less
likely to spread via lymphatics than adenocarcinomas.
Limited resection should consist of segmentectomy
instead of wedge resection whenever possible. A third
option is to perform multiple segmentectomies in
patients with limited pulmonary reserve.
Bronchioloalveolar carcinoma
Bronchioloalveolar carcinoma represents a unique subtype of NSCLC which appears to be increasing in incidence. This increase may be real, or may represent
heightened recognition of this variant by pathologists.
This disease seems to occur mainly in elderly women
with a negligible smoking history. Three distinct clinical
scenarios seem to be able to arise with BAC.
First, and most common, patients may present with
a solitary pulmonary nodule. These lesions are usually
picked up by routine chest radiograph and are asymptomatic. Mediastinal lymph nodes are uncommonly
involved. Treatment is lobectomy and long-term survival seems to be excellent.
Second, some patients with BAC will present with
small lesions that resemble infiltrates, termed groundglass opacities (GGOs). These lesions are not visible on
standard chest radiography and are increasingly being
detected on screening, low-dose, computed tomography
(Figure 10.1.2). In addition, they tend to be multiple
and also recur frequently following resection, especially
132 Textbook of Lung Cancer
be used to confirm negative margins, and when positive, further tissue should be resected. A positive bronchial resection margin can be treated by reresection of
the bronchus and performance of a bronchoplastic procedure, or even pneumonectomy if necessary. Carcinoma
in situ remaining at the bronchial stump may not adversely
effect prognosis,49 but this has not conclusively been
proven and even this early disease should currently be
resected.
Figure 10.1.2
CT of the chest revealing a ground-glass opacity, a lesion not
visible on chest radiography. Biopsy revealed bronchioloalveolar
carcinoma.
in areas of lung distant from the primary tumor (multifocal BAC). This implies that this form of BAC may be
spread throughout the airway by means of aerosol.
Standard treatment is presently resection, but care must
be given to the conservation of lung, since these tumors
tend to recur with great frequency. Whether or not
these patients benefit from repeated attempts at resection as opposed to observation is currently unknown.
Third, a minority of patients will present with a lobar
infiltrate representing lobar replacement with BAC.
Radiologic studies give the appearance of dense consolidation that has arisen over a period of weeks to
months. This presentation of BAC carries a poor prognosis, with many patients recurring with widespread
infiltrative disease and respiratory failure following
resection. For this reason, it is unknown whether these
patients benefit at all from resection.
Prognosis in patients with BAC seems to correlate
most with the radiographic appearance of the lesion(s).47
Other factors that have been implicated as poor prognosticators in some studies, but not in others, are a
mucinous histology and the presence of vascular invasion. The effect of chemotherapy remains unknown in
patients with BAC. Isolated reports of successful double-lung transplantation for recurrent BAC with longterm survivors have been described, but this procedure
remains investigational in the treatment of BAC.48
Positive resection margins
Every attempt should be made intraoperatively to resect
with negative margins. Frozen section analysis should
Completion pneumonectomy
Patients with locally recurrent NSCLC or second primary tumors following resection should be evaluated in
a similar fashion to those who present with their first
cancer. If there is no evidence of distant disease and the
remaining pulmonary function is adequate, these patients
should be considered for completion pneumonectomy.
Completion pneumonectomy is a technically challenging operation, requiring that the surgeon review
the previous operative notes to learn about the anatomy
and potential hazards of the reoperation. Mobilization
of the lung should be performed intrapleurally whenever possible to avoid excessive bleeding and damage
to neighboring structures. Intrapericardial ligation of
the vessels also serves to reduce the chance of hemorrhage. Intraoperative use of topical hemostatic agents as
well as efficient coagulating devices is helpful.
Operative mortality following completion pneumonectomy is in the range of 10%, slightly higher than
that seen with standard pneumonectomy.50 Postoperative morbidity is in the 20% range, with a significant
proportion of complications related to bleeding. Longterm survival in patients with NSCLC who undergo this
operation is approximately 30%, indicating that completion pneumonectomy is a worthwhile procedure in
selected patients.50
PALLIATIVE SURGERY
Pleural disease
Patients with diffuse pleural disease (T4) typically present with dyspnea and a pleural effusion. The diagnosis
should be confirmed and is most easily obtained by placement of a chest tube and examining the fluid for malignant cells. Once the diagnosis of a malignant pleural
effusion is confirmed, pleurodesis with sterile talc or other
pleural irritant is warranted to prevent recurrence.
If a patient presents with obvious end-stage metastatic disease and a new pleural effusion, a simple thoracentesis may relieve some of the dyspnea and allow
Treatment of NSCLC: surgery 133
the patient to be discharged home to their family. This
strategy should be reserved for patients who are anticipated to expire within the next few weeks.
Thoracoscopic exploration is warranted in the following selected instances. First, if the fluid is negative
for malignant cells and a malignant diagnosis will affect
the treatment plan. Second, if the lung fails to re-expand after drainage of fluid, thoracoscopic intervention
may be necessary just for the strategic placement of
chest tubes to facilitate expansion, and third, after a
poor result from a bedside pleurodesis as manifested by
the rapid reaccumulation of fluid. The role of formal
decortication is very limited in these patients due to
their extremely short life expectancy.
Endobronchial disease
Unresectable endobronchial tumor is a not infrequent
occurrence in patients with NSCLC. Typically, these
patients may present with airway occlusion with distal
pulmonary collapse and pneumonia, dyspnea, and
hemoptysis. The endobronchial disease may be the
manifestation of either the primary tumor extending
proximally in the airway or of nodal disease eroding
into the proximal tracheobronchial tree. Many times
the patient has had a previous pulmonary resection and
has a recurrence at the bronchial stump.
Adequate palliation can be obtained using either laser
or stenting techniques. For bleeding lesions, laser therapy
with the Nd:YAG laser and electrocoagulation are the
preferred approaches. Obstructing lesions can be treated
using either approach. A combination of debridement
through a rigid bronchoscope and laser treatment to obtain
hemostasis is often an effective technique. Care must be
taken not to blindly laser tumor in the proximal segmental bronchi as perforation can occur. Recently, photodynamic therapy (PDT) has been used in cases of
endobronchial NSCLC. This technique needs further evaluation before it can be routinely used for this disease.
Endobronchial stents are typically of the silicone rubber or self-expanding wire variety. The type of disease
most amenable to stenting is that which is associated with
a patent airway both proximal and distal to the obstructing lesion. Silicone stents are deployed using a rigid
bronchoscope, while self-expanding wire stents are
typically deployed over a guidewire using fluoroscopy
as a guide. Silicone stents are removable, while wire stents
are not; however, the indications for stent removal in
patients with inoperable NSCLC are few. A recent development has been the introduction of an expandable,
silicone stent which is removable. However, its application for lung cancer patients remains undefined.
SUMMARY
Surgery for NSCLC has evolved considerably over the
past 50 years. Resection is currently indicated for patients
with early stage (I, II, selected IIIA) disease, while chemotherapy and radiation are used for more advanced
disease. The mainstay of surgical therapy remains anatomic lobectomy with complete mediastinal lymph node
dissection, provided the patient can physically tolerate
this procedure. Care must be taken to ensure a complete
resection since incomplete resections do not cure.
Recent developments in the care of resectable lung
cancer patients include the adoption of adjuvant chemotherapy for patients with completely resected stage
II–III disease, the importance of surgical resection in
the multimodal therapy regimen for stage IIIA NSCLC,
as well as the use of induction chemoradiotherapy for
superior sulcus tumors. With increasing use of lowdose, screening CT for individuals thought to be at high
risk for the development of lung cancer, the discovery
of much smaller tumors is increasing in frequency, and
further studies are necessary to establish the standard of
care for these lesions.
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48. Etienne B, Bertocchi M, Gamondes J-P et al. Successful doublelung transplantation for bronchioloalveolar carcinoma. Chest
1997; 112: 1423–4.
49. Snijder RJ, de la Riviere AB, Elbers HJJ, van den Bosch JMM.
Survival in resected stage I lung cancer with residual tumor at
the resection margin. Ann Thorac Surg 1998; 65: 212–16.
50. Gregoire J, Deslauriers J, Guojin L, Rouleau J. Indications, risks
and results of completion pneumonectomy. J Thorac Cardiovasc Surg 1993; 105: 91.
10.2 Treatment of NSCLC: radiotherapy
Merideth MM Wendland, William T Sause
Contents Introduction • Early disease • Locally advanced disease • Superior sulcus tumors
• Altered fractionation radiation therapy • Toxicity and patient selection • Prophylactic cranial irradiation
• Palliative therapy • Conclusion
INTRODUCTION
In the USA, lung cancer is the number one cause of
cancer-related death for both men and women.1 In
2005, an estimated 175 000 new cases of lung cancer
will be diagnosed and roughly 159 000 deaths from
lung cancer will occur. Approximately 80% of patients
with primary lung cancer are diagnosed with non-small
cell lung cancer (NSCLC).2
Radiation therapy remains a valuable therapeutic
modality in the treatment of NSCLC. In early stage disease, definitive radiation therapy may be employed for
patients who refuse or are medically unfit to undergo
surgical resection. Radiation therapy may also be used
as adjuvant therapy for patients with incomplete resection or node-positive disease. At initial presentation, many
patients who receive a diagnosis of NSCLC have locally
advanced disease. Historically, these patients were treated
with primary thoracic radiation therapy with poor longterm survival rates secondary to both progression of
local disease and development of distant metastases.
With the goal of improving clinical outcomes, multiple
permutations of combined-modality therapy for locally
advanced NSCLC have been investigated. The optimal
treatment for locally advanced NSCLC continues to
evolve, but combined-modality therapy has led to
improved survival rates versus treatment with radiation
alone, and is the standard of care.
EARLY DISEASE
In general, patients with stage I and II disease who are
medically fit undergo definitive surgical resection with
good results. Newer data have demonstrated that adjuvant chemotherapy after complete surgical resection
can improve overall survival.3–6 For patients who are
medically unfit for or refuse surgery, definitive radiation therapy is an alternative treatment modality that
still offers curative potential. Although outcomes with
radiation alone are inferior compared to those obtained
with complete surgical resection, five-year cause-specific
survival rates of approximately 30% in stage I and II
disease have been obtained with the use of modern radiation therapy planning and delivery techniques.7–9 Doses
considered to be ‘curative’ when using radiation therapy alone are considered to be approximately 65 to 70
Gray (Gy) with standard fractionation (1.8 to 2.0 Gy per
fraction, five fractions per week), or a radiobiologically
equivalent dose when altered fractionation is utilized.
Dose escalation with conventionally fractionated radiation therapy has demonstrated a dose–response relationship with respect to both local control and survival.10,11
Such dose escalation has not been associated with an
increase in acute toxicity when three-dimensional conformal radiation techniques are utilized.12,13 Stereotactic
body radiation therapy using hypofractionation has been
shown to produce excellent local control rates with
acceptable toxicity.14,15 A current phase II Radiation
Therapy Oncology Group (RTOG) protocol will evaluate the safety and efficacy of delivering 60 Gy in three
fractions using stereotactic techniques in patients with
early stage NSCLC.
When considering combined-modality therapy,
potential advantages of radiation therapy in the preoperative setting include possible improvement of the resectability of large tumors, prevention of dissemination of
tumor at the time of surgical resection, and the use of
lower doses of radiation. Disadvantages of this approach
include the inability to determine the precise surgical
stage and an increased risk of postoperative complications such as wound healing. Randomized data have
failed to demonstrate a statistically significant survival
benefit for the use of preoperative radiation therapy in
the treatment of early stage NSCLC.16
Postoperative radiation therapy (PORT) has also been
investigated in the context of randomized trials. The
Lung Cancer Study Group (LCSG) evaluated the role of
Treatment of NSCLC: radiotherapy 137
PORT consisting of 50 Gy in 25 fractions to the mediastinum following complete surgical resection in patients
with stage II and III squamous cell lung carcinoma.17
The rate of local failure as the site of first failure was
reduced from 20% to 1% (p <0.01) with the addition of
PORT for patients with node-positive disease. This did
not result in an overall survival benefit for stage II
patients, as approximately two-thirds of first failures
were distant. For patients with N2 disease, there was an
improvement in overall survival, although this difference was not significant.
In a randomized trial by the Medical Research Council
(MRC), patients with stage II and III disease were randomized to receive 40 Gy of PORT or no further therapy.18 In subgroup analysis, patients with N1 disease did
not have improved outcomes with the addition of PORT.
For patients with N2 disease, the addition of PORT
resulted in a one month improvement in median overall survival, delayed time to local recurrence, and a longer interval to the development of bone metastases.
A meta-analysis performed by the PORT Meta-analysis
Trialists Group confirmed that PORT does not confer a
survival benefit for patients with early stage NSCLC and
may actually decrease survival for patients with stage I and
II disease, with a reduction in two-year survival rate from
55% to 48% with the addition of PORT.19 Other studies
have supported the conclusion that PORT may result in
increased toxicity without survival benefit in stage I and II
disease, but it may be advantageous in stage III disease.20–24
LOCALLY ADVANCED DISEASE
Definition
It is estimated that 30% of patients with NSCLC have
locally advanced disease without distant metastases at
presentation, but few such patients present with disease
amenable to primary surgical resection with curative
intent.25 The term locally advanced as applied to NSCLC
generally implies stage III disease.26 Stage III disease is
subdivided into IIIA and IIIB. Generally speaking, patients
with stage IIIA disease (e.g. ipsilateral mediastinal nodal
involvement) have potentially resectable disease at presentation, while those with stage IIIB disease (e.g. mediastinal invasion, contralateral nodal involvement) do
not. Further, the volume of ipsilateral mediastinal nodal
disease has prognostic value.27 Thus, individuals with
stage III NSCLC comprise a heterogeneous group of
patients with a range of prognoses based upon disease
extent at diagnosis. As such, these patients present a
unique therapeutic challenge.
Single-modality therapy
While treatment with radiation therapy alone for patients
with locally advanced NSCLC is potentially curative,
long-term survival rates are disappointing and generally are less than 15%.28,29 Analyses of the patterns of
failure following treatment with radiation therapy alone
demonstrate that the poor survival rates are related not
only to the inability of local therapy to control the primary tumor, but also to the development of distant
metastases.29,30
The RTOG established prognostic groups determined
by recursive partitioning analysis (RPA) based on four
RTOG trials of patients with inoperable NSCLC treated
with definitive radiation therapy.31 Patterns of failure of
1547 patients with stage II, IIIA, or IIIB NSCLC treated
with radiation therapy alone were then determined
based on RPA prognostic group.32 The median survival
and the rates of primary and distant failures varied significantly based on RPA class, suggesting that specific
cohorts of patients may benefit from more aggressive
treatment directed at specific sites of failure.
Combined-modality therapy
When local control is defined by complete clinical,
radiographic, endoscopic, and histologic remission, the
local failure rate is as high as 92% at 5 years.30 Distant
failure rates after radiation therapy alone are approximately 80%.29 These findings have led to the exploration
of combined-modality therapy utilizing chemotherapy
in the treatment of such patients.
Many possible combinations of induction therapy
have been investigated in a multitude of trials evaluating the role of combined-modality therapy in the treatment of locally advanced NSCLC. Interpretation of the
data and comparisons of results between even well
designed trials are difficult for many reasons. There have
been several changes in the staging systems over time
and the terms ‘unresectable’, ‘marginally resectable’, and
‘locally advanced’ have been variably defined. Additionally, no standards exist regarding the extent of surgical
staging or resection, the dose of radiation therapy delivered, or the chemotherapeutic agents used and in what
combinations and doses. The optimal treatment of
locally advanced NSCLC continues to be defined, but
long-term survival rates have improved with combinedmodality therapy, which is now considered the standard
of care.33–35
There are two basic treatment protocols for administering combined chemotherapy and radiation. Sequential
treatment with chemotherapy followed by radiation therapy was the first widely utilized combination in locally
138 Textbook of Lung Cancer
advanced NSCLC. Concurrent chemoradiation has demonstrated promising results with respect to prolonging
survival, and is considered the current standard of care.
Sequential chemoradiation
When radiation therapy follows induction chemotherapy, the effects of chemotherapy decrease the local
tumor burden and may permit delivery of radiation to
a reduced tumor volume. Induction chemotherapy may
also eliminate or prevent the growth of subclinical systemic disease. Increased drug delivery with less overall
toxicity is also more likely compared to concurrent
administration. Potential drawbacks of sequential administration include a prolonged overall treatment time,
excessive toxicity due to chemotherapy preventing or
delaying the delivery of radiation, induction of accelerated repopulation, and chemotherapy-induced tumor
cell resistance resulting in reduced radiation efficacy.36–38
Many phase II trials have been designed to evaluate
whether or not survival is improved with the addition of
induction chemotherapy to radiation therapy in patients
with locally or regionally advanced NSCLC. Although
these trials have had conflicting results, several phase
III trials (Table 10.2.1) and three meta-analyses have
demonstrated a survival benefit, and recent updates have
provided relatively long-term data.
In North America, the Cancer and Leukemia Group
B (CALGB) 8433 trial is the landmark study of sequential chemoradiation versus radiation therapy alone for
the treatment of locally advanced NSCLC.39 A total of
155 eligible patients with clinical or surgical T3 or N2
NSCLC without evidence of distant metastases were
randomized to induction chemotherapy with cisplatin
and vinblastine followed by radiation therapy or radiation therapy alone. Radiation therapy to a total dose of
60 Gy in 30 fractions was the same in both arms and
began on day 50 in the combined-modality arm. All
patients had a good performance status and minimal
weight loss prior to study entry. The addition of chemotherapy did not impair the ability to deliver radiation
therapy, with 88% of patients in the combined-modality
arm and 87% of patients on the radiation therapy alone
arm completing radiation therapy per protocol. Longterm seven-year followup confirms that induction
chemotherapy improves median survival compared to
radiation therapy alone.40 Three other modern cisplatinbased trials have confirmed the CALGB experience.
A US Intergroup trial randomized 458 eligible patients
with good performance status, minimal weight loss, and
unresectable, localized NSCLC to receive once daily
radiation therapy to 60 Gy in 2 Gy fractions with or
without induction cisplatin and vinblastine.41 Patients
Table 10.2.1 Randomized trials of chemotherapy and radiation therapy versus radiation therapy alone
Trial
CT
RT dose (Gy)
Median survival (months)
p value
Three-year survival (%)
VP
60
60
13.7
9.6
VP
60
60
69.6 BID
13.8
11.4
12.3
VCPC
65
65
12.0
10.0
0.02
6b
3b
MIC
50c
50c
13.0
9.9
0.056
14
10
CALGB39,40
0.012
23
11
US Intergroup41,42
5b
8b
6b
a
0.03
French43,44
MRC45
CT: chemotherapy; RT: radiation therapy; CALGB: Cancer and Leukemia Group B; MRC: Medical Research Council; VP: vinblastine, cisplatin;
VCPC: vindesine, cyclophosphamide, cisplatin, lomustine; MIC: mitomycin, ifosfamide, cisplatin; BID: twice daily.
a
Versus the sequential arm.
b
Five-year rates.
c
Median RT dose.
Treatment of NSCLC: radiotherapy 139
randomized to a third arm received radiation therapy
alone twice daily to a total dose of 69.6 Gy. Median survival was statistically superior for the combined-modality
arm versus either the standard radiation therapy arm or
the twice-daily radiation therapy arm. Final results of this
study confirmed combined-modality therapy improves
median survival, but five-year survival rates remained
poor at less than 10%.42
In another phase III trial conducted in France, 353
patients with unresectable locally advanced squamous
cell or large cell lung carcinoma were randomized to
receive either radiation therapy alone (65 Gy in 2.5 Gy
fractions) or three monthly cycles of cisplatin-based
chemotherapy followed by the same radiation therapy
regimen.43 There was a significant decrease in distant
metastases for the combined-modality arm and the median
and two-year survival rates (21% vs 14%, p = 0.02,
overall).44 Re-analysis revealed that only 8% of patients
had continued local control at five years.30 Five-year
survival rates remained poor at 6% and 3%, likely secondary to the high rate of local failure on both arms.
The MRC randomized 447 eligible patients with good
performance status and localized, inoperable NSCLC to
receive radiation therapy alone or cisplatin-based induction chemotherapy followed by radiation therapy.45 On
both arms, the median radiation therapy dose was low
at 50 Gy. Median survival was improved with the addition of chemotherapy, although this difference was of
borderline significance.
As demonstrated by the above randomized trials, the
addition of platinum-based induction chemotherapy to
radiation therapy results in improved survival as compared to radiation therapy alone. This is particularly
true for short-term survival, but modest improvements
in long-term survival have been observed as well. Several smaller randomized trials have failed to confirm a
survival benefit for the addition of induction chemotherapy, but these trials may have lacked the power to
detect small differences in survival.46–49 Three large
meta-analyses have demonstrated a small but consistent
survival benefit in the order of 5–10% at one year for
the addition of induction chemotherapy to radiation
therapy for locally advanced NSCLC.50–52
Sequential versus concurrent chemoradiation
The benefit of combined-modality treatment with radiation therapy and chemotherapy was established by the
CALGB 8433 trial and confirmed by other randomized
phase III studies.40,42,44,45 These trials, however, did not
address the optimal sequencing of the two modalities.
Potential advantages of concurrent chemoradiation
include sensitization of tumor cells to radiation and
reduced overall treatment time.53 Potential disadvantages
of concurrent chemoradiation include increased morbidity requiring reductions in the dose intensity of chemotherapy and unplanned delays in the administration
of radiation therapy.37,38,54
An important early European Organization for Research
and Treatment of Cancer (EORTC) trial randomized 331
patients with unresectable stage I, II, or III NSCLC to
treatment with radiation therapy alone, radiation therapy with weekly cisplatin (30 mg/m2), or radiation therapy with daily cisplatin (6 mg/m2).55 On all three arms,
the same definitive split-course radiation therapy schedule consisting of 60 Gy in 20 fractions with a three-week
rest after the first 30 Gy was utilized. The administration of daily cisplatin was shown to significantly improve
overall survival (16% vs 2% at three years, p = 0.009
overall) and disease-free survival (31% vs 19% at two
years, p = 0.003 overall) compared to radiation therapy
alone. The weekly cisplatin arm also revealed a trend
towards improved survival compared to the radiation
alone arm. The survival benefit observed with the addition of low-dose daily cisplatin was likely due to radiation sensitization and improved local control.
While the EORTC trial above addressed the feasibility
of administering chemoradiation in a multicenter setting
and confirmed a survival benefit for combined-modality
therapy, it still did not address the optimal timing of
the two modalities. Several additional randomized trials
were designed to answer this question (Table 10.2.2).
The West Japan Lung Cancer Group (WJLCG) conducted a large phase III trial to directly compare survival for sequential versus concurrent cisplatin-based
chemoradiation.56 A total of 314 eligible patients with
unresectable stage III NSCLC were entered on the trial.
Both the response rate and the median survival were
significantly improved for patients who received concurrent chemoradiation as compared to sequential
treatment.
The RTOG also compared sequential versus concurrent
chemoradiation in a phase III randomized trial (RTOG
94-10).57,58 In this trial, patients with unresected stage
II–III NSCLC and good performance status were randomized to receive sequential chemoradiation, or concurrent chemoradiation with radiation delivered either
once or twice daily. With a median follow-up of 6.0 years,
the concurrent arm receiving once-daily radiation therapy had an improved median survival compared to the
sequential arm. The median survival of patients on the
concurrent twice-daily radiation therapy arm was not
statistically different from the sequential arm.
140 Textbook of Lung Cancer
Table 10.2.2 Randomized studies evaluating sequential versus concurrent administration of chemotherapy and radiation
therapy
Trial
Arm
WJLCG56
Sequential
Concurrent
Sequential
Concurrent, RT qd
Concurrent, RT BID
Sequential
Concurrent
Sequential
Concurrent
RTOG 94-10
Czech59
French
60
57
Response rate (%)
66.6
84.0
NR
NR
NR
47
80
NR
NR
p value
0.0002
NR
NR
0.001
NR
Median survival (months)
13.3
16.5
14.6
17.0
15.2
12.9
16.6
13.8
15.0
p value
0.04
0.046a
0.296a
0.023
0.41
WJLCG: West Japan Lung Cancer Group; RTOG: Radiation Therapy Oncology Group; qd: once daily; BID: twice daily; NR: not reported.
a
Versus the sequential arm.
Two additional randomized phase III trials, one conducted in the Czech Republic and another conducted
in France, both demonstrated a significant improvement with respect to median survival for concurrent
chemoradiation versus sequential treatment.59,60 Based
in part on the results of the above randomized trials, the
administration of chemotherapy and radiation therapy
concurrently, rather than sequentially, is considered
the standard of care for patients with locally advanced
NSCLC.
Induction chemoradiation
Once the efficacy and feasibility of concurrent chemoradiation for locally advanced NSCLC was established,
this approach replaced chemotherapy alone as the induction regimen prior to surgery in many trials. An important example is SWOG 8805, a phase II trial designed
to test the feasibility of concurrent chemoradiation followed by surgical resection in 126 patients with stage
IIIA and IIIB disease.61 Induction therapy consisted of
cisplatin and etoposide given concurrently with thoracic irradiation to 45 Gy. Patients with unresectable
disease, incomplete resection, or positive mediastinal
nodes received an additional two cycles of chemotherapy and radiation therapy to a total dose of 59.4 Gy.
Morbidity and mortality associated with this trial were
high. Mature results revealed no survival difference
between patients with stage IIIA and IIIB disease, with
a median survival of 13 months and 17 months, respectively.62 Absence of tumor in mediastinal nodes at surgery was the strongest predictor of long-term survival
after thoracotomy, with a median survival of 30 months
versus 10 months, and three-year survival of 44% vs
18% (p = 0.0005).
With the encouraging results of the above SWOG
phase II trial and others, an Intergroup phase III trial
conducted by the RTOG was initiated.63 In this trial, all
patients received induction chemoradiation and were
then randomized to surgical resection or further chemoradiation. Induction chemoradiation consisted of cisplatin and etoposide given concurrently with 45 Gy of
radiation therapy. Patients with responsive or stable
disease following induction therapy underwent surgical
resection followed by two postoperative cycles of chemotherapy, or continued radiation therapy to a total
dose of 61 Gy concurrent with two additional cycles of
chemotherapy. A total of 429 patients were entered on
the study, all with stage IIIA, N2 disease. These patients
were highly selected in that they had to be potential
candidates for pulmonary resection and eligibility criteria also required a Karnofsky Performance Status (KPS)
of 70 or greater. Of the 396 analyzable patients, 202
were randomized to undergo surgical resection following
induction chemoradiation and 194 received definitive
chemoradiation. The most recent results were reported
with a minimum of 2.5 years of follow-up per patient
(Table 10.2.3). There were 16 (7.9%) deaths on the
chemoradiation and surgery arm and 4 (2.1%) deaths on
the chemoradiation only arm. A higher rate of death was
observed following pneumonectomy versus lobectomy
(26% versus 1%, respectively). Although progression-free
survival was significantly improved with the addition of
surgery, median survival and five-year survival rates
were not significantly different between the two arms.
Treatment of NSCLC: radiotherapy 141
Table 10.2.3 Results of Intergroup trial 0139 (RTOG 9309), comparing induction chemoradiation followed by surgical resection
versus definitive chemoradiation63
Arm
Number of patients
ChemoRT
ChemoRT + S
p value
Progression-free survival
(months)
194
202
10.5
12.8
0.017
Median survival
(months)
Five-year
survival (%)
22.2
23.6
0.24
20.3
27.2
0.10
ChemoRT: chemoradiation; S: surgery; NR: not reported.
Pathologic N0 disease at the time of surgical resection
predicted for long-term survival. These results suggest
that, while surgical resection after induction chemoradiation increases progression-free survival compared to
definitive chemoradiation in patients with stage IIIA
NSCLC, the addition of surgery may also increase the
morbidity and mortality of treatment without improving overall survival. Surgical resection following induction chemoradiation may be considered in fit patients,
particularly if a lobectomy is to be performed.
The German Lung Cancer Cooperative Group (GLCCG)
conducted a phase III randomized study to investigate
the timing and fractionation of radiation therapy when
surgery is planned in patients with locally advanced
NSCLC.64 In this trial, 558 patients with stage IIIA and
IIIB disease received induction chemotherapy consisting of three cycles of cisplatin and etoposide. Patients
were then randomized to receive hyperfractionated
radiation therapy with concurrent carboplatin and vindesine followed by surgery, or surgery followed by
standard fractionated radiation therapy to 54 Gy without concurrent chemotherapy. There was no difference
between the two arms with respect to response rate
after induction, complete resection rate (45% in both
arms), treatment-related mortality, and three-year progression-free survival and overall survival.
SUPERIOR SULCUS TUMORS
Tumors of the superior sulcus, also known as Pancoast’s
tumors, are a distinct subset of locally advanced NSCLC.
Previously considered inoperable and fatal, the use of
single-modality radiation therapy has led to five-year
survival rates as high as 46%.65
The use of trimodality therapy is now considered standard of care for patients with tumors of the superior
sulcus. This is based primarily on a phase II (Intergroup
0160, SWOG 9416) study in which 110 eligible patients
with T3–4, N0–1 tumors of the superior sulcus received
induction therapy consisting of cisplatin and etoposide
given concurrently with thoracic irradiation to 45 Gy.66,67
This induction regimen was identical to that given in
SWOG 8805.61 A total of 95 (86.4%) patients had stable
disease or response to induction chemoradiation and
underwent surgical resection followed by an additional
two cycles of chemotherapy. Complete resection was
performed in 83 (94.3%) of the 88 patients who underwent thoracotomy. Pathologic complete response was
seen in 32 (36.4%) of the thoracotomy specimens and
an additional 26 (39.5%) revealed minimal microscopic
disease. The five-year and median survivals were 53% and
71 months, respectively, for patients who had a complete resection, and 41% and 33 months, respectively,
for all patients who were eligible for resection. This represented a significant improvement over historical data
for NSCLC of the superior sulcus.
ALTERED FRACTIONATION RADIATION THERAPY
Hyperfractionated and accelerated fractionation radiation
therapy have been investigated as potential approaches
to improve outcomes in patients with locally advanced
NSCLC. Delivering multiple fractions per day works to
counteract the effect of accelerated repopulation that
occurs during normal treatment breaks. An adequate
interval between fractions, generally six hours or longer,
allows for repair of sublethal damage in normal tissues,
thus minimizing any increase in acute side-effects. Late
effects are also decreased due to the lower dose per
fraction.53
A European multicenter trial randomized 563
patients with locally advanced NSCLC and good
performance status to either conventional radiation
therapy or continuous hyperfractionated accelerated
radiotherapy (CHART).68 The CHART regimen consisted of 36 fractions of 1.5 Gy each given three times
per day on 12 consecutive days. The use of CHART was
associated with a 9% improvement in overall survival at
142 Textbook of Lung Cancer
two years (29% vs 20%, p = 0.004). CHART was also
associated with an increase in severe dysphagia (19%
vs 3%), but this occurred primarily after the completion of radiation therapy and thus did not interfere with
radiation delivery. Subgroup analyses revealed the greatest benefit was for patients with squamous cell histology.
Jeremic and colleagues randomly assigned 131 patients
with stage III NSCLC to receive twice daily radiation
therapy to a total dose of 69.6 Gy with or without lowdose daily carboplatin and etoposide.69 The combinedmodality arm demonstrated an improved median
survival (22.0 vs 14.0 months) and an improved four-year
survival (23% vs 9%, p = 0.021). This represents an
approximately six-month improvement in median survival as compared to the concurrent chemoradiation arms
utilizing once daily radiation (Table 10.2.2).56,57,59,60
A randomized study by the Eastern Cooperative Oncology Group (ECOG 2597) compared once-daily radiation
therapy to hyperfractionated accelerated radiation therapy
(HART) following two cycles of induction chemotherapy
with carboplatin and paclitaxel.70 Once-daily radiation
therapy was delivered with 2.0 Gy fractions to a total dose
of 64 Gy. HART consisted of a total dose of 57.6 Gy using
1.5 Gy fractions delivered three times per day. The study
was closed early due to poor accrual. Based on the 141
patients who were enrolled, median survival was 20.3
months on the HART arm and 14.9 months on the daily
radiation therapy arm (p = 0.28). This also represents an
approximately 6-month improvement in median survival as compared to the concurrent chemoradiation
arms utilizing once-daily radiation (Table 10.2.2).56,57,59,60
While the initial results of altered fractionation radiation therapy in the treatment of locally advanced NSCLC
are promising, at this time there is no confirmed additional survival benefit for altered fractionation radiation
therapy alone over concurrent chemotherapy and radiation therapy. The hyperfractionated radiation therapy
arms of the United States Intergroup trial and RTOG
94-10 trial were unable to confirm a significant survival benefit when compared to conventional radiation
therapy, even with long-term follow-up.42,58 Combining chemotherapy with altered fractionation radiation
therapy has shown promise, but this approach has yet
to be optimally defined and continued investigation is
warranted.
TOXICITY AND PATIENT SELECTION
In locally advanced NSCLC, combined-modality therapy improves disease control at the cost of increased
toxicity. Without exception, patients enrolled on the
combined-modality or ‘more aggressive’ treatment arms
of clinical trials experience increased toxicity as compared to single-modality controls.39,41,55–57
Important factors that influence outcome in patients
with locally advanced NSCLC include age, performance
status, and degree of weight loss.71–73 Aggressive combinedmodality treatments require a ‘fit’ cohort of patients and
proper patient selection is critical, as highlighted by the
results of RTOG 90-15.74 This phase I/II trial utilized
cisplatin and vinblastine concurrent with twice-daily
radiation (1.2 Gy twice daily to 69.6 Gy) to treat patients
with unresected stage II, IIIA, or IIIB NSCLC. All patients
had a good performance status (KPS ≥70), but this trial
was initiated while RTOG 88-08 was still in progress
and, due to competition for enrollment, minimal weight
loss was not included in the eligibility criteria. Of the
42 eligible patients, 76% had greater than 5% weight
loss preceding study entry. Grade 4 or higher acute toxicity was observed in 45% of patients, with 7% of patients
dying of sepsis related to chemotherapy-induced leukopenia. Median survival was 12.2 months in all patients
and 17.5 months for the ten patients with less than 5%
weight loss.
Consideration must also be given to the timing of
surgical resection and the type of surgery that is planned
after induction therapy. In general, preoperative chemotherapy has not been shown to increase postoperative morbidity and mortality.75,76 Review of the Memorial
Sloan Kettering experience, however, has revealed that
right pneumonectomy following induction chemotherapy significantly increases the risk of surgical complications, with 24% of patients dying postoperatively.76 The
mechanism behind the increased mortality after right
pneumonectomy is not well understood and the role of
radiation therapy, if any, in increasing the risk of death
is not known.
PROPHYLACTIC CRANIAL IRRADIATION
The risk of central nervous system (CNS) failure is low
in patients with early stage disease who undergo surgical
resection. For patients with locally advanced disease,
15–30% will experience CNS failure as the site of first
relapse.62,77,78 The overall CNS failure rate increases with
increasing survival and is on the order of 20–50%.62,77–79
Prophylactic cranial irradiation (PCI) has been shown
in prospective randomized trials to delay and reduce
the incidence of failure within the brain, but it has not
been shown to improve survival.80,81 These studies have
Treatment of NSCLC: radiotherapy 143
been criticized for poor control of extracranial disease,
which was the cause of death in the majority of patients
and also likely contributed to reseeding of the brain
after whole brain radiation therapy was completed.
An ongoing North American Intergroup phase III
trial conducted by the RTOG randomizes patients with
stage III NSCLC who have been treated with definitive
combined-modality therapy and have responsive or
stable disease to receive 30 Gy in 15 fractions of whole
brain radiation therapy or no PCI. A study by the West
German Cancer Center will randomize patients with
locally advanced NSCLC to one of two fractionation
schemes of PCI (24 Gy in 12 fractions or 30 Gy in 15
fractions), or no PCI. These trials, which will collect data
on both survival and neuropsychologic sequelae of treatment, will hopefully clarify the role of PCI in patients
with locally advanced NSCLC.
PALLIATIVE THERAPY
Palliative endobronchial therapy can provide symptomatic improvement for bronchial symptoms such as
hemoptysis and obstructive pneumonia. Radiation can
be delivered with low-dose rate sources or, more commonly, with a high-dose-rate source using a remote afterloading device. Common treatment regimens include
21 Gy in three fractions delivered at 1.0 cm depth with
a high-dose-rate source and 30 Gy delivered at 1 Gy per
hour for low-dose-rate sources. No significant differences between the two techniques with respect to bronchoscopic response rate or complications have been
identified.82,83 Symptomatic improvement is usually
rapid and is generally seen in 50% of patients.84,85
Radiation therapy remains a useful palliative tool in
the treatment of patients with distant metastatic NSCLC.
Common sites of metastatic disease include brain and
bone. For patients with brain metastases, radiation therapy is generally employed, either as a sole modality or
in combination with surgical resection. The role of stereotactic radiosurgery, particularly in patients with controlled extracranial disease, continues to be defined.86
Between 20 and 40% of patients with NSCLC will
develop osseous metastases.87 Focal external beam radiation therapy is the most common method used to treat
symptomatic bone metastases. Several fractionation schemes
are commonly employed, but recent data in patients with
metastatic breast or prostate cancer suggest that 8 Gy in
a single fraction provides equivalent pain control to the
more protracted schedule of 30 Gy in 10 fractions,
although the retreatment rate is significantly higher.88
Superior vena cava (SVC) syndrome results from
compression of the SVC with compromised return of
venous blood flow to the heart. SVC syndrome occurs
in approximately 5% of all patients with lung cancer
and it is characterized by presentation with dyspnea,
facial and neck swelling, and distention of the veins of
the upper chest wall. Initial management may consist of
medical therapy such as diuretics and/or corticosteroids. Effective palliation is often quickly achieved by
the use of radiation therapy. Commonly, several large
fractions of 4 Gy are given for the first several days of
treatment.89,90 Palliation of the symptoms associated
with SVC syndrome is seen in approximately 90% of
patients within three weeks of initiation of therapy.91,92
CONCLUSION
Lung cancer is a very common disease and even relatively small advances in treatment have the potential to
impact the survival of thousands of patients. In the past
two decades, many trials of combined-modality therapy
have been conducted in an attempt to improve the survival of patients with NSCLC. The role of radiation
therapy is limited in patients with early stage disease
and is best suited to treat patients who are medically
unfit or refuse to undergo surgery. Radiation therapy
may also be used in this setting for patients who do not
undergo a complete surgical resection.
The best overall therapeutic regimen remains unclear
in patients with locally advanced disease, but the use of
combined-modality therapy in the treatment of such
patients has resulted in a modest but reproducible survival benefit compared to single-modality therapy.
Concurrent administration of chemotherapy and radiation therapy for patients with locally advanced NSCLC
has been shown to significantly improve survival as
compared to sequential therapy in randomized trials
and is the standard of care. The role of surgery in this
setting continues to be defined.
Based on patterns of failure, attention has focused on
improving local control and preventing progression of
distant disease. It is hoped that with continued advances
in all therapeutic modalities, the survival of patients
with NSCLC will continue to improve.
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10.3 Treatment of NSCLC: chemotherapy
Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias
Contents Introduction • Adjuvant chemotherapy after surgical resection • Preoperative (neoadjuvant)
chemotherapy • Chemotherapy for locally advanced unresectable (IIIA and IIIB) NSCLC • Chemotherapy
for patients with advanced NSCLC • Patients populations with special considerations • Second-line therapy
• Targeted therapies in advanced NSCLC
INTRODUCTION
The clinical development of chemotherapeutic agents
in non-small cell lung cancer (NSCLC) was initially
focused in the setting of stage IV disease. During the
1980s and early 1990s, six drugs, namely cisplatin,
ifosfamide, mitomycin C, etoposide, vindesine, and
vinblastine, were considered active against NSCLC,
with response rates reported in excess of 15%.1,2
Combination chemotherapy, most commonly cisplatin-based, was also investigated. Generally, higher
objective responses were achieved but still the benefit
for the patients was unclear by that time. Subsequent
randomized trials and meta-analyses established the
value of chemotherapy in the treatment of patients
with advanced NSCLC.3,4 The next steps were aimed
at the development of chemotherapy from a palliative
measure to a curative one, through its incorporation
into aggressive combined modality treatments for
locoregionally advanced disease, and/or its administration as adjuvant to radical surgery. More recently,
during the 1990s, a new generation of compounds
such as the taxanes (paclitaxel and docetaxel), the topoisomerase inhibitors (irinotecan, topotecan), active
analogs (gemcitabine), antimetabolites (pemetrexate),
and vinka alkaloids (vinorelbine) were integrated in
the treatment of NSCLC.5 These drugs administered
in patients with metastatic disease obtained singleagent activity in the range of 20–30%. When used in
combination with other active agents such as the platinums, significant response rates, often in excess of
40%, were reported in pilot phase II studies. The
newer agents have been also successfully used in chemotherapy regimens for the treatment of patients with
earlier stages of disease as well as in combined-modality treatment programs.
ADJUVANT CHEMOTHERAPY AFTER
SURGICAL RESECTION
Surgery remains the only curative treatment modality
for patients with NSCLC. However, even after complete
resection the overall survival remains disappointing,
with the five-year survival rates ranging from 67% for
patients with T1N0 disease to 23% for patients with N2
disease.6 Efforts to improve the survival of patients with
operable NSCLC have examined the addition of chemotherapy (CMT) and/or radiotherapy (RT) in the
postoperative setting. The rationale for the use of systemic therapy in completely resected NSCLC lies in the
detection of early micrometastatic disease at the time of
surgery and in the clinical observation that distant
recurrence is the predominant cause of relapse and
death after surgery.
From the first randomized trials to the 1995
meta-analysis
Early trials of postoperative chemotherapy started in
the 1960s failed to demonstrate any benefit on survival
by the incorporation of alkylating and immunotherapeutic agents.7 The vast majority of subsequent trials
employing cisplatin-based regimens8–11 did not show
any significant effect of chemotherapy on survival.
Common drawbacks in these studies were the overestimation of the potential benefit of adjuvant chemotherapy in the calculation of the sample size, the imbalance
in patient and treatment characteristics, the unfeasibility of reaching the planned accrual, and, finally, the low
compliance with most chemotherapy regimens used.
In 1995 a meta-analysis on the role of chemotherapy in
the treatment of NSCLC separately reviewed eight trials, assigning a combined total of 1394 patients to cisplatin-based adjuvant chemotherapy.12 A 13% reduction
148 Textbook of Lung Cancer
in the risk of death [hazard ratio (HR) 0.87 (95% CI:
0.74–1.02)] corresponding to an absolute survival benefit of 3% at two years (95% CI: 0.5% detriment to 7%
benefit) and 5% (95% CI: 1% detriment to 10% benefit)
at five years, in favor of chemotherapy, was reported.12
Despite the marginal statistical significance (p = 0.08),
these findings encouraged the initiation of several randomized trials investigating the role of platinum-based
regimens in patients with completely resected stage I,
II, and IIIA NSCLC (Table 10.3.1). These trials used
different types of chemotherapy and included different
proportions of stages I to IIIA NSCLC.
The North American Intergroup Trial INT0115 was
the only trial that compared the combination of chemotherapy plus thoracic radiotherapy versus radiotherapy
alone in patients with completely resected stage II or
IIIA NSCLC.13 INT0115 was negative, but yet, the trial
was underpowered to detect the small survival benefit
suggested by the meta-analysis and used thoracic radiotherapy as the comparator that is not considered as the
standard reference arm. The Big Lung Trial was also
clearly underpowered to look at differences in survival
in the range of 5%. With a median follow-up of only
2.9 years no significant benefit was shown by the addition of cisplatin-based chemotherapy pre- (4%) or postoperatively (96%).14
In the next sections the most important recent trials
of adjuvant chemotherapy are presented.
Adjuvant Lung Project Italy (ALPI trial)
The ALPI trial randomized 1209 patients with surgically staged I–IIIA NSCLC to receive MVP (mitomycin
8 mg/m2, day 1; vindesine 3 mg/m2, days 1 and 8; CDDP
100 mg/m2, day 1, every three weeks) for three cycles
(n = 606), or no treatment (n = 603).15 Stratification
factors included center, tumor size, lymph node involvement, and the intention to perform radiotherapy.
After a median follow-up of 64.5 months the study
failed to demonstrate any significant difference in terms
of overall survival [HR 0.96 (95% CI: 0.81–1.13); p =
0.589] and progression-free survival [HR 0.89 (95%
CI: 0.76–1.03); p = 0.128]. Median overall survival was
55 months in the chemotherapy arm and 48 months in
the surgery alone arm, while progression-free survival
was 37 and 29 months for the treatment and control
arms, respectively. No significant effect between treatment and stage of the disease emerged.
Treatment compliance data indicate that 69% of the
patients received the per protocol planned three cycles
of chemotherapy, although half of them required some
dose adjustment or omission. Chemotherapy was never
started in an additional 9%, mainly due to consent
withdrawal. Radiotherapy was completed in 65% of the
patients initially planned in the MVP arm and in 83%
of the control group.
International Adjuvant Lung Cancer trial (IALT trial)
The IALT trial randomly allocated patients with surgically resected stage I, II, or III NSCLC to receive cisplatin-based chemotherapy or observation.16 The primary
endpoint was overall survival and secondary endpoints
were disease-free survival (DFS), second-primary cancers, and adverse events. A total of 3300 patients was
required for the trial to have 83% power with a twosided test to detect an absolute improvement of 5%,
and 90% power to detect a 5.6% difference in overall
survival at five years. However, the trial was terminated
prematurely after the enrollment of 1867 patients out
of the 3300 initially planned because of a slow down in
patient recruitment rate.
Each participating center had to determine the pathologic stage of the disease to include, the dose of cisplatin
(80, 100, 120 mg/m2 per cycle for 3–4 cycles), the drug
to be combined with cisplatin (etoposide, vinorelbine,
vindesine, or vinblastine) and the administration of
sequential chest radiotherapy.
Finally, 932 patients were enrolled in the chemotherapy arm and 935 in the control group. Approximately
37% had disease stage I, 24% stage II, and 39% stage
III. Twenty-seven percent of patients received postoperative radiotherapy, while cisplatin plus etoposide was
the most frequently utilized regimen.
After a median follow-up period of 56 months, the
DFS rate at five years was 39.4% for the chemotherapy
arm vs 34.3% for the observation arm [HR 0.83 (95%
CI: 0.74–0.94; p <0.003)]. Furthermore, overall survival favored the chemotherapy arm [44.5 vs 40.4% at
five years; HR 0.86; (95% CI: 0.76–0.98); p <0.03].
Compliance with chemotherapy was relatively poor, with
74% of the patients in the chemotherapy arm receiving
at least three treatment courses. Moreover, 70% of the
patients treated with chemotherapy and assigned to
chest radiotherapy completed their course, compared
with 84% of these who did not receive chemotherapy.
Seven (0.8%) patients died of chemotherapy-related
toxicity.
The results observed in the IALT trial are in the same
range as those reported in the 1995 meta-analysis.7 The
large number of patients in the IALT analysis may explain
the significance of the results compared with the smaller
number of analyzed patients in the ALPI trial. Moreover, the use of a three-drug regimen and the higher
No of
488
1209
1867
381
119
ALPI trial15
IALT trial16
Big Lung
Trial14
JCOG 9304
trial28
patients
INT011513
Trial
IIIA (N2)
I–IIIA
I–IIIA
I–IIIA
II–IIIA
Disease
stages
included
VP-16 (120 mg/m2,
d 1–3); CDDP
(60 mg/m2, d 1)/
radiotherapy only
(both arms received
a total of 50.4 Gy
radiotherapy)
Mit 8 mg/m2, d 1;
VND 3 mg/m2,
d 1 & 8; CDDP
100 mg/m2, d 1,
q3w, for three
cycles/observation
CDDP + vinka
alkaloids or
VP-16/observation
CDDP/VND,
CDDP/mit/If,
CDDP/mit/
vinblastine or
CDDP/VNB/
observation
CDDP 80 mg/m2,
d 1; VND 3 mg/m2,
d 1 & 8: ×3 cycles/
observation
CT regimen/
control arm
Table 10.3.1 Reported phase III trials of adjuvant chemotherapy in NSCLC
58
64
74
69
69
Compliance
to CT (%)
Median
NR
34.6
56
64.5
44
follow-up
(months)
Hazard
0.86
1.02
—
−2b
−7.9c
0.96
0.93
ratio of
death
4.1
1
−6a
Five-year
absolute
survival
benefit (%)
(Contiuned)
0.89
0.90
<0.03
0.589
0.56
p
149
840
ANITA trial24
IB–IIIA
IB
65
CDDP (50 mg/m2,
d 1 & 8 q 4w);
VNB (25 mg/m2)/
observation
PCL 200 mg/m2/
carboplatin AUC
6/observation
CDDP 100 mg/m2/
VNB 30 mg/m2/
observation
56d
85
74
(at 12 mo)
61
(at 24 mo)
80
Compliance
to CT (%)
UFT
(250 mg/m2/day)
for 2 years/
observation
UFT/observation
CT regimen/
control arm
>70
48
6.44
(years)
60
72
Median
follow-up
(months)
8.6
3
15
4.6
3
Five-year
absolute
survival
benefit (%)
0.79
0.80
0.69
0.77
—
Hazard
ratio of
death
0.013
0.32
0.011
0.011
0.047
p
b
Estimated 5-year survival rates were 39% for the RT only group and 33% for the CT-RT group.
Estimated 2-year survival rates were 60% for the observation group and 58% for the CT group.
c
5-year survival rates were 28.2% in the chemotherapy arm and 36.1% in the control group.
d
Dose density of vinorelbine.
CT: chemotherapy; RT: radiotherapy; q3W: every three weeks; VP-16: etoposide; UFT: oral uracil-tegafur; CDDP: cisplatin; Mit: mitomycin; VND: vindesine; If: Ifosfamide; VNB: vinorelbine; PCL: paclitaxel;
carboplatin AUC 6: carboplatin Area Under Curve 6.
a
344
IB–II
482
CALGB 9633
trial22,23
I–III
2003
UFT metaanalysis18
NCIC-JBR10
trial19
I
Disease
stages
included
999
No of
patients
UFT trial17
Trial
Table 10.3.1 Continued
150
Treatment of NSCLC: chemotherapy 151
frequency of postoperative radiotherapy in the ALPI
trial might also have led to the negativity of this trial.
UFT adjuvant trials
Uracil-tegafur (UFT) is a combination of uracil, an
inhibitor of dihydropyrimidine dehydrogenase (DPD),
and tegafur, a prodrug of 5-fluorouracil, that has been
extensively studied in Japanese patients with NSCLC.
UFT has been studied either as single-agent therapy following surgery or following one or more cycles of cisplatin-based chemotherapy. In all those trials, UFT was
administered as a single daily oral dose over a prolonged period of time.
The largest trial on postoperative UFT therapy randomly assigned 999 patients with completely resected
pathologic stage I adenocarcinoma to receive either oral
uracil-tegafur (250 mg/m2/day) for two years (498
patients) or no treatment (501 patients).17 Stratification
factors were tumor stage (T1 vs T2), sex, and age. The
median follow-up period was 72 months in the UFT
group and 73 months in the control group. The fiveyear overall survival rate was 88% (95% CI: 85–91) for
the UFT group and 85% (95% CI: 82–89) for the control group. Survival benefit was significant in patients
with T2 tumors (85% vs 74% for the UFT and observation groups, respectively; HR 0.48; 95% CI: 0.29–0.81;
p = 0.005), while for patients with T1 disease no significant difference was observed. Although toxicity was
minimal, compliance was only 74% at 12 months and
61% at 24 months.
Recently, a meta-analysis examining the effectiveness
of UFT as postoperative treatment of NSCLC was published.18 This meta-analysis included 2003 eligible
patients; most (98.8%) had squamous cell carcinoma
or adenocarcinoma, and stage I disease; the tumor classification was T1 in 1308 (65.3%), T2 in 674 (33.6%), and
the nodal status was N0 in 1923 (96.0%). The median
duration of follow-up was 6.44 years. The survival rates
at 5 and 7 years were significantly higher in the surgery
plus UFT group (81.5% and 76.5%, respectively) than in
the surgery alone group (77.2% and 69.5%, respectively;
p = 0.011 and 0.001, respectively). The overall pooled
hazard ratio was 0.74 (95% CI: 0.61–0.88; p = 0.001).
National Cancer Institute of Canada (NCIC)
JBR10 trial
This trial randomly assigned 482 patients with completely resected, pathologic stage IB and II (patients with
T3N0 disease were excluded) to receive either postoperative adjuvant chemotherapy with cisplatin (50 mg/m2,
days 1 and 8 every 4 weeks for four cycles) and vinore-
lbine (25 mg/m2, reduced from 30 mg/m2 for unacceptable toxicity, weekly for 16 weeks) or no chemotherapy.19
The study endpoints were overall survival, recurrencefree survival, quality of life, and toxicity.
At five years of follow-up, the five-year survival rates
were 69% for the chemotherapy arm and 54% for the
control arm [HR 0.69 (95% CI: 0.52–0.92); p = 0.011],
with an absolute survival benefit of 15% for patients
receiving chemotherapy. Subgroup analyses according
to stratification factors did not demonstrate significant
improvement in survival for patients with disease stage
IB receiving chemotherapy compared to the observation
group (p = 0.79). In the planned stratified Cox regression analysis, significant factors associated with improved
survival included chemotherapy as compared with observation (HR for the difference in survival, 0.67; 95% CI:
0.51–0.89; p = 0.006) and squamous histology as compared with adenocarcinomas (p = 0.005). Despite the
positive results, compliance with chemotherapy was
relatively low, with only 65% of the patients receiving
three or four cycles. Moreover, 77% had at least one
dose reduction or omission and 55% required one or
more dose delays. Nineteen percent of the patients who
received at least one dose required hospitalization for
medical problems related to toxicity. There were two
chemotherapy-related deaths. Furthermore, treatment
was associated with a significant negative impact on
quality of life.20
A retrospective analysis evaluated the influence of age
on survival, chemotherapy delivery, and toxicity in the
BR.10 trial.21 Overall survival for patients older than
65 years was better with chemotherapy versus observation [HR 0.61 (CI: 0.38–0.98); p = 0.04) despite the fact
that older patients received significantly fewer doses of
cisplatin and vinorelbine. Fewer elderly patients completed treatment and more refused treatment compared
to the young (p = 0.03). The authors concluded that
patients older than 75 years require further study.
Cancer and Leukemia Group B (CALGB) 9633 trial
This trial randomly assigned 344 patients with completely resected stage IB (T2N0) NSCLC to four cycles
of paclitaxel/carboplatin chemotherapy (paclitaxel 200
mg/m2/carboplatin AUC 6) versus surgery alone. Like
the NCIC CTG study, there was no planned thoracic
radiotherapy. In this trial compliance with chemotherapy was high, with 85% of the patients receiving three
or four treatment cycles. In the first report of the trial,22
after a median follow-up time of 34 months, 71% of
patients who had received chemotherapy were alive
compared with 59% of those who had surgery alone
152 Textbook of Lung Cancer
[HR 0.62 (95% CI: 0.41–0.95); p = 0.028]. Overall survival at four years and failure-free survival also favored
the chemotherapy group. However, an updated analysis after 54 months of median follow-up showed a nonsignificant trend towards improvement of overall
survival by the addition of chemotherapy [HR 0.80
(90% CI: 0.60–1.07); p = 0.1]. A significant prolongation in DFS favoring adjuvant chemotherapy was still
present [HR 0.74 (90% two-sided CI: 0.57–0.96); p =
0.027].23 It should be noted though that the trial does
not have adequate power to detect small differences in
overall survival that may be clinically significant.
Adjuvant Navelbine International Trialists
Association (ANITA) trial
Patients participating in the ANITA trial were required
to have completely resected, stage IB–IIIA NSCLC. This
trial randomized 840 patients to postoperative chemotherapy (four cycles of cisplatin 100 mg/m2 every
4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly)
or observation only.24 The five-year survival rates favored
the chemotherapy arm; 51.2% vs 42.6% of the patients
were alive in the chemotherapy and the control group,
respectively [HR 0.79 (95% CI: 0.66–0.95); p = 0.013]. In
a subset analysis, chemotherapy significantly improved
survival in stages II and IIIA, but not in stage IB.
ANITA confirmed the results of the NCIC and CALGB
trials in a less selected population (disease stage IB–IIIA)
observed for a longer follow-up period (>70 months).
However, in this trial significant chemotherapy-related
toxicity was also reported, with 84.6% and 12.5% of
the patients experiencing grade 3–4 neutropenia and
febrile neutropenia, respectively. The median percentage of chemotherapy dose delivered was only 56% and
76% for vinorelbine and cisplatin, respectively.
Recent meta-analyses
Eleven randomized controlled trials including a total of
5716 patients reported after the 1995 meta-analysis were
reviewed in an abstracted-data-based meta-analysis.25
In this analysis, hazard ratio estimates suggested that
adjuvant chemotherapy yielded a significant survival
advantage over surgery alone [HR 0.872 (95% CI: 0.805–
0.944); p = 0.001]. In a subgroup analysis, cisplatinbased chemotherapy regimens (3786 patients) showed
consistent results, with the HR estimates in most trials
favoring adjuvant chemotherapy (HR 0.891 (95% CI:
0.815–0.975); p = 0.012). In addition, single-agent UFT
therapy (1751 patients) resulted in a significant survival
benefit, with an HR of 0.799 (95% CI: 0.668–0.957;
p = 0.015).
A second meta-analysis based on abstracted data from
19 randomized adjuvant trials that enrolled 7200 patients
was reported by Sedrakyan et al.26 This meta-analysis
added summary data from seven trials and approximately 5000 patients to information provided by the
1995 meta-analysis.12 An 11% reduction in the mortality was reported for cisplatin-based regimens and 17%
for UFT treatment, as compared to surgery alone. It
should be noted that neither meta-analysis included the
newer trials that reported substantial benefits associated with adjuvant chemotherapy.19,22,24
A third meta-analysis pooled individual patient data
from the five largest trials (ALPI, ANITA, BLT, IALT, and
JBR10) of cisplatin-based chemotherapy in completely
resected patients conducted after the 1995 meta-analysis.27 With a median follow-up of 5.1 years the overall
HR of death was 0.89 (95% CI: 0.82–0.96; p <0.005),
corresponding to a five-year absolute benefit of 4.2% by
the addition of chemotherapy. The benefit varied with
stage, with the HR for stage IA 1.41 (95% CI: 0.96–2.09),
stage IB 0.93 (95% CI: 0.78–1.10), stage II 0.83 (95%
CI: 0.73–0.95), and stage III 0.83 (95% CI: 0.73–0.95).
The recent data from randomized adjuvant trials
have changed the standard of care for patients with
completely resected NSCLC. Consistent reductions in
the risk of death have been observed with cisplatinbased adjuvant chemotherapy. Subset analysis of the
large randomized trials,16,19,24 as well as the recent metaanalysis,27 suggests that the benefit is greatest in patients
with stages II and III. The role of chemotherapy in earlier disease stages and the optimal drug to combine
with cisplatin remain to be determined. Advantages in
disease-free survival and three-year survival might support the consideration of adjuvant paclitaxel/carboplatin in stage IB NSCLC. Up to now there are no
confirmatory data on the efficacy of UFT in the adjuvant treatment of NSCLC outside of Japan.
Considering the significant chemotherapy-associated
toxicity, one might suggest that this treatment should
be restricted to those patients with good performance
status, rapid recovery from surgery, and no significant
comorbidity. No prospective data are available on the
postsurgical management of elderly patients with
resected disease.
PREOPERATIVE (NEOADJUVANT) CHEMOTHERAPY
Induction chemotherapy before surgery
Preoperative chemotherapy presents several theoretic
advantages, including reduction of tumor volume that
Treatment of NSCLC: chemotherapy 153
could enhance local control, evaluation of response to
chemotherapy, early eradication of micrometastatic disease, and higher patient compliance compared to postoperative chemotherapy.
Phase II studies evaluating the role of preoperative
chemotherapy in patients with stage IIIA disease demonstrated an average response rate of 60%, with 55% of
patients undergoing thoracotomy and 49% having
complete resections; median survival time was approximately 16 months, and five-year survival rate was 30%
in chemoresponsive patients, with 50% of patients
achieving a pathologic complete response.5 Phase III
trails of neoadjuvant therapy in NSCLC, are presented
in Table 10.3.2. In a randomized trial by Rosell et al,
patients with stage IIIA NSCLC were randomly assigned
to undergo either immediate surgery, or surgery preceded by three cycles of chemotherapy with mitomycin
(6 mg/m2), ifosfamide (3 g/m2), and cisplatin (50 mg/m2).29
In another trial, patients with stage IIIA NSCLC
were randomly allocated to three cycles of preoperative
chemotherapy with cyclophosphamide (500 mg/m2,
day 1), etoposide (100 mg/m2, days 1 to 3), and cisplatin (100 mg/m2, day 1) or to upfront surgery alone.30 In
both studies, radiotherapy was administered in over
half of the patients. An interim analysis revealed a statistically significant difference in favor of the induction
chemotherapy arm in both studies, resulting in a termination of the accrual after only 60 patients (out of the
120 initially planned) had been enrolled. The observed
survival differences also remained highly significant in
subsequent analyses after almost seven years of followup.31,32 It should be noted that the small number of
patients included in these studies weakens the power of
their observations. Furthermore, the trial by Rosell et
al29 has been criticised because of the poor survival outcomes of the control arm.
One study randomly assigned patients with stage
IIIA (T0–3) or T3 (N0–1), or locally treatable stage IIIB
(T4, N3), NSCLC to receive neoadjuvant docetaxel
(100 mg/m2 every three weeks) (n = 134) or no chemotherapy (n = 140) before surgery or curative-intention
radiotherapy.33 Median survival was 14.8 months in the
docetaxel group and 12.6 months in the control group
(p = non-significant). Median times to disease progression were 9.0 months (docetaxel arm) and 7.6 months
(control arm).
Preoperative chemotherapy might also have a role in
earlier disease stages. In a multicenter phase III study
conducted by the French Thoracic Cooperative Group,
355 patients with clinical IB–IIIA disease were randomly
assigned to receive two cycles of induction mitomycin
(6 mg/m2, day 1), ifosfamide (1.5 g/m2, days 1 to 3), and
cisplatin (30 mg/m2, days 1 to 3) followed by surgery
and two postoperative cycles or surgery alone.34 Patients
with pT3 or pN2 received postoperative radiation. The
overall response to induction chemotherapy was 64%.
Although median survival favored the chemotherapy
arm, the difference failed to reach statistical significance
(37 months for the chemotherapy arm vs 26 months
for the surgery alone arm, p = 0.15). Subgroup analysis
Table 10.3.2 Phase III trials of neoadjuvant chemotherapy in NSCLC
Trial
No of patients
Disease stages
included
CT regimen/
control arm
Median survival
(months)
p
CEP ×3→surgery→
CEP ×3 vs surgery
PIM→surgery→RT
vs surgery→RT
PE ×2→surgery→
PE ×4 vs surgery
MIP ×2 → surgery →
MIP ×2 vs surgery
64 vs 11
0.008
26 vs 8
<0.001
28.7 vs 15.6
NS
37 vs 26
NS
14.8 vs 12.6
NS
42 vs 37
NS
MD Anderson30
60
IIIA (N2), some IIIB
Spain29
60
IIIA (N2)
NCI36
27
IIIA (N2) biopsy
French Thoracic
Cooperative
Group34
Mattson et al33
355
IB–IIIA
274
III
Pisters et al35
354
IIA–IIIA
T×3→surgery vs
surgery
Ta/Carbo ×3→
surgery vs surgery
C: cyclophosphamide; E: etoposide; P: cisplatin; I: ifosphamide; M: mitomycin; T: docetaxel; Ta: paclitaxel; Carbo: carboplatin, NS: non-significant.
154 Textbook of Lung Cancer
revealed a significant benefit in patients with N0–1 disease
[relative risk (RR) 0.68 (95% CI: 0.49–0.96); p = 0.027],
but not for the group with N2 disease [RR 1.04 (95%
CI: 0.68–1.60); p = 0.85].
Finally, a recently reported phase III study evaluated
neoadjuvant chemotherapy in patients with clinical
stage T2N0, T1–2N1, and T3N0–1 (excluding superior
sulcus tumors). Patients were stratified by clinical stage
(IB/IIA vs IIB/IIIA) and were randomized to receive
either paclitaxel and carboplatin (every three weeks for
three cycles) plus surgery or surgery alone.35 The primary endpoint was a 33% increase in overall survival
over the expected 2.7 years median for surgery alone.
After a median follow-up of 28 months during which
354 patients had been enrolled, the trial was prematurely terminated due to the positive data coming from
the adjuvant chemotherapy trials. Median progressionfree survival was 29 months for the neoadjuvant group
and 20 months for the surgery only group [HR 0.85
(CI: 0.63–1.14); p = 0.26]. Median overall survival was
42 months and 37 months, for the preoperative and surgery only arms, respectively [HR 0.88 (CI: 0.63–1.23);
p = 0.47].
In general, preoperative chemotherapy induces a high
rate of objective responses. Further investigation is
required to select the ideal regimen in terms of efficacy
and safety and to identify subgroups of patients and/
or predictive factors associated with greater benefit.
Randomized trials evaluating the comparative efficacy
of adjuvant and neoadjuvant chemotherapy are also
warranted.
Induction chemoradiotherapy before surgery
The concurrent administration of chemotherapy with
radiotherapy has been used before surgery in patients
with stage III disease in an effort to improve survival
outcomes. Although surgery might be associated with
higher morbidity and mortality after preoperative treatment, the feasibility of this approach has been demonstrated in several phase II studies.
In the North American Intergroup trial 0139 (INT
0139), 429 patients with T1–3 pN2 disease deemed
resectable at presentation were randomized either to
induction concurrent chemoradiotherapy with 45 Gy
and cisplatin (50 mg/m2 on days 1, 8, 29, and 35) and
etoposide (50 mg/m2 days 1 to 5 and 29 to 33) followed
by surgery (for non-progressors) or to definitive chemoradiation (with cispaltin and etoposide) to 61 Gy.37 Both
groups received consolidation chemotherapy with two
cycles of cisplatin and etoposide. Although progressionfree survival was significantly prolonged in the surgery
arm (14.0 vs 11.7 months; p = 0.02), overall survival was
not different (22 months) between arms. There were
more early non-cancer deaths on the surgical arm, but
overall survival curves crossed so that, by year 3, the
overall survival favored the surgery arm (38% vs 33%).
Long-term follow-up of the INT 0139 confirmed the
superior progression-free survival and showed a trend
for superior five-year overall survival for the trimodality
therapy.38 In a subgroup analysis, patients who achieved
pathologic N0 disease had a favorable long-term survival. Moreover, patients who underwent lobectomy
had superior survival over patients receiving definitive
chemoradiotherapy (p = 0.002).
The German Lung Cancer Cooperative Group randomly assigned 558 patients with selected pathologic
stages IIIA and IIIB NSCLC subsets to chemotherapy
with cisplatin/etoposide for three cycles followed by
hyperfractionated radiotherapy to 45 Gy concurrently
with carboplatin/vindesine and then surgery or chemotherapy with cisplatin/etoposide for three cycles followed
by surgery and then radiotherapy to 54 Gy.39 Both
groups received additional radiotherapy if a complete
resection was not achieved. Of note, both arms received
radiotherapy but the timing and fractionation, as well
as the chemotherapy drugs, differed. No significant differences were observed regarding the three-year progression-free survival (18% vs 20%, p = non-significant)
and the three-year survival (26% vs 25%, p = non-significant). This study has been criticized because of the
low resection rates, and the inclusion of radiotherapy in
both arms.
The role of aggressive induction therapies in the
management of resectable stage III disease remains to
be determined. It seems that in N2 disease, patients
who achieve significant downstaging experience prolonged survival. However, the optimal management of
these patients with surgery versus definitive chemoradiation needs further clarification. The role of chemoradiation before surgery in earlier disease stages needs
to be identified.
CHEMOTHERAPY FOR LOCALLY ADVANCED
UNRESECTABLE (IIIA AND IIIB) NSCLC
Up to one-third of patients with NSCLC present with
disease that remains localized to the thorax, but is
considered too extensive for surgical treatment (stages
IIIA and IIIB). Historically, radiotherapy (RT) represented the standard of care for these patients.40 However, results were disappointing with five-year survival
Treatment of NSCLC: chemotherapy 155
rates of less than 5%, due to the high incidence of
both locoregional relapses and distant metastases. This
observation led to efforts for the development of more
active, multimodality therapies that incorporate
chemotherapy.
Chemotherapy followed by radiotherapy
Several randomized phase III studies compared RT with
the bimodality therapy of induction chemotherapy, followed by RT. Generally, studies with larger sample size
incorporating more intensive chemotherapeutic regimens demonstrated a significant survival benefit in
favor of the combined modality treatment (Table 10.3.3).
It was also suggested that the main impact of systemic
chemotherapy was a reduction in the rate of distant
relapses.41 The positive results of these randomized trials have been confirmed by two meta-analyses.12,42
Concurrent chemoradiotherapy
The simultaneous administration of chemotherapy and
RT provides the advantages of early administration of
systemic treatment as well as the additional theoretic
benefit of increasing locoregional control. Furthermore,
concurrent chemoradiotherapy offers a reduction in the
treatment time compared to the sequential approach.
In the clinical setting, concomitant chemoradiotherapy is associated with significant toxicities including
esophagitis, risk of radiation pneumonitis, and increased
myelosuppression.
The results of several phase II studies provided preliminary evidence supporting the feasibility of the addition of chemotherapy to RT.45 Subsequent randomized
trials, employing either the concurrent or the sequential
mode, compared the combined therapy with RT alone
(Table 10.3.4). Several trials demonstrated a significant
Table 10.3.3 Selected phase III trials comparing sequential chemo-RT vs RT only, in patients with advanced NSCLC
Trial
n
Stage
Regimen
Survival (median)
CALGB 843343
155
III
PV→RT (60 Gy) vs RT (60 Gy)
RTOG, ECOG,
and SWOG44
452
III
PV→RT (60 Gy) vs RT (60 Gy)
vs HFx-RT (69.6 Gy)
CMT + RT 13.8 months; RT 9.7
months (p = 0.0066)
3-year survival: CMT + RT 23%;
RT 10% (p = 0.012)
7-year survival: CMT + RT 13%;
RT 6% (p = 0.012)
Median survival: CMT + RT 13.2
months (p = 0.04 vs RT); RT 11.4
months; HFx-RT 12 months (NS)
3-year survival; CMT+RT 17%; RT
11%; HFx-RT 14%
5-year survival: CMT+RT 8%
(p = 0.04 vs RT); RT 5%; HFx-RT
6% (NS)
P: cisplatin; V: vindesine; HFx-RT: hyperfractionated RT; CMT: chemotherapy.
Table 10.3.4 Randomized phase III trials comparing combined chemoradiotherapy versus radiotherapy alone
Trial
n
Regimen
Survival (median)
Le Chevalier46
Schaake-Koning47
354
331
Soresi48
Morton49
Blanke50
95
121
215
PLVC + RT (65 Gy) vs RT (65 Gy)
P (weekly) + RT vs P
(daily) + RT vs RT
P + RT (50 Gy) vs RT (50 Gy)
MACCu + RT vs RT
P + RT ×3 cycles vs RT
2-year survival: 21% vs 14% (p = 0.02)
2-year survival: 19% vs 26% vs 13%
(p = 0.009; daily P + RT vs RT)
16 months vs 11 months; p = NS
2-year survival: 21% vs 16%; p = NS
43 weeks vs 46 weeks; p = 0.394
P: cisplatin; V: vindesine; L: lomustine; C: cyclophosphamide; M: methotrexate; A: doxorubicin; Cu: CCNU; NS: non-significant.
156 Textbook of Lung Cancer
survival benefit in favor of the combined modality
treatment,46,47 whereas others did not.48–50 Two large
meta-analyses suggested a small, but statistically significant improvement in survival with the combinedmodality regimens. In the meta-analysis by Pritchard
and Anthony, a significant decrease in the relative risk
of death with combined therapy was shown at both
one and three years in patients with unresectable stage
III disease.51 Similarly, Marino et al reported a 24%
reduction in the risk of death at one year and a 30%
reduction at two years for combined cisplatin-based
chemotherapy and radiotherapy.42
Definitive testing of concurrent chemoradiotherapy
versus the sequential approach in the phase III setting
has been also performed (Table 10.3.5). The concurrent administration of platinum-based chemotherapy
with radiotherapy demonstrated a modest although statistically significant survival benefit compared with the
sequential administration. Median survival was 15–17
months in the concurrent arm versus 12.9–14.6 months
in the sequential arms.52–55 It is interesting that the two
largest randomized trials have demonstrated remarkably similar results.52,54
The West Japan Lung Cancer Group randomly assigned
320 patients to a combination of cisplatin (80 mg/m2,
days 1 and 29), vindesine (3 mg/m2, days 1, 8, 29, and
36), and mitomycin (8 mg/m2, days 1 and 29) given
concurrently with 56 Gy of radiotherapy, split into two
28 Gy courses separated by 10 days, versus the same
chemotherapy given as induction followed by 56 Gy of
continuous radiotherapy.52 The concurrent approach
was significantly superior (p = 0.03998), with a median
survival of 16.6 versus 13.3 months and five-year survival rates of 15.8% versus 8.9%, respectively.
RTOG 9410 evaluated the use of cisplatin (100 mg/m2,
days 1 and 29) and vinblastine (5 mg/m2 weekly for five
Table 10.3.5 Phase III trials comparing sequential versus concurrent chemoradiotherapy
Trial
n
Regimen
Survival (median)
p
West Japan52
320
P/Vin/M + RT
(56 Gy; split course) vs
P/Vin/M → RT (56 Gy;
continuous)
Concurrent 16.6 months;
sequential 13.3 months
0.03998
Two-year survival: concurrent
34.6%; sequential 27.4%
Five-year survival: concurrent
15.8%; sequential 8.9%
Concurrent 15 months;
sequential 13.8 months
Two-year survival: concurrent
35%; sequential 23%
Sequential 17 months;
concurrent (daily RT)
14.6 months; concurrent
(HFx-RT) 15.6 months
Four-year survival: sequential
12%; concurrent (daily RT)
21%; concurrent (HFx-RT)
17%
Concurrent 16.6 months;
sequential 12.9 months
Three-year survival:
concurrent 18.6%;
sequential 9.5%
NR
GLOT-GFPC57
RTOG 94–1054
Czech Republic55
212
610
102
PE + RT (66 Gy) → PV
vs PV → RT (66 Gy)
PVi → RT (60 Gy) vs
PVi + RT (60 Gy) vs
PE + HFx-RT (69.6 Gy)
PV + RT (60 Gy) vs
PV → RT (60 Gy)
P: cisplatin; Vin: vindesine; M: mitomycin; E: etoposide; V: vinorelbine; Vi: vinblastine; HFx-RT: hyperfractionated RT; NS: non-significant;
NR: not reported.
NR
NS
NS
0.046
0.046
0.023
NR
Treatment of NSCLC: chemotherapy 157
doses) followed by once-daily radiotherapy (60 Gy) versus cisplatin and vinblastine at the same doses given concurrently with the same radiotherapy, or cisplatin (50
mg/m2, days 1, 8, 29, and 36) and oral etoposide (50 mg
twice daily for 10 doses on weeks 1, 2, 5, and 6) given
concurrently with hyperfractionated radiotherapy (69.6
Gy given in 1.2 Gy fractions twice daily). In this trial 610
patients with unresectable NSCLC were randomly
assigned to one of three arms. Both the median survival
and the four-year survival were significantly better in the
concurrent daily radiotherapy arm when compared with
the sequential arm (17 vs 14.6 months; p = 0.038) and
(21% vs 12%), respectively. The hyperfractionated radiotherapy arm showed a median survival of 15.6 months,
that did not reach statistical significance compared with
the sequential treatment.54 Movsas et al reported on the
quality adjusted time without symptoms of toxicity analysis of RTOG 9410.56 Although reversible non-hematologic toxicity was higher in the sequential arm, the
overall mean toxicity was highest in the sequential arm,
further supporting the use of concurrent chemoradiation
in locally advanced unresectable disease.
Multiple efforts in the phase I/II setting focused on
the incorporation of the newer chemotherapeutic agents
such as paclitaxel, gemcitabine, vinorelbine, and topoisomerase I inhibitors into chemoradiotherapy treatment. In general, acceptable toxicity and high response
rates have been demonstrated. In a randomized phase
III trial by Fournel et al, a trend towards better survival
was observed in favor of the concurrent approach.57
However, chemotherapy was different between the two
arms. In the sequential arm, cisplatin (120 mg/m2 days
1, 29, and 57) and vinorelbine (30 mg/m2 weekly for
12 doses) was followed by thoracic irradiation (66 Gy in
33 fractions). In the concurrent arm, cisplatin and etoposide for two cycles were given with the same radiation
dose. Patients received consolidation chemotherapy
with cisplatin (80 mg/m2 on days 78 and 106), plus
vinorelbine (30 mg/m2 weekly for eight cycles). The
median survival was 13.8 months for the sequential and
15 months for the concurrent arm (p = non-significant).
The two-year survival showed a trend in favor of concurrent chemoradiotherapy (35% vs 23% for sequential),
with updated results awaited.
Induction chemotherapy followed by concurrent
chemoradiotherapy
The potential advantage of using both induction and
concurrent modality treatments lies in the enhancement
of both the exposure to systemically active doses of chemotherapy and locoregional control of the disease.
Two hundred and eighty-three patients with inoperable stage III NSCLC were entered into a randomized trial
by the Cancer and Leukemia Group B (CALGB) and the
Eastern Cooperative Oncology Group.58 All received
induction chemotherapy with vinblastine and cisplatin
for five weeks followed by radiation therapy or radiotherapy concomitantly with weekly carboplatin. There
was no difference with respect to overall survival (13%
with carboplatin and 10% with radiotherapy alone) at
four years.
CALGB also conducted a trial which randomly
assigned 303 patients with stage IIIA/B disease to receive
induction paclitaxel (200 mg/m2) and carboplatin (AUC
6) for two cycles, followed by either radiotherapy alone
(60 Gy) or the same radiotherapy concurrently with
weekly paclitaxel (60 mg/m2). Median survival was
19.2 months versus 14.6 months in favor of the concurrent chemoradiotherapy arm, but the difference did not
reach statistical significance.59
Another CALGB trial randomly assigned 366 patients
to either induction paclitaxel (200 mg/m2) and carboplatin (AUC 6) followed by chemoradiotherapy [66 Gy
concurrently with weekly carboplatin (AUC 2) and
paclitaxel (50 mg/m2)] versus immediate chemoradiotherapy alone. Both median and one-year survival were
similar between the two arms (14.0 months, 48% versus
11.4 months, 58%; p = 0.154).60
The role of consolidation therapy after concurrent
chemoradiation has also been investigated. Southwest
Oncology Group (SWOG) reported on a phase II study
of concurrent chemoradiation with full doses of cisplatin (50 mg/m2, days 1, 8, 29, and 36) and etoposide
(50 mg/m2, days 1 through 5, and days 29 through 33)
followed by three cycles of docetaxel single agent (75 to
100 mg/m2). In this group of patients with pathologically documented stage IIIB disease, a promising median
survival of 27 months was achieved.61 However, only
59% of the 83 relevant patients received all three cycles
of docetaxel, illustrating the difficulties of consolidation
chemotherapy after definitive chemoradiation.
In a randomized phase II non-comparative study by
Belani et al, patients with unresected stage IIIA and IIIB
disease received two cycles of induction paclitaxel and
carboplatin followed by sequential RT (n = 91), or two
cycles of induction paclitaxel and carboplatin followed
by weekly paclitaxel and carboplatin with concurrent
RT (n = 74), or weekly paclitaxel and carboplatin plus
concurrent RT followed by two cycles of paclitaxel and
carboplatin (n = 92).62 The three arms were to be compared with a historical control using the sequential chemoradiotherapy arm of the RTOG 8808 trial, for which the
158 Textbook of Lung Cancer
available reported median survival time was 13.7 months.63
Median survival times for the sequential and concurrent arms were 13 and 12.7 months, respectively. The
concurrent/consolidation arm was associated with the
best outcome (median overall survival 16.3 months,
p = 0.34) and greater toxicity rates.
Currently, concomitant chemoradiotherapy is considered the standard therapy of unresectable stage III
NSCLC. However, it applies only to patients with good
performance status. For the present, there is no value of
adding induction chemotherapy with currently established agents. The role of consolidation chemotherapy
remains to be confirmed in randomized trials.
CHEMOTHERAPY FOR PATIENTS WITH
ADVANCED NSCLC
Patients with advanced NSCLC (stage IIIB with pleural
or pericardial effusion or stage IV), treated with best
supportive care (BSC) alone, have a median survival of
4–5 months and a one-year survival of approximately
10%.64 Throughout the 1970s and 1980s, combination
chemotherapy (usually cisplatin-based) resulted in objective responses rates in 20 to 30% of lung cancer patients,
but median survival was only six to eight months, and
few patients survived longer than one year. The most
frequently used regimens were the combinations of cisplatin with etoposide, vindesine, or vinblastine. Several
randomized trials, addressing the question of whether
the benefit of chemotherapy outweighed the cost of
toxicity over best supportive care alone, demonstrated
a small, but statistically significant survival benefit for
patients receiving chemotherapy.5 Due to limitations in
most of these studies, meta-analyses were performed to
address the same question.42,65,66 In the largest of these
meta-analyses, alkylating agents were associated with a
detrimental effect on survival, while cisplatin-based
chemotherapy conferred a 27% reduction in the risk of
death, and a 10% absolute increase in one-year survival
rates.12 Thus systemic cisplatin-based chemotherapy
has since been considered as standard care in most
patients with advanced NSCLC.67
First-line therapy
Platinum-based chemotherapy
Between 1981 and 1991, several randomized trials,
with more than 1900 patients enrolled, evaluated a wide
range of first-generation cisplatin-based chemotherapy
regimens.68–71 No significant differences emerged between
regimens, or between studies.
Le Chevalier et al were the first to compare the combination of a second-generation over a first-generation
cisplatin-based doublet.72 In this trial, patients treated
with cisplatin/vinorelbine had significantly longer median
survival compared to those treated with cisplatin/
vindesine (40 weeks vs 32 weeks; p = 0.04). Moreover,
this study demonstrated that cisplatin was necessary
since a cisplatin/vinorelbine combination was superior
to vinorelbine alone (40 weeks vs 31 weeks; p = 0.01)
(see Table 10.3.6.). Further randomized trials addressing
the same question demonstrated that second-generation
regimens are generally associated with improved efficacy,
toxicity, quality of life, or a combination of these endpoints, although statistically significant survival gain was
not uniformly found.
More recently, second-generation cisplatin-based
regimens have been more widely used. Direct comparison of these regimens in randomized phase III trials
failed to demonstrate a particular combination to be
clearly superior for NSCLC. The results of appropriately
sized trials comparing second-generation platinumbased doublets are presented in Table 10.3.7.
ECOG 1594, one of the largest randomized trials,
assigned a total of 1207 patients with advanced NSCLC
to a reference regimen of cisplatin and paclitaxel or to
one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and
paclitaxel. Patients were stratified according to ECOG
performance status (0 or 1 vs 2), weight loss in the previous six months (<5% vs ≥5%), the stage of disease (IIIB
vs IV or recurrent disease), and the presence or absence
of brain metastases. In this study no difference was
observed in terms of response rate or overall survival
between the different chemotherapy regimens; response
rates ranged from 17 to 22% and median survival from
7.4 to 8.1 months. The cisplatin/gemcitabine arm showed
significantly longer time to tumor progression when
compared with the reference arm (4.2 vs 3.4 months,
p = 0.001). Differences in the toxicity profiles of each
regimen were identified, with cisplatin/gemcitabine causing more thrombocytopenia, cisplatin/docetaxel causing more neutropenia, and the carboplatin/paclitaxel
arm causing the lowest rate of potentially life-threatening
adverse events.81
TAX 326 was another large trial that randomized
1218 patients to one of three treatment groups: docetaxel/
cisplatin (DC regimen), docetaxel/carboplatin (DCb
regimen), or the control arm of vinorelbine/cisplatin (VC
regimen). Patients treated with DC had a median survival of 11.3 versus 10.1 months for VC-treated patients
(p = 0.044). The two-year survival rate was 21% and
Treatment of NSCLC: chemotherapy 159
Table 10.3.6 Randomized trials of cisplatin plus a new agent versus cisplatin plus an old agent
Trial
Therapy
Le Chevalier72 V/P
Vi/P
Bonomi73
Ta (low)/Pa
Ta (high)/P
E/P
Giaccone74
Ta/P
Ten/P
Cardenal75
G/P
E/P
Niho76
CPT/P
Vi/P
Negoro77
CPT/P
Vi/P
Kubota78
T/P
Vi/P
No of patients
206
200
198
201
200
166
166
68
67
100
103
129
122
151
151
Odds ratio (%)
Median survival (weeks)
30
19
25.3
27.7
12.4
28
41
41
22
29
22
44
32
37
21
40
32
41.2
43.3
32.9
42.9
42.0
37.7
30.3
45
50
50
46
49.3
41.9
One-year survival (%)
40
32
37.4
40.3
32
41
43
26
32
43
48
46
38
48
43
p
0.04
0.048b
NS
NS
NS
NSc
NS
a
Paclitaxel (low): 135 mg/m2 intravenously over 24 hours; paclitaxel (high): 175 mg/m2 intravenously over 24 hours plus granulocyte colony-stimulating
factor.
b
Comparing the two paclitaxel groups combined with the etoposide/cisplatin group; other comparisons were not significant.
c
Survival differences were significant in the stage IV subset.
P: cisplatin; Vin: vindesine; E: etoposide; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; Ten: Teniposide; G: gemcitabine; T: docetaxel; Vi: vindesine;
CPT: irinotecan; NS: non-significant; NR: not reported.
Table 10.3.7 Selected phase III trials comparing second-generation platinum-based doublets
Trial
n
Regimen
Median survival (months)
p
SWOG 950979
ILCSG80
ECOG 159481
TAX 32682
408
607
1207
1218
P/V vs Carbo/Ta
Carbo/Ta vs P/V vs P/G
P/Ta vs P/G vs P/T vs Carbo/Ta
P/V vs P/T vs Carbo/T
8.0 vs 8.0
9.9 vs 9.5 vs 9.8
7.8 vs 8.1 vs 7.4 vs 8.1
10.1 vs 11.3 vs 9.4
NS
NS
NS
0.04a
NSb
a
P/V vs P/T, p = 0.04 in favor of P/T.
P/V vs Carbo/T, p = NS.
P: cisplatin; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; G: gemcitabine; T: docetaxel; Vi: vindesine; CPT: irinotecan; NS: non-significant;
NR: not reported.
b
14% for DC and VC, respectively. Overall response rate
was 31.6% for DC and 24.5% for VC (p = 0.029).
Median survival (9.4 vs 9.9 months, p = 0.657) and
objective response rate (23.9% vs 24.5%) were similar
for patients treated with DCb and VC, respectively. The
incidence of neutropenia, thrombocytopenia, infection,
and febrile neutropenia was similar with all three regimens. Patients treated with either docetaxel regimen
had a consistently improved quality of life compared to
those treated with VC.82
Non-cisplatin-containing chemotherapy
Cisplatin-based chemotherapy is associated with considerable cisplatin-related toxicity.83 Thus, nausea and
emesis are often severe and delayed, whereas neurotoxicity, renal toxicity, and ototoxicity are dose-related
and difficult to handle. Cisplatin administration requires
additional hydration that is intolerable to a significant
proportion of NSCLC patients due to old age and/or
concomitant cardiac or cardiopulmonary diseases.
Additionally, a prolonged hospital stay is mandatory,
160 Textbook of Lung Cancer
critical from the convenience as well as the economic
aspects.84,85
Cisplatin versus carboplatin
The substitution of cisplatin for carboplatin has been
employed as a means to overcome cisplatin-related incovenience. Several randomized trials have compared cisplatin with carboplatin doublets.82,86,87 In a trial by Rosell
et al, 618 patients were randomized to receive paclitaxel in combination with either cisplatin or carboplatin.
The study was designed to demonstrate a non-inferior
response rate with carboplatin.This was the only trial to
demonstrate a statistically significant improvement
in overall survival in favor of the cisplatin arm (9.8 vs
9.2 months, p = 0.019).86
TAX 326, although not designed to directly compare
the 814 patients randomized to docetaxel/cisplatin and
docetaxel/carboplatin arms, demonstrated a statistically
significant improvement in survival for docetaxel/cisplatin compared to the control arm of cisplatin/vinorelbine. Cisplatin/vinorelbine itself resulted in numerically
superior survival outcomes compared to the carboplatin/docetaxel combination.82
Finally, a meta-analysis using abstracted data identified eight trials including 2948 patients that evaluated
the substitution of cisplatin for carboplatin. Cisplatinbased chemotherapy resulted in higher response rates
without any difference in overall survival [HR 1.050
(95% CI: 0.907–1.216); p = 0.515). Based on the above
data it is reasonable to conclude that cisplatin might be
slightly superior to carboplatin. Although this difference is slim, it might have an impact for earlier disease
stages. The choice of the compound to be used should
be made on a case to case basis and should be tailored
to the patient’s needs.88
Platinum versus non-platinum doublets
The development of the newer agents led to novel, effective non-platinum-containing chemotherapy regimens
and to the initiation of several randomized trials designed
to determine whether these regimens are comparable to
platinum-based combinations in terms of efficacy.89–95
In general, these trials did not demonstrate a statistically significant survival benefit in favor of patients
treated with platinum-based doublets (see Table 10.3.8).
In three trials, a trend towards better overall survival
was observed in patients treated with platinum-based
combinations.91,92,95 On the other hand, another study
demonstrated that the combination of vinorelbine and
gemcitabine was superior to vinorelbine plus carboplatin
Table 10.3.8 Platinum- versus non-platinum-based doublets
Author
Regimen
Georgoulias89
T/P
T/G
Ta/C
Ta/G
G/V
G/P
P/V
G/P
Ta/P
Ta/G
G/P
G/P/V
G/V → V/If
GVP
GV
V/P
T/G
Kosmidis90
Gridelli91
Smit92
Alberola93
Laack94
Georgoulias95
No of
patients
441
248
254
501
490
557
287
117
134
Response
rate (%)
Median TTP
(months)
32
31
28
35
25
}30
9.5
8
6.3
6.1
17 weeks
22 weeks
22 weeks
5.6
4.4
3.9
6.3
10
9.5
10.4
9.8
32 weeks
38 weeks
38 weeks
8.9
8.1
6.7
9.3
5.7
19.3
22.3
8.5
8
8.1
32.4 weeks
35.9 weeks
9.7
9
37
32
28
42
41
27
28.3
13
39.2
30
Median OS
(months)
p
One-year
survival (%)
NR
NS
0.32
0.08
NS
41.7
41.4
NR
32.6
35.5
26.5
38
NS
NS
0.96
5
P: cisplatin; V: vinorelbine; G: gemcitabine; T: docetaxel; If: Ifosfamide; Ta: paclitaxel; C: carboplatin; Epi: epirubicin; NR: not reported;
NS: non-significant; TTP: time to tumor progression; OS: overall survival.
34
27.5
33.6
34.3
40.8
Treatment of NSCLC: chemotherapy 161
in terms of response rate, progression-free survival,
overall survival, and clinical benefit.96
In most trials, non-platinum doublets were associated
with a more favorable toxicity profile.89,91,93–95 However,
in two of them no significant differences in terms of
toxicity were reported.90,92 Two trials evaluating the issue
of cost-effectiveness reported contradictory results,
with one study demonstrating superiority of platinumbased doublets,92 whereas in the other no difference
between the two arms was reported.90
It should be noted here that none of the above mentioned trials was adequately sized to test equivalence,
precluding safe conclusions regarding the comparative
activity of platinum versus non-platinum doublets.
A recently published meta-analysis reviewed 37 randomized phase II and III studies comparing a platinumbased regimen with the same regimen either without
cisplatin or with cisplatin replaced by a non-platinum
compound, in patients with advanced NSCLC.97 This
meta-analysis included a total of 7633 patients and
reported on the response rates, activity, and survival of
platinum- versus non-platinum-based chemotherapy.
A 62% increase in the odds ratio (OR) for response was
attributable to platinum-based therapy (p <0.0001).
When the analysis was restricted in trials that had combinations of the newer agents as the comparator, the
benefit was 17% in favor of platinum (14 trials including
3204 patients; p = 0.042).
Overall, the one-year survival rate was 34% and 29%
for the platinum- and non-platinum-containing regimens,
respectively (p = 0.0003). However, when platinumbased therapies were compared to combinations of the
newer agents, no statistically significant increase in oneyear survival was found (36% vs 35%, p = 0.17). When
the toxicity of platinum-based regimens was compared
with newer, non-platinum combinations, significantly
higher hematologic toxicity, nausea and vomiting, and
toxic death rate were observed, but no significant increase
in febrile neutropenia rate, neurotoxicity, or nephrotoxicity was reported.97
Accordingly, the current American Society of Clinical
Oncology (ASCO) guidelines make no distinction between
platinum-based and non-platinum doublets as the preferred first-line treatment in patients with advanced
NSCLC.98
Two drugs versus one drug
A third way to deal with the chemotherapy toxicity in
patients with advanced NSCLC is to use a single-agent
chemotherapy rather than combination treatments.
Several trials have compared a doublet versus a singleagent therapy (Table 10.3.9).
Most studies evaluated a platinum-based doublet
versus the corresponding non-platinum monotherapy,102–104,106,107 some tested a new drug versus a
platinum older drug combination,99,101 and others compared cisplatin monotherapy versus a platinum new
drug combination.84,85,105,108
In general, new single agents were shown to be
equally effective and less toxic than the old cisplatinbased doublets.99,101 However, most of the studies evaluating the newer agents over a platinum new drug
combination have clearly demonstrated a superiority
for the combination therapy.85,102,104,105 Similarly, most
of the studies comparing platinum agents to newer
platinum-based doublets demonstrated a superiority
for the combination therapy.105,108
Based on the above data, ASCO guidelines98 suggest
that two-drug combination chemotherapy remains the
standard first-line treatment of patients with advanced
NSCLC.
Triplets for the treatment of advanced NSCLC
Several randomized trials evaluated the potential role of
three-drug combinations as a means of improving survival outcomes in NSCLC. The most recent studies are
presented in Table 10.3.10. Although three drug combinations led to significantly higher response rates, they
failed to demonstrate any benefit in terms of time to
tumor progression and overall survival, while they were
associated with significantly higher toxicity.
Duration and timing of first-line therapy
The optimal duration of treatment in patients with
advanced NSCLC has also been evaluated in randomized trials. In a trial by Smith et al, 308 patients were
randomized to receive three or six cycles of mitomycinvinblastine and cisplatin.112 No survival difference was
observed between the two arms, while patients receiving six treatment cycles experienced significantly higher
toxicity. In a randomized trial by Socinski et al, 230
patients received the paclitaxel/cisplatin doublet for
either four cycles, or until disease progression.113 Upon
progression, all patients were treated with weekly paclitaxel. The median survival did not differ significantly
between the two arms (8.5 months for the ‘until progression’ group vs 6.7 for the ‘four cycles’ group, p = 0.63).
It is interesting to note that in the treat ‘until progression’ arm the median number of cycles administered was
four. Toxicity was higher in this arm due to the cumulative neuropathy. Accordingly, ASCO guidelines support the administration of no more than six cycles of
first-line chemotherapy. In non-responding patients
treatment should be stopped at four cycles.98
162 Textbook of Lung Cancer
Table 10.3.9 Randomized studies comparing single-agent versus combination therapy
Author
Regimen
Manegold99
G
P/E
P/Vin
P/CPT-11
CPT-11
G
P/Vin
P/Vin
P/V
V
G/C
G
Ta/P
Ta
P/G
P
P/Tir
P
T/P
T
Negoro100
Vansteenkiste101
Le Chevalier102
Sederholm103
Lilenbaum104
Sandler105
von Pawel85
Georgoulias106
No of patients
156
ORR (%)
17.2
7
31.7
43.7
20.5
20.2
20
19
30
14
30
12
30
16
30.4
11.1
27.5
13.7
36.5
21.7
398
169
612
229
586
522
446
319
Median TTP
(months)
4.2
3.7
NR
Median OS
(months)
p
NR
45.6 weeks
46 weeks
50 weeks
9.2
6.7
13.7
5.5
NR
8.0
9.2
7.2
6
11
4
9
8.5
NR
6.5
5.6
9.1
3.7
7.6
12.9 weeks 34.6 weeks
11.6 weeks 27.7 weeks
4.0
10.5
2.5
8
One-year
survival (%)
NR
NR
NS
38.3
41.8
0.13
0.01a
NS
0.023
0.004
0.0078
NS
22
19.3
NR
NR
36
31
39
28
33.9
22.5
44
43
a
P/V vs V.
G: gemcitabine; P: cisplatin; E: etoposide; Vin: vindesine; V: vinorelbine; C: carboplatin; T: docetaxel; Ta: paclitaxel; Tir: tirapazamine; NR: not reported;
NS: non-significant; ORR: overall response rate; TTP: time to tumor progression; OS: overall survival.
Table 10.3.10 Randomized trials comparing triplets versus doublets for the treatment of advanced NSCLC
Author
Regimen
Alberola93
P/G
P/G/V
G/V
G/V/P
P/G
M/I/P
Ca/G
M/I/P
M/Vin/P
P/V
P/G
P/G/V
Laack94
Crino109
Danson110
Comella111
No of patients
370
287
307
372
180
ORR (%)
Median survival (months)
42
41
13
28
38
26
30
33
9.3
8.2
8.3
7.5
8.6
9.6
8.5
8.7
25
30
47
8.1
9.7
11.8
p
NS
NS
NS
NS
NS
P: cisplatin; G: gemcitabine; V: vinorelbine; M: mitomycin; I: ifosfamide; Ca: carboplatin; Vin: vinblastine.
The optimal time for the patients to be started on
chemotherapy has not been studied in randomized trials. However, since chemotherapy clearly prolongs survival and patients with impaired performance status
(PS) demonstrate poor tolerance to chemotherapy, the
current recommendations suggest the initiation of treatment as soon as possible, prior to any deterioration of
patients’ PS.98
Treatment of NSCLC: chemotherapy 163
PATIENT POPULATIONS WITH SPECIAL
CONSIDERATIONS
Elderly populations
About 40% of patients diagnosed with NSCLC are aged
70 years or older. It is estimated that only 25% of elderly
patients finally receive chemotherapy.114 Elderly patients
were frequently excluded from large co-operative group
trials due to considerations for increased toxicity. However, in an analysis of the Statistics, Epidemiology, and
End Results (SEER) database, the efficacy of chemotherapy in the elderly is equivalent to that in younger
patients.115 Moreover, age has not been established as
an independent prognostic factor for survival.
The Elderly Lung Vinorelbine Italian Study (ELVIS)
was one of the first large prospective randomized trials to
evaluate the role of chemotherapy in elderly patients.116
A total of 161 patients 70 years of age or older were
randomized to receive vinorelbine (30mg/m2, days 1
and 8, every three weeks) or BSC. Overall survival was
significantly better in the vinorelbine arm (28 weeks
versus 21 weeks, p = 0.03) and quality of life was significantly improved with chemotherapy. The same group
of investigators subsequently conducted the Multicenter
Italian Lung Cancer in the Elderly Study (MILES),
designed to test whether the combination of vinorelbine and gemcitabine was superior to either single agent
alone.117 This trial, which enrolled 698 patients, failed
to demonstrate any difference in terms of response rate
or overall survival between arms. However, a smaller trial
(n = 120) that compared vinorelbine monotherapy to
the vinorelbine-gemcitabine combination reported a survival benefit in favor of the combination arm (median
overall survival 6.7 months vs 4.2 months, p <0.01).118
Currently, ASCO guidelines recommend single-agent
therapy for the treatment of elderly patients with
NSCLC.98
Patients with poor performance status
PS has been consistently identified as one of the most
important prognostic factors in patients with advanced
NSCLC.5 It has also been established that patients with
ECOG PS of 0–1 derive significant benefit from systemic chemotherapy, while patients with ECOG PS 3–4
should be offered palliative care.5 However, it is less
clear which is the optimal treatment of patients with PS 2.
Generally, these patients have short survival and are
anticipated to experience high toxicity rates when combination chemotherapy is considered.81,119,120 For the
present, most of the data regarding the management of
this particular patient population are mainly derived
from subgroup analysis of larger trials. It should be
noted though that PS 2 patients constitute only a small
proportion of patients enrolled in first-line treatment
trials, despite the fact that they account for 30–40% of
the total NSCLC population.
In an interim analyis of ECOG 1594 trial, PS 2 patients
experienced high rates of severe toxicity in all three
cisplatin-based doublets.81 However, patients treated in
the carboplatin/paclitaxel arm had acceptable toxicity
rates, suggesting that this regimen could be suitable for
further evaluation in this patient population.81 Subgroup analysis of PS 2 patients from a CALGB trial that
randomized patients to receive paclitaxel monotherapy
or a combination of carboplatin and paclitaxel demonstrated significantly superior survival and tolerable toxicity for patients treated with the combination.104
Until definitive data derived from trials focusing on
this particular group of patients emerge, single-agent
chemotherapy with the newer agents should be the preferred option for PS 2 patients.121 Carboplatin- or lowdose cisplatin-based chemotherapy might also be used.121
In any case, patient preferences, the existing co-morbidities, and the anticipated chemotherapy-related toxicity should be considered prior to the final decision.
SECOND-LINE THERAPY
The availability of new active regimens in the first-line
setting has prompted several investigators to consider
second-line therapy for patients with advanced NSCLC,
since a substantial percentage of patients maintain a
good PS upon recurrence. Initial studies employing the
newer agents either alone122,123 or in combination124,125
showed significant activity in pretreated patients with
advanced NSCLC. However, most of these studies were
small, and many did not report details on prior treatment or patient characteristics; in addition, although all
the studies reported response rates, very few provided
median survival times or one-year survival rates, thus
precluding safe conclusions for the value of second-line
chemotherapy.
Docetaxel was the first agent to be tested as secondline therapy in randomized phase III trials. In a study
by Fossella et al, 373 patients pretreated with platinumcontaining regimens were randomized either to two
dose levels of docetaxel (75 mg/m2, or 100 mg/m2) or to
a single agent (ifosfamide or vinorelbine) control arm.126
Although no statistically significant difference was
observed in terms of overall survival between the three
arms, docetaxel 75 mg/m2 resulted in a longer time to
164 Textbook of Lung Cancer
progression and higher one-year survival rates compared
to the control arm (32% vs 19%, p = 0.025). Furthermore, about 30% of patients in the control group eventually received docetaxel, a fact that may have diminished
observable differences between the two arms. In a trial
by Shepherd et al, 204 patients with platinum refractory disease were randomized to receive docetaxel 100
mg/m2 or best supportive care alone.127 An interim
analysis that identified significant toxicity in the docetaxel arm led to the reduction of docetaxel dose to 75
mg/m2. The final analysis showed that, although the
response rate was only 7%, patients treated with docetaxel achieved a higher time to tumor progression (2.5
vs 1.6 months, p <0.001) and overall survival (7 vs
5 months, p = 0.047) compared to the control group. The
study by Shepherd et al established docetaxel as the standard comparator arm for subsequent randomized trials.
Based on the results of these studies, the FDA approved
docetaxel as second-line therapy in NSCLC.
A non-inferiority phase III study compared docetaxel
with pemetrexed, a multitargeted antifolate, as secondline therapy in NSCLC.128 Five hundred and seventy-one
patients were randomized to receive docetaxel (75 mg/m2)
or pemetrexed (500 mg/m2) plus vitamin supplementation. No significant difference was observed in overall
(pemetrexed 8.3 months vs docetaxel 7.9 months) or
one-year survival (29.7% for both drugs). Furthermore,
neutropenia and febrile neutropenia were significantly
lower with pemetrexed. This trial led to the approval of
pemetrexed in the second-line treatment of NSCLC.
A weekly schedule of docetaxel was compared with
the classic every three weeks schedule in two randomized phase III trials.129,130 In the trial by Gridelli et al,129
comparable overall survival rates were reported (6.7 vs
5.8 months for the weekly arm) but the weekly schedule
was associated with better safety and quality of life profiles. In contrast, in the trial by Schuette et al,130 a trend
towards better survival was observed for patients in the
weekly arm (>8 months versus 5.8 months, p = 0.08).
Additional investigations in the field of second-line
therapy focused on the introduction of two-drug combinations in the second-line setting that generally resulted
in high toxicity rates without any survival benefit over
monotherapy.131
TARGETED THERAPIES IN ADVANCED NSCLC
Although chemotherapy has resulted in some progress
in the overall management of patients with lung cancer
in recent years, with increasing use of neoadjuvant and
adjuvant strategies and second-line chemotherapy, treatment outcomes for NSCLC continue to be disappointing.
Fortunately, the picture is changing with the introduction of targeting therapies. Inhibition of the epidermal
growth factor receptor (EGFR) family is at the forefront,
led by the tyrosine kinase inhibitors gefitinib (Iressa®)
and erlotinib (OSI-774 Tarceva®), but angiogenesis
inhibition with bevacizumab (Avastine®) has also produced interesting data from recent trials. The basis for
the development of this mode of therapy is described
elsewhere in this book.
Erlotinib has been approved by health authorities in
many countries for the treatment of patients with locally
advanced or metastatic NSCLC after failure of at least
one prior chemotherapy regimen. The study by the
Canadian Clinical Trials Group delivered the backbone
of the data for this decision. The study included a total
of 731 patients randomized using a 2:1 randomization
scheme: 488 in the erlotinib arm and 243 in the placebo arm. EGFR status was determined for 238 of the
731 study patients for whom tissue samples were available prior to the study. A positive EGFR expression status was defined as having at least 10% of cells staining
for EGFR. Survival of erlotinib-treated patients was
superior to that of placebo-treated patients and median
survival duration of erlotinib-treated patients was 6.7
months, compared with 4.7 months for placebo-treated
patients. Exploratory univariate analysis showed a larger
survival prolongation in two subsets of patients: those
who never smoked and those with EGFR-positive
tumors. Erlotinib was also superior to placebo in terms
of progression-free survival, and had a response rate of
8.9 versus 0.9%. Severe rash occurred in 8% and severe
diarrhea occurred in 6% of erlotinib-treated patients.132
Similar results have been obtained in phase II trials
with erlotinib. The clinical and biologic features associated with EGFR have been analyzed in studies performed in the US, Europe, South Korea, Taiwan, China,
and Japan, and considerable efforts have been made to
identify predictive factors for response to elucidate the
molecular mechanisms involved. The most important
advance has been the identifiation of somatic mutations
in the 90% or so of patients with objective responses to
gefitinib or erlotonib. In addition to non-smoker females
and adenocarcinoma, Asian descent has turned up as
an important predictive prognostic factor associated
with the response and survival benefit of both gefitinib
and erlotinib.
In addition to the phase III trials with the two tyrosine
kinase inhibitors, several articles have been published
based on experience with a compassionate-use program
Treatment of NSCLC: chemotherapy 165
in patients with advanced NSCLC who have failed prior
chemotherapy or were unfit for chemotherapy. Some of
the studies have specifically analyzed the efficacy and
tolerability of gefitinib in patients with poor performance status or in elderly patients. All studies have
shown that gefitinib has clinical antitumor activity and
also good tolerability, with higher response rates in the
Asian studies than in European or European-heritage
Americans.133
With respect to bevacizumab, a monoclonal antibody
directed against the vascular endothelial growth factor
(VEGF), the results of a randomized trial in 444 patients
with metastatic NSCLC were presented at the ASCO
meeting in 2005. Bevacizumab was added to paclitaxel
and carboplatin (PCB) and compared with chemotherapy alone (PC). The response rate (27% versus 10%,
p <0.0001), progression-free survival (6.4 months
versus 4.5 months, p <0.0001), and median survival
(10.2 months versus 12.5 months, p = 0.0075) were
higher in the bevacizumab arm. Both regimens were well
tolerated, but hemorrhage was more frequent in the
PCB arm (4.1% versus 1.0%). There were 11 treatmentrelated deaths (9 in the PCB arm and 2 in the PC arm),
of which 5 were due to hemoptysis, all in the PCB arm.
It is noteworthy that the trial excluded patients with
squamous cell carcinoma, and thus mainly included
patients with adecarcinoma.134,135
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11
Treatment of small cell lung cancer
11.1 Treatment of SCLC: surgery
Hisao Asamura, Riken Kawachi
Contents Introduction • Primary surgery • Induction chemotherapy plus adjuvant surgery
• Salvage surgery
INTRODUCTION
The role of surgery in the management of small cell
lung cancer (SCLC) remains a controversial and as yet
undecided issue despite re-examination of this role over
the past 30 years. The British Medical Research Council
performed two large, randomized, prospective trials of
surgery versus radiotherapy in the 1960s and 1970s,
which reported the failure of surgery alone to control
this disease when compared to radiotherapy.1,2 Although
the results of this trial set the standards for non-surgical
treatment for SCLC thereafter, this study must be criticized
from the present view point for the following issues:
•
•
•
•
SCLC located in the peripheral lung was excluded
from the study since only tumors diagnosed by rigid
bronchoscopy prior to the treatment were enrolled.
Complete resection of the tumor could be achieved
in only 48% of the patients assigned to the ‘surgery’ arm.
No intraoperative staging was done.
Modern clinical staging techniques (CT scan and
mediastinoscopy) were not used. As a result, these
studies included very few patients with very early
stage disease (T1–2N0M0) who are thought to
benefit from surgery most.
In the late 1960s and mid-1970s, surgery for early
stage SCLC was championed by other reports, where
survival was significant for tumors located in the periphery of the lung confined to the lung, with N0 status,
and treated by lobectomy.3,4 Reports in the late 1970s
and early 1980s further demonstrated that surgical
therapy alone could provide curative treatment in up to
25% of such patients.5,6 A report by the Veterans
Administration Surgical Oncology Group showed a
23% five-year survival rate for 132 patients resected,
and concluded that resection was definitely indicated in
patients with T1N0 lesions, and probably indicated in
those with T1N1 or T2N0 lesions.6
Since these earlier studies, the arrival of new diagnostic tools, such as the higher resolution CT scan and
positron emission tomography, has enabled identification of very limited disease with a higher potential for
cure. In addition, platinum-based combination chemotherapeutic regimens have become available since the
early 1980s, with an objective response rate as high as
80%. With the addition of postoperative chemotherapy,
even better long-term survival in this very early stage of
disease has been reported. In stage I disease, up to 70% of
patients will be cured. In more advanced disease (stages
II and IIIA), when the tumor is totally excised at surgery
and treated with postoperative chemotherapy, five-year
survivals in the range of 20–30% can be expected.7,8
However, as for non-small cell lung cancer (NSCLC),
the prognosis of patients with N2 disease is quite poor,
and the chance of surgical intervention is least.9,10
The role of surgery in multimodality therapy to improve
control of the primary site has been investigated by utilizing induction chemotherapy prior to surgical
resection.11–13 These programs have also included consolidation chemotherapy as well as mediastinal radiotherapy with or without prophylactic cranial irradiation.
The final role that has been suggested for surgery in the
treatment of SCLC is that of ‘salvage’ treatment when
primary chemo-irradiation fails to control the local disease or when recurrence occurs and only the primary
site is affected.14 In these instances, surgical treatment
after reinduction chemotherapy has been utilized as a
‘salvage’ procedure.
In summary, the present-day role of surgery in the
management of SCLC can be categorized into four
groups:
•
•
•
•
primary surgery (surgery alone);
primary surgery followed by systemic adjuvant
chemotherapy;
induction (neoadjuvant) chemotherapy/chemoradiotherapy followed by surgery; and
salvage surgery after definitive chemoradiotherapy.
Treatment of SCLC: surgery
Upfront surgery without any following additional treatment is becoming less common since the higher activity
in extensive disease (ED) SCLC has been established
and become well known. Another reason for upfront
surgery is preoperatively undiagnosed tumors, especially clinical T1 and T2N0 diseases in peripheral locations, which continue to be resected by surgeons and
are found to be SCLC postoperatively.
PRIMARY SURGERY (SURGERY ALONE AND SURGERY
WITH POSTOPERATIVE CHEMOTHERAPY)
Complete resection of SCLC, often without prior knowledge of the cell type, will result in significant five-year
survival. Several reports have suggested that early stage
SCLC can be cured by surgical resection alone
(Table 11.1.1).10,12,15–29 For instance, Shah et al15 retrospectively analyzed the prognosis of 28 patients who
received surgery alone for SCLC; and reported a fiveyear survival of 43.3%. They have stated that the prospects of cure by operation are similar to those with
NSCLC. However, the most recent series reporting their
data suggest that postoperative chemotherapy is a necessary part of treatment (Table 11.1.1).23 In most centers, following surgical resection, a minimum of four to
six courses of adequate two- or three-drug regimen chemotherapy is advised. In a co-operative international
lung cancer multimodality treatment trial, 112 patients
with SCLC underwent initial surgical resection and
were then randomized to receive one of two intensive
postoperative chemotherapy regimens.30 The projected
36-month survival rate for 43 patients with N0 disease
was 65%; for 43 with N1 disease, 52%; and for 26 with
N2 disease, 29%. If hilar and mediastinal lymph node
disease is found at the time of surgery, postoperative
mediastinal irradiation is also advised, although its role
is not certain. The role of prophylactic cranial irradiation has yet to be decided as well.
More recently, Brock and co-workers emphasized that
highly selected patients with SCLC might benefit from
surgery and adjuvant chemotherapy, particularly if the
chemotherapy was platinum-based.23 In the retrospective study, the five-year survival for patients with stage
I disease who received adjuvant chemotherapy was 63%,
and among them, the five-year survival for patients
receiving platinum chemotherapy was 86%. In the Japan
Clinical Oncology Lung Cancer Study Group trial
(JCOG9101), the study also reported better survival for
early stage SCLC patients.22 Sixty-one patients with
completely resected SCLC received chemotherapy.
Ninety percent of the patients received two to four
171
courses of chemotherapy consisting of cisplatin and
etoposide. Three-year survival was 61%, 68% in clinical
stage I disease.
Badzio and co-workers, in their retrospective analysis,
demonstrated a beneficial effect for surgical resection.21
They used matched case–control methodology to minimize
selection bias. A group of 134 patients were selected for
comparative analysis; 67 were treated with surgical resection followed by chemotherapy and 67 were managed
with chemoradiotherapy. They demonstrated a significant
difference in survival between operated and non-operated
patients. Five-year survival in patients treated with and
without surgery was 27% and 4%, respectively. The relative hazard ratio of death in patients treated with surgery was 0.42 (95% confidence interval 0.28–0.61). In
their study, survival advantage was observed in patients
with N0/N1 except for N2 disease, and they suggested
that surgery added to chemotherapy might benefit in
limited SCLC.
However, it is still difficult to compare this multimodality surgical approach to chemoradiation alone, since
medical oncologists on the whole do not classify these
‘very limited’ tumors as a separate entity.31 Despite this,
some retrospective analyses have been performed. Osterlind and co-workers, in their retrospective analysis,
failed to demonstrate any beneficial effect for surgical
resection.32 While they demonstrated a significantly
better prognosis for 79 patients who met criteria for surgical resectability prior to treatment than for 696 patients
who did not, there was no significant difference in survival between 33 operated and 46 non-operated patients.
Again in this study, however, only 33% of the operated
patients underwent complete resection, which suggested
that the criteria for resectability were not predictive
enough, and the authors’ unfavorable statement regarding
the benefit of surgery was not conclusive. On the other
hand, Shepherd and co-workers have suggested a twofold improvement in survival utilizing surgery as part of
the treatment, by improving control of the primary site.12
It must be emphasized that the description of stage of
patients in such a study, by not only limited disease
(LD)–ED but also the tumor, node, metastasis (TNM)
system is crucial to make the comparison possible
between primary surgery and chemoradiation alone.
INDUCTION CHEMOTHERAPY PLUS ADJUVANT
SURGERY
The role of surgery in more proximal tumors with clinical N1 or minimal N2 disease (but still resectable by
172 Textbook of Lung Cancer
Table 11.1.1 The clinical outcome of patients who underwent primary surgery with or without postoperative adjuvant
chemotherapy for SCLC
Author
No of patients
Median survival (months)
(a) Surgery + chemotherapy
ISC-LCSG16
183
Coolen17
15
Davis18
37
Muller19
45
18
Toronto Group12
Salzer10
Cataldo20
79
25
60
21
Badzio21
67
JCOG22
61
Brock23
45
(b) Surgery ± chemotherapy
Lucchi24
127
Miyazawa25
Merkle26
Maassen27
12
25
170
124
(c) Surgery alone
Coolen17
15
Shah15
28
Sorensen28
Shore29
76
40
a
30-month survival.
3-year survival.
b
18
Five-year survival rate (%)
63a (TN0M0)
37b (TN2M0)
27
60 (stage I)
50 (stage I)
35 (stage II)
21 (T3N2)
36
57 (stage I)
28 (stage II)
34 (stage IIIA)
40
25 (N2 disease)
40 (stage I)
36 (stage II)
15 (stage III)
27
59 (stage I)
31 (stage II)
4 (stage III)
57
76 (stage I)
38 (stage II)
39 (stage III)
63 (stage I)
25 (stage II/III)
22.6
47.2 (stage I)
14.8 (stage II)
14.4 (stage III)
50 (latter period)
8 (former period)
18
20
13
12 (stage I)
43.3
57.1 (stage I)
55.5 (stage II)
12
27
Treatment of SCLC: surgery
173
Table 11.1.2 The clinical outcome of patients who underwent induction (neoadjuvant) chemotherapy followed by surgery
for SCLC
Author
No of patients
Median survival (months)
17
Salzer37
Holoye38
Johnson39
Lad40
Wada41
11
37
25
38
11
13
14
14
26
24
70
17
Fujimori43
21
61.9
Eberhardt42
Veronesi44
46
23
36
24
Prager33
Baker34
Williams35
Shepherd36
33
21
Not reached (stage I)
16 (stage II)
12 (stage III)
Five-year survival rate (%)
65a
48
36
47
25
19
15.4
30.70
80 (c-stage I/II)
50.3 (p-stage I/II)
66.7a
73.3a (c-stage I/II)
46
25a
91a (stage I)
14a (stage II/III)
a
3-year survival.
NSCLC criteria) is less apparent. The results of ever
published studies are summarized in Table 11.1.2.33–44
Among these, the experience of the Toronto Group12
and the Innsbruck Group10 suggested that with this
combined modality treatment, utilizing surgery as an
adjuvant, five-year survival rates in the range of 40%
can be obtained (Table 11.1.3). Those tumors with
good responses to chemotherapy, having been downstaged by the time of surgery to an N0 level, have a
five-year survival rate as high as 60–70%. Persisting
nodal disease yields a less satisfactory 20–30% five-year
survival rate. An interesting side-light of such therapy
is the fact that many of the resected tumors contain no
remaining SCLC, but do contain persisting elements of
NSCLC.
The North American Lung Cancer Study Group
reported the results of a randomized trial comparing
the non-surgical to the adjuvant surgical approach in
limited disease (Figure 11.1.1).40 Although most of the
146 patients randomized following induction chemo-
Table 11.1.3 Induction chemotherapy followed by surgery
for SCLC (the Toronto Group results)
Stage
Overall
N0
N1
N2
No of patients
Median
survival
(years)
Estimated
five-year
survival rate (%)
38
11
13
14
1.8
Not reached
1.3
1
38
45
30
40
therapy were initially staged as ‘limited’ (versus ‘very
limited’), the results of this randomized trial showed no
difference in survival of either arm. In 70 patients in the
surgery group, complete resection was possible in 77%,
and the pathologic complete response rate after induction chemotherapy was 19% compared with the clinical complete response rate of 40%. This study also
174 Textbook of Lung Cancer
Registration
Induction chemotherapy (CAV) × 5
Objective response
therapy followed by surgery, the comparative, randomized study between standard chemoradiotherapy and
multimodality treatment including surgery is not realistic. The future directions of the study should be, therefore, the well-prepared phase II trial with novel regimens
as an induction treatment after the most updated preoperative staging, including PET scanning.
Randomize
Thoracotomy
No surgery
Thoracic and brain radiation
Figure 11.1.1
Diagram of study design of Lung Cancer Study Group Study 832.
failed a subset analysis that attempted to isolate the
‘very limited’ group, although very few patients were
included in this subset.
Eberhardt and co-workers reported an excellent local
control and remarkable long-term survival in LD-SCLC
patients undergoing aggressive trimodality treatment.42
Of 46 patients with LD-SCLC undergoing induction
therapy (chemotherapy for stage I/II, chemoradiotherapy including hyperfractionated accelerated radiotherapy for stage IIIA/IIIB), 32 patients underwent surgical
resection with a complete resection rate of 72%. The
authors reported that the median survival and five-year
survival rate of all 46 patients were 36 months and
46%, respectively. Especially for 32 completely resected
patients, 68 months and 63% were reported, as well as
a 100% local control rate. This kind of aggressive multimodality approach using intensive local therapy such
as surgery and hyperfractionated accelerated radiotherapy might be promising in the treatment of LD-SCLC,
and may be one of the future directions for trials in
these patients.
Looking at the results of the ever published studies,
the five-year survival rates of patients who underwent
induction (neoadjuvant) chemotherapy and subsequent
surgery ranged from 25 to 65%, and many were at
around 40%. These data clearly indicated that such a
multimodality approach to LD-SCLC is feasible, and
promising in terms of prognosis. However, the role of
surgery in the multimodality treatment has not been
clearly defined by the small to medium sized one-arm
study. On the other hand, considering the limited number of patients who might be candidates for induction
SALVAGE SURGERY
The Toronto Group has promulgated the concept of
‘salvage’ surgery for SCLC, in which two situations are
clearly defined.14 Tumor recurrence might happen at
exactly the same place as the primary site, even after a
complete response (CR) has been achieved by definitive
chemoradiotherapy (Figure 11.1.2a). Alternatively the
persistent primary tumor might grow after definitive
chemoradiotherapy is over (Figure 11.1.2b). Salvage
surgery is generally indicated in these two special cases
with a curative intent. Patients with mixed SCLC/
NSCLC at diagnosis and persistent NSCLC after induction chemotherapy are also prime candidates for this
type of surgery, since the non-small cell component of
the primary tumor might remain because of the difference in the response to the systemic chemotherapy. For
this category of surgery for SCLC, it is important to differentiate the concept of salvage surgery from that of
planned induction chemoradiotherapy followed by surgery. In the latter setting, the surgery is planned upfront
as a part of treatment plan, usually for resectable, histologically proven SCLC, where the schedule and dose
are determined on the premises of the following surgery. In salvage surgery, the chemoradiotherapy is
planned definitively for itself, and the indication for
surgery arises only when the clinical situation after
definitive chemoradiotherapy fits the criterion for it.
For this purpose, mediastinoscopy is utilized to eliminate patients with unresectable disease. In the Toronto
study, 28 patients with limited SCLC who did not have
a complete remission with standard treatment, or who
had only local recurrence after treatment and appeared
to be completely resectable, underwent surgery. Pathologic examination showed only SCLC in 18 patients,
mixed SCLC and NSCLC in 4, and only NSCLC in 6.
A median survival of 74 weeks and a five-year survival
rate of 23% were reported. This study suggests the existence of occasional SCLC patients who will benefit from
salvage surgery after relapse or failure to respond to
chemotherapy and radiotherapy.
Treatment of SCLC: surgery
175
Salvage
surgery
(a)
PR
Cx-Rx
Salvage
surgery
(b)
CR
Cx-Rx
Recurrence
Figure 11.1.2
Indication of ‘salvage’ operations in the treatment of SCLC. Surgical resection is considered when the recurrent tumor shows up at exactly
the same site as the primary tumor after a complete response (CR) has been achieved by definitive chemoradiotherapy (a), or when the
persisting primary tumor grows after the definitive chemoradiotherapy is over (b).
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Fox W, Scadding JG. Medical Research Council’s comparative
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Lennox SC, Flavell G, Pollock DJ. Results of resection for oatcell carcinoma of the lung. Lancet 1968; 2: 925–7.
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Shields TW, Higgins GA, Matthews NJ, Kiihn RJ. Surgical
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Karrer K, Shields TW, Denck H et al. The importance of surgical and multimodality treatment for small cell bronchial carcinoma. J Thorac Cardiovasc Surg 1989; 97: 168–76.
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Shepherd FA, Ginsberg RJ, Feld R et al. Surgical treatment for
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17. Coolen L, van den Eeckhout A, Deneffe G et al. Surgical treatment of small cell lung cancer. Eur J Cardiothorac Surg 1995;
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18. Davis S, Crino L, Tonato M et al. A prospective analysis of
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11.2 Treatment of SCLC: radiotherapy
Christopher M Lee, William T Sause
Contents Introduction • Where are we now? • Current recommendations
• Radiotherapy for palliation • Future directions
INTRODUCTION
Small cell carcinoma of the lung (SCLC) comprises
approximately 20% of newly diagnosed bronchogenic
malignancies.1 Multiple studies have revealed SCLC to
be a highly aggressive carcinoma that is clinically and
biologically very different from non-small cell carcinoma of the lung (NSCLC). Due to significant chemosensitivity and the known high propensity of spread beyond
the chest, chemotherapy was utilized as the primary
treatment of this disease several decades ago.2–4 Despite
the extreme chemosensitivity and remarkable initial
response rates in patients with limited stage disease, the
use of chemotherapy alone led to intrathoracic failures
in up to 80% of patients and mean survivals of only
10–14 months.2 After it was revealed that radiotherapy
could decrease locoregional failures, it became increasingly utilized in the 1970s and 1980s. It was only after
two separate meta-analyses reported improved survival
outcomes with the use of radiation therapy in combined
modality treatment that thoracic irradiation (TI) was
accepted as a necessary part of the standard of care.
Both meta-analyses reported a 5–7% improvement in
two- and three-year survival and an approximate 25%
improvement in local control rates with the addition of
radiotherapy treatment.5,6
Concurrent thoracic irradiation with platinum-based
chemotherapy is now considered the standard treatment in limited stage SCLC. The use of a concurrent
cisplatin/etoposide regimen has significantly decreased
the toxicity observed from prior regimens containing
cyclophosphamide, doxorubicin, and vincristine, leading to significant improvement in patient tolerability to
combined modality therapy.2–4,7–9 A survival benefit
with the use of prophylactic cranial irradiation (PCI) in
patients with limited stage disease who have experienced a complete response to initial concurrent therapy
with TI and systemic chemotherapy was also confirmed
in a meta-analysis.10
Despite recent advances in treatment, the optimal
treatment strategies for individual patients with newly
diagnosed SCLC remain elusive. A number of questions
require further study in this disease, such as optimization of both chemotherapy (schedule, choice of agents,
timing, dosing) and radiation therapy (dose, fractionation, timing, volume treated) regimens. In addition,
statistical analysis cannot replace clinical judgment
when considering the individual patient, tumor characteristics, and the potential risks and benefits of specific
therapies. Hopefully with further information gained
from ongoing and future research endeavors, appropriate therapy will be utilized to decrease the death rate
from this thoracic malignancy. Future work is also
needed to continue to delineate clinical and biologic factors which can guide treatment and account for disparities in outcome between varied subsets of patients.
As will be further addressed in this chapter, the optimal
timing, dose, and fractionation schedules for PCI continue to be under study.
WHERE ARE WE NOW?
Thoracic irradiation
Many practical issues, such as radiation dose, volume,
fractionation, and optimal integration with chemotherapy, remain unresolved. Trying to ‘fine-tune’ combinedmodality treatment for SCLC is a formidable challenge.
It must be accepted that the individual benefits attributable to the different parts of this puzzle are likely to be
numerically small, and manipulation of one aspect may
produce a cascade of events with conflicting effects on
overall outcome. These methodologic problems have
resulted in substantial difficulty in designing appropriate randomized trials to address these questions.
No large randomized trials have been performed
looking at radiation dose as the only variable. Previous
retrospective analyses of thoracic radiation used after
cyclophosphamide- and doxorubicin-containing chemotherapy regimens have suggested that radiation doses as
high as 50–60 Gy are necessary for durable local control (standard fractionation). Even in the current era of
178 Textbook of Lung Cancer
concurrent thoracic radiation therapy and chemotherapy, a major site of recurrence continues to be within
the previously irradiated field (30% in-field alone recurrence and 20% in-field recurrence combined with systemic recurrence).11,12 Choi et al reported improved local
control for doses of 40–50 Gy compared with doses of
<40 Gy.11 An additional study by Papac et al reported
local control of 97% after use of 60 Gy.13 Choi and coworkers from the Cancer and Leukemia Group B
(CALGB) identified 70 Gy to be the maximum tolerated
dose of radiation using standard fractionation for treatment in combination with chemotherapy.12 In addition,
the CALGB reported results from a phase II trial of 70
Gy thoracic irradiation in combination with three cycles
of concurrent carboplatin and etoposide, following an
induction with two cycles of paclitaxel and topotecan.
Their reported median failure-free survival was 12.9
months and median overall survival was 19.8 months,
with a one-year survival of 70%.14 Miller et al have also
reported supporting evidence that higher radiation
doses are tolerable.15 They retrospectively evaluated
outcomes of 65 patients treated with 58–66 Gy (standard fractionation), with either concurrent or sequential chemotherapy, and found that the treatment was
extremely tolerable. Komaki et al reported on the Radiation Therapy Oncology Group (RTOG) 9712 study,
which was a phase I dose-escalation study, of thoracic
radiation therapy with concurrent cisplatin/etoposide
in limited stage SCLC. Thoracic radiation was given in
1.8 Gy daily fractions to a total dose of 36 Gy, followed
by smaller boost fields encompassing only the gross
disease delivered with escalations of 1.8 Gy bid during
the final days to establish the maximum tolerated dose
(MTD). The MTD was found to be 61.2 Gy in 34 fractions of 1.8 Gy when given with two cycles of cisplatin/
etoposide (concurrently) and followed by two additional cycles of cisplatin/etoposide.16
A further practical question concerns the optimal target volume for thoracic irradiation. This issue is increasingly debated now that the standard of care has changed
from sequential to concurrent thoracic radiation with
chemotherapy. The tradition of irradiating large volumes
covering all ‘prechemotherapy tumor involvement’ with
generous margins or prophylactic irradiation of distant
lymphatic drainage sites may no longer be necessary,
and more modest radiation treatment volumes will lead
to lower rates of serious pulmonary toxicity. There
remains no consensus at this point as to whether prechemotherapy or postchemotherapy visible volumes
should be treated.17–20 The optimal safety margin around
the visible tumor and necessary elective nodal radiation
also remain sources of study and debate. A common
treatment policy constructs treatment fields to encompass
the original tumor with 1.5–2.0 cm margins. One prospective trial by Kies et al revealed no difference between
large-field thoracic radiation therapy and limited-field
therapy, although conflicting results are apparent in the
literature.15–18,20,21 A balance must be made with each
individual patient which evaluates potential toxicity of
enlarging radiation fields versus the risk of local recurrence of disease. New imaging modalities such as positron emission tomography (PET) are also expected to
help answer key questions regarding optimal treatment
volumes.
With recent increased interest in altered fractionation
schedules for radiation therapy, accelerated hyperfractionation appears to be a logical choice for SCLC due to
the high sensitivity of cancer cells, the normal-tissuesparing effect of twice-daily fractionation (with a greater
than six-hour interval between fractions), and the ability to defeat rapid proliferation of tumor cells. Several
phase II studies of radiation given in multiple daily
fractions, either concurrently with cisplatin and etoposide or in an interdigitated sequence, have been followed by a large intergroup randomized trial.22,23 In
this study, 417 patients were treated with concurrent TI
starting with the first cycle of etoposide and cisplatin
(PE) chemotherapy and randomized between a standard schedule (1.8 Gy in 25 daily fractions over five
weeks to a total dose of 45 Gy) or a hyperfractionated
schedule (45 Gy in 1.5 Gy fractions twice daily over three
weeks). With mature follow-up, the five-year survival
rate was significantly improved in the twice-daily arm
(26 vs 19%). However, the hyperfractionated arm had
higher rates of acute toxicity, as would be expected.23
An additional trial studying this issue was a North Central Cancer Treatment Group (NCCTG) study, which
compared concurrent cisplatin/etoposide (two cycles)
and either twice-daily, split-course TI to 48 Gy in
5.5 weeks or once-daily TI to 50.4 Gy in daily fractions
of 1.8 Gy, both given after three cycles of cisplatin/
etoposide. They found no difference in three-year overall survival and locoregional control between the splitcourse/twice-daily fractionation and daily fractionation
treatment schemas.24 Schild et al reported the median
and five-year survival rates to be 20.4 months and 22%
for twice-daily versus 20.5 months and 21% for oncedaily thoracic radiation, respectively (p = 0.7).25 In analyzing these studies side-by-side, it appears that one
possible explanation is that the split-course regimen is
an inferior regimen due to an extension of overall
treatment time allowing for tumor cell regeneration.
Treatment of SCLC: radiotherapy 179
The issue of radiotherapy timing is also not resolved.
An early three-arm randomized CALGB trial suggested
that the best survival/toxicity ratio can be obtained by
delaying radiation until the fourth cycle of chemotherapy.26 This may be in part due to a marked reduction in
the chemotherapy dose when thoracic radiation was
applied early and also due to high rates of treatmentrelated fatalities in schedules using concurrent radiation
with cyclophosphamide, methotrexate, lomustine, and
doxorubicin. More recent trials which utilize cisplatin/
etoposide or cisplatin/etoposide alternating with
cyclophosphamide/doxorubicin/vincristine show clear
superiority for early (cycle one or two of chemotherapy)
utilization of TI.27–29 These randomized trials testing
the timing of thoracic irradiation are illustrated in
Table 11.2.1.20,26–29 Fried et al performed a meta-analysis which evaluated the timing of TI in combined
modality therapy for limited-stage SCLC.30 This analysis of 1524 patients revealed a significantly higher twoyear survival in the early group, and there was a
suggestion of a similar trend at three and five years. This
advantage was also thought to be due to the significantly improved outcomes found in trials employing
platinum-based chemotherapy and hyperfractionated
radiation therapy regimens. Once-daily regimens and
doxorubicin-based chemotherapy were found not to
provide any statistically significant improvements in
overall survival.
Brain metastases and prophylactic
cranial irradiation
Brain metastases are common sites of failure in SCLC
and multiple reports have confirmed that prophylactic
cranial irradation (PCI) has a role in the therapeutic
strategy among patients with limited stage disease who
are complete responders to systemic chemotherapy and
thoracic irradiation.5,10 At diagnosis, 20% of patients
have evidence of spread into the brain, which rises to
50% at two years and to more than 80% postmortem.31–34
The concept of PCI, taken from settings such as acute
lymphoblastic leukemia, demonstrated 20 years ago
that moderate radiation doses can significantly reduce
the rate of brain metastases. In multiple small historical
trials, no evidence of survival benefit was seen and the
short overall survival underestimated the degree of the
observed risk. In addition, initial reports of CNS morbidity subsequent to cranial irradiation tempered the
enthusiasm for PCI in the past.35–39 Nevertheless, the
problem of CNS disease and its control have continued
to evolve in clinical practice. The modest effectiveness
of radiotherapy or chemotherapy for patients with
established brain metastases as well as the subsequent
functional consequences and negative impact that brain
metastases have on quality of life has lead to re-evaluation
of PCI in a series of second-generation trials. These were
designed to address issues of effectiveness as well as
morbidity of treatment.
Table 11.2.1 Trials evaluating the timing of thoracic irradiation
Author
RT timing
RT dose
Five-year survival rate (%)
p
Cycle 1
Cycle 4
50 Gy/24 fx
7
13
0.08
Week 3
Week 15
40 Gy/15 fx
20
11
0.008
Week 1
Week 18
40–45 Gy/22 fx
11
12
0.4
Week 1
Week 6
54 Gy/36 fx
30
15
0.052
Cycle 1
Cycle 4
45 Gy/30 fx
24
18
0.097
Perry26
Murray28
Work20
Jeremic27
Takada29
RT timing: radiation therapy timing with respect to chemotherapy; RT dose: radiation therapy prescribed dose; fx: number of fractions.
180 Textbook of Lung Cancer
Oncologists have found through multiple recent
studies that the use of PCI alone with lower dose-fractionation schedules (<3 Gy), and without concomitant
chemotherapy, does not lead to significant long-term
neurotoxicity.33,40 It should be emphasized that these
recent trials have included patients who have experienced
complete remission following systemic chemotherapy
and thoracic irradiation for limited stage disease. This
has been confirmed by multiple recent prospective trials which have included neurologic assessments (before
and after therapy) in their study requirements. These
have revealed that, on initial pretreatment neuropsychologic assessments (prior to PCI administration), 40–60%
of patients had documented abnormalities, and initial
results have not shown any significant differences in
neurocognitive function when comparing those patients
who received PCI with those who did not.10,33,40–42 The
only prospective trial which documented a significant
decrease in cognitive function in a PCI group was a
CALGB trial which utilized concurrent chemotherapy
with brain irradiation. All patients in this trial had PCI
administered with chemotherapy and there was a noted
significant change in neurocognitive function during
the course of treatment, which suggests that the combination of chemotherapy and PCI has a negative impact
on cognitive functioning.43 These studies concluded that
PCI should be administered without concomitant chemotherapy and lower fractionation schedules (<3 Gy)
should be considered for all patients who experience a
complete response after initial treatment with systemic
chemotherapy and thoracic irradiation.
CURRENT RECOMMENDATIONS
Radiotherapy plays an important role in the treatment
of SCLC patients. Its optimal utilization requires close
collaboration between all the specialists involved in the
care of these patients, and thoracic radiation oncologists should be an intrinsic part of the multidisciplinary
team. Only in this way can safe and efficient progress
be made in this regard. Limited stage patients with
SCLC should be managed by specialists using a formal
multimodality protocol of treatment, and preferably in
the context of a clinical trial. The accepted standard
practice in many centers is to use concurrent chemotherapy with radiation delivered early in the course of
chemotherapy treatment to a dose equivalent of 50 Gy
with standard fractionation (approximately 10 Gy/
week). Concurrent chemoradiotherapy with drugs
other than cisplatin and etoposide may necessitate dose
modifications and reductions on the grounds of toxicity.
Having selected the patients who are likely to go on to
TI and possibly PCI, it is important to obtain a prechemotherapy radiologic series that will inform subsequent radiotherapy planning. This preferably would
include a computed tomography (CT) scan of the thorax and upper abdomen. These must be available,
together with a contemporary and comparable series of
radiologic investigation, to the radiation oncologist at
the time of treatment planning (Figure 11.2.1). The
decision on what radiotherapy treatment volume to use
will depend on the extent of original tumor involvement, the degree of response to and the choice of chemotherapy, the patient’s lung function and performance
status, and the dose, fractionation, and timing of the
radiotherapy course.
In practice, most radiation oncologists would irradiate areas of prechemotherapy involvement with a margin consistent with safety. This is a minimum of 1 cm
on the transverse and 2 cm in the sagittal plane of
involvement. Prophylactic irradiation of nodal sites
remote from the initial sites of involvement, such as
routine irradiation of the supraclavicular fossa in
patients with upper lobe tumors, is probably not necessary and adds considerably to toxicity. Because SCLC
often presents in the vast majority of cases with a bulky
central tumor and extensive mediastinal involvement,
these treatment volumes are large. In addition, irradiation of large intrathoracic tumor volumes to a high and
homogeneous dose represents a technical challenge.
The main trade-offs are between the radiation dose
delivered to surrounding normal lung, esophagus, and
heart, and the radiation tolerance of the spinal cord. A
safe approach requires composite and sophisticated
planning techniques (Figures 11.2.2 and 11.2.3), similar
Figure 11.2.1
Prechemotherapy axial CT image illustrating a newly diagnosed
small cell carcinoma of the left lower lung lobe.
Treatment of SCLC: radiotherapy 181
to those used in the treatment of NSCLC, often using
phased or ‘shrinking’ field techniques.
The choice of volume for PCI is simple. The entire
cranial cavity and contents need to be irradiated, usually using opposing lateral portals (Figure 11.2.4). The
areas needing particular attention are the meningeal
reflections of the cribriform fossa and middle cranial
fossa. TI and PCI administered using conventional
doses and fractionation after chemotherapy lead in
most cases only to trivial acute side-effects. Tiredness,
esophagitis, and lymphopenia are the most common.
They are self-limiting, and in the vast majority of cases
do not require further treatment beyond simple symptomatic measures. Administration of concurrent chemotherapy and hyperfractionated accelerated TI regimens
is much more toxic, with esophagitis and hematologic
toxicity often being dose-limiting. These may be slow
to recover from, and may compromise further treatment tolerance. The most significant side-effects are
late pulmonary toxicity, late CNS toxicity of PCI: spinal
cord damage, and cardiac failure due to irradiation of
large areas of the heart and to anthracyclines.
RADIOTHERAPY FOR PALLIATION
The exquisite radioresponsiveness of SCLC makes
radiotherapy a useful agent for palliative treatment of
metastatic, symptomatic, or recurrent disease in patients
resistant to or unsuitable for systemic chemotherapy.
The approach will best be individualized and similar to
that used in NSCLC. In general, short and undemanding courses of irradiation including single-fraction
treatments can be used, aimed at symptom control
through tumor shrinkage and associated with little or
no additional toxicity. Commonly used regimens
include 37.5 Gy in 15 fractions, 30 Gy in 10 fractions,
20 Gy in five fractions, or single treatments of 8–10 Gy.
FUTURE DIRECTIONS
Figure 11.2.2
Anterior-posterior digitally reconstructed radiograph (DRR)
illustrating a typical radiation portal which includes the primary
tumor mass and adjacent hilar/mediastinal lymph nodes.
(See color plate section, page xv)
Future clinical trials are necessary to evaluate optimal
treatment schedules for patients newly diagnosed with
SCLC. The current vogue for accelerated hyperfractionated regimens, with their associated increased survival
rates and increased levels of acute toxicity, also needs
continual future critical evaluation. The optimization of
scheduling of thoracic irradiation and chemotherapy is
another area where further work is needed. The current
Figure 11.2.3
Conformal radiotherapy planning techniques allow
escalated radiation doses to be delivered safely
with simultaneous sparing of surrounding critical
structures. In this example, a combination of
anterior-posterior and oblique fields (four fields in
total) are utilized to decrease radiation dose to the
nearby spinal cord. (See color plate section, page xvi)
182 Textbook of Lung Cancer
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1.
2.
3.
4.
5.
6.
Figure 11.2.4
Right lateral digitally reconstructed radiograph (DRR) illustrating
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(See color plate section, page xvi)
7.
8.
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11.3 Treatment of SCLC: chemotherapy
Heine H Hansen, Morten Sørensen
Contents Introduction • Second-line chemotherapy • Treatment of elderly and poor-prognosis patients
• Targeted therapies
INTRODUCTION
In the last decade much attention has been directed
towards the treatment of non-small cell lung cancer
(NSCLC), resulting in considerable progress in its management, which is in contrast to small cell lung cancer
(SCLC). The treatment of SCLC has, unfortunately,
been at a standstill in recent years, with relatively few
large clinical randomized trials, which may reflect the
lack of innovative treatment options but also a declining proportion of lung cancer patients presenting with
SCLC, which now in many countries constitutes less
than 20% of all newly diagnosed lung cancers. Thus, in
the US the proportion of SCLC among all lung cancer
histologic types decreased from 17.26% in 1986 to
12.95% in 2002. Noteworthy, in the same study, the
proportion of women with SCLC increased from 28%
in 1973 to 50% in 2002.1 Still, the treatment of SCLC
continues to represent a major challenge. Despite a high
rate of initial response, most patients will eventually
relapse and long-term survival remains a disappointing
10–15%. The disseminated nature of SCLC, displaying
a high frequency of metastases at the time of diagnosis
combined with a high sensitivity to cytostatic agents,
has led to the use of chemotherapy as the primary treatment of choice in all its stages. In the overview provided in this chapter, the current standard chemotherapy
in the management of SCLC will be discussed.
The most effective agents are listed in Table 11.3.1.
The most commonly used combinations include a platinum compound together with the podophyllotoxins,
usually etoposide. Combinations including vincristine,
cyclophosphamides/ifosfamides, doxorubicin, or taxanes are also highly active. Examples of frequently used
treatment schedules are listed in Table 11.3.2.2,3 In a
trial by Sundstrøm et al,4 including 436 eligible patients
with limited (n = 214) and extensive disease (n = 222),
a combination of etoposide and cisplatin was shown to
be superior to a three-drug combination of cyclophosphamide, epirubicin, and vincristine. For all patients
the two- and five-year survival rates in the EP (etoposide and platinum) arm (14% and 5%) were significantly higher compared with the three-drug arm (6%
and 2%, p = 0.0004). Patients with limited disease
received thoracic radiotherapy concurrently with chemotherapy cycle three, and those achieving complete
remission during the treatment period also received
cranial irradiation.
Among the new agents, much attention has been
given to the incorporation of the new topoisomerase
inhibitors in combination with either cisplatin or carboplatin (Table 11.3.3).
In a Japanese study5 that included only patients with
extensive disease, survival rates with a combination of
irinotecan plus cisplatin were superior to those with
etoposide and cisplatin, with one-year survival being
58.4% versus 37.9%, and median survival 12.8 months
versus 9.4 months; also response rates of 84% versus
68% were in favor of irinotecan and cisplatin. Grade 3
and 4 diarrhea occurred in 16% in the irinotecan combination compared with none in the etoposide arm.
The study was prematurely stopped after the enrollment of 152 patients out of the planned 230 patients,
as recommended by a preplanned interim analysis. A
confirmatory randomized study was initiated in the US
by Hanna et al,6 with randomization of 331 patients to
either irinotecan or etoposide, both in combination
with cisplatin. An unequally balanced randomization
was performed, allocating one-third of patients to
etoposide and two-thirds to the irinotecan arm. In both
arms, four cycles were delivered every three weeks. After
the enrollment of 30 patients, inclusion was restricted
to patients in performance status 0 and 1 due to an
excessive toxic death rate among patients with performance status 2. As in the Japanese study, myelotoxicity
and febrile neutropenia were more frequent in the
etoposide arm, whereas gastrointestinal toxicity was
more common in the irinotecan arm, including 21%
of patients suffering from grade 3–4 diarrhea. Unfortunately, this study could not confirm the encouraging
Treatment of SCLC: chemotherapy 185
Table 11.3.1 Agents used in SCLC: most frequently chosen
agents for inclusion in combination regimens
Alkylating agents
Cisplatin
Carboplatin
Ifosfamide
Cyclophosphamide
Antimitotic agents
Vincristine
Paclitaxel
Topoisomerase inhibitors
Etoposide
Irinotecan
Topotecan
Doxorubicin
Table 11.3.2 Commonly used regimens in SCLC
Regimen
PE
Cisplatin
Etoposide
CE
Carboplatin
Etoposide
ICE
Ifosfamide
Carboplatin
Etoposide
– with or
without
midcycle
vincristine
Dosage and schedule
25 mg/m2 iv on days 1–3 or 60–80
100 mg/m2 iv on days 1–3 or
115 mg/m2 iv days 3–5 q 3 wks
AUC 6 day 1 iv
100–120 mg/m2 iv days
1–3 q 3 wks
5000 mg/m2 iv day 1 +
300–400 mg/m2 iv day 1
100–200 mg/m2 iv days
1–3 + mesna 500 mg/m2 day 1
and 3000 mg day 2
1.0 mg/m2 day 14
Japanese data and no significant differences were seen
in the overall survival, time to progression, or response
rate. Median survival times were 9.3 versus 10.2 months
in the irinotecan/cisplatin and etoposide/cisplatin arms,
respectively.
The differences observed between the American and
the Japanese studies might be related to differences in
the scheduling of both cisplatin and irinotecan. Also
other factors, such as pharmacogenetic variations in the
two study populations might contribute to the different
results. Polymorphisms exist between Asians and
Caucasians with regard to the gene responsible for the
glucuronidation of SN-38, the active metabolite of
irinotecan. Preliminary data from a German study on
59 evaluable patients have also been published and the
study will proceed as a phase III trial comparing, again,
irinotecan versus etoposide, but in this study combined
with carboplatin rather than cisplatin.7 It is conceivable
that the data from the latter trial combined with existing data may determine whether etoposide or irinotecan is the superior drug in combination with platinum
compounds in SCLC.
In one of the largest randomized trials ever conducted
in patients with extensive SCLC, topotecan given orally
together with cisplatin was compared with iv etoposide
plus cisplatin in 784 patients with extensive SCLC. Overall survival was equal, 9.1 vs 9.3 months.8
With respect to some of the other newer agents, paclitaxel has been tested in several trials combined with
standard etoposide and platinum-based chemotherapy.
Used as single agent, paclitaxel has shown response rates
of 29–41% in both previously treated and untreated
SCLC patients. Based on survival data, none of three
randomized trials published increased median survival
in patients with extensive disease, but add to the risk of
toxic death in frail patients with extensive disease.9
Results from other trials trying to incorporate epirubicin or gemcitabine have also been rather disappointing,
with no differences in response rates or progression-free
or overall survival compared to standard regimens.9
With respect to scheduling of drugs, it has been demonstrated that etoposide is more effective when given as
a five-day course than when the same dose is given over
24 hours. Prolonged periods of three to four weeks of
continuous treatment of etoposide are being explored
at present. In that regard, it is noteworthy that oral
etoposide has been shown to be inferior to combination
chemotherapy administered iv.10
For both limited and stage I–III and extensive stage IV
disease, the overall response rates achieved are >70%,
whereas complete response with no clinical or histopathologic evidence of malignancies is initially obtained
in 30–40% of patients with limited disease and 15–20%
of patients with extensive disease. The median survival
for patients with limited disease is about 14–18 months,
and usually 8–10 months for extensive disease, whereas
long-term survival (beyond five years) is 10–15% and
3–5%, respectively, for the two stages. One should be
aware that survival results vary according to selection criteria and more representative results from national studies may be less encouraging. With respect to the duration
186 Textbook of Lung Cancer
Table 11.3.3 Major randomized trials evaluating topoisomerase I inhibitors in combination with platinum in extensive SCLC
No of patients
Etoposide + CDDP
Irinotecan + CDDP
Etoposide + CDDP
Irinotecan + CDDP
Etoposide + carboplatin
Irinotecan + carboplatin
Etoposide + CDDP
Topotecan (oral) + CDDP
Response rate (%)
154
331
59
784
68
84
44
48
50
71
69
63
Median survival (months)
9.4
12.8
10.2
9.3
12
10
9.3
9.1
Author
Sundstrøm4
Noda5
Hanna6
Schmittel7
CDDP: cisplatin.
of treatment needed to produce optimal results, a period
of 4–6 months, usually corresponding to 4–6 cycles of
chemotherapy, is currently an acceptable standard.
A meta-analysis of published, randomized controlled
trials suggests, however, that maintenance or consolidation therapy improves survival. New randomized clinical trials are therefore needed to further refine the place
of this approach in the treatment of SCLC.11
In recent years, new approaches to chemotherapy
have been undertaken to improve the treatment results,
including dose-dense chemotherapy, which has the theoretic potential to augment tumor cell kill. The role of
dose-dense therapy remains controversial in SCLC due
to conflicting results in various randomized studies
conducted over the years.12
Intensity of chemotherapy can be increased, particularly as a consolidation treatment by the use of autologous
bone-marrow infusion, and more recently by peripheral blood stem cells. One of the most recent trials to
evaluate this treatment concept has been performed by
British investigators, who randomly assigned 318 ‘better-prognosis patients’ to standard combination chemotherapy with ifosfamide, carboplatin, and etoposide (ICE)
delivered at four-week intervals or to dose-dense ICE in
similar doses, but given at two-week intervals supported
by granulocyte colony-stimulating factor (GCSF) (filgrastim) and autologous blood transfusions.13 Chest
radiotherapy was performed according to local guidelines, which for all patients consisted of sequential
radiotherapy. Approximately 10% of all patients had
extensive disease. The median relative dose intensities
were 99% and 182% in the standard and dose-dense
arms, respectively. Response rates, median survival times,
and two-year survival rates were 80% versus 88%, 13.9
versus 14.4 months, and 22% versus 19% in the standard
and dose-dense arms, respectively. The authors
concluded that the dose-dense strategy has reached a
plateau and further attempts to pursue this strategy in
SCLC do not seem justified.13
In a French study, more intensive treatment with four
instead of two drugs resulted in an improved one-year
survival (40% versus 27%), but with more severe hematologic toxicity.14
Other treatment approaches include scheduling of
drugs based on cell-kinetic observations15 or the use of
anticoagulants such as warfarin, but the results are
inconclusive. Noteworthy in that regard are the data by
Altinbas et al,16 who randomized 84 limited and extensive disease patients to combination chemotherapy with
or without the addition of low molecular weight heparin (LMWH) (dalteparin, 5000 U daily). Treatment was
safe, with no treatment-related deaths and only a few
manageable bleeding episodes. Overall survival increased
significantly in the LMWH arm to 13 months, compared
with 8 months in the chemotherapy-alone arm. The study
represents a very small sample size and the hypothesis
needs to be evaluated in a properly sized randomized
phase III study.
Another attempt to improve chemotherapy is alternating combination chemotherapy using different noncross-resistant combinations, because resistant clones
of SCLC cells, which are present either at the time of diagnosis or develop during chemotherapy, are thought to be
the reason for treatment failure in most patients. Again,
the impact on survival is modest. The use of biologic
response modifiers, such as interferon as maintenance
therapy or adjuvant vaccination with Bec2/bacille
Calmette-Guerin, has also been tested, but again with
disappointing results.17,18 GCSF and granulocyte macrophages CSF, given to counter the hematologic effects
of combination chemotherapy, lessen the severity of
neutropenic episodes, but they do not appear to influence survival significantly, in spite of the increased doses
of chemotherapy.19 Nor did the addition of GCSF to
Treatment of SCLC: chemotherapy 187
primary antibiotic prophylaxis result in cost savings in
the study by Timmer-Bonte et al.20
SECOND-LINE CHEMOTHERAPY
Because of its high relapse rate, the management of relapsed
SCLC is a very common clinical problem. Good-quality
studies to guide the decision-making process are very
scarce, even though new evidence has emerged from
recent studies. Using non-cross-resistant regimens at
multifocal relapse, a response rate of 20–25% is obtained,
with a median duration of survival of 3–4 months. If
there is a longer chemotherapy-free interval before
relapse, the same drug combination that initially produced a response may be repeated, with response rates
up to 50%, but again the effect is rather shortlasting.
Until recently it was not known whether second-line
therapy influences survival as no randomized trials had
compared chemotherapy against best supportive care
(BSC). To answer this important question, 141 relapsed
patients were randomly allocated to oral topotecan
2.3 mg/m2 on days 1–5 every three weeks or to best supportive care.21 Prognostic and predictive factors for
response were equally balanced. Approximately twothirds of the patients had performance status 0 or 1.
Topotecan resulted in a modest response rate of 7% and
44% of patients achieved stable disease. Median survival
time with BSC was 13.9 weeks (95% confidence interval
(CI) 11–18.6 weeks), and with topotecan 25.9 weeks
(95% CI 18.3–31.6 weeks), and the overall six-month
survival rate was 49% compared with 26% on the best
supportive care arm (p = 0.01). The largest numerical
survival benefit was seen in patients with the longest
treatment-free interval. Dyspnea and pain were reduced
in the topotecan arm compared with best supportive care
(3% versus 9% and 3% versus 6%, respectively), indicating better symptom control in the topotecan arm.21
It is still an open question which type of second-line
therapy is superior. Randomized trials have found that
intravenous topotecan resulted in equal response rates
and survival compared with a combination of cyclophosphamide, doxorubicin, and vincristine (CAV).22 Furthermore, iv and oral topotecan showed similar responses in
a randomized trial.23 It is also noteworthy that amribucin, a totally synthetic 9-aminoanthracycline, has shown
significant activity with an overall response rate of 50%
(CL25–75%) in a phase II study including 60 Japanese
patients with refractory or relapsed SCLC.24 If the patient
has a local relapse and has not received irradiation previously, palliative radiotherapy is often the treatment of
choice as second-line treatment.
TREATMENT OF ELDERLY AND POOR-PROGNOSIS
PATIENTS
Knowledge of the optimal treatment of the elderly is
limited, as most large randomized trials tend to exclude
elderly patients. This occurs despite the fact that more
than one-third of patients with SCLC are >70 years old
and the proportion of elderly in the population is continuously increasing, as the average expected lifetime
increases in the general population.25
In patients >70 years old, Ardizzoni et al26 evaluated
two regimens of cisplatin and etoposide – full dose (FD)
and reduced dose (RD) – in a two-stage, randomized,
non-comparative phase II design. The primary endpoint
was the rate of treatment success defined as the proportion of patients receiving at least three courses of the
planned dose of full dose chemotherapy on time and
achieving an objective response without grade 3 and 4
toxicity or any chemotherapy-related complications.
The median number of adminstered cycles was four in
both arms and approximately the same percentage of
patients completed the treatment per protocol in both
arms (75 vs 22%). Median survival times and one-year
survival rates were 31 versus 41 weeks and 18% versus
39% on the RD and FD arms, respectively. RD chemotherapy thus offers no advantage over FD chemotherapy,
which is in accordance with previously randomized trials, indicating that presumably less toxic treatment
regimens can compromise the goal of palliation, symptom control, and survival. In another study with an
elderly population in which more than 90% of the 220
patients were >70 years old and 25% of patients had
performance status 2 or 3, split-dose cisplatin was compared with carboplatin in combination with etoposide.
Response rates, palliation score, and progression-free
and overall survival were equal, indicating that carboplatin can substitute for cisplatin in a palliative setting
without compromising clinical outcome.27
TARGETED THERAPIES
The use of therapies based on mechanisms that target
critical molecular pathways of tumors has also been
tested in SCLC, but to a lesser degree than in NSCLC.
Phase II trials have explored the use of maintenance
therapy with the antiangiogenic drug thalidomide, and
the drug has also been evaluated in a phase III trial with
119 patients, which was stopped prematurely because
of low accrual rate.28,29 The data from the study of 92
randomized patients are inconclusive, but noteworthy is
the longer median survival on the thalidomide arm
188 Textbook of Lung Cancer
compared with the placebo-treated arm (11.7 months
versus 8.7 months). Other interesting phase II trials
have used temsirolimus, which targets the mTOR
kinase,30 and also bortezomib, which is a proteasome
inhibitor,31 while other agents tested include G3139, an
antisense oligonucleotide directed at the BCL2 gene.32
In addition the EGFR tyrosine kinase inhibitors gefitinib and imatinib, a KIT receptor tyrosine kinase, and
the farnesyltransferase inhibitor R115777 have been
evaluated in patients with relapsed SCLC,33–35 but the
studies are too small to justify firm conclusions.
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12 Malignant mesothelioma
Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney
Contents Introduction • Epidemiology • Pathogenesis • Pathobiology • Global transcriptional
profiling in MM • Immunobiology • Animal models • Clinical presentation and course • Diagnosis
• Management • Future directions
INTRODUCTION
Malignant mesothelioma (MM) is an aggressive malignant tumor of serosal surfaces. It most commonly affects
the pleura, but also involves peritoneal and occasionally other serosal surfaces. It was considered a rare disease before about 1960, but has increased dramatically
in incidence since that time, almost certainly owing to the
widespread use of asbestos fibers in the postwar industrial boom.
Our aim in this chapter is to summarize the main
features of the disease and provide an update of recent
developments. The latter should be of substantial interest to the reader, since there have been a number of
recent publications in mesothelioma research that not
only have begun to unravel the mysteries of the disease,
but have also provided a new palliative standard of
care, and the prospect of further new approaches to
therapy for this otherwise treatment-resistant problem.
Advances have been in the area of pathogenesis and
mechanisms, particularly the identification of the growth
factors involved in the disease, the potential role of nonasbestos agents such as the SV40 virus, and the identification of tumor suppressor gene lesions in this disease.
Advances have also been made in the immunobiology
and immunotherapy of the disease, in the development
of new chemotherapy trials, and in the areas of epidemiology and medicolegality.
In this chapter, we shall begin by reviewing the epidemiology and biology of MM, particularly with regard
to its pathogenesis and immunobiology. We shall then
summarize the clinical aspects of the disease, and finish
the chapter with a discussion of possible future directions based upon these recent advances.
EPIDEMIOLOGY
In 1960 Wagner et al1 reported an association between
asbestos and both pleural and peritoneal MM in a case
series of the North Western Cape Province of South
Africa, where blue asbestos (crocidolite) was mined. Since
then, many reports supporting the relationship between
occupational or environmental exposure to asbestos
and the subsequent development of MM have been
published from all parts of the world.2,3 The relationship
is clearly one of cause and effect. This has been shown
in case series and cohort studies.
Wagner’s initial study identified the difference in risk
from direct occupational exposure and brief or indirect
exposure to asbestos. The risk of development of MM is
directly related to the duration and intensity of exposure to asbestos. Therefore, if asbestos exposure
occurred at a young age then the lifetime risk of development of MM is higher than in someone whose exposure occurred at a later age. Asbestos workers had direct
occupational exposure to asbestos, and their families
received brief or indirect exposure via clothes and hair
brought home from the work-place.4 Other employees
working in the same area as asbestos workers were also
subject to greater risk.
Epidemiologic studies have shown that 50–80% of
individuals with MM have an identifiable exposure to
asbestos.5 Therefore in 20–50% of cases there is no
obvious exposure to asbestos, and examination of the
lung mineral fiber content shows that in many of these
subjects there is a lower lung fiber burden than seen in
subjects with asbestosis.6 This supports the evidence
that MM may occur after brief and indirect exposure to
asbestos. As a group, however, patients with MM have
markedly increased lung fiber burdens when compared
with a reference population.
Asbestos fiber dimensions and type play an important role in the development of MM, with longer and
thinner asbestos fibers causing more damage than
shorter and wider fibers because they can deposit within
and penetrate the lungs (see below). The critical fiber
dimensions appear to be less than 0.25 mm in diameter
and greater than 5 mm in length to produce MM, and,
Malignant mesothelioma 191
while the risk of developing MM from exposure to
chrysotile fibers is lower than that from amphibole
fibers, large amounts of chrysotile can cause MM, possibly because of contaminating tremolite fibers.7 A potential role for SV40 is also described.
PATHOGENESIS
Mesothelial tissues
Mesothelial tissues include all those that line the cavities that were derived from the embryonic mesodermal
celomic cavity. The tissue develops as a continuous epithelial layer, which covers the pleura, the pericardium,
and the peritoneal cavity. In the pleura, it exists as a
single layer of mesothelial cells, resting on a basement
membrane. The cells are variable in shape, from flat to
cuboidal to columnar. Their rate of division is generally
slow, but it is increased in response to inflammatory
damage. Mesothelial cells are actively phagocytic in culture, and they can take up asbestos fibers.8 This may be
important in their susceptibility to transformation, since
they are not normally exposed to chronic insults.
Etiologic agents
Asbestos
Asbestos is a collective name for a group of fibrous minerals composed of hydrated magnesium silicate. They
divide into serpentines, which are short and curved,
such as chrysotile, and amphiboles, which are long and
needle-like, such as crocidolite. Not all of the different
forms have had widespread commercial use – in fact,
90% of industrial asbestos is chrysotile. The mining
and use of asbestos were maximal in 1973, and are now
in decline because it has become clear that exposure to
asbestos can cause a number of pulmonary conditions.
These include pleural plaques, diffuse pleural thickening, rounded atelectasis, and asbestos-related pleural
effusions. As mentioned above, there is an association
between asbestos and MM, and it now seems reasonably clear that the duration and dose of exposure to
asbestos correlate with the risk of developing MM.9
The physical characteristics of the asbestos fibers are
important in the development of MM. It is generally
thought that the amphiboles, particularly crocidolite,
are more carcinogenic for mesothelial tissues.5 Some
cases of MM occur following exposure to chrysotile,
although this apparent association may be due to contamination of this form with amphiboles. However, in
experimental situations, the two groups of asbestos
fibers are equally mutagenic to mesothelial cells. In
these studies, the chrysotile was introduced intrapleurally, and it may be that the shape of these fibers makes
it less likely that they would penetrate the intact lung
after inhalation. Consistent with this hypothesis, the
most carcinogenic fibers in animal studies have been
shown to have a diameter of less than 1.5 µm and a
length of greater than 8 µm, i.e. a high length-to-width
ratio.10 The disease progresses through the formation of
granulomatous lesions that have a surface layer of mesothelium, with subsequent neoplastic transformation.
Mesothelial cells have been shown to be 10 times more
sensitive than bronchial epithelial cells to the direct
cytotoxic effects of asbestos fibers,11 but, after intraperitoneal injection of asbestos, the initial response is from
macrophages, with resultant inflammation and cytokine
production.12 The fibers cause iron-catalyzed generation
of reactive oxygen metabolites, which have a direct
toxic effect, causing DNA point mutations and strand
and chromosomal breaks.13 These events usually lead
to cellular apoptosis, but particular mutations, combined with the direct mitotic damage of cells by asbestos
fibers14 and the increased proliferation induced by
inflammation, may increase the risk that these cells survive despite their genetic changes. The end result is
malignant transformation.
SV40
The double-stranded DNA virus SV40 has been suggested as a possible etiologic agent in the development
of MM. In 1994, Carbone and co-workers found SV40like sequences in 60% of frozen MM specimens by
polymerase chain reaction (PCR). The majority of these
patients also had a history of asbestos exposure, raising
the possibility of SV40 acting as a co-carcinogen. SV40
is a papovavirus whose normal host is the monkey. As
a small virus, it is dependent on its host for the enzymes
of replication except for the large T antigen (TAG).
When the virus infects a cell, the TAG is transcribed
from the viral genome. TAG binds to the specific SV40
origin of replication, pulling apart the DNA strand,
allowing viral DNA synthesis. In this way, the virus is
able to bypass the normal cellular controls on replication, and will even do so in quiescent cells. This process
is facilitated by TAG binding to both p53 and the retinoblastoma protein (pRb), with inactivation of these cell
cycle checkpoints.
It is presumed, but not proven, that SV40 was introduced into humans as a result of the Salk polio vaccines
used in the 1950s. It has been estimated that up to 30%
of vaccines used were contaminated by SV40 as a result
of culturing the poliovirus in rhesus monkey kidney
192 Textbook of Lung Cancer
cells. SV40 had long been known to be tumorigenic in
rodents, but in 1992 Bergsagel et al15 found evidence of
TAG sequences in childhood tumors. This discovery
was followed by evidence obtained by Carbone’s group,16
suggesting an oncogenic role of SV40 in causing MM in
hamsters. They found that 100% of hamsters that were
injected with intrapleural SV40 developed MM, and
this led to the sequencing of SV40 in human MM by
this group.17
Since then, a number of other studies have confirmed
Carbone’s findings, with the proportion of cases ranging from 44 to 86% of MMs tested. One dissenting
group has been that of Strickler,18 who examined MM
tissue from 50 patients with two separate primer sets
and did not detect any SV40 sequences. This group also
undertook a retrospective cohort study comparing
those people who were likely to have received contaminated polio virus against those who did not, and found
no increase in the incidence of a number of cancers,
including mesothelioma.19 As Strickler’s group concedes, the cohort studied has not yet reached the age of
peak incidence for MM.
In two separate studies, Carbone’s group have gone
on to study possible mechanisms by which SV40 may
contribute to the pathogenesis of MM. They have found
that the SV40 sequences present in MM tissue samples
retain the ability to inactivate both p5320 and pRb.21
The potential to overcome these checkpoints in cellular
proliferation could be crucial in enabling a tumor to
survive and progress. While such speculation is inviting, reservations remain about the place of SV40 in cancer. Clearly SV40 is not essential for the development
of MM, since many cases do not express TAG sequences.
Are such tumors different in their behavior – and what
of those that do not express TAG? There may be as yet
undiscovered co-factors that are more important for
tumorigenesis. If we are to accept the polio vaccine
contamination hypothesis then why is TAG expressed
in tumors of children who were too young to be immunized in this setting? Artefactual presence would call
into question all of the above research, but there must
otherwise be previously undescribed vertical transmission of the virus or some other means of human infection. Further investigations and more accurate
molecular and proteomic reagents are required to determine more clearly how SV40 fits into the pathogenesis
of MM.
Other agents
One-quarter of people who develop MM have had no
known exposure to asbestos. While some of these cases
may arise from occult exposure, a number of other possible agents have been proposed to cause the disease.
These include thoracic radiotherapy, intrapleural thorium dioxide, and other silicates, including erionite and
zeolite. The numbers of cases attributed to radiation
exposure are very small. A genetic predisposition has
also been suggested by occasional reports of clusters of
disease within a family, but again numbers are small
and co-exposure is difficult to exclude. Although asbestos exposure and smoking have been shown to be synergistic in terms of the likelihood of development of
bronchogenic carcinoma, there is no known association
between smoking and MM.22
Pathogenesis
The molecular evolution of most tumors is currently
believed to follow that of the classic model described for
the development of colon cancer by Volgelstein et al.23
In this model, a single cell develops a genetic mutation
that enables it to proliferate despite absent or even negative growth-stimulatory signals from normal tissue.
Such mutations can occur in response to a carcinogen
such as asbestos in MM, as discussed above. The multistep accumulation of further mutations to cells in this
clone leads to the development of the hallmarks of a
frank malignancy, namely autocrine growth, invasion,
and the ability to metastasize. This whole process may
occur over a period of many years. Alterations enabling
this malignant pattern of growth to occur may include
oncogene activation or mutation, loss of tumor suppressor genes, and autocrine or paracrine secretion of
growth factors. Determining which changes a cell
undergoes to develop this malignant phenotype has the
potential to provide insights into new methods of treatment for a tumor. In MM, considerable progress has
been made over the last ten years in elucidating candidate factors, but no clear single pathogenic pathway has
yet been found.
Chromosomal abnormalities
Asbestos is known to induce chromosomal mutations
directly. This may occur by the production of reactive
metabolites as mentioned above, by interference with
the mitotic spindle at division, or by direct chromosomal adherence resulting in fragmentation. The majority of cases of MM subjected to cytogenetic study have
shown karyotypic changes,24 and a wide range of complex and heterogeneous chromosomal abnormalities
have been described. Chromosomal gains have been
found to be as frequent as losses, and some of these are
relatively common, such as loss of 4, 22, 9p, and 3p,
Malignant mesothelioma 193
and gain of 7, 5, and 20.25 Significant correlation between
certain losses (1 and 4) and a high content of asbestos
fibers in lung tissue has been shown. The mean chromosomal number has also been shown to correlate with
survival in patients with MM. Those patients with a normal chromosome number and no clonal abnormalities
had the longest average survival.26
Of the many abnormalities described, there are some
alterations that are of particular interest in terms of
pathogenesis. Monosomy 22 is the most common
numerical cytogenetic change, and has been correlated
with mutations in the neurofibromatosis type 2 (NF2)
gene.27 The loss of at least one locus in 1p (nearly all in
1p22) was found in 74% of examined specimens,28 and
42–62.5% of cases of MM have been found to have loss
of heterozygosity of one or more loci on chromosome
3p.29 These changes are of interest in that there is a gene
for cellular senescence on chromosome 1 and a tumor
suppressor gene located on chromosome 3.13 Polysomy
of chromosome 7 is common, and the number of copies
of the short arm of this chromosome has been found to
be an adverse prognostic feature.24 The loci for the epidermal growth factor receptor (EGFR) and the plateletderived growth factor A chain (PDGF-A) are both
present on this chromosome (see below). In one study,
83% of cell lines had deletions of 9p,30 which is the
location of the gene for p16INK4 (see below). Sixty-one
percent of MM specimens were also found to have allelic
losses in 6q in four discrete locations, most of which
had losses in more than one of these regions.31 As was
postulated by Bell et al,31 the consistent losses seen in
certain areas may imply that these regions are the sites
of tumor suppressor genes, the loss of which is central
to the development of the tumor.
Oncogenes
Specific oncogenes have been found to be central to the
progression of many malignancies, but as yet this has
not been particularly well studied in MM. Of interest,
however, are the findings that the v-src gene has been
shown to cause MM in chickens32 and that the EJ-ras
gene causes tumorigenic transformation of mesothelial
cells when transfected.33 There is no evidence that these
oncogenes play a role in human MM. The most promising candidates have been c-fos and c-jun, which have
been implicated in animal models. The levels of both
c-fos and c-jun mRNA have been shown to be upregulated when rat pleural mesothelial cells are exposed to
asbestos.34 This pathway has been further investigated
by showing that these changes are prevented by the use
of N-acetylcysteine35 and by calphostin C, a protein
kinase C inhibitor.36 Such findings could implicate
these proto-oncogenes in the pathogenesis of MM, but
the levels of c-Fos protein were found to be similar in
MM and non-neoplastic mesothelial tissue.37 Wild-type
K-Ras was found in all 20 MM cell lines examined by
Metcalf et al.38 c-Myc immunocytochemical expression
is common,39 but c-myc was not found to be amplified
in murine MM cell lines.40
Tumor suppressor genes
In order for a tumor to continue to proliferate in the
face of genomic damage, it is necessary that it avoid the
normal cellular processes for the detection of such damage. Tumor suppressor genes enable the cell either to
arrest the cell cycle with the possibility of repair or to
undertake programmed cell death (apoptosis). Mutation
or loss of a tumor suppressor gene enables an altered
cell to continue through the cell cycle unchecked, and
allows further proliferation. The most well-described of
the tumor suppressors is TP53, which is known to be
mutated in a majority of human cancers.41 Alterations
in TP53 have been found in 75% of murine MM cell
lines,42 but wild-type p53 was normally expressed in
most human MM cell lines38 and demonstrated by
immunohistochemistry in primary tumors.43
The retinoblastoma protein pRb prevents progression of a damaged cell into S phase when it is hypophosphorylated. Its level of expression in human MM
cell lines has been shown to be normal.44 Mouse double-minute 2 (MDM2), a protein that can inhibit the
function of both p53 and pRb, is not overexpressed in
human MM,45 although a proportion has been shown
to have positive staining for MDM2.46 The possibility of
expressed pRb being abnormal in this tumor has been
raised by the finding that a monoclonal antibody specific for the epitopes between exons 21 and 27 showed
no immunoreactivity by immunohistochemistry, whereas
a polyclonal antiserum showed staining in all MMs
examined.47
In keeping with the frequent loss of chromosome 9,
the product of the CDKN2 gene, p16INK4, was found to
be abnormally expressed in 12 of 12 primary MMs and
15 of 15 MM cell lines.48 p16INK4 normally inhibits
phosphorylation of pRb, and thus its loss would allow
uncontrolled progress through this stage of the cell cycle.
Deletions of the portion of chromosome 9 containing
CDKN2A, but not CDKN2B, were also found in MM cell
lines,49 whereas p16 has previously been found to be
deleted in 85% of MM cell lines but only 22% of primary tumors.50 Seventy-two percent of primary MMs
have also been found to have co-deletions of p15 and
194 Textbook of Lung Cancer
p16.51 p16/CDKNA2 was homozygously deleted in 59
out of 80 human tumors52 and patients with intact p16
had a significant survival advantage.53
The third tumor suppressor of particular interest in
MM is the NF2 gene. This was found to be mutated in
41% of MM cell lines examined by Sekido et al54 and
53% of cell lines examined by Bianchi et al.55 This latter
group also found that three-quarters of these mutations
were confirmed to be present in the primary tumor.
This finding for MM in humans does not correlate with
the disease in rats, where mutations were not found.56
The Wilms’ tumor gene (WT1) is expressed in normal mesothelium during embryogenesis. It is potentially interesting in view of the fact that one of the
actions of the WT1 protein is to control the transcription of genes such as those for PDGF-A,57 insulin-like
growth factor (IGF)-II,58 transforming growth factor
(TGF-β),59 and the IGF-I receptor (IGF-IR).60 All of
these have been described as potential autocrine growth
factors in MM, and the deletion of WT1 could allow
excessive production. Expression of WT1 mRNA has
been found in most human MM cell lines examined and
in most primary tumors.61,62 The level of expression has
been found to be variable, but there was no inverse correlation found between expression of WT1 and IGF-II
or PDGF-A.63 A further study using mutational screening found no significant changes to WT1, and also
found no correlation between WT1 immunostaining
and EGFR or IGF-IR levels.64
PATHOBIOLOGY
The diagnosis of MM is usually made on the basis of
histologic analysis, from which the tumor can be classified as follows:
1.
2.
3.
4.
Epithelial: the tumor mass consists of papillary,
tubular, acinar-like, or solid tissue in which cuboidal tumor cells form a pavement-like appearance.
The amount of stroma within the tumor is variable.
Sarcomatous: the tumor mass consists of spindleshaped cells forming organized bundles, though
whirls, ‘herring bone’, or irregular patterns of
tumor cells also occur.
Desmoplastic: the tumor mass consists of a sizable
connective tissue component with variable cellularity and pleomorphism. Epithelium-like structures are not present in this form.
Biphasic: the tumor mass consists of a mix of the
epithelial and sarcomatous forms. This is the most
common type.
Differential diagnosis of MM from reactive mesothelium or adenocarcinoma is an important aspect of analysis of biopsy samples. Cytologic diagnosis is based first
on the malignant nature of the samples by generally
applicable criteria (nuclear polymorphism, irregularity
of nuclear membrane, chromatin distribution), followed
by confirmation of the mesothelial characteristics. These
characteristics include a characteristic cytoplasmic
appearance, a brushlike border and multinucleation.
Further confirmation can be obtained by ultrastructural
analysis, showing long microvilli and numerous intermediate filaments.65 The differential diagnosis of MM
from metastatic adenocarcinoma has been facilitated by
the availability of extensive immunohistochemical panels, including mesothelial markers such as calretinin,
mesothelin, podoplanin, and thrombomodulin, and
glandular markers such as CEA, LeuM1, and B72.3. In
addition more specific markers of lung adenocarcinoma
such as TTF-1 are now available.66 However, distinguishing MM from benign mesothelial cells remains a
challenging area in cytologic diagnosis. Strong membrane staining for EMA on the majority of mesothelial
cells is considered indicative of malignancy.67
GLOBAL TRANSCRIPTIONAL PROFILING IN MM
Using various global transcription profiling ‘microarray’
strategies, several studies have been performed in MM
with various aims: to understand the genetics and biology
of MM, to identify genes that may be useful for early
diagnosis, for determining prognosis, and to identify
potential targets for the development of new therapies.
Experimental models examining asbestos-induced
transformation of mesothelial cells68 as well as studies
using human MM patient samples have shown activation of pathways common to the development of many
cancer types. Such functions relate to growth and proliferation, cell-cycle progression, apoptosis, invasion,
and metastasis. Pathways including the insulin-like
growth factor-1, p38 MAPK, Wnt/β-catenin, and integrin signaling have been found to be important for MM
development.69,70
Diagnostic strategies for distinguishing MM from
lung adenocarcinoma have been suggested based upon
gene expression profiling.71,72 As well, specific markers
such as osteopontin were shown in gene expression
studies to be upregulated in MM, and may be of possible value as a serum marker for MM.73
Some studies have concentrated on finding gene
‘signatures’ that can be used as to predict prognostic
Malignant mesothelioma 195
indicators for MM.74–77 However, it appears that clinical
prognostication based on gene expression profiling is
not significantly superior to that achieved using classic
clinical parameters such as age, sex, epithelial histology, lymph node status, and tumor stage.77 Global
microarray profiling, however, has revealed potential
new clinical targets such as the aurora kinases.77
IMMUNOBIOLOGY
The human disease
In contrast to many other tumors, there is little evidence in MM that specific immune responses are initiated against the tumor during the course of the disease.
Some descriptions of leukocytic infiltrations have been
reported in the literature, but these examples are rather
non-systematic and use very broad characterizations.
What is evident is that the extent of infiltration depends
on the individual tumor.78,79 One unusual form of MM
is termed lymphohistiocytoid MM – so called because
there is evidence of lymphocytes infiltrating the tumor
mass.80 Although suggestive of specific immune recognition of the tumor, there is no direct evidence that
supports this hypothesis, and these cells may simply
reflect a non-specific inflammatory response. In fact,
early attempts to isolate MM-reactive killer cells from
patients proved unsuccessful.81 Overall, the lack of
tumor-infiltrating lymphocytes (TILs), as with many
other tumors, has been attributed either to a lack of
tumor antigen expression or to other factors, such as
the secretion of immunosuppressive cytokines, that
diminish the overall immunogenicity of the tumor.
However, more recent work has suggested that an
immune response is generated in a significant proportion (28%) of MM patients.82 In these studies, patient
sera reacted with a panel of human MM cell lines as
determined by Western blot analysis. When sequential
sera were analyzed, it was found that the titer increased
with the progression of the disease. Importantly, the
MM-reactive antibodies within the sera were of the IgG
class, indicative of immunoglobulin class switching,
and hence the involvement of the cellular arm of the
immune response, which is obligatory for this process.
These are important data, which will lead to identification of a number of potential tumor-associated antigens
(TAAs), the characterization of which will be invaluable
in the context of potential vaccination strategies or
immunotherapeutic treatments.
In addition, clinical studies have suggested that, even
if an immune response is not a normal event in the
disease process, this malignancy may be susceptible to
immunotherapy. In a small trial using intralesional therapy with granulocyte–macrophage colony-stimulating
factor (GM-CSF), while there was no direct evidence of
a tumor-specific immune response, the one patient who
showed a partial response also had an intense lymphocytic infiltration in biopsy samples.83 Apart from using
this direct administration of a cytokine, efforts have
been made to utilize gene therapy techniques in treatment. In particular, the use of genes encoding cytokines
has been the most prevalent, in the hope that they will
boost or enhance any ongoing antitumor response.
Although gene therapy has provided some encouraging
results in animal models, the difficulty with this technique in solid tumors, such as MM, is the inability to
transduce all tumor cells with the gene of interest.
Therefore some emphasis has been placed on trials in
which cytokine genes are transferred via viral vectors
such as vaccinia.
The growth of tumors is often considered to be
immunosuppressive, and MMs have been shown to
secrete a number of cytokines or factors that are known
to modulate immune responses, including PDGF,
TGF-β, and interleukin-6 (IL-6). As is quite often the
case with such products, they are responsible for coordinating or mediating a number of processes, and
PDGF and TGF-β have also been shown to be growth
factors for MMs. The role of these molecules in influencing the immune response to MM has not been investigated deeply, and what we know has been elucidated
in animal models (see below).
Another potential mechanism whereby MMs might
evade immune recognition is by the downregulation of
HLA class I molecules, such as has been reported for
melanoma. However, a survey of a panel of human and
murine lines has shown that these tumors all express
class I molecules, and therefore they can still be targets
for the immune response.
ANIMAL MODELS
A number of different models of MM have been established in animals to understand the pathogenesis of the
disease and to test potential therapeutic agents. Spontaneous mesotheliomas have not been described in mice
or hamsters and occur very rarely in rats. However,
natural and synthetic fibers, chemicals, and metals have
been shown to induce pleural and peritoneal mesotheliomas in rodents.84 Additionally, intrapleural inoculation of hamsters with SV40 virus causes pleural
196 Textbook of Lung Cancer
100
% Survival
mesotheliomas in 100% of cases.85 The injection of
asbestos fibers into pleural and peritoneal cavities produces malignant mesotheliomas in 20–30% of mice.86,87
These mouse mesotheliomas are comparable to the
human disease with respect to latency, superficial
growth of tumor on the serosal surface, and the accumulation of ascites.88 Although this is not a viable working model for the testing of therapies due to the long
latency period and low incidence of disease development, it has led to the generation of many asbestosinduced mesothelioma cell lines.86 Subcutaneous
inoculation of these mesothelioma cell lines into syngeneic mice induces solid tumors which grow rapidly and
are easily accessible for monitoring efficacy of drug
treatments. As these tumors exhibit the diagnostic characteristics of the human tumor, despite their anatomic
dislocation, they have been used extensively to study
the immunobiology of MM89 and to evaluate efficacy of
chemotherapies, immunotherapies, and combination
therapies.90–92
More recently, genetically modified transgenic mouse
mesothelioma models, with features of asbestos-induced mesothelioma, have been devised and it is hoped
that these new models will enable further testing of
drug therapies and study of the disease. Although loss
or mutation of p53 is not considered a trait of mesothelioma, the first transgenic model used was a p53 knockout mouse, originally created to study a range of cancers.
Although a proportion of homozygous p53−/− knockout mice developed disease soon after asbestos inoculation, these mice have a short lifespan of only 22 weeks
and the rest died of other causes, rendering them unsuitable for modeling this disease.93 More promisingly, the
heterozygous p53+/− knockout mice have a longer
lifespan and 76% of these mice had developed asbestos-induced mesothelioma compared to 32% wild-type
mice, at 44 weeks after initial asbestos exposure. These
p53+/− heterozygous mice have been used in further studies investigating loss of heterozygocity in asbestos-induced tumors.94
Human malignant mesotheliomas frequently accumulate genetic alterations affecting the Nf2 and
CDK2A/Arf tumor suppressor gene loci. When Nf2+/−
knockout mice are exposed to asbestos, they develop
mesothelioma more rapidly and at a higher incidence
than wild-type littermates.95,96 Analysis of the tumors
showed that they recapitulated the most common
molecular features of human malignant mesothelioma.
They had frequent deletions in the Arf/CDK2A locus,
inactivation of p53, and activation of the AKT signaling
pathway.97
80
line 299h
line 304i
60
line 266s
wild type
40
20
0
0
10 20 30 40 50 60 70 80 90 100
Weeks after asbestos exposure
Figure 12.1
Mice expressing SV40 are more susceptible to asbestos-induced
MM. Mice bearing the SV40 Large T gene driven by the mesothelin
promoter showed increased sensitivity to asbestos-induced MM.
Shown is the survival of these mice (‘MexTAg transgenic mice’)
after two injections of 3 mg asbestos were given in the peritoneum, 4 weeks apart. Mouse lines 299h, 304i, 266s, and wt
(wild-type) contain 100, 30, 1, and 0 copies of TAg, respectively.
The number of animals in each group is noted. Median survival
times were line 299h, 24 weeks; line 304i, 36 weeks; line 266s,
55 weeks, and wt, 56 weeks. Log rank tests showed survival was
significantly different between all mouse lines, with the exception
of 266s and wt. p Values were 0.005 or less.98
The injection of asbestos fibers into the peritoneum
of mice induces mesotheliomas in less than a third of
mice, between 7 months and 2 years after the first asbestos exposure. Although this method has provided the
mouse mesothelioma cell lines that are useful tools in
the subcutaneous model, the model itself is impractical
for further studies of the disease, such as assessment of
drug efficacy. We have constructed a novel transgenic
mouse model, MexTAg, which directs SV40 TAg
expression to the mesothelial compartment using the
mesothelin promoter. When MexTAg mice, containing
100 copies of the TAg transgene (299h mice), are
injected with asbestos, not only do all of the animals
develop MM but disease occurs much more rapidly
than in wild-type mice (Figure 12.1).98 At 38 weeks all
299h mice had developed MM, whereas 87% of wildtype mice remained healthy. Furthermore, at the end of
the experiment, only 25% of wild-type mice had developed MM. Thus, this model is suitable to examine the
efficacy of preventative and therapeutic drugs and also
to investigate the molecular events occurring at the
early stages of MM development. While MexTAg mice
unexposed to asbestos did not develop MM, in another
transgenic mouse model, which expresses SV40 TAg
under the control of the cytokeratin 19 gene, MM and
other tumor types developed; however it was unfortunate that these mice were unable to breed.99
Malignant mesothelioma 197
Applications to therapy
As mentioned above, immunomodulatory molecules
such as TGF-β are produced by MM cells as obligate
growth factors. One could therefore hypothesize that
interventions that target such factors may be very effective from two aspects: first, by interfering with the
growth cycle of the tumor cells, and, second, by allowing an immune response to be generated. In experiments in which TGF-β production was reduced by
inhibiting translation of these proteins using antisense
DNA technology, tumor growth could be inhibited but
not eradicated.100 Inhibition of tumor growth was concomitant with treatment – the effects were lost on cessation of treatment. No evidence of an improved antitumor
response was noted in these experiments. This result
may have several explanations, including that the amount
of TGF-β required for tumor cell growth is significantly
greater than that required for immunosuppression.
Such approaches are worthy of further investigation –
possibly in combination with other treatments. See the
section below on ‘Future directions’.
CLINICAL PRESENTATION AND COURSE
MM usually develops in males with a history of occupational exposure to asbestos. The latency period
between asbestos exposure and the development of
MM is at least 20 years.1,101 Therefore patients are usually over 50 years of age.102 However, non-occupational
exposure does occur, and in some of these cases the
exposure occurred in childhood. Patients with pleural
MM usually present with symptoms of chest pain or
discomfort, dyspnea, and cough. In fact, the presence
of chest wall pain in any at-risk patient is a strong clue
to the possible presence of MM. Early in the course of
the disease, dyspnea is the commonest symptom, and
is due to the presence of an effusion. The majority of
patients with pleural MM will have a malignant pleural
effusion, which is usually bloodstained, often loculated,
and of large volume. As the tumor progresses, chest discomfort or tightness may occur. The dyspnea may improve
because of fusion of the pleural surfaces and resolution
of the effusion, or therapeutic talc pleuradesis. Unremitting chest pain may occur as the tumor locally invades
the intercostal nerves. Eventually, the lung becomes
encased by tumor, leading to worsening of dyspnea and
chest tightness. The tumor commonly spreads by direct
extension to involve the chest wall, the mediastinum,
other pleura or the diaphragmatic surface, the pericardium, and the liver. Invasion of the pericardium leads
to a pericardial effusion, which worsens the dyspnea.
Spread to local lymph nodes occurs in 40% of cases,
but hematogenous spread is less common and rarely
clinically significant. Weight loss occurs in the late
stages of the disease.
Examination findings in the early stages of the disease usually reflect the presence of a pleural effusion,
with dullness to percussion and reduced breath sounds.
As the tumor progresses and encases the entire hemithorax, the hemithorax may contract, chest expansion
becomes noticeably restricted, and dullness to percussion and reduced breath sounds are found over the
affected area. Breathing sounds can be ‘harsh’ rather
than reduced, and sometimes are frankly ‘bronchial’ in
nature. Protrusion of tumor through the intercostal spaces
tends to occur at sites of previous thoracocentesis, chest
tube insertion, or thoracotomy incision. Supraclavicular lymphadenopathy and ascites may be present if the
tumor has spread to these areas. Paraneoplastic syndromes are rare, but can include hypercalcemia, autoimmune hemolytic anemia, and inappropriate secretion
of antidiuretic hormone (SIADH).103 Thrombocytosis
with a platelet count of greater than 400 000/µl occurs
in approximately 30% of cases,102 but does not commonly lead to increased thrombotic events. Those with
peritoneal disease experience abdominal pain and distension, weight loss, anorexia, and bloating. Peritoneal
MM rarely invades superiorly through the diaphragm.
DIAGNOSIS
Radiology
The most common chest X-ray abnormality in early
stage disease is the presence of a pleural effusion. Pleural thickening or small focal pleural masses may be seen
on computed tomography (CT) of the chest, and CT is
useful in differentiating pleural fluid from pleural
thickening,104 although ultrasound is often required. CT
scanning also provides information on the state of the
pulmonary parenchyma, the mediastinum, and invasion of the chest wall.105,106 As the disease progresses
there is diffuse involvement of the pleura and larger,
pleurally-based masses may become obvious. The pleural
effusion often becomes loculated. Eventually, the lung
becomes encased in a thick pleural rind of tumor that
compresses the underlying lung. Magnetic resonance
imaging (MRI) is useful for delineation of chest wall
invasion. MM is also FDG-PET avid; however the role
of PET scanning in staging, prognosis, and treatment
planning is still under investigation.107,108
198 Textbook of Lung Cancer
•
Cytology
Most patients with MM present with a pleural effusion,
and therefore thoracocentesis is often the first diagnostic procedure. Large amounts of pleural fluid should be
obtained and sent for cytologic examination; this will
be diagnostic in 30–50% of cases.103 The fluid should
be examined using light microscopy and immunochemical stains for cytokeratins and vimentin and
immunohistochemical stains (especially CEA and EMA)
to differentiate adenocarcinoma from MM (see above).
The accuracy of EMA in cytologic studies depends upon
the clone of antibody used in the analysis. The combination of cytologic assessment of pleural fluid and histopathology on closed pleural biopsy specimens can
increase diagnostic accuracy for pleural malignancy,
including MM.112
Biomarkers
Measurement of tumor markers in effusions may provide a complementary tool to aid in effusion diagnosis.
Differential levels of CEA, cancer antigen (CA)15.3,
CA72.4, CA19.9, CA549, neuron-specific enolase, or
cytokine fragment 19 (CYFRA 21-1) differentiate malignant from benign effusions.113,114 However, there are
fewer data available for the differential diagnosis of MM
from other cancers. Low levels of CEA in effusions of
MM patients provide a strong negative predictive value
for this disease.115–117 However, there are few studies
reporting markers with a positive predictive value for
MM. Elevated CA15-3 levels have been reported in
MM,114–116 and in one study as being able to differentiate
MANAGEMENT
MM is an almost uniformly fatal disease that is not usually
curable with surgery, chemotherapy, or radiotherapy.
1.5
1.0
0.5
0.0
Asb-Exposed
•
lack of useful pleural tissue;
difficulty in interpretation of small biopsy
samples;111
the need to distinguish MM from reactive mesothelial inflammation and metastatic pleural tumors;
difficulty in differentiating histologic subtype on a
small specimen.
MM
•
•
between MM and bronchial cancer.116 Higher levels of
hyaluronic acid have been reported in effusions from MM
patients compared to those with other malignant diseases;
however the difference was too small for diagnostic
purposes,117 whereas there is discrepancy in the literature on the ability of CYFRA 21-1 levels to differentiate
between MM and other pleural malignancies.116,117
Recently, we showed that mesothelin levels in effusions
above 20 nM are highly suggestive of malignancy, particularly of MM; at this cut-off value the assay had a sensitivity of 77% for non-sarcomatoid MM, and a specificity
of 98% relative to non-malignant effusions and 86%
relative to non-MM malignancies (Figure 12.2).118
Mesothelin levels have also been shown to be useful in
monitoring disease progress/regression.118
Elevated mesothelin levels were observed in some
effusions before a definitive cytologic and/or histologic
diagnosis could be made. One patient, an 87-year-old
male, who presented with recurrent blood-stained exudative effusions which were negative for malignancy by
cytologic examination, had elevated mesothelin levels
in his effusion. In this case a definitive diagnosis
of MM was made 10 months after the initial mesothelin-positive effusion sample.
SMRP(OD 420 nm)
Histopathology
Accurate diagnosis of MM can be time-consuming, and
may require more than one diagnostic procedure because
of the difficulty in obtaining malignant tissue for histopathologic assessment. Pleural biopsies, obtained via
closed or open (thoracoscopy/thoracotomy) procedures,
improve the diagnostic yield. Pleural biopsy samples
should be assessed by immunohistochemistry and electron microscopy, since these are the important studies
to assist in making a definitive diagnosis.109,110 The major
problems associated with closed pleural biopsies are:
Figure 12.2
Serum mesothelin in MM patients versus asbestos-exposed
controls. Individual patient data are plotted as the mean
absorbance measurement at 420 nm of duplicate serum samples
diluted 1 in 100. Dashed line represents the normal range.
(Adapted from Robinson et al,119 with permission.)
Malignant mesothelioma 199
The potential treatment options are the same as for other
malignancies, namely surgery, radiotherapy, chemotherapy, immunotherapy, gene therapy, supportive care, or
combination therapy utilizing some or all of the above
treatments. However, there are major differences from
other cancers, because in MM it is often difficult to objectively quantify the location and extent of disease, and
the patients are older and often have underlying illness
that makes them unfit for aggressive, rigorous treatment
plans. The relative rarity of the condition means that few
large prospective clinical trials have been published,
and clinicians must rely on retrospective clinical trials
with small numbers of patients. Here, we concentrate
on the palliative management of patients with advanced
disease, the most common presentation. However, surgery with the aim of cure will also be discussed.
Chemotherapy
Until 2003, there were no randomized clinical trials
demonstrating an improvement in survival, quality of
life, or lung function for any palliative chemotherapy
regimen in MM. In 2003, a landmark clinical trial was
published by Vogelzang et al, comparing overall survival, response rates, toxicity, and quality of life in 226
patients with advanced MM randomized to cisplatin
plus pemetrexed, and 222 to single-agent cisplatin.120
Patients receiving cisplatin and pemetrexed had a significantly longer median survival than those on cisplatin alone (12.1 months versus 9.3 months, p = 0.02).
Forty-one percent of patients on the combination arm
had objective tumor responses, compared with 17% in
the single-agent arm (p <0.0001). The combination
arm experienced greater toxicity; however this was
rarely clinically significant and was in part ameliorated
by supplementation with folate and vitamin B12. This
trial also demonstrated small but statistically significant
benefits for combination chemotherapy in global quality of life and symptom distress measures, and larger
benefits for pain, dyspnea, and cough after 18 weeks of
treatment.121 Similar results have been obtained for
another combination chemotherapy using cisplatin and
raltitrexed, significantly improving overall survival as
compared with cisplatin alone.122 Single-arm studies
also suggest good response rates for cisplatin and
gemcitabine,123,124 but this combination has not been
tested in phase III clinical trials. Overall, these studies
have shown that combination chemotherapy, in appropriate patients, can give palliative benefits by decreasing tumor bulk, increasing survival, improving lung
function, and improving quality of life. The timing of
chemotherapy (on diagnosis versus when symptomatic)
and duration of chemotherapy (four versus six versus
more cycles of treatment) are questions for further study.
There are currently no predictive markers of response
to chemotherapy, although patients with ECOG performance status of 2 or worse may be less likely to
benefit.121,124
Radiotherapy
Hemithoracic radiotherapy has a limited role in the palliative management of MM due to the difficulty in delivering adequate doses to a large treatment field. However,
low-dose palliative radiotherapy to limited fields can
very effectively relieve pain from enlarging chest wall
masses.125 Radiotherapy also has an important prophylactic role in preventing chest wall infiltration and
development of masses at the sites of previous invasive
instrumentation such as chest drains or pleural biopsies.126 All patients at risk of local chest wall infiltration
should be considered for this simple procedure.
Immunotherapy and gene therapy
These are relatively new treatment options, and their
role alone or in combination with surgery or radio- or
chemotherapy has not yet been adequately evaluated. It
is known that systemic interferon-α (IFN-α),127,128
IL-2,129 and GM-CSF83 have some activity in selected
cases of MMs, but none has achieved a response rate
sufficient to warrant their recommendation in all
patients. Combining IFN-α with chemotherapy has
also produced no added benefit.130
Surgery
Four types of operation have been performed as treatment for mesothelioma: extra pleural pneumonectomy
(EPP), pleurectomy/decortication, limited pleurectomy,
and thoracoscopy with talc pleurodesis. EPP involves
an en bloc resection of the pleura, lung, ipsilateral
hemidiaphragm, and pericardium. Butchart et al131
reported that this procedure carried an operative mortality rate of 30%, but since then there have been a few
studies reporting a reduction in operative mortality rate
to 6–9%.132–135 This was most likely due to improved
patient selection, experience, and better postoperative
care. Median survival in these studies ranged from 8 to
16 months. Pleurectomy/decortication involves attempting to remove all obvious pleural disease without
removing the underlying lung. The operative mortality
rate is 1.8%;136 however, long-term survival is not significantly increased in most patients. Limited pleurectomy
is a palliative procedure designed to resect part of the
parietal pleura to control a pleural effusion. Thoracoscopy
200 Textbook of Lung Cancer
with talc pleurodesis is an effective palliative procedure for
control of effusion.
Overall, in most cases, surgical procedures alone will
not lead to any significant improvement in survival.
However, Sugarbaker et al137 showed that trimodality
therapy (resection of tumor, chemotherapy, and radiotherapy) in highly selected patients can lead to a small
proportion of patients with long-term survival. In this
study, operative morbidity rate was measured at 17%,
mortality rate was 6%, and overall survival was 16
months. There are no completed randomized clinical
trials to support this practice; however the MARS trial,
run out of the United Kingdom, is currently randomizing patients to surgery as part of trimodality therapy,
or palliative management (including chemotherapy)
alone. Patient selection for ‘curative’ surgery is not standardized; however an aggressive approach to staging
and preoperative investigation that may include PET
scanning, mediastinoscopy, contralateral thoracoscopy
with blind biopsies, and laparoscopy has been advocated.138 Optimal surgical technique is also debated.139,140
Referral to a thoracic surgeon with experience in EPP
should be considered in fit patients with early stage,
potentially resectable disease.
Chemotherapy and radiotherapy
Chemotherapy and radiotherapy are components of socalled ‘trimodality’ therapy; however the optimum timing (pre- or postoperative), regimen, and duration of
chemotherapy are unclear. Clinical trial results are not
yet available to inform these decisions. In clinical practice, a common approach is to use cisplatin and pemetrexed due to the demonstrated activity of this
combination in advanced disease.120 However, it is still
unclear whether chemotherapy is best used preoperatively or postoperatively. Neoadjuvant chemotherapy
may avoid a morbid operation in patients with rapidly
advancing and treatment-resistant disease, and patients
are fitter preoperatively. However, some surgeons consider EPP to be more technically challenging postchemotherapy, and would prefer an adjuvant approach. A
disadvantage of adjuvant chemotherapy is that not all
patients will be fit enough for treatment after surgery.
There are several approaches to integrating postoperative radiotherapy into the trimodality program. The
lowest locoregional recurrence rates post-EPP are in
those series using high-dose postoperative hemithorax
irradiation.141 Recent guidelines for three-dimensional
conformal radiotherapy suggest a dose of 54 Gy in 30
fractions five days per week to the ipsilateral thoracic
cavity, chest wall incisions, and drains, with attention
to normal tissue tolerance for the contralateral lung,
spinal cord, heart, esophagus, and other vital structures.142 Intensity-modulated radiotherapy (IMRT) is a
promising newer technology that may deliver better
local control results;143 however it is not widely available, and there have been reports of subsequent fatal
pneumonitis which suggest caution in implementing
this technology.144 Nevertheless, only patient series
using an aggressive multimodality approach achieve
clinically meaningful five-year survival rates.145
FUTURE DIRECTIONS
In this section, we shall highlight directions in which
MM research is heading, focusing on aspects that could
prove to be clinically useful.
Diagnosis
There has recently been an upsurgance of interest in the
use of tumor biomarkers for the clinical management of
MM. Soluble mesothelin-related proteins in particular
are being intensively investigated. Mesothelin is a differentiation marker of mesothelial cells. Through various post-transcriptionally and post-transcriptionally
processed soluble forms of mesothelin can be detected
in the serum and in the pleural fluid of patients with
MM. Approximately 50% of MM patients have elevated
levels at the time of diagnosis, and up to 84% with
advanced disease.118,146
There is considerable interest in screening asbestosexposed individuals for the early detection of MM. Given
that mesothelin levels have been observed to be elevated
in some individuals up to five years before clinical presentation, mesothelin represents a strong candidate for
a screening program.146 However, the sensitivity of the
screening program will be limited, given that at diagnosis not all individuals have detectable mesothelin proteins in their sera. Currently, methods of combining
different biomarkers and a program that measures
changes in biomarker values, rather than absolute values, are being evaluated. The principle reason for developing a screening strategy for MM would be to commence
treatment on early stage tumors which would hopefully
prove more effective than treatment in more advanced
disease. However, prospective studies and randomized
trials would be required to test such an hypothesis.
Therapy
Future therapies in MM will have two aims. The first is to
alleviate symptoms. Patients with MM often experience
Malignant mesothelioma 201
profound weight loss, fevers, hypoalbuminemia, and
pain. Recent studies have identified cytokines that are
likely to contribute to this, particularly IL-6. In animal
studies, blockade of IL-6 has had a profound effect on
animals’ clinical status, although the actual antitumor
effect was modest, and possibly related to the improvement in the host’s well-being. If a simple method of
inhibiting IL-6 activity in vivo can be established, it is
likely that this could be given to patients with MM to
alleviate their systemic symptoms. Such therapy might
involve receptor blockade or IL-6-signaling blockade
(e.g. via the SOCS molecules).147
The second area in which new developments in therapy might occur is in the generation of antitumor
effects.
Development of new agents
Anti-angiogenic agents
VEGF is an autocrine growth factor in MM,148 and
VEGF expression in MM is correlated with microvessel
density,149 a poor prognostic feature in this disease.150
Bevacizumab is a recombinant humanized anti-VEGF
monoclonal antibody which acts by blocking VEGF
binding to the VEGF receptor. A clinical trial of bevacizumab in combination with chemotherapy is completed
but as yet unreported. Other anti-angiogenic agents
including thalidomide are currently in clinical trials in
mesothelioma.
Immunotherapy
Trials have begun of immunotherapy in its various
forms in MM, and it is likely that in the future the limited but clear success of this approach will be augmented, probably in combination with other therapies.
While established agents such as recombinant IFN-α
have had limited but surprising effects,127 combining
this approach with chemotherapy has not proved more
efficacious.130 This may be partly because of the toxicity
of chemotherapeutic approaches. It is therefore likely that
future immunotherapeutic approaches to MM will
involve other strategies, particularly the local administration of immunomodulatory agents The continuous
infusion of GM-CSF into MM produced some tumor
shrinkage and mononuclear cell infiltrates, but proved
technically demanding.83 Less technically demanding
means to improve delivery of these agents to the tumor
are likely to be developed. There are three possibilities:
improved continuous-infusion technology, depot release
preparations, and gene therapy. The last is the most
advanced. Initial studies using immunologic gene therapy in MM have involved the administration of virus–
cytokine constructs. In one pilot study, this approach
was shown to be feasible to produce a T-cell infiltrate
in the tumor and to be free of side-effects in the patient
and in contacts.151 These are very early days for the
immunologic gene therapy of MM, and there is no
doubt that in the future we shall see further developments in this area. Other gene therapy strategies that
have been utilized have included herpes simplex TK
‘suicide gene’ therapy, which has produced some
responses, and which may be working by a combination of tumor shrinkage and necrosis generating antitumor immune effects. Other gene therapy approaches
that have been utilized preclinically include the use of
antisense oligonucleotides to block MM growth factors
such as PDGF and TGF-β. This approach has proved
most efficacious in vivo, and has caused a profound
reduction in tumor growth in animal models.100 It is
likely that future treatment of MM will involve such
gene therapy approaches, provided that the concentration of antisense oligonucleotides can be increased
within tumors to a level sufficient to cause the required
biologic effects.
Recently, the autolgous MM tumor has been used in
vaccine studies, with local GM-CSF used as the adjuvant. This approach clearly induced anti-MM immune
responses, although substantial tumor regressions were
not seen.152
Combination therapies
It seems likely that the most effective treatment of MM
will require combination therapy. Combinations include
some of those described above, for example molecular
approaches to increase the sensitivity of tumor cells to
chemotherapeutic agents combined with systemic
administration of such agents, or a combination of suicide gene therapy with immunotherapy. In addition, it
is possible that chemotherapy can be strategically combined with immunotherapy in a way that augments the
efficacy of each; for example, it is possible that cycles of
drug therapy may alter the antigenic profile of tumor cells
so that they provide new targets for immunotherapy.
The future development of effective therapies in MM
is likely to rely on two fundamental principles. First, it
will be essential to understand the basic biology and
immunology of the disease before optimal therapies can
be developed. MM is a disease that has remained mysterious for many years, yet over the past five years or so the
underlying pathogenic mechanisms and immunobiology
have begun to be elucidated. Second, it is likely that
combined therapy will be necessary, and that each component will need to have independently proven efficacy,
202 Textbook of Lung Cancer
i.e. it will be important to build on treatments that
already have a track record of clear success at reducing
tumor bulk.
Tumor biology and epidemiology
In terms of epidemiology, it would be interesting to see
whether, in the future, other agents besides asbestos are
either sole etiologic agents in MM or act as co-factors
with asbestos. The recent identification of the SV40
virus as a potential factor in the development of MM is
of interest,20 and it will also be interesting to see if other
infectious agents that have known oncogenic effects are
identified. A number of viruses are at least partially
trophic to the pleural mesothelium (e.g. causing the
clinical syndrome of viralpleurisy), and a potential role
for such viruses in the generation of MM may be identified in the future. Similarly, there are a large number of
cases of MM in whom the level of asbestos exposure is
no higher than that of the background population. It
has been assumed that these cases represent the unfortunate small proportion of patients who develop a tumor
with low levels of carcinogen (similar to the small proportion of sun-exposed individuals who develop UVinduced skin cancers). Nevertheless, it remains possible
that other agents may be identified as etiological agents
in MM. For example, many patients with MM are farmers,
and, while it has always been assumed that this is because
they have been exposed to asbestos in their farming
activities, it would be interesting to determine whether
or not inhalation of potentially carcinogenic pesticides
may contribute to the development of the disease.
Finally, the future may see the development of preventive measures in MM. There are some populations
that are at extremely high risk of developing MM, for
example, those exposed to crocidolite as children. A
number of studies have been undertaken in an attempt
to reduce their risk, such as the use of prophylactic
vitamin A. This has shown some efficacy, but many
of these individuals still develop MM.153 The abovementioned identification of MM antigens raises the possibility that a tumor vaccine may be developed for MM.
Such at-risk groups would welcome such a vaccine.
However, there are two major hurdles to overcome.
First, these vaccines are difficult to test because they
need to be given to large numbers of patients and
followed for a long period of time before any valid efficacy can be determined: for example something like
5000–10 000 patients, followed over a period of five
years or so. Second, as most tumor antigens are selfantigens, the risk of autoimmune disease in vaccinated
patients would be substantial. This may cause pleurisy,
peritonitis, or pericarditis. It is thus possible that the
development of an MM vaccine may be limited by the
almost inevitable occurrence of such side-effects in a
significant proportion of those vaccinated. If these sideeffects are minimal then the benefit may outweigh the
risk, but the logistics of determining this are substantial. Most tumor vaccines are used in an adjuvant setting, i.e. they are used in patients once the disease is
already diagnosed.
In many ways, the future directions in MM research
and treatment will parallel those for other tumors, and
yet, in other ways, in view of the rather unusual clinical
and biologic behavior of MM, they will be unique to
that disease. Certainly MM is a very aggressive disease
that has been largely resistant to all therapeutic attempts
tried. In view of the increasing incidence of this disease
and the poor success rate with current therapies, it is
hoped that in the future the application of modern
molecular and biologic techniques to the problem, in
association with the commitment of managing clinicians to utilize novel therapeutic approaches, combined
with the courage of the afflicted population, will lead to
the development of improved methods of diagnosis,
therapy, and prevention of MM.
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152. Powell A, Creaney J, Broomfield S et al. Recombinant GMCSF plus autologous tumor cells as a vaccine for patients with
mesothelioma. Lung Cancer 2006; 52: 189–97.
153. de Klerk NH, Musk AW, Ambrosini GL et al. Vitamin A and
cancer prevention II: comparison of the effects of retinol and
beta-carotene. Int J Cancer 1998; 75: 362–7.
13 Summary of treatment
Heine H Hansen
Contents Introduction • Small cell lung cancer • Non-small cell lung cancer • Mesothelioma
INTRODUCTION
A short summary of the management of small cell lung
cancer (SCLC), non-small cell lung cancer (NSCLC),
and mesothelioma is given in this chapter based on the
evidence from randomized trials, even though it should
be realized that patients included in clinical trials are not
representative of the patient population as a whole.
Additional information on the management of lung cancer can be found in recent review articles.1–8
SMALL CELL LUNG CANCER
Limited disease
Surgical resection, followed by postoperative chemotherapy, is the treatment of choice for the rare patient who
presents with stage I or II disease. The results for SCLC
are equivalent to the treatment of stage I and II NSCLC.
For the more typical SCLC patient who presents with
bulky limited disease, combination chemotherapy is
the mainstay of treatment, in conjunction with radiotherapy. For chemotherapy, the combination of etoposide and cisplatin (EP) has become the most commonly
recommended regimen. The combination of carboplatin
and etoposide produces similar results to cisplatin and
etoposide, and has a more favorable toxicity profile.
Maintenance chemotherapy does not result in any substantial improvement in survival.
Based on meta-analyses, chest irradiation has shown
superior survival results in patients receiving combination chemotherapy and radiotherapy compared with
those receiving chemotherapy alone. The optimal timing and dosing of chest irradiation are still uncertain,
but there is a tendency to initiate radiotherapy early
during the first two courses, at total doses of at least 50
Gy. Hyperfractionated radiotherapy given twice a day
has yielded superior survival data in one randomized
trial compared with conventional radiotherapy when
combined with cisplatin and etoposide.
Prophylactic cranial irradiation (PCI) has also been
demonstrated to have a statistically significant impact
on survival in patients with limited disease who achieve
a complete remission, and it also reduces the lifetime
risk of cerebral metastases. The optimal dose and timing of radiotherapy are again uncertain; most frequently,
the total dose should not exceed 30 Gy given in fractions of 2.5 Gy daily.
Extensive disease
A combination of etoposide and cisplatin is the preferred standard treatment. The replacement of etoposide with irinotecan given together with cisplatin has
resulted in significantly better median and one-year
survival in one randomized trial, whereas no difference
was observed in a subsequent trial. Again, carboplatin
can be substituted for cisplatin because of similar activity and fewer side-effects, even though myelosuppression is greater. Recent results have indicated that a
four-drug combination of etoposide, cisplatin, epirubicin, and cyclophosphamide may be superior to etoposide and cisplatin alone.
With regard to maintenance therapy, the hypothesis
has been tested of adding either oral etoposide or topotecan to the treatment regimen in patients demonstrating a response to initial therapy. The results showed a
slight improvement with etoposide in terms of median
progression-free survival, whereas topotecan did not
show any significant difference. The impact of dose
intensification remains uncertain.
None of the phase III trials incorporating new agents
have shown superior results compared with classic combinations such as cisplatin/carboplatin and etoposide.
With respect to PCI, very recent data has also demonstrated benefit as measured by improvement in median
survival in patients presenting with extensive SCLC.
In patients presenting with poor prognostic factors,
such as performance status 3–4, involvement of the liver
and bone marrow, or severe co-morbid diseases, the initial dose of chemotherapy should be reduced, and careful monitoring is recommended over the first weeks.
Elderly patients with poor performance status and
widespread disease have a substantially higher risk of
208 Textbook of Lung Cancer
incurring treatment-related complications, and generally
have a poor outcome. Supportive measures alone are
often the best option for some of these patients.
Recurrent disease
The treatment options depend on the anatomic site of
relapse, symptomatology, and previous treatment. Local
relapse in patients without prior chest irradition is best
treated with palliative radiotherapy. Late relapse in
patients who initially responded to a platinum-containing regimen should be treated with the same regimen
again. Otherwise, single-agent chemotherapy with topotecan or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine is the treatment of
choice. Newer agents are being tested in this group of
patients, either as single agents or in combinations, but
usually yield response rates of < 20%.
NON-SMALL CELL LUNG CANCER
Stages I, II, and resectable IIIA
Stage IA
The standard therapy for stage I NSCLC continues to be
complete surgical resection when possible. This should
include lobectomy plus sampling of all mediastinal
nodal stations or complete lymph node dissection.
However, the surgical technique to perform a lobectomy
or pneumonectomy and mediastinal exploration may
change as experience with minimally invasive surgery
grows. Recent data have revealed encouraging results
with video-assisted thoracic surgery (VATS) lobectomy
and mediastinal sampling or dissection. With minimally
invasive surgery becoming more popular, the efficacy of
minimal resections such as segmentectomy and wedge
resection is also being readdressed as smaller tumors
(<1–2 cm) are being identified with spiral computed
tomography (CT) scans. Another critical question is the
relationship of tumor size to nodal metastasis. Data
have been presented suggesting that histology and size
may be beneficial in determining nodal risk.
For patients who are medically inoperable, advances
in radiotherapy such as three-dimensional (3D) conformal and stereotactic radiosurgery are producing more
durable results with decreased toxicity, and five-year
survival rates up to 40%.
Stage IB–IIIA
The results of several large randomized trials of postoperative chemotherapy have been published, but these
results differ and are therefore difficult to interpret.
It appears that the weight of evidence indicates that
postoperative cisplatin-based chemotherapy improves
survival after surgery in patients with stage IB to IIIA
NSCLC, resulting in an absolute survival advantage at
five years. Similar results have been obtained by Japanese investigators using an oral drug combination
of uracil and tegafur (UFT), both in individual trials
and when meta-analyses of the results were performed.
The results were most impressive in patients with
adenocarcinomas.
Alternatively, neoadjuvant therapies are increasingly
being used. Although large randomized trials investigating this important topic continue to enroll patients,
recent experience has indicated that neoadjuvant chemotherapy does not significantly increase surgical morbidity or mortality.
For patients with operable stage III (N2) disease, the
number of lymph nodes involved and the ability to eradicate tumor from the lymph nodes with neoadjuvant
therapy have been found to be important prognostic
factors. The pivotal question about the role of surgery
in the treatment of stage IIIA (N2) disease is still open and
awaits the results from several ongoing trials. As multimodality therapy leads to improved survival for patients
with operable NSCLC, an increased frequency of isolated
brain metastases has been observed, and the potential
value of PCI is being tested in selected subgroups.
Inoperable stage III
Concurrent chemotherapy/radiotherapy is the standard
of care for patients with inoperable stage III NSCLC.
However, numerous questions remain regarding the
optimal means to combine these two modalities and
whether there is a benefit of additional therapy before
or after chemotherapy/radiotherapy. Randomized phase
II trials with newer cytotoxic agents given with concurrent radiation or trials incorporating an induction or
consolidation chemotherapy approach have failed to
show median survivals beyond the standard 16–18
months in most instances. Trials evaluating altered
radiotherapy fractions have also not improved survival.
Important areas of future research include the roles of
3D conformal radiotherapy, intensity-modulated radiotherapy (IMRT), hyperfractionated radiotherapy, and
the addition of targeted agents, with several of the latter
demonstrating radiosensitization capabilities.
Stage IV (and IIIB with pleural effusion)
Doublet chemotherapy for stage IIIB with pleural effusion and stage IV NSCLC patients with adequate performance status has been shown in multiple randomized
Summary of treatment 209
studies to improve survival and quality of life, and
remains the standard of care. Numerous randomized trials have been performed during the last decade in order
to identify the best platinum-based regimen; no major
differences have been observed with respect to efficacy
– only with regard to toxicity and cost. Current trials
have continued to support this finding. Furthermore,
randomized trials that included a non-platinum regimen have shown such regimens to be equivalent in efficacy to platinum regimens, but with a more favorable
toxicity profile. Controversy continues over the number
of cycles of chemotherapy to be administered in the
first-line setting. Several guidelines suggest a maximum
of six cycles, but there is an accumulation of data indicating that three or four cycles are sufficient. Although
numerous phase II cytotoxic regimens have been evaluated, none has produced amazing results. The major
focus has therefore switched to targeted therapies.
A variety of targeted agents are currently being evaluated. At the forefront of the promising agents are the
epidermal growth factor receptor (EGFR) inhibitors,
gefitinib (Iressa), erlotinib (Tarceva), and a monoclonal
antibody against the vascular endothelial growth factor
receptor (VEGFR), bevacizumab (Avastin). Among
these, gefitinib and erlotinib have been approved by
health authorities in various countries as second- or
third-line treatment for NSCLC patients resistant to conventional combination chemotherapy.
A host of targeted agents are in earlier stages of clinical evaluation, such as cyclooxygenase-2 (COX-2)
inhibitors, the preapototic inhibitor exisulind, proteasome inhibitors, bexarotene (Targretin), and vaccines.
Improving upon the efficacy of second-line docetaxel,
investigators have focused on the addition of a second
cytotoxic agent or on giving taxanes in a weekly schedule. Among the targeted agents, erlotinib has resulted
in improved survival and quality of life in a large randomized trial comparing erlotinib with placebo. When
added to platinum containing chemotherapy, bevacizumab has also yielded higher response rates, progression-free survival, and median survival in advanced
NSCLC, with the majority of patients having adenocarcinoma, and it has recently been approved in the US
and in Europe for this group of patients.
Several small studies showed a favorable survival
improvement for doublet therapy, but further investigation is needed. Pemetrexed (Alimta), a novel multitargeted antifolate, has in a randomized trial resulted in
similar reponse rates, median survival, and overall
survival to docetaxel, but toxicity favored the pemetrexed arm, with significantly less neutropenia.
For the elderly population or patient with poor performance status, two-drug cytotoxic combinations,
single-agent chemotherapy with vinorelbine or gemcitabine, and targeted therapy with gefitinib or erlotinib
have proved to be of therapeutic value.
MESOTHELIOMA
Surgery should be considered when mesothelioma
remains localized, usually as extrapleural pneumonectomy, with excision of the diaphragm and the pericardium en bloc. Palliative local procedures include partial
pleurectomy, decortication, or pleurodesis. Chemotherapy and/or radiotherapy have not yet proved to be effective in preventing local recurrence, nor has the use of
photodynamic therapy or intracavitary chemotherapy.
With respect to chemotherapy, quantitative and qualitative overviews of the literature have suggested that cisplatin may play an important role in combination therapy.
It is also emerging that response rates of 30–40% can be
obtained when combining cisplatin with other agents,
e.g. raltitrexel and pemetrexed. A combination of cisplatin and pemetrexed has in one randomized trial been
superior to cisplatin alone, resulting in superior response
rate, duration of response, and quality of life.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
Laskin JJ, Sandler AB. State of the art in therapy for non-small
cell lung cancer. Cancer Invest 2005; 23: 427–42.
Grunenwald DH. The role of surgery in non-small-cell lung
cancer. Ann Oncol 2005; 16 (Suppl 2): ii220–2.
Buter J, Giaccone G. Medical treatment of non-small-cell lung
cancer. Ann Oncol 2005; 16 (Suppl 2): ii229–32.
Giaccone G. Twenty-five years of treating advanced NSCLC: what
have we achieved? Ann Oncol 2004; 15 (Suppl 4): iv81–3.
Movsas B. Will future progress in non-small-cell lung cancer be
step by step … or by leaps and bounds? J Clin Oncol 2005; 23:
5859–61.
Ceresoli GL, Gridelli C, Santoro A. Multidisciplinary treatment
of malignant pleural mesothelioma. The Oncologist 2007; 12:
850–63.
Stahel R (ed). Acheving survival improvement in thoracic
tumors: from therapeutic strategy management to pharmacogenomics. Lung Cancer 2007; 57: Suppl 2.
Lally BE, Urbanic JJ, Blackstock AW et al. Small-cell lung cancer: have we made any progress over the last 25 years? The
Oncologist 2007; 12: 1096–1104.
14 Therapeutic bronchoscopy for palliation
of lung tumors
Peter WA Kunst, Pieter E Postmus, Thomas G Sutedja
Contents Introduction • Indications • Techniques to remove endobronchial tumors • Bronchoscopic
treatment of extraluminal tumors • General remarks, economic aspects, and recommendations
INTRODUCTION
Lung cancer, although rare at the beginning of the
20th century, is currently known to be the most
lethal cancer in Western society, and its incidence is
rising very fast in the developing countries. All societies with an increase in tobacco consumption will
face increasing morbidity and mortality due to their
smoking habits, including a steep increase in lung
cancer incidence and mortality.
The overall progress in therapeutic outcome during the last three to four decades has been small. The
large majority of lung cancer patients are still doomed
to die of their disease. For the patients with metastatic disease with or without locoregional tumor
progression, optimal palliation to improve quality of
life (QoL) is the main aim of treatment. This includes
relief of symptoms such as shortness of breath,
hemoptysis, pain, weight loss, and depression. Several approaches are available to establish temporary
relief of symptoms including optimal pain medication, radiotherapy, chemotherapy, bronchodilation,
and, in rare cases, even surgical resection.
INDICATIONS
The clinical tumor classification (TNM) and the
patient’s general condition are important factors in
the treatment strategy. Improving symptoms in central airway tumors is only meaningful if:
•
•
•
the larger airways obstructed by tumor are accessible to bronchoscopic instruments;
airway collapse due to loss of integrity of the
tracheobronchial wall can be prevented, for
instance by stenting the airway;
additional information on extraluminal disease
and/or vascular involvement can be obtained
by computed tomography (CT) or endobronchial ultrasonography (EBUS) to get additional
information;
•
•
information about the regions with low gas
exchange (i.e. after radiation or due to significant
peribronchial disease) is taken into account, as
these regions will improve little after treatment;
a potential interference of immediate action, i.e.
stenting and debulking, with additional treatment can be prevented. Such anticipation
requires a conscious decision to apply a tailored
strategy.1–7
For the majority of patients, relief of dyspnea, hemoptysis, severe cough, or obstructive pneumonia is the
major goal. Improvement in gas exchange is the aim
of airway reopening. Any bronchoscopic treatment
may only enhance the dead-space ventilation if local
perfusion is hampered by tumor growth. A disproportionate loss of regional perfusion together with CT
findings of extensive peribronchial disease are good
indicators for gross extraluminal involvement.8–14
TECHNIQUES TO REMOVE ENDOBRONCHIAL
TUMORS
Mechanical obstruction removal
After the introduction of the most simple example
of the rigid bronchoscope by Killian late in the
19th century, new therapies became available. The rigid
bronchoscope could be used to core out tumor mechanically to obtain airway patency and immediately
improve quality of life. Even after the introduction of
the fiberoptic bronchoscopes and videobronchoscopes, the advantages of the rigid bronchoscope for
the purpose of obstruction removal are clear. The
larger working channel of the rigid scope provides
better access, facilitating safer manipulation and the
passage of larger instruments such as forceps and
large-bore suction tubes to aspirate secretions and
blood.9,10 This is a considerably more attractive option
to using the fiberoptic scope, in which bleeding is
expected and large amounts of tissue or secretions
Therapeutic bronchoscopy for palliation of lung tumors 211
need to be evacuated.9,15 The rigid method safeguards
better ventilation during the procedure of recanalization and allows additional stenting in the case of
extraluminal obstruction to be carried out more
easily. The disadvantage of the rigid technique –
requirements for expertise, adequate sedation, or
general anesthesia – may pose some hurdles. It is
therefore important to consider whether interventional pulmonologists should limit their expertise to
proficiency with the fiberoptic procedures alone
when dealing with imminent suffocation in the worst
possible scenario, while the majority of patients are
at highest risk from locally advanced cancers that
have failed previous conventional treatment modalities.
Laser resection
Laser is an acronym for light amplification by stimulated emission of radiation. Lasers produce a beam of
monochromatic, coherent light that can induce vaporization, coagulation, hemostasis, and necrosis. Several
types of lasers [argon, KTP, carbon dioxide (CO2),
neodymium:yttrium–aluminium–garnet (Nd: YAG)
can be used, depending on the considerations of
physics and laser–tissue interaction. The most commonly used lasers are the CO2 laser, which is mainly
used for superficial treatment in water-containing tissue, and the Nd: YAG laser, which has a much deeper
scattering effect for treating bulky tumor in many
oncologic disciplines. The latter has been the main
choice to obtain a much greater penetration due to
the deep scattering of 1064 nm wavelength light by
tissue containing hemoglobin, hence its superior coagulative properties. The enormous heat-sink effect leads
to obtaining late necrosis at a depth which cannot be
determined, hence the use of a red pilot light and
forward firing.
In 1976 the first report on endobronchial use of a
laser to vaporize the obstructing tumor was published by Laforet et al.16 Afterwards the use of lasers
became popular, especially in the USA, because of an
excellent promotion campaign by equipment manufacturers.17 Cavaliere and co-workers showed the
benefits of the procedure in more than 2000 patients
with over 90% immediate recanalization after treating obstruction in the main bronchi or trachea.
The overall mortality is lower than 0.5%.18,19 Serious
complications, which occur in less than 3% of
all patients, are hemorrhage, pneumothorax, and
cardiorespiratory failure over time. These are due
to the profound heat transfer into tissue from the
laser beam, which causes necrosis deep beyond
the surface of impact. Awareness of the anatomic
relationship within the mediastinal organs is therefore necessary.
The uncontrolled application of high power can lead
to disastrous effects, such as perforation of the bronchial wall and too-extensive necrosis, because the
depth effect of the Nd: Yag laser is not always immediately apparent. Therefore it is necessary to know
the extent of the endobronchial mass to define the
treatment area. Bronchography has been used prior
to treatment to assess the length of the bronchial
obstruction.20,21 Nowadays, CT scanning or EBUS
might be useful for defining the extent of the endobronchial and peribronchial mass.22,23 A large observational study of the value of EBUS in therapeutic
bronchoscopy showed that EBUS guided or changed
therapy significantly in 43% of cases. Changes included
adjustment of stent dimensions, termination of tumor
debridement when nearing vessels, and referral for surgical interventions rather than endoscopic treatment.23
Electrocautery and argon plasma coagulation
Electrocautery (EC) and argon plasma coagulation
(APC) are the use of local heat application with probes
that conduct electrons toward the target tissue (tissue
welding). An alternating electrical current conduit is
used to prevent neural and muscular responses. Many
cheap, reusable applicators are available. Electrocautery and APC are other ‘hot’ alternatives to Nd:YAG.24
Although the costs of the EC and APC technique are
far lower than for Nd:YAG, it has not become very
popular in the USA, apparently without any obvious
reason since the results are more or less comparable
to the Nd:YAG laser and APC is superior in obtaining
hemostasis of large mucosal hemorrhagic surfaces.25
The technique is simply based on the use of electrons to produce heat in the target tissue while the
equipment is a standard facility in every operating
theatre. An applicator or probe is needed which can
be passed through the working channels of the rigid
or flexible bronchoscope. This technique has a lower
risk of airway perforation due to the superficial effects
of electrons as they dissipate easily in tissue.
APC uses ionized argon gas for the non-contact
mode of tissue spraying conduit, which can superficially coagulate large hemorrhagic surfaces in a matter
of seconds. Electrons always seek the pathway
of least resistance; coagulation can be limited to a depth
of only a few millimeters by choosing an appropriate
energy setting. This self-limiting effect is especially
exploited in APC, as the ionized argon gas
deviates electrons towards the area of least resistance,
212 Textbook of Lung Cancer
i.e. hemorrhagic wet surfaces, and away from crusted,
already treated, tissue.
APC has been used in surgery for more than 20 years,
particularly for the hemostasis of superficial bleeding.
Although APC has become well established in gastrointestinal endoscopy since its introduction in 1991,
very few reports of its use in bronchoscopy exist.
Reichle et al showed that recanalization of malignant
airway stenoses had good results in 67% of patients.
Despite less penetration compared with the Nd:YAG
laser, extensive bronchial tumors were treatable, and
coagulated tumor fractions were removed either with
forceps or the rigid bronchoscope tip.25 The second
indication was bleeding in the central airways; good
hemostasis was achieved in over 98% of patients.25 No
head to head comparison of Nd:YAG laser and EC or
APC has been done; from several phase II type studies
the results seem to be more or less comparable. The
estimated incidence of clinically significant bleeding
in patients treated with EC is 2.5%.26 The most
important advantage is the fact that, with EC and
APC, the immediate coagulative effect is clearly visible and matches the histologic depth of necrosis – the
principle of ‘you immediately see what you get’. Too
much heat, however, can lead to extensive scarring.
Cryotherapy
Cryotherapy is repetitive rapid cooling (Jules Thompson
effect) and spontaneous thawing of the target tissue,
using liquid gas and specially designed flexible applicators to crystallize the cellular contents of the target
tissue, causing late necrosis.27–31 The ultimate effect is
caused by delayed disintegration of water-containing
tissue. Thawing restores circulation, hence this
technique is not suitable for quick palliation of
a hemorrhagic mass, despite sparing cryoresistant
cartilage and fibrous tissue. The simple equipment,
reusable applicator, and easy principles are clear
advantages. In a report by Forest et al,28 necrosis was
found near the cryoprobe impact site and was maximal two hours after treatment; a second peak was
observed after four days. Around this central necrotic
area, apoptotic cells were found. Apoptosis was maximal after eight hours. Thus a second bronchoscopy
is necessary to remove slough. No large series on
local treatment with cryotherapy for early stage lung
cancer are available in the literature; only a few reports
have shown good results (complete response) when
used for palliation.29,30 In a study in which patients
with an obstructive tumor were treated with cryotherapy followed by irradiation, no sign of residual
tumor was found in 17 of 26 patients.30
Endobronchial brachytherapy
Brachytherapy comprises intraluminal irradiation of
a tumor area within the tracheobronchial tree by
means of a catheter. The catheter is connected to an
afterloading device that transports the tiny radioactive source, iridium-192, to preprogrammed positions
during the session, in a step wise fashion, according
to precalculated volume dosimetry. Accurate sausagelike dosimetry with rapid fall-off towards the periphery is theoretically attractive. However, a tumor is not
perfectly oval in shape, with the irregular extensions
to smaller bronchi, while delivery of an accurate dose
to the target volume is hampered by the patient’s
breathing and cough, which may lead to movement
of the catheter, despite the short (10–15 minutes)
duration. Irradiation damages all tissue. Data from
good randomized trials are available.32–35 Fractionated
external radiotherapy is preferred over brachytherapy
as an initial treatment in better performing patients
because it provides better overall and more sustained
palliation, with fewer retreatments and a modest gain
in survival time.32 However, when both techniques
are combined it increases local control,33 especially
in the cohort of squamous cell cancer, in alleviating
symptoms caused by local tumor recurrence,34 and
provides higher rates of re-expansion of collapsed
lung, resulting in (transient) lower levels of dyspnea.
However, this beneficial effect was only observed
among patients with obstructing tumors in the central
airways.35 Elusive accuracy in dosimetry, expensive
equipment, need for repeated doses and non-selective
damage causing radiation stenosis, fibrosis, and
late fatal hemorrhages or bronchial fistula are
disadvantages.36,37
Photodynamic therapy
Photodynamic therapy (PDT) is bronchoscopic illumination of tissue containing photosensitizers to
initiate a photochemical cascade reaction due to the
formation of oxygen radicals.12,38 Although photosensitizer molecules are selectively retained in the target
tissue after injection, in vivo and histologic studies
do not show selective tumor damage which may lead
to deep eschar formation and extensive fibrosis.
The degree of intra- and extraluminal tumor mass
and tumor location may limit the efficacy of PDT,
since optimal or homogeneous illumination is difficult to achieve.39,40 Cautious interpretation of apparent complete response by bronchoscopy is advocated
since residual tumor might be present by microscopic
evaluation. A cure cannot be expected in patients
with tumor infiltration of the cartilage and bronchial
Mechanical
crushing
Iatrogenic
foreign body
Efer–Dumon
set + various
stents
Hemostasis
Equipment
Disadvantages
Lifesaving!
Outward
displacement
High expertise
Outward
displacement
Teams’ expertise
for emergency
Extraluminal
only alternative!
Result
Performance
Tissue damage
Mechanism
Indication
Logistics
Stent
Electrocautery and
argon plasma
coagulation
Cryotherapy
Photodynamic therapy
Brachytherapy
Special laser
Standard facility and Liquid coolant
Special laser and
Special radiation
requirements
applicators
with applicators
requirements
facility
Intraluminal only, with different depth necrosis depending on each mechanism and technical application with
or without dosimetric calculations; deep dosimetry in non-selective technique causes damage to the normal
tissue surroundings of the central airways including the tracheobronchial wall!
Extreme heat
Shallow heat
Rapid cooling
Formation of
Ionizing radiation
transfer
transfer
slow thawing
oxygen radicals
High expertise
Easy
Easy
Complex process
Complex process
Profound
Superficial
Crystallization
Thrombosis and
Structural damage
carbonization
coagulation
of watery tissue
secondary hypoxic
necrosis
Immediate,
Immediately
Hours–days +
Hours–days +
Days to weeks;
invisible depth
visible depth
secondary
secondary necrosis
non-selective
necrosis
Profound
Superficial
Vascular
Primary vascular
Systemic vascular
coagulation
coagulation
disruption!
thrombosis
disruption
Burn, explosion,
Superficial
Delayed effect
Prolonged skin
Fibrosis, stenosis,
and perforation
scarring
photosensitivity
and hemorrhage
Expensive
Standard
Liquid
Special laser + special
Expensive
laser + laser
facility + cheap
coolant + applicators
fibers + sensitizers!
radiation facility
fiber
probes
Laser (Nd:YAG)
Table 14.1 Advantages and disadvantages of each technique for palliative treatment of tumor blockage in the central airways
213
214 Textbook of Lung Cancer
Table 14.2 Results of large series regarding palliative bronchoscopic treatment
Technique
Results
Complications
Remarks
Stent (Dumon4)
1574 prostheses
(1058 patients)
Tracheal 54%;
LMB 21%;
RMB 18%
Migration 9.5%;
granuloma 7.9%;
obstruction 3.6%
Nd:YAG
(Cavaliere19)
2610 resections
(1838 patients)
93% good
results
60 cases (0.3%);
mortality 0.4%
Elecrocautery
(Sutedja24)
56
39/56 (70%)
complete
1 bleeding 3.7%
Argon plasma
(Reichle25)
Cryotherapy
(Maiwand30)
PDT (review
Moghissi38)
HDR
Brachytherapy
(Speiser60)
364 (482 sessions)
67% good result
153
Dyspnea 64%;
hemostasis 93%
CR >70%
11 patients (7.2%)
Average time
stent will be
in place minimum
4 months
maximum
4.7 years
Mortality due
to cardiovascular
and respiratory
problems
Non-responders;
extraluminal
disease
Excellent
hemostasis
No mortality
295
80%
recanalization
Fatal bleeding
7%; stenosis 11%
ERT 60 Gy vs
+ HDR 2 × 4.8 Gy
(Huber33)
Randomized
42 vs 56
Med. survival
similar 28 vs
27 weeks!
Fatal bleeding
14.2%!
636
muscular layer.41–43 Secondary necrosis, due to tumor
hypoxia, and fibrin plug formation make it necessary
to perform a ‘clean-up’ bronchoscopy to prevent
respiratory failure. Due to skin photosensitivity, which
may occur in 20–40% of patients, although not leading to irreversible skin damage,44 new photosensitizers are sought.45 Fatal bleeding after PDT has been
reported.44,46 As the PDT effect is known to be mainly
vascular, caution is necessary in treating tumors close
to large vessels.
Cell culture studies and animal studies indicate a
possible synergistic effect of combining PDT with ionizing radiation. One randomized study in a limited
number of patients reported the benefit of PDT additional to external radiotherapy, with regard to quality
of life and physiologic scores. PDT plus external
radiotherapy provided a better and more durable local
control compared to external radiotherapy alone.47
Various: non-fatal
Up to 28% skin
photosensitivity
No different
effect of dose
fractions,
ND:YAG
precanalizing
procedures
Squamous cell
cohort 7 weeks
longer median
survival
Another study assessed the safety and effectiveness of
combined brachytherapy and PDT in patients with
bulky endobronchial lung cancer. Thirty-two patients
were treated; tumors were extensive, with lengths
ranging from 10 to 60 mm along the bronchus and
estimated volumes ranging from 40 to 3500 mm3. At
a mean follow-up of 24 months, 26 patients were
free of residual tumor and local recurrence.48
BRONCHOSCOPIC TREATMENT OF
EXTRALUMINAL TUMORS
Stenting
Stenting is the insertion of tailored endoprostheses to
recanalize large airways and restore airway patency.
It is the only possible solution for obstruction caused
by extraluminal tumor compression. Since 1965,
Therapeutic bronchoscopy for palliation of lung tumors 215
with the introduction of the Montgomery tube, many
different kinds of stents have been developed.49 However, despite many improvements the optimal stent
is still being sought. Nowadays there are rigid and
flexible stents, made of different materials. The main
point of consideration is the anatomic size of the airways and the cause of the limited airway patency. In
benign disease a silicone stent is definitely preferred
over a metallic one, whereas in malignant disease no
stent is in favor.50–54 Depending on the position of
the compression, either a Y-shaped stent or a normal
one can be inserted.
The second goal of stenting could be considered to
be the sealing of fistulas between the respiratory tract
and the digestive tract.55,56 The best way to introduce
a stent is still by the rigid bronchoscope, although
some stents can be inserted by the flexible scope. The
literature has shown that stenting improves QoL and
has a good acceptance and tolerance.57,58
Stent insertion can be simple; however dealing with
the complications such as migration, perforation,
granuloma, and infection can be a great challenge, and
requires a certain level of expertise of the team.
GENERAL REMARKS, ECONOMIC ASPECTS, AND
RECOMMENDATIONS
Current bronchoscopic techniques provide the bronchoscopist with alternatives for local palliation. Each
technique has its own merits and limitations. Treatment choice is based upon the following: clinical
presentation, the experience and skill of the bronchoscopist, the availability of additional techniques,
anesthetic care, intensive care for the post-treatment
period, and technical support in the hospital. Economic aspects may further influence the choice.
When the indications have been properly assessed,
any of the treatments can be equally successful in dealing with an emergency situation, when a technique is
chosen to immediately relieve the symptoms
(Tables 14.1 and 14.2). as long as the bronchoscopist
is aware of the limitations and dangers of each approach
and is confident about the benefit of treatment. The
frequent occurrence of emergency situations in patients
with a poor prognosis makes it impossible, and maybe
even unethical, to perform a randomized study to look
for the best palliative technique. The population at
risk is not homogeneous and the follow-up period
might be expected to be relatively short. Many patients
will die due to disease progression outside the treatment area. So the question about the best palliative
technique is and remains academic. However, what
technique to use depends first on the availability in the
center, second on the expertise with the technique,
and third, on the oncology principle (curative vs palliative). Although some techniques might appear simple, it might be wise to concentrate a particular
procedure in a limited number of centers, in order to
minimize the complications, improve treatment of the
complications, and to have a better local control or
cancer-specific survival. The latter has never been
proven for endobronchial therapy, but from other
studies we know that the outcomes that measure
tumour control relate to the surgeon’s expertise.59
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15 Complications of lung cancer
Vincenzo Minotti, Michele Montedoro, Maurizio Tonato
Contents Introduction • Infections • Major hemoptysis • Chest pain • Pleural effusion
• Superior vena cava syndrome • Cardiac tamponade • Extrathoracic complications
• Paraneoplastic syndromes
INTRODUCTION
The majority of patients with lung cancer will have troublesome symptoms at some time during the course of
their disease due to the disease itself or its complications.
Complications in lung cancer patients depend on the
location of the tumor, its locoregional spread, and the
presence of metastatic growth. Moreover, lung cancer,
especially small cell lung cancer (SCLC), is associated
with paraneoplastic syndromes more frequently than
any other type of cancer is.
Clinicians must keep in mind the most frequent
complications of lung cancer, since a timely diagnosis
and adequate treatment are essential in order to ameliorate symptoms.
Although a multitude of signs and symptoms may be
manifested by patients with lung cancer, the focus of
this chapter will be on the more frequent and severe
complications due to intrathoracic growth of tumor
and to remote effects that are not related to direct invasion or metastasis (Table 15.1).
INFECTIONS
Pulmonary infections frequently complicate the course
of patients with lung cancer, and are often the direct
cause of death. Infections can be present at the time of
cancer diagnosis, complicate the treatment course, and
result in death. Causes of infection include bronchial
obstruction, aspiration, immunosuppression from radiation and/or chemotherapy, disruption of local host
defenses due to tumor invasion, and necrosis of both
normal and tumor tissue. To determine the causes of
infection, Nagata and colleagues1 reviewed the case
records and autopsy data of 304 patients who died of
lung cancer. They showed that the local and systemic
effects of the lung cancer itself were probably more
important than either antineoplastic agents or cortico-
steroids in predisposing the patient to bacterial infections. Perlin and colleagues2 reviewed retrospectively a
cohort of 121 lung cancer patients in an attempt to
identify the frequency of infection and to determine its
impact on the survival of those patients. Infections were
documented in 85 patients (70%); the most common
organisms were streptococci, Staphylococcus aureus,
Klebsiella pneumoniae, Enterobacter aerogenes, and
Pseudomonas aeruginosa. The median survival of all
infected patients was 4.2 months, which was significantly shorter than that of uninfected patients, who had
a median survival of 12.9 months. In the only prospective study done to date, involving 96 consecutive lung
cancer patients at diagnosis, Putinati and colleagues3
reported an incidence of secondary respiratory infections in 33 patients (34%). Major pathogens responsible for infection were Haemophilus spp., S. aureus, and
P. aeruginosa.
In a review, Berghmans et al4 reported 435 episodes
of fever and/or infection occurring in 275 patients with
lung cancer. The majority of infections involved the
upper and lower respiratory tract (56%).
Pulmonary infections depend on the particular pattern of growth of the lung cancer. Centrally located
tumors produce airway obstruction, which may cause
an obstructive pneumonitis, while peripheral large tumor
masses occasionally cavitate and present as malignant
abscesses. Such patients suffer from typical symptoms
of pneumonia, including fever, chills, and a productive
cough with streaky hemoptysis. Non-small cell lung
cancer (NSCLC), particularly squamous cell carcinoma,
may present with a shaggy cavitary opacity, indistinguishable from a conventional anaerobic lung abscess on
chest radiograph. Extensive central necrosis is responsible for the cavitary appearance. Several clinical clues may
suggest the presence of cancer, including persistent
hemoptysis, relative absence of fever and leukocytosis,
and radiographic location in a region of the lung
with minimal surrounding pneumonitis. A rare and
Complications of lung cancer 219
Table 15.1 Most frequent and severe complications of lung
cancer
•
•
•
•
•
•
•
•
Infections
Major hemoptysis
Chest pain
Pleural effusion
Superior vena cava syndrome
Cardiac tamponade
Paraneoplastic syndromes
Extrathoracic complications (brain metastases,
spinal cord compression)
severe complication of lung cancer is the formation of
a tracheo- or broncho-esophageal fistula, which can
manifest by paroxysmal violent cough after meals and
recurrent aspiration pneumonia.
Bronchoscopy is useful to establish a microbiologic
diagnosis5 and to search for an underlying lung cancer
in patients with atypical resolution of pneumonia by
chest radiography. For example, in a study of 115 cases
with a clinical profile of chronic bacterial pneumonia,
bronchoscopy disclosed newly diagnosed NSCLC in
14% of cases.6 Identification of a definitive etiologic
agent is of great importance for rational antimicrobial
treatment of pulmonary infections. Because infecting
flora can include aerobic Gram − and Gram + species as
well as anaerobes, broad-spectrum antimicrobial therapy is warranted, as for postobstructive and aspiration
pneumonias, but the duration is typically prolonged
(weeks to months).7 Endobronchial obstruction with
distal uncontrolled pneumonia or a lung abscess can be
treated by endoscopic removal of tumor with laser or,
in the case of an abscess, by percutaneous or bronchoscopic drainage of the abscess.
MAJOR HEMOPTYSIS
Hemoptysis is the presenting symptom in 7 to 10% of
patients with lung cancer. Approximately 20% will
have hemoptysis some time during their clinical course.
However, massive hemoptysis is a rare event, with 3%
having terminal massive hemoptysis. Most patients
experience blood-streaked sputum. Santiago and colleagues8 reviewed the records of 264 patients who
underwent bronchoscopy for unexplained hemoptysis
in order to determine its causes. Bronchogenic carcinoma was the most common cause, accounting for 29%
of the cases. The diagnosis of bronchogenic carcinoma
was established endoscopicalIy in 65 (82%) of 78 patients.
Four patients with carcinoma had normal chest radiographs. These four patients had centrally located lesions
that were diagnosed endoscopicalIy. Massive hemoptysis is arbitrarily defined as expectoration of at least 100
to 600 ml of blood in a 24-hour period, or intrabronchial bleeding at such a rate as to present a threat to
life.9 Massive hemoptysis due to lung cancer has a much
poorer prognosis than hemoptysis of other etiologies.
The mortality of massive hemoptysis may be as high as
59 to 100% in patients with bronchogenic carcinoma.10
Death from hemoptysis is usually attributed to asphyxia
rather than to exsanguination. This horrific complication is associated more frequently with central squamous
cell carcinoma. These tumors tend to be large and
angioinvasive, and to undergo spontaneous necrosis
and cavitation. Hemoptysis results from necrosis and
destruction of lung parenchymal support for vessels, as
well as from neovascularization of the tumor. The initial priority of therapy is to maintain the airway to optimize oxygenation and to stabilize the hemodynamic
status.11
Clinically stable patients should be positioned with
the bleeding side in a dependent position, to reduce aspiration of blood into the contralateral lung. Supplemental oxygen, sedatives, bed rest, mild cough suppression,
and avoidance of excessive thoracic manipulation are
helpful. Traditionally, a rigid rather than a flexible
bronchoscope is generally preferred with massive bleeding, when the need to remove large clots is anticipated.
Because of its larger diameter, a rigid bronchoscope is
particularly effective in suctioning, oxygen administration, and airway control. Usually the airway can be protected from blood aspiration by inflating a Fogarty
balloon catheter proximal to the bleeding site. The balloon can be left in place while the patient is stabilized
and considered for additional therapy.
Another approach to protect functional airways
involves placing a special endotracheal tube with inflatable distal cuff into the non-bleeding right or left main
stem bronchus. The use of a double-lumen tube permits adequate suctioning of blood. However, placement
of the tube requires experienced personnel. Urgent surgical intervention should be considered when bleeding
is associated with persistent hemodynamic and respiratory failure.
In patients who are not candidates for surgery because
of severe prognosis, extensive disease, co-morbid
conditions, prior pulmonary resection or inadequate
pulmonary reserve (predicted postoperative FEV1 less
220 Textbook of Lung Cancer
than 0.8–1l), several non-operative techniques have
been reported to control massive hemoptysis. Prolonged
tamponade with a Fogarty balloon catheter, ice-saline
lavage, and arteriography with therapeutic embolization of bronchial arteries have been reported to be successful in controlling bleeding. However, no prospective
comparative trials have been conducted on the efficacy
of these various techniques, and it is well known that
conservative non-surgical management of massive
hemoptysis carries a high mortality rate.
Radiation therapy (endobronchial or external beam)
and laser therapy may be useful in controlling bleeding
lung tumors. Palliative management should also be aimed
at reducing awareness and fear. A combination of a
parenterally administered strong opioid and a benzodiazepine is usually required.
CHEST PAIN
Pain is a significant problem in cancer patients in general and lung cancer patients in particular. Chest pain
is reported at presentation in one-quarter to one-half of
patients with lung cancer,12 and usually arises via direct
invasion or metastatic involvement of pain-sensitive
intrathoracic structures (mediastinum, pleura, or chest
wall). Marino and colleagues13 reported early thoracic
pain in 40% of 164 patients with lung cancer without
extrathoracic or distant metastasis. Pain was present on
the side of the neoplasm in 80% of the patients.13
Peripheral tumor invading the costal parietal pleura
and chest wall gives rise to sharp, intermittent, pleuritic
pain. This type of pain may also be caused by obstructive pneumonitis or associated pulmonary embolus.
Brachial plexus
(arm and
shoulder pain)
Sympathetic trunk]
(Horner’s
syndrome)
Subclavian
artery
and vein
Other patients suffer from a poorly localized, vague,
persistent discomfort, sometimes associated with central tumors with mediastinal extension and possible
involvement of perivascular and peribronchial nerves.
It is important to distinguish the chest pain that accompanies direct contiguous chest wall extension from rib
metastases.
A characteristic pain syndrome is caused by local
extension of an apical lung tumor at the superior thoracic inlet. Such a tumor is called a superior pulmonary
sulcus tumor, and the associated pain is known as Pancoast’s syndrome (Figure 15.1). The most common initial symptom is shoulder pain, produced by neoplastic
involvement of the brachial plexus, parietal pleura,
endothoracic fascia, vertebral bodies, and first, second
and third ribs.14 The pain is often severe and unrelenting; while initially confined to the shoulder and scapula, it later radiates down the arm, following an ulnar
distribution, reflecting involvement of the C8 and T1
nerve roots. Pulmonary symptoms and signs are conspicuously absent, while arm weakness signifies
advanced brachial plexus invasion. With further extension through the intervertebral foramina in 5% of
patients initially, but in as many as 25% later in the
course of the disease, compression of the spinal cord
and paraplegia may result.15 The majority of cases of
Pancoast’s syndrome are caused by NSCLC, most commonly squamous, followed by adenocarcinoma and
large cell carcinoma. SCLC is only rarely associated
with this syndrome.
Although in the past a histologic diagnosis was not
considered necessary before therapy, the wide variety of
diseases that can result in Pancoast’s syndrome (other
primary thoracic neoplasms, metastatic and hematologic
Vertebral body
Vagus nerve
Recurrent nerve
(vocal cord
paralysis)
T4
A tumor of any size with
invasion of the mediastinum, or
involving heart, great vessels,
trachea, (a) esophagus, (b)
vertebral body or carina or
presence of malignant pleural
effusion
Figure 15.1
Schematic of International Staging System definitions
for superior sulcus tumors, including Pancoast’s
syndrome. (Reproduced with permission from
Mountain CF. A new international staging system for
lung cancer. Chest 1986; 89: 225S).
Complications of lung cancer 221
neoplasms, infectious processes, neurogenic thoracic
outlet syndrome) now mandates a conclusive diagnosis
before definitive treatment is started. The chest radiograph may show an obvious apical mass, but frequently
only a subtle increase in density is visible at the apex,
and is often missed. Magnetic resonance imaging (MRI)
has become the diagnostic modality of choice, because
of its superiority to CT in delineating tumor extension
to vascular and neural structures, vertebrae, and the
spinal canal.
Therapeutic modalities for superior sulcus tumors
involve combinations of preoperative, intraoperative,
and postoperative radiotherapy, and either surgery or
radiotherapy alone. Surgical resection after preoperative
radiotherapy has been the most common treatment of
superior sulcus tumors. However, there is no conclusive
scientific evidence to recommend the standard use of
preoperative radiotherapy for such tumors. Proponents
of these treatment modalities based their recommendations on retrospective data. Standard resection is usually
performed by en bloc resection of the tumor, generally
by lobectomy, including chest wall, and may also be
accompanied by resection of the involved paravertebral
sympathetic chain, stellate ganglion, lower trunks of
the brachial plexus, and, in some cases, the subclavian
artery and portions of the thoracic vertebrae.
Contraindications to surgical treatment include extensive involvement of the brachial plexus and paraspinal
region, especially the intervertebral foramina, bodies,
and laminae of the vertebrae. Radiotherapy at doses
of at least 60 Gy (dose range 20–70 Gy) can be used
alone as a primary treatment, especially for inoperable
superior sulcus tumors, palliating pain in up to 90% of
patients.16
The role of intraoperative and postoperative radiotherapy is unclear at present, and they should be used
mainly in patients who are found to have unresectable
tumors after a surgical attempt.17 Recently, induction
chemoradiotherapy has been reported to enhance complete resection rates and improve survival compared with
historical controls and is likely to become the new standard treatment for localized superior sulcus tumors.18
Clinical factors associated with improved survival
include good performance status, a weight loss of less
than 5% of total body weight, and achievement of local
control and pain relief after treatment.19 Standard pain
management techniques, including stepwise analgesics
and radiation therapy, are usually effective in controlling pain initially in many patients. Some patients may
require additional measures, including nerve blocks,
spinal analgesia, or even palliative surgery.
PLEURAL EFFUSION
Approximately 25% of patients with lung carcinoma
develop a malignant effusion during the course of their
disease. Impaired drainage from the pleural space is the
predominant mechanism for the accumulation of fluid
associated with malignancy. Tumor cells either seed the
mesothelial surface or invade the subserous layer. When
the mesothelial surface is involved, tumor cells are
abundant in pleural fluid; with subserous involvement,
only a few malignant cells are exfoliated into the pleural
space. Peripheral tumors, most commonly adenocarcinomas, may directly seed the pleural space.
Patients usually present symptoms that compromise
their quality of life, including progressive dyspnea, cough,
and/or chest pain.20 Symptoms appear to be closely
related to the rate of pleural fluid accumulation rather
than to the total volume. Accompanying fever is usually
a sign of atelectasis and infection. About one-quarter of
patients with malignant pleural effusions are asymptomatic. The fluid itself may be serous, serosanguineous, or grossly bloody, and typically it is ipsilateral to
the main tumor and of moderate to large volume. The
finding of malignant cells in the fluid confirms stage
IIIB disease and a relatively poor prognosis. However,
not all pleural effusions associated with lung cancer are
due to pleural metastasis. Occasionally, fluid formation
is only indirectly related to the tumor. Patients are at
increased risk for pleural effusions from postobstructive
pneumonia, atelectasis, pulmonary emboli, and drug or
radiation reactions. In one series, 4 of 73 NSCLC patients
with pleural effusion had surgically resectable tumors
and survived for intervals ranging from 3 to 14 years.21
The diagnosis should be made on physical examination and confirmed by chest radiograph. The latter may
be the only clue to the presence of pleural effusion.
Approximately 300 ml of fluid is required for detection
of a pleural effusion on a standard posteroanterior chest
film. The lateral decubitus chest film is extremely useful
in cases of subpulmonic effusion, detecting significantly
smaller quantities of pleural fluid. Loculated effusions
can be localized with ultrasonography or CT scan. The
most definitive and simplest method of identifying a
malignant pleural effusion is by cytologic examination.
A sample of 250–1000 ml of fresh pleural fluid should
be sent to the cytology laboratory for examination. The
diagnostic efficacy increases on repeated aspirations, from
approximately 50% positivity on initial thoracentesis to
65% on the second sample and to 70% on the third.22
The management of malignant pleural effusions depends
on the treatment options of the primary malignancy.
222 Textbook of Lung Cancer
Systemic treatment may control pleural effusion due to
SCLC, although therapeutic thoracentesis may still be
required to control symptoms. Patients with SCLC who
present ipsilateral effusions as their only manifestation
of metastatic spread beyond the primary tumor and
regional lymph nodes may have an overall response
rate, complete response rate, and survival equivalent to
patients staged as having limited disease.23
If effective systemic treatment is not available, treatment is often palliative, usually consisting of sequential
thoracentesis or tube thoracostomy with or without
sclerotherapy. Therapeutic thoracentesis may improve
patient comfort and relieve dyspnea. The subjective
response to drainage and the rate of fluid reaccumulation should be monitored. Repeated thoracenteses are
reasonable if they achieve symptomatic relief, if fluid
reaccumulation is slow, and if the patient’s expected
lifespan is very short. Used alone it is not an effective
means for preventing recurrence. The mean time to fluid
reaccumulation in one series was as short as 4 days, with
a 98% recurrence rate at 39 days.24
If life expectancy is reasonable, obliteration of the
pleural space, either by parietal pleurectomy or by
instillation of sclerosants that cause inflammation and
subsequent pleural symphysis, can prevent recurrent
accumulation of fluid. The efficacy of chemical pleurodesis depends upon complete evacuation of pleural
fluid by tube thoracotomy followed by introduction of
an effective sclerosing agent into the pleural space and
retention of the agent in the chest for sufficient time to
induce an inflammatory fibrosis.25
Several agents have been used for pleurodesis, including talc, tetracycline, doxycycline, bleomycin, and others, with variable efficacy rates.25 In two meta-analyses
of trials of adults who underwent pleurodesis for malignant pleural effusion, talc was the most effective sclerosant.26 Talc may be delivered as a slurry by way of a
chest tube after drainage or at the time of thoracoscopy,
using insufflation. The efficacy of these two approaches
was compared in a prospective randomized trial.27 Survival rates and success of the pleurodesis were similar
in both arms, but quality of life scores were higher in
the group that was treated thoracoscopically. Traditionally, large bore (20–28 Fr) chest tubes have been used
for drainage before pleurodesis. In recent years several
studies have indicated that small-bore (8–14 Fr) catheter
drainage and sclerosis may be comparable in efficacy.28
Another approach involves placement of an indwelling pleural catheter through which the patient can
drain pleural fluid in the ambulatory setting. Advantages include the ease of insertion, rapid drainage of
recurrent symptomatic effusion, and minimal hospitalization required for catheter insertion and care.29 A
phase III trial compared the efficacy of an indwelling
pleural catheter with chest tube and doxycycline sclerotherapy for recurrent symptomatic malignant pleural
effusion in 144 patients. The pleural catheter had similar efficacy to doxycycline pleurodesis in relieving
symptoms that were secondary to pleural effusion.
Patients who were treated with the pleural catheter had
a shorter hospital stay.30
SUPERIOR VENA CAVA SYNDROME
The principal vascular syndrome associated with extension of lung cancer into the mediastinum is superior
vena cava syndrome (SVCS), most commonly caused
from compression by a large primary tumor or its mediastinal lymph node metastases, but also from intraluminal thrombosis. Patients characteristically complain
of headache, swelling of the face, neck, and upper
extremities, or a host of thoracic symptoms, such as
dyspnea, cough, chest pain, and dysphagia. Physical
examination may show facial edema, neck vein distension, and striking collateral engorgement over the anterior chest wall and upper abdomen. The degree of
collateral vein formation reflects the time over which
superior vena cava obstruction has developed and the
relative anatomic site of the blockade, since obstruction
above the azygos vein is better tolerated. Signs of airway obstruction (e.g. stridor) or intracranial pressure
(stupor or convulsion) should prompt rapid evaluation
and treatment. When typical signs are present, complete SVC obstruction is easily diagnosed. The CT scan
is likely to show tumor masses, and can also reveal the
presence of thrombi and collateral vessels.
Lung cancer accounts for 65–90% of patients with
SVCS, with approximately 85% of primary lung tumors
occurring on the right, primarily in the right upper lobe
or right mainstem bronchus. Among 2000 patients presenting lung cancer, 4% had SVCS.31 By cell type, SCLC
predominates as the cause of SVCS, followed by
squamous cell carcinoma. In addition to lung cancer,
lymphoma, and other malignancies, benign causes of
obstruction of the SVC include fibrosing mediastinitis,
thrombosis, inflammatory adenopathy, postirradiation
fibrosis, and aneurysms.
Contrary to prior clinical wisdom, it has been convincingly demonstrated that the SVCS does not constitute a true medical emergency requiring urgent treatment
without a tissue diagnosis.32 The immediate causes of
Complications of lung cancer 223
death directly related to SVC obstruction are airway
obstruction and intracerebral hemorrhage. In the
absence of significant airway obstruction and signs of
severely elevated intracranial pressure, definite diagnosis can be obtained before therapy. An accurate diagnosis is also especially important in view of the diverse
etiologic considerations mentioned above. Bronchoscopy and, depending on the clinical circumstances,
node biopsy, mediastinoscopy or even thoracotomy can
be employed safely and effectively to diagnose lung
cancer in this setting.
Most patients with SVCS secondary to lung cancer
have resolution of symptoms after initiation of radiation or chemotherapy.33 Before instituting radiotherapy
in SVCS, general medical maneuvers, including oxygen
support, bed rest with elevation of the head of the bed,
and corticosteroids, may be used as temporizing measures.
Chemotherapy is particularly useful when SVC
obstruction is secondary to SCLC, although radiotherapy has been used in selected series. There is no difference in outcome or in time to resolution between the
two,34 but chemotherapy offers the advantage of simultaneous management of systemic disease and avoidance
of large-field irradiation to the heart and lung. Resolution of the syndrome is prompt (7–10 days), and is
achieved in 43–100% of cases.35 If the chemotherapy
drugs include vesicants, these should not be injected
into the dilated, high-pressure, upper-extremity veins.
The right upper extremity should be avoided for any
drug administration, since the rate of blood flow is
markedly decreased, and thrombosis, phlebitis, and
erratic drug distribution are likely.
Radiation is generally indicated in the management
of the patient with SVCS secondary to NSCLC. Initial
treatment with two to four fractions of 300–400 cGy,
followed by conventional fractionation to a total dose of
3000–5000 cGy, has been advocated on the basis of
limited evidence suggesting a prompter response with
this schedule. One study evaluated the efficacy of treating patients with SVCS with a short course of hypofractionated irradiation.36 The study compared a regimen of
8 Gy fractions once a week (to a total dose of 24 Gy)
within two weeks, versus a program of delivering
only two fractions of 8 Gy (to a totaI dose of 16 Gy)
within a week. In both regimens, a good palliative result
was established; however, the results of the 24 Gy regimen were superior. Using the 24 Gy regimen, partial
responses were obtained in 96% of patients, and 56%
achieved complete response. The 16 Gy regimen yielded
a complete response in only 28% of patients. Median
overall survival was longer with the higher-dose regimen
(nine months), compared with the low-dose regimen
(three months). Anticoagulation with heparin may be
of benefit in SVCS resulting from intraluminal thrombosis of the SVC. Rapid onset obstruction that causes
respiratory compromise must be treated emergently;
percutaneous stenting may be the treatment of choice.37
Analysis of 23 retrospective trials that assessed the efficacy of superior vena cava stenting showed that 151 of
159 patients (95%) had relief of SVC obstruction after
stenting.38
CARDIAC TAMPONADE
Neoplastic cardiac tamponade is one of the true emergencies of clinical oncology. It may appear abruptly and
cause death in a patient who otherwise has good shortterm life expectancy. Carcinoma of the lung is associated with the highest frequency of malignant pericardiac
effusion, accounting for 37% of reported cases.39 Haskell
and French40 reported on 23 patients in whom cardiac
tamponade was the initial presentation in malignancy:
7 of these patients had lung cancer. Pericardial involvement arises either from direct extension of the tumor or
because of retrograde spread through mediastinal and
epicardial lymphatics. Cardiac tamponade may also be
caused by postirradiation pericarditis with fibrosis or
by encasement of the heart by tumor. The amount of
fluid necessary to cause tamponade may be small (less
than 200 ml) when the effusion accumulates rapidly or
when the pericardium is non-compliant owing to fibrosis. When the pericardial effusion is chronic, over 1 liter
may accumulate before causing tamponade.
The symptoms of cardiac tamponade are non-specific.
The most frequent complaints are apprehension, chest
pain, and dyspnea. Occasionally, cough, hoarseness,
hiccups, nausea, and abdominal pain are prominent
complaints. Elevated jugular venous pressure, tachycardia, and narrow arterial pulse pressure are almost always
seen. Pulsus paradoxus, an abnormally large drop in arterial systolic pressure during inspiration (>10 mmHg), is
a hallmark of cardiac tamponade. The chest radiograph
may show a large globular (‘water bottle’) heart, but
cardiac silhouette may appear normal when the effusion has accumulated rapidly or is less than 250 ml.
Sinus tachycardia and low voltage (QRS complex < 5 mV)
are usually present on a 12-lead electrocardiogram.
QRS complex electrical alternans, pathognomonic of
cardiac tamponade, is infrequently seen. A pericardial
effusion may be quickly and accurately diagnosed by
224 Textbook of Lung Cancer
echocardiogram. Two-dimensional echocardiography
is more sensitive than M-mode, because it displays virtually the entire circumference of the heart. Certain
two-dimensional echocardiographic findings help to
determine the functional significance of a pericardial
effusion. Diastolic right atrial and right ventricular collapse occur early during the development of cardiac
tamponade. However, physical examination and noninvasive tests may not elucidate the functional significance of pericardial effusion, particularly in patients
with associated cardiopulmonary disease. In such cases,
right heart catheterization or diagnostic pericardiocentesis is indicated.
Definitive treatment of cardiac tamponade requires
decompression of the heart either surgically or by pericardiocentesis. Supportive therapy, including intravenous fluids, pressor agents, and oxygen, is of limited
benefit. Acute pericardial tamponade with hemodynamic instability is life threatening, and must be alleviated
by prompt fluid removal – most rapidly by pericardiocentesis. If the patient develops cyanosis, dyspnea,
shock, or impaired consciousness, a pulsus paradoxus
greater than 50% of pulse pressure, or a decrease of
more than 20 mmHg in pulse pressure, emergency
pericardiocentesis must be performed. If the patient is
hemodynamically stable, a more definitive procedure
should be performed. Zwischenberger and Bradford41
recommend echocardiography or CT-guided percutaneous tube pericardiotomy to accomplish both diagnosis and therapy at the initial intervention. Once the
pericardium has been drained, these authors use doxycyclin or bleomycin for sclerotherapy. If sclerotherapy
does not control the effusion, they proceed with subxiphoid pericardiotomy for evacuation of the effusion.
A subxiphoid pericardial window can be performed under
local anesthesia, and is reported to control the effusion
in almost all patients. The high control rate and low
incidence of complications with subxiphoid pericardiotomy have also led other investigators to conclude
that this procedure can be used instead of pericardiocentesis for initial treatment of cardiac tamponade.42
EXTRATHORACIC COMPLICATIONS
Lung cancer frequently metastasizes to distant organs.
More than 60% of patients with SCLC, and approximately
30–40% of those with NSCLC, have stage IV metastatic
disease. The usual sites of distant metastatic disease
include the adrenals, brain, liver, lung and bone, although
virtually any organ can be affected. Metastases may
present at the same time as the primary tumor or may
occur much later, and they may be single or multiple,
clinically silent or requiring urgent diagnosis and treatment. Manifestations resulting from distant metastases
depend on the specific organ involved and are similar
to those for other kinds of cancer.
Brain metastases
The most frequent metastatic neurologic complications
of lung cancer are metastases to the brain. Clinically
diagnosed brain metastases are present at initial presentation in 4–19% of SCLC patients,43 and the incidence
rises to 50% in patients not receiving prophylactic cranial irradiation.44 Patients with NSCLC, especially those
with adenocarcinoma, often develop brain metastases
during the course of their disease.45
Brain metastases may be detected before the primary
tumor is found or at the same time (synchronous presentation), but more commonly (80%) the diagnosis of
the lung cancer antedates the development of the brain
metastases (metachronous presentation). Focal neurologic abnormalities and global deficit of higher mental
function are the commonest findings, with headaches
being the most frequent symptom at presentation. Headaches occur in approximately 50% of patients with brain
metastases, more commonly in those with multiple
metastases and with metastases in the posterior fossa.
Headeache may be associated with other symptoms
characteristic of increased intracranial pressure, such as
vomiting, visual blurring and confusion. Focal weakness is the presenting symptom in 20–40% of patients.
Deficits of higher mental function (memory problems
and mood or personality changes) are reported by onethird of patients, whereas cognitive dysfunction as
detected by standard tests of mental status may be present in as many as 75%. Seizures occur in approximately
10% of patients as the first sign of metastases. CT and
MRI are the primary radiographic means of evaluating
patients suspected of having brain metastases. MRI is
more sensitive in detecting multiple lesions, and allows
improved visualization of the brainstem.
The prognosis for patients with brain metastases is
very poor, and depends on their functional and neurologic status, evidence of systemic tumor involvement,
and whether the brain metastasis is truly solitary. Twothirds of patients will have improvement in their neurologic signs and symptoms with the use of steroids,
but only for a short time (maximum one month). Dexamethasone is the most commonly used glucocorticoid,
because it has minimal mineralcorticoid activity as
compared with other steroids.
Complications of lung cancer 225
Conventional dosing with dexamethasone for brain
edema is 16 mg/day. Currently there are three treatment options available for patients with a known NSCLC
and a solitary intracranial metastasis: surgical resection,
whole brain radiation therapy (WBRT), and stereotactic
radiosurgery (SRS). Most often, some combination of
these methods of treatment is preferable. Surgical resection plus postoperative WBRT is currently the treatment
of choice for patients with surgically accessible single
brain metastases.
The data supporting surgery for single brain metastases come from many retrospective studies46 and two
randomized prospective trials,47,48 the results of which
show that surgical resection is of benefit in selected
patients. In the first randomized trial, by Patchell et al,47
patients with known systemic cancer were treated either
with biopsy of the suspected brain metastases plus
WBRT or with complete surgical resection of the metastases plus WBRT. A statistically significant increase in
survival time was found in the surgical group (40 weeks
versus 15 weeks). In addition, patients receiving surgery also had a significant decrease in recurrence at this
surgical site and an improved quality of life. A second
randomized study48 evaluated 63 patients randomized
either to complete surgical resection plus WBRT or to
WBRT alone. Survival was significantly longer in the
surgical group (10 months versus 6 months), and a
non-significant trend towards longer duration of functional independence was seen in the surgically treated
patients. On the basis of these data, surgery and radiotherapy are usually recommended for good performance status patients with a solitary cerebral metastasis.
However, over 50% of isolated brain lesions are not
amenable to surgery. SRS is an alternative method able
to deliver a highly focused, single dose of radiation to a
well-defined, small intracranial target, thus minimizing
exposure to the normal surrounding brain. No randomized prospective trials have compared SRS to surgery.
Many studies of SRS for patients with intracranial
metastases have reported similar median survival times
to surgery.49
A retrospective study has demonstrated equal local
tumor control rates and equal neurologic death rates
between surgery and SRS.50 A prospective but nonrandomized study of patients with lung cancer (both
SCLC and NSCLC) demonstrated significantly longer
median survival for SRS with or without WBRT over
WBRT alone (10.6 months and 9.3 months vs 5.7
months, p <0.0001).51 A randomized study of WBRT
alone versus WBRT plus SRS in patients with two to
four intracranial metastases showed significantly
improved local control, with a trend toward increased
survival for WBRT plus SRS.52 Based on the available
data, the appropriate SRS dose following WBRT is 20
Gy in tumors less than 2 cm in size, 18 Gy in tumors
2 to 3 cm in size, and 15 Gy in tumors more than 3
cm. The majority of patients with brain metastases
present with multiple lesions, and are not candidates
for aggressive local therapy. The mainstay of treatment
is palliative WBRT.53 Many studies have compared different radiation schedules and doses. Final results
from the Royal College of Radiologists’ trial54 suggest
that a hypofractionated course of WBRT could palliate
symptoms with minimal toxicity. Patients with NSCLC
who are elderly or have a poor performance status
could benefit from a short course of treatment. Some
studies indicate that chemotherapeutic agents may
cross the blood–brain barrier in patients with brain
metastases.55 The observed response rate to chemotherapeutic agents was reported to be similar in the brain
(16–35%) to other organs.56,57 Two studies on concomitant radiotherapy and chemotherapy for brain metastases in NSCLC reported higher objective response
rates (58–76%).58,59 Moreover, both studies demonstrated a neurologic improvement in more than 50%
of patients. Whether there is a definitive role for chemotherapy or combined chemoradiotherapy in the
treatment of brain metastases in patients with NSCLC
will have to be determined by prospective studies,
taking into account survival and quality of life as their
main endpoints. Patients with SCLC and brain metastases at presentation should be treated with primary
chemotherapy. Whether consolidating cranial radiotherapy should be given after a few courses of initial
chemotherapy is unclear. In patients who are unfit for
chemotherapy or who have brain relapses during or
immediately after chemotherapy, some palliative effect
can be obtained with a short course of WBRT. As with
NSCLC, combined chemoradiotherapy should be considered only in the context of a clinical trial.
Spinal cord compression
After brain metastases, spinal cord compression (SCC)
is the most frequent neurologic complication of lung
cancer. Five percent of patients with lung cancer
develop SCC, more frequently at an interval after the
diagnosis, usually six months.60 In a retrospective
study on metastatic SCC secondary to lung cancer,
Bach et al61 observed some variations between the
different types of lung cancer. In SCLC, 75% of the
cases of SCC were diagnosed during the first month
after the primary malignant diagnosis was established,
226 Textbook of Lung Cancer
which contrasts with 12 months for adenocarcinoma
and 21 months for squamous subtypes. Lung cancer
has a predeliction to metastasize to the spine. The
most common mode of SCC is that due to expansion
or collapse of the vertebral body (85%) or neural
arch. Paraspinal lung cancer may also directly invade
the extradural space through the intervertebral
foramen, producing SCC without vertebral body
involvement.
Malignant SCC is a medical emergency, and the key
to successful management is early diagnosis and prompt
treatment. All too often, the diagnosis is made too late
for useful treatment. Those patients who present paraparesis, sensory symptoms, and sphincteric dysfunction usually pose no difficulty in diagnosis. Patients
with more subtle presentations must be identified, and
an appreciation of the earliest clinical manifestation is
therefore essential. Isolated back pain is the initial
symptom in 70–95% of patients, and it always antedates diagnosis of SCC by several days to many months.
Pain can be local or radicular. Symptoms other than
pain suggest compromise of neural structures. Weakness is present in approximately 80% of patients, and
may be most evident when it affects proximal muscles
of the lower extremity, creating difficulty when climbing stairs or rising from chairs. Non-painful sensory
symptoms include paraesthesias, which in SCC usually
begin in the feet and gradually ascend, ultimately stopping at a specific level that the patient may indicate.
Loss of proprioception, producing ataxia, and sphincteric dysfunction are often late manifestations. Careful
neurologic examination usually identifies the neurologic level and establishes the diagnosis.The evaluation
of the patient with SCC must be speedy and resolutive.
Although 80% of patients show abnormalities on plain
spinal radiography, normal spine films do not exclude
epidural metastases. MRI is being recognized as the
diagnostic method of choice in SCC.
Patients diagnosed with epidural cord compression
should be treated urgently. Loss of ambulation or
sphincter function before treatment is associated with a
poor response to treatment and an adverse prognosis.
About 80% of patients with little or no ambulatory dysfunction retain the ability to walk. Patients who are
paraparetic recover ambulation in 20–60% of cases.
Paraplegia improves in response to treatment in no
more than 16% of cases.62,63 When the diagnosis of epidural compression has been made, dexamethasone
should be administered. There is good evidence that
the administration of high-dose steroids (dexamethasone 96 mg intravenous bolus, then 24 mg orally four
times a day for three days, then taper over ten days)
improves the postradiation ambulatory rate compared
with those who do not receive any steroids.64 However,
the utility of moderate-dose steroids (dexamethasone
10 mg intravenous bolus, then 4 mg intravenously,
with a taper over two weeks) remains unclear. There
is fair evidence that dexamethasone does not need to
be given to asymptomatic ambulatory patients with
radiographic cord compression who are receiving radiotherapy.65 The decision to proceed with surgery or radiotherapy is based on the individual patient’s specific
circumstances.
Although based on inconclusive evidence, some general treatment recommendations can be suggested.66,67
Patients who present spinal instability or bony compression of their spinal cord, with no histologic diagnosis, with redevelopment of epidural compression in a
previously radiated site, and with neurologic deterioration during radiotherapy, should be considered for surgical resection. Postsurgically ambulatory patients may
benefit from postoperative radiotherapy. Other patients
can be treated effectively with radiotherapy alone, specifically those with a life expectancy of three months or
less, more than one level of simultaneous SCC, paraplegia of greater than 12–24 hours’ duration, and co-morbid conditions that preclude surgery.
PARANEOPLASTIC SYNDROMES
Complications of lung cancer that are not related to
direct invasion, obstruction, or metastatic effects of the
tumor are generally termed paraneoplastic. Paraneoplastic syndromes comprise a group of disorders mediated
by the production of circulating factors by, or in response
to, lung cancer. These syndromes are numerous and
occur in 10–20% of lung cancer patients, and include
endocrine, neurologic, cardiovascular, skeletal, and
cutaneous manifestations (Table 15.2). In this review,
we focus only on the most common syndromes.
Paraneoplastic endocrine syndromes
Syndrome of inappropriate antidiuretic hormone
Syndrome of inappropriate antidiuretic hormone
(SIADH) results from inadequate secretion of antidiuretic hormone (ADH, vasopressin), which is almost
exclusively associated with small cell histology. Up to
50% of SCLCs have elevated levels of ADH, but fewer
than 10% have clinically apparent disease. SCLC is estimated to account for 75% of tumor-associated SIADH.
Complications of lung cancer 227
Table 15.2 Paraneoplastic syndromes of lung cancer
Syndrome
Clinical frequency (%)
Isotype
Endocrine
Inappropriate ADH
Ectopic ACTH
Humoral hypercalcemia
5–10
3–7
10
SCLC
SCLC
Most frequently with
squamous cell types
Neurological
Lambert–Eaton
Peripheral neuropathy
Encephalopathy
Myelopathy
Cutaneous and musculoskeletal
Clubbing/hypertrophic pulmonary
osteoarthropathy
Dermatomyositis
Acanthosis nigricans
Vascular and hematologic
Hypercoagulable state
Thrombophlebitis
Non-bacterial thrombotic endocarditis
6
Rare
Rare
Rare
}
SCLC
10
}
More with adenocarcinoma
}
More with adenocarcinma
Rare
Rare
10–15
Uncommon
Uncommon
The main features of SIADH are water intoxication and
hyponatremia. Diagnostic criteria include:
•
•
•
•
hypo-osmotic hyponatremia;
inappropriately concentrated urine (urine osmolarity >100 mosmol/kg);
euvolemia;
normal renal, adrenal, and thyroid function.
The clinical features are related to osmotic water shift
that leads to increased intracellular fluid (ICF) volume,
specifically brain cell swelling. More often, hyponatremia develops insidiously, and adaptive mechanisms
tend to minimize the increase in the ICF volume and its
symptoms. Most patients experience minimal symptoms, and are discovered on routine laboratory evaluation when they have hyponatremia. Symptoms most
frequently associated with hyponatremia include
anorexia, nausea, vomiting, headache, and mildly altered
mental status. In severe or rapid-onset hyponatremia,
patients may experience symptoms related to cerebral
edema, resulting in confusion, irritability, seizures, coma,
and, ultimately, respiratory arrest.
In evaluating a patient with hyponatremia, the physician must carefully exclude other causes and non-malignant conditions associated with SIADH. The first
step in the diagnostic process is to assess volume status.
As SIADH is one of the so-called euvolemic hyponatremic states, the physician must recognize all diseases
associated with volume overload, such as congestive
heart failure, nephrotic syndrome, and severe liver disease. On the other hand, it is also important to exclude
causes of hypovolemic hyponatremia that develops as a
consequence of electrolyte-free water retention.
Once the patient has been determined to be euvolemic, other causes of hyponatremia associated with a
normal extracellular fluid volume must be ruled out,
including glucocorticoid deficiency, hypothyroidism,
and renal disease. Finally, other causes of SlADH must
be excluded before the disorder is accepted as a paraneoplastic syndrome. Well-known non-malignant conditions associated with SIADH include pulmonary
infections, central nervous system disorders (e.g. head
trauma, space-occupying lesions, and cerebrovascular
accidents) and drugs (most commonly chlorpropamide,
carbamazepine, tricyclic antidepressants, thiazide
diuretics, morphine, cyclophosphamide, and vincristine). List and colleagues68 reviewed 350 cases of SCLC
and noted that 40 (11%) met a strict definition of
SIADH similar to that outlined above, and 33 of them
had the syndrome at initial presentation. Chemotherapy of the associated SCLC is generally associated with
228 Textbook of Lung Cancer
improvement in the syndrome. SIADH has not been
shown to be a negative prognostic factor in terms of
response to chemotherapy. In 80% of patients, the
serum sodium returns to normal within three weeks of
the start of chemotherapy, and this may predate other
indices of response. Additional management of the
hyponatremia may be necessary while waiting a response
to chemotherapy, or when the tumor is resistant to
therapy.
Supportive measures such as fluid restriction and pharmacologic therapy can be undertaken to treat SIADH.
For patients with sodium levels below 130 mmol/l,
placement on free-water restriction (500 ml/day) is
generally recommended, in addition to treatment of the
primary malignancy. In the event that this measure does
not bring the serum sodium level above 130 mmol/l,
the tetracycline antibiotic demeclocycline (150–300 mg,
6–8 hourly) can be used, which induces nephrogenic
diabetes insipidus such that the distal tubule becomes
refractory to the effect of arginine vasopressin. In
patients with more severe or life-threatening symptoms
related to hyponatremia (serum sodium less than
115 mmol/l), treatment consists of intravenous fluids
with 0.9% saline (rarely, hypertonic saline) and diuresis
with a loop diuretic such as intravenous frusemide
(furosemide). The rate of correction of hyponatraemia
depends on the absence or presence of neurologic
dysfunction. This is, in turn, related to the rapidity of
onset and magnitude of the fall of the serum sodium.
The rate of correction of the sodium is best limited to
1–2 mmol/l/h, or a maximum of 20 mmol/l/day until a
Ievel of 120–130 mmol/l is reached. More rapid correction has been associated with the development of central pontine myelinolysis, which is characterized by
flaccid paralysis, dysarthria, and dysphagia.
Ectopic adrenocorticotropic hormone syndrome
Cushing’s syndrome is due to the chronic effects of an
excess of glucocorticoid hormone, most often iatrogenic
resulting from therapy with glucocorticoid drugs. Adrenocorticotropic hormone (ACTH)-secreting pituitary
microadenomas (Cushing’s disease) account for some
80% of cases of endogenous Cushing’s syndrome. About
15–20% of cases of Cushing’s syndrome are due to
ectopic ACTH or corticotropin-releasing hormone
(CRH) production. SCLC and bronchial carcinoid
tumors account for most of these cases.69 The classic
signs and symptoms include truncal obesity, cutaneous
striae, moon face, buffalo hump, proximal myopathy
and weakness, osteoporosis, diabetes mellitus, hypertension, and personality changes. However, lung cancer
patients with Cushing’s syndrome often do not have the
classic clinical finding. The commonest physical findings are edema (83%) and proximal myopathy (61%).70
Myopathy with weakness and muscle wasting is much
more common in ectopic ACTH production. Moreover,
hyperpigmentation is found in ectopic ACTH production, but not in Cushing’s disease. Most patients will
have a hypokalemic alkalosis, and about half will be
hyperglycemic. This difference in presentation may be
due to the rapid growth of the malignancy, relatively
high levels of ACTH, and the fact that patients may not
live long enough to develop the more classic features of
the syndrome.
Cushing’s syndrome occurs in approximately 5% of
cases of SCLC, although raised concentrations of immunoreactive corticotropin can be detected in as many as
50%. In a review of more than 500 patients with SCLC,
23 cases (4.5%) of Cushing’s syndrome were identified.70 Thirteen patients had the syndrome at initial
diagnosis, and ten developed it at the time of relapse of
their disease after therapy. All of these patients had a
shorter survival compared with patients without the
syndrome. This may be due in part to the observed
complications (infections and gastrointestinal ulceration) related to prolonged exposure to high levels of
corticosteroids secondary to ectopic ACTH production.
The diagnosis of Cushing’s syndrome is best established
by 24 hour urine-free cortisol measurements or lowdose dexamethasone suppression testing (0.5 mg every
six hours for eight doses).71 The primary therapy of
ectopic Cushing’s syndrome secondary to lung cancer
is treatment of the underlying tumor. If patients experience significant clinical effects from the hypercortisolism, cortisol production blockers (steroid synthesis
inhibitors), such as aminoglutethimide, mitotane,
metyrapone, and ketoconazole, are said to be beneficial. Because of its rapid onset of action and favorable
toxicity profile, ketoconazole (300–400 mg twice a day)
has become the therapy of choice for ectopic ACTH.72
Suppressors of ACTH production, such as the somatostatin analog octreotide,73 have shown some efficacy.
Humoral hypercalcemia
Hypercalcemia is probably the most common metabolic
complication of cancer and, since determination of the
serum calcium level became routine, the recognition of
patients with hypercalcemia associated with cancer has
increased. Hypercalcemia may be related to direct bone
destruction or to secretion of a parathyroid hormone
(PTH)-related protein or other bone-resorbing substances
(cytokines) secreted by the tumor. A PTH-related
Complications of lung cancer 229
protein that shares an N-terminal sequence with PTH,
but has a unique C-terminal portion, has been shown
to be responsible for most cases of hypercalcemia of
malignancy. Elevated levels of PTH-related protein by
radioimmunoassay were found in 30 of 42 patients
(71%) with hypercalcemia of malignancy, but only in 3
of 23 patients with cancer (13%) but with normal calcium levels.74 In a study of 200 consecutive patients
with untreated bronchogenic carcinoma, the overall
frequency of hypercalcemia was 12.5%.75 Of these 25
patients, 14 did not have evidence of bony metastases.
Humoral hypercalcemia was most commonly observed
in those with squamous cell histology, and was uncommonly observed with adenocarcinoma and SCLC.
The symptoms associated with hypercalcemia generally correlate with the magnitude and rapidity of the
rise in serum calcium. Mild hypercalcemia is generally
asymptomatic. More severe hypercalcemia is frequently
associated with neurologic, gastrointestinal and renal
symptoms. The neurologic manifestations range from
mild drowsiness, progressing to weakness, depression,
lethargy, stupor, and coma. Gastrointestinal symptoms
may include constipation, nausea, vomiting, anorexia,
and peptic ulcer disease. Hypercalcemia-induced nephrogenic diabetes insipidus often results in polyuria,
leading to extracellular fluid (ECF) volume depletion
and a reduction in the glomerular filtration rate (GFR),
which may lead to a further increase in calcium concentration. Cardiovascular effects include shortened QT
interval, broadened T wave, heart block, ventricular
arrhythmia, and asystole. Individual patients may manifest any combination of these signs and symptoms to
varying degrees.
Hypercalcemia may be completely reversible with
effective treatment of the underlying cancer; it is important to recognize that hypercalcemia per se does not
rule out the possibility of curative therapy, including
surgery, if indicated. The prognosis for patients with
hypercalcemia and no further treatment of the underlying malignancy is extremely poor, with median survivals of 30–45 days.76 The symptoms and the magnitude
of the hypercalcemia are key considerations in determining the need for aggressive therapy. If the serum
calcium concentration is greater than 14 mg/dl, immediate treatment is indicated, even if symptoms are
absent. In the case of mild calcium elevation (<12 mg/dl)
in patients with widely metastatic and incurable malignancy, it may be most appropriate to give supportive
care only, without specific therapy for the hypercalcemia. Otherwise, most patients with serum calcium values of 12–14 mg/dl should be treated. The approaches
to the management of hypercalcemia can be divided
into four specific areas:
•
•
•
•
treating the underlying tumor;
correcting dehydration;
enhancing renal excretion of calcium;
inhibiting accelerated bone resorption.
The intravenous administration of isotonic saline is
an important component, and is the first step in the
management of severe hypercalcemia with associated
symptoms. A widely used regimen is to administer 3 l
of isotonic saline daily, recognizing that the rate of fluid
administration may need to be varied if symptoms and
signs of fluid overload appear. The next step is to add a
loop diuretic, such as frusemide, that will increase calcium excretion.
This initial treatment usually has little effect on calcium
levels, effecting a median decrease of only 1.0 mg/dl.
Specific therapy to inhibit accelerated bone resorption
is often necessary. Bisphosphonates are potent inhibitors of bone resorption that have dramatically changed
the therapeutic approach to hypercalcemia. These compounds have poor gastrointestinal absorption, and are
best used intravenously. Pamidronate and zoledronate
are the most useful of the commercially available compounds. Normalization of serum calcium is obtained
after three days (range 1–11 days), and normocalcemia
is maintained for a variable length of time (median of
one to two weeks). Bisphosphonates are well tolerated;
the only clinically detectable side-effect is transient fever
in about 20% of the cases.
Other inhibitors of osteoclast activity include calcitonin, plicamycin, and gallium nitrate. Calcitonin inhibits bone resorption, increases renal calcium excretion,
and has a rapid onset of action. The hypercalcemia effect
begins within hours, with a nadir in serum calcium within
12–24 hours, but the effect on calcium concentrations
is modest and transient, and calcitonin alone has no
place in the treatment of severe hypercalcemia. However,
in very severe cases, it is an excellent addition to the lateracting bisphosphonates or plicamycin. Plicamycin (mithramycin) inhibits osteoclastic RNA synthesis. It lowers
the serum calcium more quickly than bisphosphonates
do, but significant side-effects (raised transaminases,
nephrotoxicity with proteinuria, thrombocytopenia, nausea, and local inflammation or cellulitis at sites of extravasation) decrease enthusiasm for this agent unless the
calcium concentration needs to be lowered very rapidly.
Gallium nitrate also inhibits bone resorption. As with
bisphosphonates, it takes several days before a nadir in
230 Textbook of Lung Cancer
serum calcium is reached, and this lasts about a week.
Side-effects are frequent and severe, and include nephrotoxicity, hypophosphatemia, and anemia. The need
to treat patients for five days with a continuous infusion
and its toxicity limit the use of this compound in the
treatment of hypercalcemia.
Paraneoplastic neurologic syndromes
Paraneoplastic neurologic syndromes have long been
recognized, and these disorders are now thought to
result from the cross-reaction of antitumor antibodies
with antigen also present in neural tissue.77
One such antigen is the nuclear-associated HuD protein, which has been cloned by use of high-titer antibodies from the serum of patients with paraneoplastic
syndromes.78 In health, the antigen is expressed only in
neural tissue, but is expressed by all SCLCs, perhaps
reflecting the apparent neuroendocrine origin of this
tumor. Why high titers of anti-HuD antibodies develop
in some patients with SCLC is unknown.
Neurologic paraneoplastic syndromes include sensory,
sensorimotor, and autonomic neuropathies and encephalomyelitis. Neurologic symptoms of encephalomyelitis
include dementia (limbic encephalitis), cerebellar degeneration, brain-stem encephalitis, and myelitis. Sensory
neuropathy and encephalomyelitis often occur together,
and are associated primarily with SCLC.
Symptoms may precede the diagnosis of lung cancer
by many months, or they may be the first sign of tumor
recurrence. Direct metastatic effects as well as metabolic
or infectious processes must be excluded as contributors to the neurologic findings. The severity of neurologic symptoms is not related to tumor bulk; in fact, a
primary malignant lesion may be undetected before
death, despite disabling symptoms. In a patient with the
appropriate neurologic findings, positive anti-Hu antibody, and significant smoking history, a diligent diagnostic evaluation should be undertaken. The most helpful
diagnostic test is probably CT of the chest, with careful
attention to mediastinal or hilar nodes.
Fluorodeoxyglucose (FDG)-PET scanning has also
been used with some success.79
Lambert–Eaton myasthenic syndrome
The neurologic syndrome most commonly recognized
is the Lambert–Eaton myasthenic syndrome, reported
to occur in up to 6% of cases of SCLC. Clinically, this
syndrome is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction due to impaired
release of acetylcholine from the cholinergic nerve terminals. Symptoms are most pronounced in the pelvic
girdle and thigh muscles, making it difficult for patients
to climb stairs or get out of a bathtub. Other symptoms,
such as dysarthria, dysphagia, diplopia, and ptosis, may
occur. It is distinguished from myasthenia gravis by the
absence or minor involvement of bulbar or extraocular
muscles. Standard electromyography characteristically
demonstrates a reduced amplitude of the compound
muscle action potential, which increases immediately
after 10–15 seconds of maximal voluntary contraction,
or during high-frequency nerve stimulation, while there
is a steady decrease in classic myasthenia. The manifestations of the disease may occur as long as two to four
years before the diagnosis of SCLC.
The syndrome is thought to result from autoantibodymediated impairment of presynaptic neuronal calcium
channel activity, which impairs the nerve stimulusinduced release of acetylcholine.80 Treatment-induced
remission of the SCLC may cause attenuation or remission of the syndrome in some patients. The use of
acetylcholinesterase inhibitors is of limited benefit. 3,4Diaminopyridine enhances the release of acetylcholine,
and has been shown to be effective in treating both the
motor and the autonomic deficits of the syndrome.81
Immunosuppressive treatment may provide benefit, but
its effects are usually delayed and incomplete. Many
patients become severely debilitated from their motor
dysfunction, regardless of the status of their lung cancer.
Paraneoplastic cerebellar degeneration
Paraneoplastic cerebellar degeneration (PCD) is a disorder that is charaterized by ataxia, nystagmus, diplopia,
dysarthria, and dysphagia. It is most often associated
with SCLC, and 44% of patients have elevated anti-Hu
antibodies. Individuals with anti-Hu antibodies are more
likely to be women, have extracerebellar manifestations
(encephalomyelopathy or sensory neuropathy), have
severe disability, and have localized or undetected tumor
at the time of death. Less that one half of patients with
PCD have abnormal neuroradiologic studies. Pathology
reveals inflammatory infiltrates, perivascular lymphocytic cuffing, and loss of Purkinje cells. Neither treatment
of the tumor, nor the immune modulating therapy alters
the course of PCD. Those with PCD and small cell carcinoma have a shorter survival than those without PCD.82
Progression of neurologic disease is the cause of death in
most patients with PCD who have positive anti-Hu antibodies and in a few who are anti-Hu negative.82
Peripheral neuropathy
Patients with cancer who suffer from a peripheral
neuropathy usually do so from causes other than
Complications of lung cancer 231
paraneoplastic syndromes (e.g. neoplastic invasion, chemotherapeutic agents, and nutritional and metabolic
disorders). Therefore a careful evaluation for other
causes of peripheral neuropathy should be made before
the disorder is accepted as a paraneoplastic syndrome.
One exception is the subacute sensory neuropathy
occurring in patients who have the anti-Hu antibody,
where the presence of the antibody establishes the diagnosis as a paraneoplastic syndrome and the cancer as
highly likely to be SCLC. In about 20% of all patients
with a subacutely developing pure sensory neuropathy,
cancer is the underlying cause. Subacute sensory neuropathy is usually a rapidly developing severe disorder
in which patients lose all modalities of sensation, usually in all four extremities. The disorder is clinically distinguishable from cisplatin sensory neuropathy, because
cisplatin neuropathy causes loss of proprioception and
spares pain and temperature sensation. Although the
disorder may begin in the face or trunk, it commonly
begins distally in the extremities and extends proximally. The sensory loss is so severe that patients may be
unable to walk, use their hands, or co-ordinate movements. The neurologic symptoms may precede the
diagnosis of SCLC by several months.83 Electrodiagnostic tests show absent sensory potentials. Motor nerve
conduction and F waves may be entirely normal. The
neuropathologic findings include drop-out of neurons
in the dorsal root ganglia, inflammatory infiltrates
mainly composed of T cells, and anti-Hu antibody on
the surface and in the nuclei of the remaining sensory
neurons.
Other neurologic syndromes
Among the other SCLC-associated neurologic syndromes
are limbic encephalopathy, necrotizing myelopathy, intestinal dysmotility syndrome, opsoclonus-myoclonus, and
cancer-associated retinopathy (CARS).
Anti-Hu antibody has been noted in patients with
SCLC presenting these rare neurologic paraneoplastic
syndromes.84 Limbic encephalopathy is characterized
by memory loss and behavioral changes, including
dementia, which often antedate the diagnosis of cancer.
Necrotizing myelopathy is an unusual neurologic paraneoplastic syndrome, and is characterized by a relatively acute, rapidly ascending paraplegia that culminates
in rapid deterioration and death.
Intestinal pseudo-obstruction of the bowel is the
most well-defined isolated autonomic symptom. Patients
may suffer weight loss, refractory constipation, and
abdominal distension. Neurologic studies show loss of
neurons in the myenteric plexus with inflammatory
infiltrates. Serum antibodies to myenteric and submucosal neural plexus of the jejunum and stomach have been
found in patients with SCLC.85 Opsoclonus-myoclonus
is another paraneoplastic syndrome commonly associated with SCLC. Neurologic manifestations involve
myoclonus, truncal ataxia, and progressive involuntary
rapid eye movements. The cerebrospinal fluid reveals
increased protein with mild pleocytosis. Imaging studies are often interpreted as normal. Treatment of the
SCLC can lead to partial or even complete recovery.
CARS is a rare paraneoplastic syndrome and it is
most commonly associated with SCLC. CARS is suspected to be caused by autoimmune degeneration of
the retinal photoreceptors. The triad of photosensitvity,
scotomes, and attenuated retinal arteriole caliber suggests the diagnosis of CARS. The use of steroids has
been reported to result in some improvement of visual
symptoms.86 Most cases progress to blindness, even
with treatment of the cancer.
Paraneoplastic cutaneous and musculoskeletal
syndromes
Digital clubbing and hypertrophic pulmonary osteoarthropathy are the other major paraneoplastic syndromes
that are associated with lung cancer, almost exclusively
with NSCLC.87 Digital clubbing is characterized by subungual soft tissue thickening, most commonly involving
the fingernails, which are often bulbous in appearance
(Figure 15.2). Clubbing of the digits is one of the most
commonly discussed findings on pulmonary medicine
clinical rounds. Etiologic factors include hereditary and
both non-pulmonary and pulmonary diseases, including bronchogenic carcinoma.
Hypertrophic pulmonary osteoarthropathy (HPO)
is less common than digital clubbing, and is usually
associated with intrathoracic malignancy, especially
lung cancer, and often resembles rheumatoid arthritis
(Figure 15.3). It is characterized by painful symmetric
polyarthritis that generally involves the ankles, wrists,
and knees. HPO is due to proliferative periostitis of the
long bones, often with little or no evidence of clubbing.
The onset of HPO is often acute, may precede the diagnosis of cancer by months, and usually, but not invariably, is associated with inoperability. The cause of HPO
is not known, but may be due to a humoral agent.
Patients with HPO frequently have consulted a rheumatologist or orthopedic specialist before the ultimate
diagnosis of lung cancer is suspected and a chest radiograph is obtained. In patients who smoke and present
arthralgia, HPO must be included in the differential
diagnosis. Radionuclide bone scans typically show
232 Textbook of Lung Cancer
nary disease. Weakness usually moves gradually and
progressively. Although they do not occur in all patients,
muscle tenderness and aches may be very striking. The
inflammation characteristically causes elevations of serum
levels of aldolase and creatinine kinase, and alternation
of liver function tests. Although most patients respond
initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness
develops.
Figure 15.2
Digital clubbing.
Figure 15.3
Hypertrophic pulmonary osteoarthropathy.
increased uptake at the distal ends of the affected long
bones, and this may be confirmed by evidence of new
bone formation on plain-film radiographs. The spine
is spared. The syndrome may resolve with response of
the cancer; however, no effective form of treatment is
recognized, including aspirin and non-steroidal antiinflammatory agents.
Other cutaneous paraneoplastic syndromes include
dermatomyositis, acanthosis nigricans, and hyperkeratosis of the palm and soles. These conditions are rarely
seen in patients with lung cancer. Dermatomyositis is a
rare but very disabling complication of lung cancer.
The patient presents weakness and a characteristic rash.
Sometimes the disease presents as a cardiac or pulmo-
Paraneoplastic vascular and hematologic
syndromes
The association between cancer and venous thromboembolism is well known. Over a hundred years ago,
Trousseau reported cases of episodic migratory thrombophlebitis in patients with cancer. The pathogenic
mechanisms for the association include hypercoagulability due to activation of clotting by tumor cells, vessel
wall injury, and stasis. Occasionally, the thromboembolic event occurs before the diagnosis of cancer, and it
has been suggested that deep venous thrombosis may
be a predictor of the subsequent diagnosis of cancer.
Two studies have noted a significant association between
primary venous thrombosis and the subsequent development of cancer.88,89 This link seems particularly
strong in patients with recurrent deep venous thrombosis. Lung cancer and other malignancies, especially
those of the gastrointestinal tract (e.g. the pancreas),
are commonly associated with Trousseau’ s syndrome.
Pulmonary embolism has been observed at autopsy in
20% of patients with lung cancer, and may precede the
diagnosis of cancer;90 25% of adult patients with acute
pulmonary embolism may develop cancer within five
years.91 There appears to be a general activation of the
clotting system in patients with lung cancer, the clinical
consequence much more often being thrombosis rather
than bleeding.
Disseminated intravascular coagulation (DIC) is another
state of hemostatic disarray, characterized by the inappropriate co-existence of enhanced fibrin production
and fibrinolysis. DIC has been reported as a complication of many neoplastic disorders, but is most likely to
occur in carcinoma of the lung, prostate, breast, and
gastrointestinal tract, in melanoma, and in leukemia.
In its grossest form, DIC is readily recognized by prolongation of the thrombin time, prothrombin time, and
partial thromboplastin time, by a decrease in the concentration of plasma fibrinogen and other clotting
factors, by thrombocytopenia and by the presence
in serum of antigens reacting with antiserum to fibrinogen or its derivatives. However, apparent DIC, with
Complications of lung cancer 233
consumption of platelets and clotting factors and bleeding, is rare and is most commonly associated with acute
promyelocytic leukemia and adenocarcinoma.
Non-bacterial thrombotic endocarditis (NBTE), also
known as marantic endocarditis, probably relates to
this hypercoagulable state, and is generally defined as
vegetations on the heart valves or wall that contain
fibrin and platelets, but without evidence of infection.
It is particularly associated with bronchoalveolar carcinoma and adenocarcinoma of the lung. At autopsy, the
incidence of NBTE in each of these cell types is approximately 7%. The mitral valve is commonly involved,
and clinically significant emboli to the central nervous
system, kidneys, and coronary arteries have been
described in what previously was thought to be a syndrome of only pathologic interest at autopsy.92 Although
some patients may have heart murmurs, most do not.
Echocardiography picks up vegetations larger than 2 mm.
In a review of cerebrovascular complications in patients
with cancer, Graus and colleagues93 observed cerebral
embolic infarction in 42 of 86 patients with pathologically documented NBTE and careful autopsy examination
of the brain. NSCLC was the most common malignancy
in this group. Cerebral infarction was symptomatic in
32 (76%) of these patients ante mortem, and was associated with clinical evidence of other systemic emboli in
19 patients. The definitive diagnostic test is cerebral
angiography, which shows multiple arterial occlusions.
Tumor embolization to the lungs and brain is another
cause of emboli in cancer patients, in addition to
venous thrombosis and NBTE. Tumor emboli are an
unusual clinical event, although autopsy series have
reported tumor emboli in up to 23% of solid tumors.94
Lung cancer and breast cancer were the most common
malignancies in these patients, but in only one patient
was the tumor embolism correctly diagnosed ante
mortem.
The management of thromboembolic complications
in patients with lung cancer is difficult. Typically, such
patients are resistant to anticoagulation, especially with
warfarin. Long-term administration of subcutaneous
low molecular weight heparin (LMWH) may be a more
effective approach.95
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16 Quality of life and supportive care
Jean-Paul Sculier, Anne-Pascal Meert, Marianne Paesmans, Thierry Berghmans
Contents Introduction • Quality of life assessment • Critical care of the lung cancer patient
• Symptom management • Management of treatment complications
INTRODUCTION
During the last two decades there has been great interest in the patient’s well-being, particularly among
oncologists and lung cancer specialists in particular.
Quality of life (QoL) assessment is a way to obtain
objective data in order to ‘measure’ the patient’s condition and to evaluate the effectiveness of therapies administered to improve his or her situation. Unfortunately,
there are considerable methodologic difficulties in
designing adequate universal instruments to give a
global measurement of QoL. Most of the investigations
performed so far in this field have in fact assessed the
symptoms of the patient in a semiquantitative way.
The specific anticancer treatment is in many situations the obvious solution to control the disease and
thus to improve the patient’s condition, but it can be
associated with side-effects and complications, may act
with some delay, or may not always be applicable or
effective. The aim of supportive care is to manage those
problems for which anticancer therapy is not effective
or sufficient. The field covered by supportive care is
very large, from critical care to terminal care, and
includes complications management, symptomatic
treatment, psychosocial support, and palliative care.
In the present chapter we will first review QoL assessment of lung cancer patients with an analysis of the
published data, indications and principles of critical
care in oncology, management of the most common
symptoms related to bronchial neoplasms (dyspnea,
pain), and treatment of the usual complications of anticancer treatment (emesis, febrile neutropenia).
QUALITY OF LIFE ASSESSMENT
Interest in QoL evaluation began in the mid-1980s and
has increased in oncology, and in particular for lung
cancer patients, due to the disappointing progress made
in improving survival – the traditional and true endpoint for phase III clinical trials – especially for advanced
unresectable non-small cell lung cancer (NSCLC).
Improvement in evaluation is due to the development
of validated instruments for measuring QoL. Up to now
there has been no significant improvement in length of
survival of these patients, so more attention is being
paid to identifying less toxic treatments, achieving better control of symptoms, and generally improving the
QoL of the patients. However, the incorporation of QoL
assessment in lung cancer clinical trials is a challenge,
due to the practical and theoretic difficulties of data
collection, data analysis, and interpretation of results.
The definition of QoL is clearly a multidimensional
concept and agreement was needed on the dimensions
to be included for measuring it, although, most often in
medical research, the concept is restricted to the dimensions directly related to the disease, its symptoms, and
its treatment. Research is then focused on health-related
QoL, with inclusion of dimensions like physical function and impairment of physical function due to disease
symptoms, occupational function, psychologic or emotional function, and social function. There is an association between this health-related QoL and the
Karnofsky performance index, introduced much earlier
(in 1949). However, the latter measure is clearly too
limited, although worsening in performance status is
correlated to a QoL deterioration and to an increase in
the lung cancer symptoms.
The problem of measuring QoL adequately (by the
patient himself as, due to the subjective nature of the
concept, external observers are poor raters) has been
solved by the development of validated instruments
proven to be both reproducible (an unchanged measure has to been obtained when the patient’s condition
is stable) and sensitive (able to capture any change in
the patient’s condition). In lung cancer, several diseasespecific instruments are available. The most frequently
used in advanced NSCLC in recent randomized clinical
trials include:
•
the European Organization for Research and
Treatment of Cancer (EORTC) Quality of Life
Quality of life and supportive care 237
•
•
Questionnaire, including a core (QLQ C30) completed by a lung cancer module assessing diseasespecific symptoms and toxicities (QLQ LC13),1
which has the advantage of being translated into
many languages;
the Lung Cancer Symptom Scale (LCSS);2 and
the Functional Assessment of Cancer Therapy–
Lung (FACT-L).3
These three tools assess different domains including
functional scales – physical, role, cognitive, emotional,
social – (5 for QLQ C30, 4 for LCSS, and 5 for FACT-L)
and symptom scales (e.g. fatigue, nausea and vomiting,
pain). A questionnaire has also been developed in
Japanese, called QOL-ACD (QoL questionnaire for
cancer patients treated with anticancer drugs).4 Other
validated instruments less frequently used include
the Rotterdam Symptom Check List (RSCL), the Functional Living Index–Cancer (FLIC), the Hospital Anxiety and Depression Scale (HADS), and the Daily Diary
Card (DDC).
These questionnaires need to be assessed both at
baseline and at several preordained time points during
the treatment period and the follow-up. The logistics
required for QoL assessments are therefore important
and adequate monitoring is necessary to ensure patient
compliance in completing the questionnaires.
Data analysis also leads to some difficulties, for several reasons. The most important one is that the investigators are faced with significant amounts of missing
data, which are most probably related to QoL itself. The
missing data are therefore not missing at random but
due to a process of information censoring. It has indeed
been shown that a progressive worsening in clinical status induces a parallel increase in missing data. This is
clearly illustrated in the trials reporting on QoL. Consequently, data analysis is most often restricted to the first
weeks of follow-up, when the rate of missing data is not
yet too high. One helpful approach to this problem is
to look at the time of QoL deterioration and make some
assumptions about the QoL of the patients with missing
evaluations. Some statistical methods have been developed to deal with this issue of information censoring,
but are not yet in frequent use in practice.
Another problem is that a QoL assessment generates
vast amounts of data due to its multifactorial definition
and due to the need to study it over a period of time.
To control the rate of false-positive results, significance
probabilities have to be adjusted. Another solution is to
perform data reduction and to use summary parameters, but this may result in a loss of information when a
patient’s evolution is not going in the same direction on
several scales.
Nevertheless, QoL proved to be a useful secondary
endpoint when assessing the value of chemotherapy
versus best supportive care in advanced NSCLC. Indeed,
after the results of several meta-analyses showed survival benefit for chemotherapy compared to best supportive care, the issue of the positive balance between
survival benefit and chemotherapy toxicity was raised,
and none of the trials included in the meta-analyses had
been successful in investigating QoL. Some further
studies5–12 were therefore conducted in this respect, all
including QoL as an endpoint, sometimes even as primary objective (four of them), despite the methodologic
difficulties described above.
In 5 studies, attention was paid to the problem of
information censoring. It was found that at least one
parameter of QoL improved in all these series; in particular, symptoms related to lung cancer such as pain or
dyspnea were found to be reduced in chemotherapytreated patients. The side-effects of chemotherapy did
not cause a significant deterioration in the QoL. The
study by Cullen et al,6 which compared MIC (mitomycin C, ifosfamide, cisplatin) versus best supportive care,
demonstrated a significant prolongation of life in chemotherapy treatment as well as a significant improvement in QoL in treated patients, and a deterioration
with standard treatment. Thus these studies reinforce
the case for the use of chemotherapy in patients with
advanced NSCLC.
QoL is now frequently considered as an endpoint in
trials comparing different chemotherapy regimens in
advanced NSCLC, and the results of QoL assessments
are particularly interesting when no survival benefit is
demonstrated (which is indeed not infrequent). In such
circumstances, information on the relative merits of different treatments derived from the symptom scales and
QoL domains might, in conjunction with evaluation of
the side-effects of the treatments, be vital for selecting
the best treatment.
A recent unpublished review analyzed whether the
use of more recent drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine) might be associated with a further
improvement in QoL in patients with NSCLC. Among
16 selected studies, 5 were found in which attention to
information censoring was paid. Socinski et al13 compared four courses of carboplatin and paclitaxel, given
by the same regimen until progression in 230 patients
with advanced NSCLC. No effect was found on survival,
and QoL demonstrated a similar deterioration in both
groups, with time. It was concluded that four courses
238 Textbook of Lung Cancer
of chemotherapy were as good as a more protracted
therapy. Bonomi et al14 compared cisplatin and etoposide to cisplatin combined with paclitaxel in 574
patients. Survival was slightly increased with paclitaxel
and QoL was improved, compared to the other arm, at
6 months’ evaluation, but not afterwards. Kelly et al
evaluated 408 patients randomized to carboplatin and
paclitaxel or to cisplatin and vinorelbine.15 No effect of
treatment on survival or QoL was seen. Rosell et al
compared carboplatin and paclitaxel to cisplatin and
paclitaxel in 618 patients.16 Survival was better with
cisplatin, as was the control of symptoms related to
lung cancer. Scagliotti et al compared carboplatin plus
paclitaxel to cisplatin combined with either gemcitabine
or vinorelbine in 607 patients; no differences in survival
were observed and no superiority of one of the three
treatment arms was noticed in terms of QoL.17
In an additional 11 studies, in which QoL was evaluated without taking into account possible information
censorship, a positive effect on survival was seen in
3/11 series and a difference between treatment arms
related to QoL was seen in 6/11 studies. At least two
other studies reported clearly that chemotherapy
improved symptoms of disease, but without any difference being detected between study arms.
The regimens that were associated with an improved
QoL including better palliation of symptoms, were cisplatin plus paclitaxel in four studies and cisplatin (or
carboplatin) plus docetaxel in one series; cisplatin and
gemcitabine in one series and gemcitabine and vinorelbine in one series. A final series showed improved clinical benefit with gemcitabine. There was no real QoL
assessment; however the considered endpoint was a
composite one including treatment effect on symptom
control, performance status, and weight.
In more recent randomized phase III trials looking at
first-line chemotherapy in advanced NSCLC we found
two18,19 without detectable survival difference but
with a better QoL in one of the tested arms. Paccagnella
et al,18 with QoL as primary endpoint, showed that patients
reported better improvement on some symptom scales
(nausea and vomiting, appetite loss, and constipation)
with carboplatin combined with mitomycin and vinblastine compared to the regimen with cisplatin subsitituted for carboplatin. Global QoL was found with Spitzer’s
scale, but not with the EORTC scale. Georgoulias et al19
found that a gemcitabine–docetaxel combination
significantly improved QoL compared to cisplatin–
vinorelbine. For these two studies, QoL might be the
key to selecting one of the two treatments for further
studies. Three other trials20–22 showed improvement in
survival accompanied by better QoL: Fossella et al in
favor of docetaxel–platinum combinations (cisplatin or
carboplatin) compared to cisplatin and vinorelbine,20
Kubota et al in favor of docetaxel plus cisplatin compared to cisplatin and vindesine,21 and Rudd et al identified gemcitabine and carboplatin as improving results
obtained with MIC.22
A trial published by Cella et al,23 testing two doses of
gefitinib in symptomatic patients who had received at
least two prior chemotherapy regimens, showed a rapid
improvement in symptoms and, interestingly, showed
that this symptomatic improvement was associated
with tumor response and survival. They suggested that
symptom improvement might precede response assessment detected using radiologic tools.
However, comparisons between studies are seldom
possible as there is as yet no consensus about the frequency of QoL evaluations and about which results to
present, usually with selective reporting due to the significant amount of data generated by QoL evaluations.
Nevertheless, QoL assessment can play its role in the
global interpretation of clinical trial results.
CRITICAL CARE OF THE LUNG CANCER PATIENT
Intensive care is becoming more and more important in
the management of cancer patients and major cancer
hospitals have developed intensive therapy units, not
only for surgical patients but also for medical patients.
However, there is limited information in the medical
literature about intensive care in oncology, especially
concerning description of the types of patients admitted
in such units. An international inquiry performed in
anticancer centers24 has shown that 70% of the cancer
hospitals have at least one intensive care unit (ICU) especially devoted to patients with neoplastic diseases. Whether
general, surgical, or medical, those units do not depart
from the recommended guidelines for intensive care, as
far as the number of beds, the nursing staff, and the main
critical care techniques performed are concerned.
Admission of patients in an ICU is usually based on
the following three principles.25 First, the patients have
to be ‘salvageable’: patients whose chances of being cured
or having their disease put into remission are minimal
should not be admitted or should not stay in an ICU.
Second, the patient’s ‘autonomy’ must be respected: a
patient who refuses intensive supportive therapy
because he or she understands the potential poor prognosis of the underlying cancer disease should not be
admitted in the ICU. Finally, as medical resources are
Quality of life and supportive care 239
limited, even in highly developed countries, ‘distributive justice’ should be taken into account: patients with
the best chances of benefiting from intensive therapy
should be admitted in priority.
The assumption that patients with active malignant
disease should not be admitted to an ICU often predominates in general hospitals and makes it very difficult for oncologists to undertake a fruitful collaboration
with intensivists for the management of the critically ill
cancer patients. This negative opinion is not supported
by scientific data. It results from a bias of many physicians, who refuse critical care to cancer patients although
they are willing to provide it to patients with serious
non-neoplastic diseases such as advanced heart failure
or liver cirrhosis, who do not have a better short- or
long-term prognosis.26 Recently, it has been shown that
the prognosis of the cancer patient admitted in ICU for
a severe complication is not related to the characteristics of the underlying malignancy but only to the physiologic perturbations induced by the complications as
measured by severity scores.27–29 These data were confirmed in the only study specifically performed on lung
cancer with 57 patients admitted to the ICU.30
There are four main reasons to admit a cancer patient
to the intensive care unit:31
(1) postoperative recovery for advantages that are the
same as those for any high-risk postoperative
patient (availability of continuous hemodynamic
monitoring, early identification of cardiovascular
and respiratory disturbances, facilities for respiratory support, and constant skilled nursing care);
(2) critical complications of the cancer disease and its
treatment; these complications are numerous and
can be very specific for oncology, and their management has always to take into consideration the
presence of a severe chronic underlying disease;
(3) intensive anticancer treatment administration and
monitoring, useful in various situations such as
increased risk for treatment administration related
to the patient’s condition, administration of intensive chemotherapy requiring patient monitoring,
treatment of unknown toxicity in phase I trial
requiring optimal safety conditions of surveillance,
and administration of treatment that frequently
results in acute severe toxicity; and
(4) acute disease (such as myocardial infarction or
severe asthma), possibly unrelated to the malignancy or its treatment.
Advances in knowledge have been obtained during
the last decade in the use of life-threatening support
techniques for oncologic patients. Cardiopulmonary
resuscitation has been shown to be as effective in cancer
patients as in non-cancer patients.32,33 Mechanical ventilation is associated with a relatively poor outcome,34
particularly if the patient is leukopenic at the time of
intubation.35 A major advance in the management of the
cancer patient with respiratory failure has been achieved
with the development of non-invasive ventilation.36 The
ICU mortality in these patients can be reduced by this
technique from about 70–80% to 50%.37 Extrarenal
expuration by continuous venovenous hemofiltration
has also been shown to be effective in cases of acute
renal failure occurring in ICU.38 In all these situations,
the short-term prognosis is never influenced by the
characteristics of the underlying neoplasm.
SYMPTOM MANAGEMENT
The signs and symptoms manifested by patients with
lung cancer depend on the localization of the tumor, its
locoregional spread, and the effects of metastatic growth.
Dyspnea, pain, and cough are common symptoms of
lung cancer patients, with frequencies of 59%, 48%,
and 71%, respectively.2
Pain
More than 50% of lung cancer patients will present
with pain during the evolution of their disease. The first
cause of pain is related to direct tumor involvement,
bone destruction, liver metastasis, nerve compression
or invasion, or soft tissue infiltration. Pancoast’s syndrome with shoulder pain, brachial plexopathy, and
Horner’s sign occurs in apical tumors invading the brachial plexus, the chest wall, and stellate ganglion. Pleural effusion can cause pleuritic pain. Persistent pain
after surgery, radiotherapy, or chemotherapy can also
occur. Finally, some non-cancer-related causes of pain
like infection have to be looked for.
Effective management of pain can be achieved in
approximately 90% of patients. A pain severity scale
from 0 (‘no pain’) to 10 (‘pain as bad as you can imagine’) may be helpful in titrating analgesics. Careful
description of the type of pain is also essential. Some
cancer lesions, such as bone or epidural metastases,
responsible for pain can be treated by radiotherapy,
chemotherapy, or sometimes by surgical debulking.
Any analgesic medication program should be as simple as possible and non-invasive.39 Except for a minority
of patients whose pain is clearly episodic, analgesics
should be given around the clock. Treatment is decided
240 Textbook of Lung Cancer
according to ascending steps. A non-opioid drug (paracetamol) should be used as first step. Non-steroidal antiinflammatory drugs (NSAIDs) are very effective but have
a number of side-effects (e.g. gastritis and gastrointestinal bleeding, renal failure). As second step, an opioid for
mild to moderate pain (e.g. tramadol, codeine) should be
added. The third step includes an opioid for moderate to
severe pain (e.g. morphine, hydromorphone, methadone, fentanyl). Oral morphine, as an immediate or sustained-release preparation, is the analgesic of choice for
moderate to severe cancer pain. A typical starting dose of
immediate-release morphine is 5 to 30 mg every four
hours, with a relatively rapid increase if necessary. When
an effective dose of short-acting morphine has been
established, the required dose for a long-acting preparation can be calculated, with an additional supply of
short-acting morphine if necessary. A consistent need for
this supplemental morphine will dictate an upward dose
adjustment of the sustained-release morphine. Transdermal preparations (e.g. fentanyl) can be more convenient,
and with fewer side-effects (e.g. constipation) than
morphine,40 but they are more expensive. Constipation
is a frequent side-effect of opioids that should be managed prophylactically (increased fiber consumption, mild
laxative). Initial nausea and somnolence are also frequent. An anti-emetic should be administered to all
patients who are started on opioids. The combination of
opioids and paracetamol or NSAID often provides more
analgesia than can be accomplished by either class of
drugs alone, and thus facilitates the use of lower opioid
doses with fewer related side-effects. A co-analgesic (corticoid, tricyclic antidepressant, or anticonvulsant) may
be added at each step. Indeed, gabapentine, carbamazepine, valproic acid, clonazepam, and phenytoin can
be used to manage neuropathic pain. Tricyclic drugs are
useful in a variety of neuropathic pain (dysesthetic or
burning pain). Corticosteroid administration can lead to
mood elevation, relief of visceral inflammation, and
reduction of cerebral or spinal cord edema when there is
symptomatic metastasis or spinal cord compression.
Bisphosphonate (pamidronate, zoledronate) can be
administered alone or as an adjunct to external radiation
therapy for bone metastases. Other non-pharmacologic
methods exist to manage pain for example cutaneous
stimulation, nerve blocks, maintenance of regular activity, avoidance of prolonged immobilization, psychosocial
intervention, and education.
including physiologic, psychologic, and social components. It is perceived as one of the most devastating,
distressing symptoms. Its major physical evidence is
tachypnea. Dyspnea is, with cough, the most commonly
reported symptom in lung cancer patients.
There are multiple causes of dyspnea and several may
co-exist. The most common cause of dyspnea in lung
cancer patients is the primary or metastatic disease, but
it may also be related to cancer treatment (lung resection,
anemia, chemotherapy or radiation-induced lung toxicities) or to non-cancer causes (lung infection, pulmonary
embolism, chronic obstructive pulmonary disease, heart
failure). Most of the time, the cause can be easily determined by history and physical examination. Chest imaging, oximetry, blood tests, and pulmonary functions are
useful in the assessment of dyspnea. The first aim should
be to correct the cause when possible and appropriate.
Palliative management of dyspnea in the cancer patient
is often complex and difficult.39 Oxygen may be helpful.
However, there are no large studies available and, except
for hypoxemic patients who feel less breathless on
oxygen,41 it is difficult to predict which patients will
benefit.42 As bronchospasm is one important reversible
cause of dyspnea in cancer patients, bronchodilatators
(β2-agonists, anticholinergics) and aerosolized steroids
are commonly used. Systemic steroids can be used for
patients with airflow obstruction, postradio- or chemotherapy pneumonitis, or lymphangitic carcinomatosis.
Opioids are efficacious in the management of dyspnea by
decreasing the perception of breathlessness. The advised
starting morphine dose is 10 mg po or 5 mg sc/4 hours
around the clock. If the patient already receives morphine
for pain, doses must be increased to relieve dyspnea.
Intravenous continuous morphine infusion is optional
for terminal patients with severe dyspnea. In this situation, patient and family members should be aware of the
risk of hypoventilation and death. Nebulized opioids
could also be tried in less severe cases, and with fewer sideeffects, although their efficacy has not been demonstrated.
Subcutaneous scopolamine, hyoscine, or atropine can be
beneficial in drying up upper airway secretions. Anxiolytics are needed when an anxious component is obvious
(lorazepam 0.5–2 mg/day; diazepam 2.5 mg/6 hours) or
for intractable dyspnea (midazolam 10 mg iv /day). Finally,
environmental issues are important: a calm atmosphere,
relaxation, breathing techniques, and psychosocial support can reduce the perception of breathlessness.
Dyspnea
Dyspnea is a subjective experience of difficult and
uncomfortable breathing. It is a complex symptom
Cough
Cough is observed in 70 to 90% of the patients with lung
cancer. Involvement of any part of the respiratory system
Quality of life and supportive care 241
can lead to cough, predominantly lung cancer originating in the airways. Radiation- or chemotherapy-induced
fibrosis must also be considered when evaluating the
causes of cough. Finally, non-cancer causes of cough (e.g.
respiratory infection, drugs, heart failure, gastro-esophagal
reflux, chronic bronchitis) must also be looked for.
The control of cough is of particular importance
because it leads to sleep disturbance, shortness of
breath, pain, and decreased quality of life. Pharmacologic palliative treatments of cough39 are often disappointing for example non-opioid cough suppressants
(e.g. dextromethorphan, levodroproprizine), cromoglycate, bronchodilatators if bronchospasm exists, corticosteroids (in case of radio-induced pneumonitis), and
nebulized lidocaine. Narcotics, acting via opioid receptors, are the most efficacious treatment for significant
cough. Codeine (15–30 mg/6 hours) and analogs can
be tried initially and, if insufficient, morphine (5–10
mg/6 hours) can be administered.
Depression and anxiety
Psychologic distress including depression is an essential
element of the quality of life of a cancer patient. Between
15 and 44% of lung cancer patients experience some
form of depression after diagnosis, increasing according
to disease extent and associated prognosis. After curative resection, the prevalence of depression is 4 to 8%.43
In unresectable lung carcinoma patients, about 15% of
the patients have some degree of suicidal ideation,44 for
which predisposing factors are pain and depressive disorder. Female gender, living alone, no children in the
role of confidant, nurses as confidants, are predictive
factors for psychologic distress in ambulatory lung cancer patients.45 For example, in 52 newly diagnosed lung
cancer patients undergoing radio- or chemotherapy,
4% had an affective disorder, 44% expressed feelings of
sadness, 29% feelings of fear, 8% feelings of guilt, 13%
had considered suicide, and 31% had thoughts of
death.46 In the same study, 52% of the patients had
insomnia and 19% concentrating difficulties.
Anxiety and depression can be related to the
announcement of the diagnosis, the numerous investigations, the treatments, the symptoms due to cancer or
its treatment, and the fear of death. In the cancer patient,
it can be difficult to discriminate between underlying
biological/organic and psychologic factors causing
depression. Moreover, somatic symptoms of depression
can be confused with constitutional symptoms due to
the cancer or its treatment (such as fatigue).
Supportive conversation and advice must be the firstline treatment, but anxiolytics and antidepressants
could be necessary. Finally, active anticancer treatments
play a psychologic role by improving performance status or quality of life, by alleviating symptoms, and by
giving hope.
Anorexia and weight loss
Cancer-associated cachexia/anorexia occurs in almost
any late stage cancer, but is particularly common in
lung cancer, even at an early stage. Cachexia is a consequence of both decreased food intake (resulting from
loss of appetite) and metabolic abnormalities (e.g.
release of tumor-induced cytokines). Contributing factors include altered taste, pain, dysphagia, asthenia,
and depression.
As removal of the underlying causes is rarely possible, supportive measures are required. Control of nausea and vomiting is the first therapeutic step. Nasogastric
tube feeding or parenteral alimentation must be discussed case by case, as their efficacy is relative. Forcing
patients to eat has no impact on well-being and survival. Patients have to be encouraged to eat frequent,
small, enjoyable meals and to take a lot of liquids (often
better tolerated than solid food).
Most appetite stimulants are not very effective.
Steroids (dexamethasone, prednisolone, or methylprednisolone) have some short-term benefit in stimulating appetite, but their impact on weight gain is not
defined.47 Due to their side-effects, caution is necessary
for prolonged use of steroids. Progestational agents (e.g.
megestrol acetate, medroxyprogesterone acetate) stimulate appetite and, at least for megestrol, have a positive
impact on weight. In some studies, megestrol acetate
was shown to improve quality of life.47 However, the
benefit of these drugs must be counterbalanced with an
increased risk of thromboembolic episodes. Other
drugs have been tested, some with promising results.
For example, in a randomized clinical trial, 58 patients
with advanced NSCLC were randomized to receive
either 10 30-hour adenosine triphosphate (ATP) iv
infusions every two to four weeks or no treatment. An
inhibition of weight loss and appetite stabilization was
noted in the ATP group.48 In contrast, nandrolone, pentoxifylline, and hydrazine sulfate are not effective.49
MANAGEMENT OF TREATMENT COMPLICATIONS
The main complications related to the medical
treatment of lung cancer are chemotherapy-induced
aplasia, mainly neutropenia but also anemia and
thrombocytopenia, and vomiting secondary to cisplatin
administration.
242 Textbook of Lung Cancer
Neutropenia
The relationship between neutropenia and the risk of
severe infections has been established by Bodey et al.50
The risk of developing infectious complications depends
on the duration and on the level of the neutropenia.
These two variables also predict the severity of the
infection. In addition to neutropenia, lung cancer
patients are predisposed to infection due to neoplastic
bronchial obstruction favoring obstructive pneumonia
and by concomitant COPD. The impact of infections on
survival in lung cancer patients has not been well established. No statistically significant survival difference
was observed between SCLC patients presenting with
lung abscess and the others.51 In a very old study, the
authors52 observed a significant reduction in median
survival in patients with pulmonary infections.
Few studies have assessed the type and microbiologic
nature of infection in lung cancer patients. Recently, we
found that the lung is the predominant site of infection
and that, among all microbiologically documented
infectious episodes, Gram-negative bacteria were the
most prominent pathogens, mainly Escherichia coli,
Haemophilus influenzae, Pseudomonas aeruginosa, and
Moraxella catarrhalis, although Streptococcus pneumoniae
and Staphylococcus aureus were frequently observed (7%
and 9%, respectively, of all documented pathogens).53
Few data are today available concerning infection in
neutropenic lung cancer patients. In cancer patients
from any origin presenting with febrile neutropenia,
Gram-negative microorganisms are the most common
pathogens, although an increase in Gram-positive bacteria has been demonstrated in recent years.
Febrile neutropenia (FN) is a life-threatening complication requiring prompt empiric antibiotic therapy.
Guidelines have been published by the Infectious Disease Society of America (IDSA) for the use of antimicrobials in patients with cancer, not specifically addressed
for lung cancer, and FN.54 Broad-spectrum β-lactams
or carbapenem are suggested as first-line therapy. Outside of specific situations, aminoglycosides (for shock,
Gram-negative bacteriemia, etc.) and glycopeptides
(for documented resistant Gram-positive infection or
clinical signs suggesting infection with resistant Grampositive organisms) are no longer needed routinely in
first-line antibiotic combinations, monotherapy being
as effective.55,56 Oral antibiotic therapy should be
considered for low-risk patients.54 The role of new fluoroquinolones with increased sensitivity against Grampositive pathogens remains to be validated in randomized
trials. In any case, given the importance of S. pneumoniae as a pathogen in patients with lung cancer, antibi-
otics should provide adequate coverage for this
bacterium.53
Some studies have assessed the role of antibiotic prophylaxis to reduce the incidence of FN in SCLC patients.
In this setting, prophylactic cotrimoxazole appeared
effective. In pooled results from three studies,57 a global
reduction of infection from 36 to 17% was observed, in
patients with bacteriemia as well as for non-bacteriemic
infectious episodes. In a more recent study by the
EORTC,58 163 chemonaive SCLC patients were randomized between prophylaxis with ciprofloxacine (750
mg, bid) plus roxithromycin (150 mg bid) and placebo.
Prophylaxis was associated with a statistically significant reduction in the incidence of FN (43% vs 24%,
p = 0.007), fewer microbiologically and clinically documented infections, fewer hospitalizations for FN, and
a reduction in the number of infectious deaths (6%
versus 0%, p = 0.022). Nevertheless, it is not clear
at the present time if this strategy has an impact on
the overall survival of lung cancer patients undergoing
chemotherapy.
Another way to reduce the duration of neutropenia
and the incidence of FN could be the administration of
colony-stimulating factors (CSFs). In a meta-analysis of
randomized studies assessing the role of CSF in SCLC,59
we did not observe any favorable impact of CSF on survival, whatever the type of chemotherapy, although dose
intensity was generally increased with CSF administration. Yet, a detrimental impact on survival was noted in
patients treated with concomitant radiochemotherapy,60
or those receiving high-dose concentrated chemotherapy.61 No significant difference in infection-related mortality was associated with CSF administration. The
duration of neutropenia below 500/mm3 was reduced
and a statistically significant reduction in the incidence of
FN was noted in two-thirds of the trials. No meaningful
conclusions could be drawn from two small randomized studies performed in NSCLC. CSF administration
has also been tested in addition to antibiotics in established FN. Although a shorter time to neutrophil recovery was evident, overall mortality was not influenced
significantly.62 These results did not support the routine use of CSF, either for preventing FN or in addition
to antibiotics for the treatment of FN, in patients with
lung cancer.
Vaccination against S. pneumoniae and influenza
viruses might be another way to prevent infections in
lung cancer patients. Few data are currently available.
In a small study, the majority of the patients responded
fully to influenza vaccination.63 Pneumococcal vaccination was unsuccessful to prevent infection in a small
Quality of life and supportive care 243
randomized study,64 but the number of patients was
limited and new vaccines have since been developed.
Nevertheless, vaccination should be considered for
lung cancer patients as such treatment is well tolerated
and could have a beneficial impact on infection at a
low cost.
Anemia
Platinum-based chemotherapy, as well as other agents,
is frequently associated with anemia. Guidelines from
the Cancer Care Ontario Program (www.cancercare.
on.ca) recommend the use of erythropoietin (EPO) to
reduce the incidence of symptomatic anemia in patients
receiving platinum-based chemotherapy, but also for
myelosuppressive regimens that do not contain platinum derivatives. In a recent meta-analysis, the transfusion requirement was reduced by 33% with EPO
administration,65 without significantly higher toxicity.
A beneficial effect on survival was suggested (hazard
ratio 0.81).
Currently, three EPOs are marketed: epoietin alpha,
r-huEPo, and darbepoietin alpha. All three have demonstrated their efficacy in lung cancer patients. Today,
there is no evidence that the effectiveness of these drugs
is different.66 Recommended initial dosages are either
150 IU/kg three times a week or 40 000 IU once a week
for epoietin alpha and r-huEPO, and the equivalent
weekly dose of 100 µg (USA) or 150 µg (Europe) for
darbepoietin alpha.
Thrombocytopenia
Severe, potentially lethal bleeding is a frequent problem
in oncology. However, platelet transfusion requirement
is ten times less frequent in solid tumors than in hematologic patients. Half of the incidents of bleeding are
confined to the skin or mucosa. Risk factors for lifethreatening bleedings in thrombocytopenic patients are
concomitant infection, invasion of main vessels, as it
can be seen in lung cancer, and coagulation disorders.
Randomized trials conducted in the 1970s have shown
the effectiveness of a prophylactic transfusion policy on
the occurrence of bleeding. The threshold below which
platelets have to be transfused has also been the subject
of randomized trials. A level of 10 000 platelets/mm3
has been shown to be as safe as 20 000/mm3, with the
advantage of requiring significantly fewer platelet transfusions in the absence of fever or infection, in the absence
of bleeding, and when invasive procedures were not
planned. There are no specific data for solid tumors
and we could only extrapolate these results to the lung
cancer patients.
Nausea and vomiting
It was the development of cisplatin-based therapy for
lung cancer patients which initiated a strong stimulus for
the control of nausea and vomiting. The initial regimens
that were able to control severe emesis caused by highdose cisplatin consisted of high doses (2–4 mg/kg)
of metoclopramide in association with dexamethasone
and lorazepam. These regimens were complicated by
a significant number of side-effects, such as extrapyramidal motor disturbances. The introduction of the
‘setrons’, 5-HT3 antagonists, made anti-emetic therapy
in patients treated with cisplatin much easier. Once
again, the addition of corticosteroids increased the
effectiveness of all the setrons. However, setrons are
essentially active in acute emesis, and did not demonstrate a superior efficacy in delayed emesis compared
with dexamethasone plus metoclopramide. The selective NK1 antagonist, aprepitant, is more effective for
controlling delayed emesis after cisplatin compared to
5-HT3 antagonists.
Different guidelines have been reported for the prevention and treatment of chemotherapy-induced nausea
and vomiting. As well as the recommendations made by
ASCO67 and by the Cancer Care Ontario Program (www.
cancercare.on.ca), a combination of 5-HT3 antagonist
plus a corticosteroid is recommended for the prevention
of acute emesis induced by chemotherapy with high
emetogenic potential. For patients receiving cisplatin, a
corticosteroid plus metoclopramide (or domperidone)
and eventually a 5-HT3 antagonist are recommended for
the prevention of delayed emesis. The role of aprepitant
is not yet well delineated, although the consensus from
the Multinational Association of Supportive Care in
Cancer suggests its use in addition to a 5-HT3 antagonist
and dexamethasone for acute emesis and to dexamethasone for delayed emesis.68 In lung cancer patients, caution must be used with aprepitant, which is an inhibitor
of CYP3A4 and could thus theoretically increase the
concentrations of drugs metabolized this way, including
the chemotherapeutic agents frequently administered in
these patients: docetaxel and paclitaxel, etoposide, ifosfamide, vinorelbine, vincristine, and vinblastine (www.
merck.com/product/hcp.html).
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17 The cost and cost-effectiveness of lung
cancer management
William K Evans, Christopher J Longo
Contents Introduction • Types of economic evaluation • Methodologic issues • Other considerations
• The cost of lung cancer management • Estimating the costs of lung cancer in Canada
• The cost-effectiveness of lung cancer treatment • Lung cancer economics and health-care policy
• Conclusion
INTRODUCTION
Lung cancer is the second most common cancer in men
and women in North America, and the leading cause
of cancer death among both sexes in the industrialized world. In 2007, it is estimated that lung cancer
will be responsible for the deaths of over 180 000 individuals in North America.1,2 In the last decade there has
been a marked increase in the incidence of lung cancer in women.3 Worldwide, the problem of lung cancer
is escalating as the developing world succumbs to the
promotional activities of the tobacco industry. The
resulting worldwide epidemic of lung cancer is a major
public health concern, not only because of the enormous loss of life and the great morbidity it causes, but
also because of the large economic burden it places
on health-care systems and society in general.
Brown et al4 have extensively analyzed the economic burden of cancer in the United States based
largely on 1990 data sources. The total direct healthcare expenditures for cancer were estimated to be
US$ 27.5 billion, including the costs of hospital care
($17.9 billion), physician services ($6.6 billion),
nursing services ($1.3 billion), drugs ($1.1 billion),
and other ($0.5 billion). Soni5 more recently estimated the total direct health-care expenditures for
cancer at $62.2 billion (2004) using the Medical
Expenditure Panel Survey (MEPS). Although the data
from Soni on cancer expenditures are more current
than those available in Brown’s publication no breakdown across types of health services was described.
Indirect costs were estimated by Brown et al4 to be
$58.7 billion as a result of mortality costs and
$9.9 billion due to morbidity costs. Morbidity costs are
measured by lost income due to disability and absenteeism from work. In total, the direct and indirect costs
of cancer were estimated to total US$96.1 billion.
The percentage of health expenditure dedicated to
cancer appears to have changed very little in the
interval from 1963 to 1995. Although the percentage
due to cancer increased from a low of 4.35% in 1963
to a high of 6.01% in 1980, more recent figures from
Soni5 based on the MEPS data suggest the percentage
of health expenditures dedicated to cancer in 2004
had increased to 6.9%.
Based on expenditure data from the 1996 Surveillance, Epidemiology, and End Results (SEER) database, Brown has made estimates of the direct medical
care costs for all cancers and for the four most common tumor types in the United States. Expenditures
were estimated to be $6.0 billion for breast cancer,
$5.7 billion for colorectal, $4.7 billion for lung, and
$4.6 billion for prostate cancer. These four tumor
types, which together make up approximately 50%
of all cancer cases, accounted for 49.5% of the total
direct costs of cancer ($21 billion of $42.4 billion).
In California, a study of the long-term costs of treatment estimated that the cost per case for the common cancers ranged from a high of US$64 000 for
ovarian cancer to a low of $29 000 for prostate cancer.6
Breast, colon, and lung cancer were estimated to incur
long-term costs of $35 000, $42 000, and $33 000,
respectively.
From these analyses, it can be readily appreciated
that the cost of lung cancer care will be high in industrialized countries where there is a high incidence of
lung cancer and adequate resources to provide stateof-the-art clinical care. The impact of such a large
economic burden on the health-care systems of developing countries could easily overwhelm the financial
ability of a country to provide other types of appropriate care. Even in wealthy nations, fiscal constraint
is increasingly causing physicians and health-care
administrators to critically examine the value of healthcare interventions and the efficiency of health-care
delivery systems.
This concern about the value for money expended
is particularly relevant to the problem of lung cancer,
248 Textbook of Lung Cancer
where, despite recent advances, the overall prognosis
of the disease remains poor.3 New treatments for
lung cancer, particularly for early stage resected disease and locally advanced disease, add expense but
also improve survival. However, the reputation of the
disease as one with a poor prognosis can be a barrier
to the adoption of new therapies. Economic evaluations of the new treatment interventions for lung
cancer can shed light on their relative cost-effectiveness compared with other health-care interventions.
An understanding of the cost components of care can
also help to inform health-care providers on how to
deliver treatments in the most efficient fashion. This
chapter will describe some of the economic analyses
that have been conducted on lung cancer management throughout the world, particularly in the United
States and Canada. Although it is not possible to easily
extrapolate health economic evaluations directly from
one health-care system to another, there are lessons
that can be learned from a review of these studies.
Physicians have typically had little training and
only passing interest in health economics, and, therefore, may be relatively unaware of the types of health
economic analysis that can be done and their application to lung cancer. Therefore, prior to presenting
data from studies evaluating the economic burden of
lung cancer, the cost components of lung cancer
management, and the cost-effectiveness of treatment,
we will first provide some information on the types
of economic evaluation and costing methodologies
that are commonly employed.
TYPES OF ECONOMIC EVALUATION
There are four types of commonly used economic
evaluations (Table 17.1). Each involves a comparison
of the costs and consequences of alternative interventions. The main difference between each of these
evaluations is in the method used to measure the
consequences.
Cost-minimization analysis
Also called a ‘cost analysis’, cost-minimization analysis is the simplest form of economic evaluation. This
type of study assumes that the outcomes or effectiveness of the interventions are equal. Resource utilization is the only significant difference between the
options. The direct costs associated with each intervention are compared, and the least costly strategy is
the preferred choice. No assessment of the consequences of treatment is required. Although there are
some examples of cost minimization in the oncology
literature, including studies of staging procedures,7,8
radiotherapy techniques,9–11 and systemic therapy,12
this type of economic evaluation is not common
because cancer treatments rarely produce equivalent
survival or quality of life benefits.
Cost-effectiveness analysis
If the interventions being assessed are not of equal
effectiveness, a more sophisticated analysis is
required. Cost-effectiveness analysis includes a comparison of outcomes, as well as costs. In this form of
analysis, the effectiveness of alternatives is measured
in natural units, such as life years gained, cases successfully treated, or cases averted. These outcomes
are then related to the direct costs of the procedure
by calculating ratios of cost per unit of effectiveness,
such as cost per life year gained. Typically the results
are described as an incremental cost-effectiveness
ratio (ICER), since the analysis is a comparative one,
and presents both the incremental costs and the
incremental benefits.
Table 17.1 Types of economic analyses
Cost-minimization analysis
Cost-effectiveness analysis
Cost–utility analysis
Cost–benefit analysis
Compares strategies of equal effectiveness to determine
which is least expensive
Compares ratios of the incremental cost over the
incremental effectiveness of alternative strategies
Compares ratios of the incremental cost over the
incremental utility; a utility is a measure of the value
attributed to a health state, usually measured in quality
adjusted life years (QALYs)
Assigns monetary value to the health benefits of an
intervention; if the cost/benefit ratio is <1, the
intervention is attractive
The cost and cost-effectiveness of lung cancer management 249
Cost-effectiveness analysis has the advantage of
being easily understood. As a result, it is the most
common approach to economic evaluation in health
care.13 However, its value is limited by the fact that
only one measure of effectiveness can be related to
the cost of the interventions. A cost per life year gained
looks at survival, but not at toxicity, inconvenience,
or effects on quality of life. These are also important
considerations in cancer treatment. For example,
surgery for the primary treatment of a specific cancer
can be compared to radiation in terms of its costs per
life year gained, but this may lead to an invalid conclusion if their effects on quality of life are very different. Therefore, cost-effectiveness analysis can help
choose between similar treatments for a specific disease, but cannot help in choices across dissimilar
treatments and conditions.
More recently, new methodologies such as ‘net
health benefits’ or ‘net monetary benefits’ have been
introduced into cost-effectiveness analysis for health
care.14 These newer methodologies provide a more
appropriate way to deal with situations where costeffectiveness ratios might be misleading, as when
both costs and effects are negative and the resulting
ratio is positive. Standard cost-effectiveness formulas
do not deal with this scenario well, whereas the ‘net
benefit’ approach is straightforward.
Cost–utility analysis
A cost–utility analysis is similar to a cost-effectiveness
analysis, but it incorporates mortality and morbidity
data into a single multidimensional measure, usually
as a quality adjusted life year (QALY).15 The QALY is
a measure of the quantity of life gained by a treatment, weighted by the quality of that life. This is relevant in oncology because many anticancer treatments
are inconvenient and have substantial toxicities that
impair quality of life. Because the QALY is not disease-specific, it also allows comparisons between the
relative efficiency of health-care interventions for different conditions.
Quality of life is approximated by a utility, which
is a measure of preference for a given health state rated
on a scale where 0 equals death and 1 equals perfect
health. Theoretically, a utility is most accurately determined using a ‘standard gamble’ exercise, where a
subject in a particular health state finds the balance
between the chance of returning to perfect health
and the risk of possibly dying in the process. Other
techniques such as time trade-off and direct rating on
visual analog scales have also been employed.16 Alternatively, instruments such as the Health Utilities
Index17 and the EuroQoL18 can be administered alongside standard gamble exercises in order to relate their
scores to utilities. However, most quality of life instruments have not undergone such testing. An approach
often used to integrate quality and quantity of life
calculates the quality-adjusted time with and without
symptoms or toxicity (Q-TWiST).19 It is particularly
useful when looking at interventions that will have
health effects persisting beyond the duration of treatment, such as adjuvant chemotherapy.
There is controversy about whether utilities should
be derived from patients, their families, health-care
workers, or lay societal ‘jurors’ given detailed scenarios
describing the health state. Recent guidelines favor the
latter as being most consistent with the societal perspective in an economic analysis.20 However, there is
concern that people without relevant disease experience may not fully understand the health (disease)
state. Any of these approaches to defining utilities is
defensible, as long as it is clearly identified in the
report of the study.
Cost–benefit analysis
Cost–benefit analysis (CBA) differs in how it values
consequences of health-care programs. CBA values
programs in monetary terms, thus allowing a direct
comparison of a program’s incremental costs with its
incremental consequences. The result is either a net
cost or a net benefit of the program. One common
application of this methodology is to convert the
quality-adjusted life year in the denominator of an
analysis into a monetary equivalent to arrive at the
absolute benefit of the intervention. An intervention
is ‘cost beneficial’ if the benefits (measured in currency) are greater than the actual costs. Because these
analyses always produce a monetary outcome, it is
relatively easy to compare different potential uses of
resources. However, placing a monetary value on the
often intangible outcomes of health care, in particular the value of a life, is problematic. As a result, true
cost–benefit analyses are rare.
Each of these analytic techniques has its place. While
cost–utility analysis is ideal for comparing toxic treatment options, a cost-effectiveness analysis may be
adequate when deciding between two diagnostic
strategies.
METHODOLOGIC ISSUES
As the primary purpose of a cost-effectiveness analysis
is to introduce a consideration of resource consumption
250 Textbook of Lung Cancer
into medical decision-making, an economic evaluation begins by identifying all the consequences of
adopting one intervention over another.21 This
involves identifying the resources used (medical care
services, the cost of informal care-giving, and other
non-direct medical care costs) and the effects of the
treatment intervention on the health state. Both direct
and indirect health-care costs should be considered.
The term direct health-care cost refers to resource
use that is directly attributable to the medical intervention or treatment regimen. In health economics,
the term indirect refers to gains or losses in productivity related to the illness. Because indirect costs in
accounting terminology refer to overhead or fixed
costs of production, some health economists recommend the use of the term ‘productivity cost’ to define
the indirect cost associated with the morbidity or
mortality of an illness.21
Assessment of costs
Depending on the perspective taken, the resource
costs in an economic analysis can include:
•
•
•
•
direct treatment costs: the resources used by the
health sector to provide treatment (e.g. healthcare provider time, drugs, equipment, diagnostic tests, overhead);
direct non-treatment costs: the resources used by
patients and family to gain access to and participate in treatment, such as travel, parking, and
accommodation near a cancer treatment center.
Often these are measured by having patients
complete diaries of their out-of-pocket expenses.
indirect costs: costs such as lost work time for the
patient or caregiver, or the time of volunteers
assisting with treatment;
intangible costs: the costs of anxiety, uncertainty,
or pain caused by the treatment itself. These
have proven difficult to measure. Techniques,
such as ‘willingness to pay’ have been developed
to capture these ‘costs’, but can be affected by each
subject’s own economic circumstances.
The choice of time horizon for an economic evaluation is important to ensure that the analysis has considered all relevant resource utilization. If a new
treatment intervention has an impact on the natural
history of a disease, it can affect ‘downstream’ costs. For
example, when analyzing the cost of treating lung
cancer, up-front costs include the cost of physician visits, diagnostic tests and procedures, hospitalization,
as well as drugs and dispensing fees. Downstream costs
include the costs for treatment of long-term compli-
cations and terminal care. One of these downstream
costs, hospitalization for terminal care, has been found
in the Canadian health-care system to be the largest
single component of the management of cancer over
the entire course of the illness.22 Interventions that
can affect terminal care can have important impacts
on the lifetime costs of the disease23,24 that might be
missed if the time horizon only included the active
phase of disease treatment.
In addition to ensuring that all relevant resource use
has been considered, it is important to assess whether
the resource use has been quantified accurately and
valued credibly, and to know whether the analysis is
based on costs or charges. Charges for health care are
influenced by market forces, government regulations,
and taxation laws,25 and often bear little resemblance
to actual incremental resource costs.26 Medicare providers in the United States are required to provide
cost-to-charge ratios that can be used to estimate costs.
However, it is not clear how accurate these ratios are.
Another consideration is whether resource utilization data have been collected prospectively or retrospectively. Prospectively collected data, such as those
gathered during a clinical trial, are more likely to be
complete and to allow for timely availability of economic data to help decision-makers after an important
clinical result is found. However, the prospective collection of data may be expensive. Furthermore, care
in clinical trials is often more resource intense than in
routine practice. For example, trials usually take place
in expensive tertiary care teaching hospital settings,
and involve more frequent monitoring of blood tests
and use of imaging studies. As a result, retrospective data
or prospective data collected outside a clinical trial
can also be used effectively in many circumstances.
It is often necessary to estimate costs through the
use of a combination of empirical data and modeling.
Resource utilization data such as the number of hospital days might be derived from a clinical trial. These
data might then be adjusted to reflect anticipated
usual care. Last, the costs can be allocated to the
resources consumed to calculate the cost of delivering the intervention. By separating resource utilization from cost, local variations in costs or charges can
be assessed.
OTHER CONSIDERATIONS
Setting
Economic evaluations are relatively specific to the
health-care system in which they are performed.
The cost and cost-effectiveness of lung cancer management 251
Countries such as Canada have single-payer, universal
health-care systems in which the government funds
virtually the entire system. In contrast, health care in
the United States is funded by multiple payers, primarily private insurers, and providers compete for
contracts to manage the care of groups of individuals.
A third type of system, common in European countries, provides universal health care, but with patients
responsible for a co-payment.
Extrapolating the results of a study from one healthcare environment to another involves more than simply
adjusting the figures by the exchange rate. Costs for
a health-care intervention may be affected by differences in (1) demographics and disease incidence, (2)
clinical practice patterns, and (3) relative prices. Practice patterns may be influenced by the availability of
alternative treatments and diagnostic tests, as well as
incentives to professionals and institutions (e.g. salary
versus fee for service).27 There have been few studies
reported to date addressing this issue. Drummond et
al assessed misoprostal for the prevention of NSAIDinduced ulcers simultaneously in four countries
(Belgium, France, UK, USA) using identical methodology. They found misoprostol to be more cost-effective
in the United States despite the fact that the drug was
36% more expensive there, because it averted surgical procedures which were relatively more costly.28
Copley-Merriman et al29 made similar observations
when they found that the treatment of advanced
NSCLC with gemcitabine monotherapy saved more
money in the United States compared to standard
etoposide/cisplatin (excluding chemotherapy drug
costs) than in Germany or Spain because it averted
more costly hospitalization and anti-emetic use.
is said to be ‘sensitive’ to that variable. If not, it is
‘robust’. The question becomes not whether all estimates of resource use and survival were accurate, but
whether any errors would have a meaningful impact
on the results.
One of the challenges facing economists is estimating an appropriate range for sensitivity analysis for
parameters that have a high degree of uncertainty. If
patient level data are available, the use of 95% confidence intervals can be employed to determine the
‘best case’ and ‘worst case’ scenarios. In cases where
confidence intervals are not available, one form of
sensitivity analysis involves the use of non-parametric bootstrapping to derive confidence intervals for
the ‘incremental cost-effectiveness ratio’ (ICER).30–32
Bootstrapping resamples from the original data to
build an estimate of the sampling distribution, allowing the calculation of confidence intervals and hence
a plausible range of values.
Transparency
A concern with many economic papers is a lack of
transparency in the description of methods and
assumptions. Transparency refers to how easy it is to
see exactly what the authors of a study have done. After
reading the results of an economic analysis, the reader
should not be left with the impression that the study
was done in a ‘black box’. For optimal transparency,
it is best to report disaggregated data on costs, resource
use, and quality of life.33 Ideally, the numerator and
denominator of cost-effectiveness ratios should be
reported separately. Costs should be shown in the
format:
quantity⫻unit price⫽cost
Sensitivity analysis and uncertainty
Sensitivity analyses assess the effect of varying the
estimates of resource use (such as the number of treatments of a new drug, the number of hospital days for
treatment administration or for palliative care) and
effectiveness (e.g. the length of survival gained, utility
estimates) over a range of plausible possibilities. No
matter how accurately costs and benefits have been
quantified and valued, it is likely that certain assumptions will be required. Skeptics often attack these
assumptions to dismiss a study. The choice of which
parameters to include in a sensitivity analysis is
dependent on two factors: how much confidence the
researcher has in the reported parameter, and the
impact changing this parameter has on the final outcome. If altering the value of key parameters significantly changes the outcome of the study, the analysis
while effectiveness measures should be separated
from their utility weightings. Obviously, it is important to know the currency and year of the costs. However, reports should also identify instances of price
adjustment, such as the use of the consumer price
index to inflate prices from another time period, or
the date and exchange rate used to translate costs
from other countries.
Discounting
Costs and benefits that occur in the future should be
adjusted, or discounted, to their present value. This
is because of ‘time preference’. We generally prefer to
incur benefits sooner rather than later and costs later
rather than sooner. Thus, future costs and benefits
have less weight than current costs and benefits, and
252 Textbook of Lung Cancer
are usually accounted for by multiplying them by a
constant discount rate with the formula:
1
(1 + r )n
where r is the discount rate, and n is the number
of years.33 Such adjustment favors therapeutic
procedures that provide immediate benefit, while rendering preventive and screening programs, which
require immediate expenditure for future benefits,
less attractive.
There is a lack of consensus over what the appropriate discount rate should be. American guidelines
suggest 3%,20 while Canadian guidelines have recommended 5%34 and British recommendations have
been 6%.35 The choice of discount rate can seriously
affect the results of an evaluation,36 and so should be
subject to sensitivity analysis. Also there is debate as
to whether benefits and costs should be discounted
at the same rate, as empirical studies have demonstrated that people do not have the same preferences
for future health benefits as for future costs.37–40
Assessing effectiveness
Health-care benefits can be measured as:
•
•
•
direct benefits: monetary savings in treatmentrelated resource utilization;
indirect benefits: increased productivity; and
intangible benefits: alleviation of pain and suffering associated with health improvements.
As described previously, the type of study (costeffectiveness, cost–utility, etc.) will determine the
type of benefit considered.
Large, randomized controlled trials or meta-analyses
provide good measures of clinical effectiveness. However, extrapolation of economic and clinical data to
routine practice is not always straightforward. Controlled clinical trials usually test the efficacy of a procedure under strictly defined ‘ideal world’ conditions.
Differences in the demographic characteristics of the
population, variations in clinical practice, and availability of resources may mean that the procedure is
less effective in routine clinical management.41 For
example, we might expect an elderly patient with
multiple co-morbidities to have a very different experience with chemotherapy for advanced lung cancer
than the highly selected patients studied in most
clinical trials. A clinician must decide whether his
patient is likely to derive the same benefits as the
patients included in the study.
Similarly, the toxicity of therapy may differ between
the experimental and normal practice settings. The
complication rate reported in a trial of complex therapy given to highly selected patients in a tertiary care
setting might not be the same as that seen when the
treatment is moved into general practice. As a result
of the costs associated with these complications, the
treatment might prove to be more expensive than
predicted by the economic model.
When survival is the outcome of interest, it is important to accurately quantify the magnitude of this benefit. Because survival distributions are skewed, the
median survival is most often reported in cancer trials. However, this measure may disregard important
information when trying to determine the average
benefit a patient can expect from a therapy. For
example, an intervention that results in some cures
will create a long tail on the survival curve that contributes to the number of life years gained. Such an
intervention can be highly cost-effective, even if there
is little or no increase in the median survival time. As
a result, economic evaluations should use the area
between the survival curves to determine the average
benefit from treatment.
Assessing cost-effectiveness
The cost-effectiveness ratio (CE) is the incremental cost
of an intervention divided by its incremental benefits,
as given by the formula:
CE ⫽
C1 ⫺ C 2
($)
E1 ⫺ E 2 (eg. time )
where C represents the cost of each intervention and
E represents their effectiveness.
Many people use thresholds to decide whether an
intervention is cost-effective. Canadian authors have
proposed that interventions costing less than $20 000
per QALY be considered cost-effective.42 Americans
tend to set the threshold at approximately $50 000 per
QALY.25 However, these cut-off points are arbitrary.
Another type of decision rule is a ‘league table’.
Economic evaluations assume that resources are limited, and have alternative uses if not applied to the
intervention in question. Policy-makers must make
decisions that will maximize health by getting the
highest value for the resources consumed. Their decisions often reflect a ‘utilitarian’ philosophy of doing
the greatest good for the greatest number of people.
In order to do this, a technology must be assessed for
its efficiency relative to all other potential uses of the
same resources. Cost-effectiveness league tables such
The cost and cost-effectiveness of lung cancer management 253
Table 17.2 An example of a league table
Cost per life-year gaineda
Medical intervention
Liver transplantation
Screening mammography, <50 years old
Cholestyramine for high cholesterol
Routine use of non-ionic radiography contrast medium
Coronary artery bypass, two-vessel disease plus angina
Captopril for hypertension
Zidovudine for HIV infection
Renal dialysis, in-center benefit, men
Screening mammography, >50 years old
Hydrochlorothiazide for hypertension
Coronary artery bypass, left main disease plus angina
Smoking cessation counseling, men
237 000
232 000
178 000
72 000–243 000
106 000
82 600
82 000–88 500
42 000–80 300
20 000–50 000
23 500
17 400
1300
a
1992 US dollars.
With permission from Smith et al.46
as Table 17.2 rank interventions by cost per life year
or cost per QALY gained.
There are two major attractions to league tables:
they place results in the context of the cost-effectiveness of other technologies, and they offer an easy
mechanism to inform or justify resource allocation
decisions. Resources can then be spent on the most
cost-effective programs until the resources are
exhausted. There are numerous examples of league
tables published across specialties,43–45 and in oncology in particular.46
There are, however, many methodologic difficulties in creating league tables, necessitating caution
when using them for resource allocation.47 One major
problem is that they often group together studies that
were undertaken at different points in time. Cost-effectiveness figures can be adjusted to a base year, but
this requires assumptions of constancy of relative
costs, resource use, disease management, and treatment
efficacy over time. There may also be differences in
study methodology. These include the choice of treatment comparisons, the length of follow-up of patients,
the quality of life or utility instrument adopted, the
assumptions made, and the range and sources of costs
included.47 Such differences may affect the ranking
of various technologies within a league table, leading
to erroneous conclusions.
Both the threshold and league table approaches
assume that QALYs have the same value in all situations. However, empirical evidence tells us otherwise.
Society generally adheres to the ‘rule of rescue’: we
value interventions that will actually save a patient
from dying from a disease more than one that may
make many live a little longer. We are also more willing
to pay for an intervention that will save an identifiable life, such as an individual who requires a heart
transplant, than one for which a ‘statistical’ life may
be saved, as in prevention programs. Because of these
problems, neither league tables nor thresholds should
be seen as providing accurate answers to difficult
resource allocation decisions. Rather they should be
seen only as an aid to inform decision-makers.
Deciding whether to believe the results
Knowledge of the key methodologic principles that
well-conducted studies should follow21,48,49 is important in order to avoid inappropriately applying the
results of a poor study or using data that are not applicable in a certain setting. Because of this, American
guidelines have been published for reporting economic
studies,20 and useful strategies have been proposed
for critically appraising economic analyses.50,51
THE COST OF LUNG CANCER MANAGEMENT
Cost of NSCLC
A number of studies have examined the direct costs
associated with the diagnosis and treatment of lung
cancer.52–56 Evans et al53 calculated the average direct
care costs over five years for diagnosis and treatment
of NSCLC in Canada to be $19 778 in 1988 Canadian
dollars.54 The first year costs ranged from $6333 for
supportive care for stage IV disease, to $17 889 for
254 Textbook of Lung Cancer
surgery and radiotherapy in earlier stage lung cancer.
Hospital costs were found to dominate, accounting
for 36.8% of all costs. About one-third of the total
cost was for hospitalization during the initial diagnostic work-up. Terminal care accounted for about
half of the total cost, whether a patient received chemotherapy or not.
In the United States, Riley et al compared the Medicare payments for patients aged 65 and over with
common cancers.55 They found that lung cancer was
the most expensive cancer site for initial treatment at
$17 518 (1990 US$) due to high costs for hospitalization ($10 782, or 62%). However, because of the
relatively short survival of lung cancer patients, it
was among the least expensive in terms of total payments from diagnosis to death at $29 184.
Hillner et al looked at the cost of lung cancer for a
commercially insured cohort in Virginia.56 These
patients were younger, and fees were generally higher
than those for the Medicare population studied by
Riley et al.55 They found that the total cost of treatment from diagnosis to death was $47 941 (in 1992
US$), with inpatient hospital facility costs accounting for up to 65% of the total cost. Patients receiving
no active treatment still incurred significant costs
($26 597 in the first year after diagnosis). On average, patients spent 27.6 days in hospital in the last
six months of life.
Methodologic differences and different time frames
make it difficult to compare these studies; however
hospitalization consistently stands out as the dominant cost in all of them. Similar findings have been
seen in other tumor sites.57–59 This sort of research has
led to a shift of treatment to the ambulatory setting,
development of care maps and algorithms to expedite diagnostic work-up,60 and increased use of hospices for terminal care.61
Cost of SCLC
Less work has been published on the costs associated with the treatment of SCLC. Evans et al found
that direct care costs for the diagnosis and initial
treatment of SCLC ranged from $18 691 (1988
Canadian dollars) for the management of limited
stage disease, to $4739 for the supportive care
of patients with extensive disease who were not
candidates for chemotherapy.62 The average total
cost for treating SCLC was $25 988.22,62 This is comparable to the $18 234 (1990 Australian dollars) for
limited and $13 177 for extensive disease calculated
by Rosenthal et al.63 Again, hospitalization was the
dominant cost.
ESTIMATING THE COSTS OF LUNG CANCER
IN CANADA
Statistics Canada has developed information at the
population level on the economic burden of lung
cancer from the perspective of the government as the
payer in a universal health-care system.22,53,54 This
POpulation HEalth Model (POHEM) was developed
to provide a comprehensive microsimulation of
Canadian health, including such important diseases as
lung, breast, colon, and prostate cancer, cardiovascular disease, dementia, arthritis, and osteoporosis. The
model integrates risk factors for disease, diagnostic
and therapeutic approaches, health-care resource
utilization, and direct medical care costs. The lung
model within POHEM assigns a histologic cell type
(small cell versus non-small cell) and stage to each
patient in a simulated lung cancer population.22,53 It
then describes the treatment appropriate to cell type
and stage, and the anticipated progress and survival of
the cancer in response to treatment. Costs are assigned
according to tumor cell type and treatment option.
To develop this model, it was necessary to access
multiple databases for information on cancer incidence, tumor cell type, patient demographics, and
stage distribution. Questionnaire surveys of Canadian oncologists were undertaken to obtain information not accessible from provincial databases, such as
diagnostic tests used or follow-up practices. Information on the duration of hospitalization for diagnostic
work-up and initiation of therapy was obtained from
Statistics Canada’s national person-oriented hospital
morbidity database. Costs for hospital outpatient
chemotherapy treatment were extracted from an economic analysis done by the National Cancer Institute
of Canada following a clinical trial (BR5), which
compared chemotherapy and best supportive care in
advanced NSCLC.23,24
Costs were initially determined in 1988 Canadian
dollars, but have been updated periodically since the
original report.22,53,54 The economic analysis was performed from the perspective of the government as
payer in a universal health-care system. Since the fees
paid for physicians’ assessments and laboratory and
surgical procedures varied from province to province
in Canada, the fee schedule operative in the province
of Ontario under its health insurance plan was used as
the standard. Statistics Canada’s ‘Hospital Statistics’:
Preliminary Annual Report was used to determine
the average cost of hospitalization by type of hospital. The per diem rate for a Canadian teaching hospital at the time of this analysis was C$818.50.
The cost and cost-effectiveness of lung cancer management 255
Hospital costs for non-surgical care of lung cancer
cases, including terminal care, were derived from the
economic analysis of the National Cancer Institute of
Canada clinical trial of best supportive care versus
chemotherapy.24 These costs were inflated by the rate
that the national per diem rate for tertiary care facilities had inflated during the same time period. More
details of the costing methodology are included in
previous publications.22,53,54 The cost of diagnosis
and initial treatment for stage 1 and II lung cancer
(excluding relapse costs) was C$14 110. The cost of
combined-modality therapy (surgery and radiotherapy) for patients in stage 1 and II was C$17 889. For
non-surgical candidates, treated with radical radiotherapy, the initial cost of diagnosis and treatment
was estimated to be C$12 474. The costs of treating
stage IIIA and IIIB disease with radiation alone were
less, at C$11 714 and C$9347, respectively. The initial cost of diagnosis and care of stage IV (metastatic
disease) patients was C$6333. Further significant
costs would be incurred by these patients when they
relapsed and entered the terminal-care phase of their
illness (the last three months’ period to death), with
costs equalling C$10 331. Based on the fact that there
were 12 549 NSCLC patients in Canada in 1988, and
assuming that all would have access to appropriate
care as defined by the treatment algorithms, the total
cost of treatment for a cohort of patients with NSCLC
followed over five years would be C$240 236 000.53
A similar analysis for the 3075 SCLC cases according
to disease stage revealed that patients with limited
stage disease treated with combined-modality therapy
would incur costs of approximately C$18 500. Patients
with extensive disease would receive less radiotherapy and less chemotherapy, and therefore would incur
fewer costs. The total cost per case estimated in POHEM
was C$13 525. The terminal-care costs for extensive
disease patients were estimated to be C$9387, and
these costs would be added to those of the treatmentrelated costs during the year of the patient’s death.
Overall, the total burden incurred in managing all cases
of SCLC diagnosed in 1988 over five years would
total C$79 913 000.63
An analysis of the cost of the various components
of lung cancer management illustrates the value of
this type of cost analysis, in that it immediately makes
apparent the major sources of expenditure in the
health-care system for the management of lung cancer patients. For all stages of lung cancer, the use of
acute-care hospital beds accounts for more costs than
diagnostic tests, medications, and physician fees combined. Hospitalization during initial diagnosis and
management made up 35.8% of the total five-year
costs, and the cost of terminal care utilizing acutecare hospital beds was 38.7% of the total cost. Therefore, assuming the goal is to make the health-care
system as cost-efficient as possible, strategies need to
be developed that devolve inpatient care to ambulatory diagnostic assessment units for patients with a
presumptive diagnosis of lung cancer, and provide
more palliative care in the home environment or
through palliative care units.
THE COST-EFFECTIVENESS OF LUNG CANCER
TREATMENT
We performed a MEDLINE and EMBASE search
using OVID for the period 1996 to August 2007 to
identify recent studies based on the search terms costeffectiveness and lung cancer. This search identified
632 publications after removing duplicates. When the
search was restricted to NSCLC and cost-effectiveness,
the total number of publications was 178. These publications included systematic reviews, meta-analyses,
and commentaries. Below, we highlight some of the
early literature that is frequently referenced (1998 and
earlier), and in the next section we highlight more
recent publications (1999–2007).
Of interest is the fact that in the previous edition
of this book, we were only able to identify 15 economic
evaluations of lung cancer management.22,29,53,54,64–76
All but one of these studies included an evaluation of
the cost-effectiveness of chemotherapeutic alternatives in lung cancer treatment.64 The one exception
involved a comparison of two different radiotherapy
regimens for NSCLC: conventional radiotherapy
treatment versus continuous hyperfractionated accelerated radiotherapy. Despite the recognition of the
importance of quality of life effects on treatment choice,
only two studies incorporated estimates of patient’s
quality of life into quality-adjusted life years.74,76 All
studies used effectiveness data derived from clinical
trials, though not all were based on randomized evidence. Several studies examined resource consumption from those same trials,24,64,65,74–76 while others
adopted an approach whereby resource use estimates
were obtained from other sources (e.g. institutional
databases) and were combined with effectiveness data
within a modeling framework.27,65–67,69,71–73
The Canadian POHEM model has been used as a
framework within which to assess new interventions
for their cost-effectiveness. The costs of the survival
benefit associated with new treatments, such as
256 Textbook of Lung Cancer
chemotherapy for stage IV NSCLC, can be compared
against the costs and benefits of standard treatment.
Clinical practice guidelines in Canada recommend
that cisplatin-based chemotherapy be offered as a
treatment option for medically suitable patients to
improve survival, symptom control, and quality of
life.77 The cost-effectiveness of this approach was an
important understanding at a time of fiscal restraint
in health care, since many physicians and health-care
administrators questioned whether it was appropriate to offer relatively expensive and toxic agents that
only modestly impacted survival.
The National Cancer Institute of Canada (NCIC)
was the first to demonstrate in a cost analysis that
chemotherapy administration might actually reduce
the overall costs to the health-care system, primarily
by reducing the average length of hospital stay for
terminal care. Jaakkimainen et al undertook an economic analysis of the NCIC clinical trial (BR5) that
compared the use of vindesine-cisplatin (VP) chemotherapy and the combination of cyclophosphamide,
doxorubicin (Adriamycin) and cisplatin (CAP) versus best supportive care (BSC) in patients with stage
IV NSCLC.23,24 This study, which used primary
survival data from patients entered in the trial and
estimated costs from the two largest institutions contributing patients to the trial, demonstrated that CAP
was a dominant strategy, saving C$949 per case.
Vinorelbine-cisplatin was also a dominant strategy as
an ambulatory regimen, saving C$473 per case, and
was more cost-effective than the same chemotherapy
given as an inpatient regimen [C$5551 per life year
saved (LYS)].
We are now faced with a proliferation of promising
new drugs with encouraging activity in NSCLC. Each
of these drugs is, however, significantly more expensive that the older drugs. By using POHEM, information on the costs of the old standard therapies and
their outcomes can be compared with the costs of the
new agents and their survival benefits. Based on data
from a randomized trial of vinorelbine alone compared
with the combinations of vinorelbine-cisplatin and
vindesine-cisplatin,78 estimates of the cost-effectiveness
of these regimens relative to BSC were made in the
POHEM.69 Vinorelbine was a dominant strategy, saving C$1447 per case. Vinorelbine-cisplatin was also
a dominant strategy as an ambulatory regimen, saving C$473 per case, and was more cost-effective than
the same chemotherapy given as an inpatient regimen
(C$5551 per LYS).
Hillner and co-workers73,79 also undertook a costeffectiveness analysis of vinorelbine-cisplatin and
vindesine-cisplatin compared with vinorelbine alone
in stage IV, based on the same clinical trial reported
by Le Chevalier et al.78 They used American costs
(charges) and found that vinorelbine-cisplatin cost
US$17 700 per LYS relative to vinorelbine. Vindesinecisplatin had a cost-effectiveness ratio of US$22 100
per LYS relative to vinorelbine. Even in this comparison against vinorelbine alone as opposed to BSC,
the combination of vinorelbine-cisplatin was seen to
be cost-effective.
Evans undertook an economic evaluation of the
use of gemcitabine in the management of patients with
stage IV lung cancer. Based on phase II survival data
from the large EO18 trial,80 and estimates of drug
cost per treatment cycle ranging from C$800 to
C$1800, gemcitabine was observed to be cost-effective
over a range of sensitivity analyses.67 At the greatest
cost per cycle (C$1800), and with survival reduced by
50% compared with the EO18 results, the cost per
life year gained was estimated to be C$16 230.
Earle and Evans66 undertook a similar analysis of
paclitaxel alone compared with BSC, based on the
data from two phase II clinical trials.81,82 The total
costs of administering three cycles of chemotherapy
were C$8143 and C$3375 more than the strategy of
BSC. However, on the basis of the difference in survival duration between stage IV patients treated in
the BSC arm of a previous NCIC trial and those represented in the pooled phase II survival results, the
cost per life year gained was C$4778.
All of the chemotherapy regimens that were previously evaluated in POHEM were updated to current
costs and placed in a decision framework.81,82 Vinblastine-cisplatin, vinorelbine-cisplatin, and etoposide (VP-16)-cisplatin were all found to decrease the
cost of treatment per patient compared with BSC,
while increasing survival relative to BSC. Therefore,
these chemotherapy regimens can all be considered
dominant treatment strategies. This important observation is true in the Canadian health-care environment, but it may not reflect reality in other health-care
environments.
The important influence of the health-care environment on the outcome of economic analysis is seen in
the report of Lappas el al.83 They undertook a pharmacoeconomic analysis of the impact of paclitaxel-carboplatin and vinorelbine-cisplatin. To obtain survival
outcome data, they performed a meta-analysis of all
available clinical trial literature. US Medicare reimbursement figures were used to determine the total
expected cost. This was determined to be US$19 322
and US $20 790 for paclitaxel-carboplatin and
The cost and cost-effectiveness of lung cancer management 257
vinorelbine-cisplatin, respectively. Treatment with the
vinorelbine-containing regimen was 7% more costly
than the paclitaxel-containing regimen. Lower administration costs and less frequent adverse event management costs led to the lower overall cost and to the
recommendation that paclitaxel-carboplatin be the
preferred choice from an American pharmacoeconomic perspective. Estimates of the cost per case are
greater for paclitaxel-cisplatin or paclitaxel-carboplatin in the Canadian environment than for vinorelbine-cisplatin, even though generic pricing is now in
effect for paclitaxel and carboplatin in Canada. Relative to BSC, paclitaxel-cisplatin is a cost-effective intervention at C$5034 per LYS, but vinorelbine-cisplatin
is a dominant strategy.
Recent cost-effectiveness literature (1999–2007)
Cost-effectiveness literature for lung cancer continues
to inform decision-makers, and has recently been used
in the evaluation of lung cancer staging strategies,84,85
the management of chemotherapy-induced anemia,86
the use of G-CSF,87 and the use of chemotherapy in the
first-line lung cancer setting,88–94 and in the secondline setting.95–97
Verboom et al84 demonstrated that, despite the
increased cost of a PET scan, the potentially averted
surgeries and related costs more than offset the costs
of the additional tests and made it the dominant strategy (€9573 conventional, €8284 PET). Kelly et al85
demonstrated that FDG-PET imaging improved staging accuracy compared to CT scanning alone, and
reduced the need for more expensive invasive staging
methods. Kelly did not provide any cost-effectiveness
ratios, and did suggest that the cost-effectiveness is
still unclear in populations with N0–2 disease.
Chouaid et al86 presented findings at the 11th world
conference on lung cancer on the cost-effectiveness of
darbepoetin alfa in anemia management. Chouaid
included drugs, transfusions, and anemia management costs in creating the cost-effectiveness ratio and
reported that darbepoetin alfa was the dominant
strategy. Timmer-Bonte et al87 have also presented a
cost-effectiveness analysis for G-CSF as secondary
prophylaxis added to antibiotics in SCLC. Their economic analysis suggested that the mean incremental
costs associated with adding G-CSF was €681 (95%
CI ⫺36–1397) per patient. The entire treatment
period had a mean incremental cost of €5123 (95%
CI 3908–6337). The ICER was €50 per percent
decrease in the probability of febrile neutropenia (95%
CI ⫺2–433) in the first cycle of treatment. They
concluded that if policy-makers were willing to pay
€240 for each percent gain in effect (€3360 for a
14% reduction in febrile neutropenia) the addition of
G-CSF would be considered cost-effective.
In the first-line chemotherapy setting a number of
recent cost-effectiveness analyses have been reported.
Martoni et al88 undertook a cost-minimization analysis
of gemcitabine-cisplatin versus vinorelbine-cisplatin
in NSCLC, as no difference in efficacy were demonstrated. Martoni estimated that the vinorelbinecisplatin combination had an average cost of €882.24
versus €2900.91 for gemcitabine-cisplatin.
Sacristan et al89 undertook a cost-minimization
analysis of gemcitabine-cisplatin versus etoposidecisplatin in NSCLC. Again this was based on the fact
that no differences in efficacy were demonstrated.
Sacristan showed that the average cost per patient
was 584 523 pesetas for gemcitabine-cisplatin versus
589 630 pesetas for etoposide-cisplatin based on the
combined costs of chemotherapy, anti-emetics, hospitalization, medical visits, and transfusions. Further
analysis based on cost per response or cost per progression-free month was also presented, although
these endpoints are difficult to evaluate as there is
limited literature on the use of these measures of
cost-effectiveness.
Ramsey et al90 initially planned a cost-effectiveness
analysis of the Southwest Oncology Group Trial S9509
comparing vinorelbine-cisplatin to paclitaxel-carboplatin in NSCLC. However, upon determining that
no differences in efficacy existed, a cost-minimization
analysis was undertaken. Patient costs were calculated
based on a 24-month follow-up and showed that
vinorelbine-cisplatin had an average cost of $40 292
versus $48 940 for paclitaxel-carboplatin. Ramsey noted
that most of the difference related to drug acquisition
costs (difference $11 863).
Dooms et al91 presented one of the few cost–utility
analyses in lung cancer based on a comparison of
gemcitabine monotherapy with vindesine-cisplatin
in NSCLC. They incorporated utilities by transforming a visual analog scale for quality of life. An incremental cost of €1522 per patient and an incremental
QALY of 0.11 years resulted in an ICER of €13 386
per QALY, which the authors considered to be a
favorable outcome.
Chen et al92 presented what they claim to be a costeffectiveness analysis (although in effect they presented
a cost-minimization analysis) of paclitaxel-carboplatin
compared to paclitaxel-gemcitabine in NSCLC. They
included costs for admission fees, out-patient clinic
visits, emergency-room visits, and chemotherapy. The
authors reported differences in costs between the two
258 Textbook of Lung Cancer
therapies, with the paclitaxel-carboplatin regimen being
US$2214 less expensive overall, with no statistically
significant differences in efficacy being identified.
Billingham et al93 used data from the MIC2 trial
which compared mitomycin-ifosfamide-cisplatin to
best supportive care for NSCLC. They incorporated
non-parametric bootstrapping which produced a
cost differential of £2924 and a survival advantage of
2.4 months. These outcomes produced an ICER of
£14 620 per life year gained. The authors noted that
the main driver of increased costs was associated
with increased hospital in-patient days for chemotherapy-related issues.
Annemans et al94 undertook a cost-effectiveness
analysis comparing paclitaxel-cisplatin to teniposidecisplatin in advanced NSCLC. They included the costs
for drugs and chemotherapy administration, and consequences associated with anemia, thrombocytopenia, neutropenia, neuropathy, and arthralgia/myalgia.
Paclitaxel-cisplatin had a higher cost in all analyses
undertaken in a number of countries (The Netherlands,
Belgium, France, and Spain), with a net cost per patient
of US$2311. Paclitaxel-cisplatin did provide a better
response rate (37% versus 26%). The authors state that
the cost per extra responder for paclitaxel-cisplatin
was, on average, US$21 011.
In the second-line setting for NSCLC, two costeffectiveness studies have been published based on
the pivotal clinical trial comparing docetaxel to best
supportive care (BSC).95 Leighl et al96 used Canadian
costing and concluded that the incremental cost for
docetaxel was C$9577, with the lower-dose regimen
showing an incremental cost of C$10 804. Survival
benefits were 2 months in the primary analysis and
3.9 months in the low-dose analysis. The resulting
ICER was C$57 749 per life year gained in the primary analysis, and C$31 776 per life year gained in
the low-dose analysis. Sensitivity analysis included
increasing and decreasing survival outcomes by 20%
with resulting ICERs of C$18 374 to C$117 434. Holmes et al97 used United Kingdom costing (in pounds)
and reported an ICER of £13 863 in the low-dose
analysis, but did not include an analysis of the primary study as reported by Leighl et al. Sensitivity
analysis produced ICERs from £10 020 to £32 781,
based on 95% CI for mean differences in survival.
Bradbury et al98 undertook an economic analysis
based on the National Cancer Institute of Canada
study of erlotinib versus best supportive care after
cisplatin-based chemotherapy in advanced NSCLC.
Their analysis showed that the incremental costs were
C$12 303 with a corresponding benefit of 0.13 years
(1.56 months). The resulting ICER was C$95 869 per
life year gained (95% C$52 359–$429 149).
In some cases the cost-effectiveness analyses illustrated above can be roughly converted to cost-utility
estimates by assigning utilities to each of the chemotherapy regimens and to BSC. Oncologists working
as part of the Ontario Practice Guideline Initiative
have estimated utilities for the different chemotherapy regimens. The scale used ranged from 0 to 1,
where 0 represents death and 1 is perfect health. The
utilities for the chemotherapy regimens ranged from
0.5 to 0.7, with the utility estimate for best supportive care being 0.5. It is important to note, however,
that utility estimates are typically created through a
survey of the general public or patients, and hence
some bias in the utility assessment may occur with
physician estimates. With the incorporation of physician-estimated utilities into the calculation of costeffectiveness, the chemotherapy regimens actually
became more cost-effective compared with BSC.
Chemotherapy interventions for stage IV NSCLC
can be ranked for their cost-effectiveness based on
alternative threshold values.99 Depending on the
value that society is willing to pay for each unit of
outcome gained, the ranking of each intervention
will vary. In North America, the common threshold
has been estimated to be approximately C$50 000
per quality-adjusted life year, although this is not a
definitive value.100 Using this threshold, paclitaxel
followed by paclitaxel-cisplatin, vinorelbine-cisplatin
(ambulatory), and gemcitabine would be the preferred
regimens. If the threshold was for therapies costing
only C$10 000 per life year gained, vinblastine-cisplatin would be the preferred regimen, followed by
vinorelbine-cisplatin given on an ambulatory basis,
etoposide-cisplatin, and vinorelbine alone.
The cost-effectiveness for combined-modality therapy for stage IIIA and IIIB disease has been evaluated
using the POHEM.65 For stage IIIA, combinedmodality therapy consisting of pre- and postoperative chemotherapy and radiotherapy, as described by
Kris et al,101 was modeled for patients with clinically
evident N2 disease. For patients with stage IIIB disease, the costs associated with delivering two cycles
of vinblastine-cisplatin followed by radical radiotherapy (60 Gy in 30 fractions), as reported by CALGB,102
have been modeled.
Although the incremental cost per case was high,
particularly for combined-modality therapy for stage
IIIA disease (C$22 963 more than standard radiotherapy), the estimated life years gained were also substantial and the cost-effectiveness was C$14 958 per
The cost and cost-effectiveness of lung cancer management 259
life year gained. The combined-modality approach of
vinblastine-cisplatin followed by radical radiotherapy
for stage IIIB patients was more expensive than standard
Canadian radiotherapy (C$22 303 versus C$13 391).
However, the estimated number of life years gained
with combined-modality therapy was large, and resulted
in a cost-effectiveness ratio of C$3348 per life year
gained.
A report by Winton et al in 2005, from the National
Cancer Institute of Canada Clinical Trials Group
demonstrated a dramatic increase of 15% in absolute
5-year survival with the use of post-operative vinorelbine-cisplatin in patients with completely resected
Stage IB and II NSCLC.103 An economic analysis of
this trial showed the chemotherapy to be highly
cost-effective at C$10 096 per life year gained.104
The increased volume of economic and pharmacoeconomic literature brings with it some challenges. As
can be seen from the results shown here, the methodologies are often unclear, with cost-minimization
analyses sometimes presented as cost-effectiveness
analyses. The analyses are also less informative when
the comparator therapies chosen do not always represent current standards of care. Additionally, not all
the analyses used the same measure of effectiveness.
Although many used life years or quality-adjusted
life years, other less well established outcomes were
sometimes incorporated. When the incremental evaluations do not use consistent methodology, the current standard of care as the comparator, or a typical
effectiveness measure, the analysis becomes more
difficult to interpret for researchers and policy-makers alike. It is advised that readers be wary of published studies that use atypical methods, comparators,
or measures of effectiveness.
LUNG CANCER ECONOMICS AND
HEALTH-CARE POLICY
The expenditures associated with medical practice
are coming under increased scrutiny. Both public and
private payers are demanding increased efficiency
and ‘value for money’ in the provision of health-care
services. As a result, policy-makers in both Australia
and the Province of Ontario (Canada) have developed
formal guidelines for economic analyses that are to
be part of drug reimbursement submissions.105,106
Clinical practice guidelines have recommended
that it is ‘reasonable to offer cisplatin-based chemotherapy to medically suitable patients as a treatment
option’ for survival, symptom control, and quality of
life outcomes in metastatic NSCLC patients.77,107 As
Evans et al have reported,108 the average cost of managing a lung cancer patient from diagnosis to death
without palliative chemotherapy is just under
$20 000. Therefore, for all 17 128 cases diagnosed in
Canada in 1992, the total cost was ∼$350 million. Even
though palliative chemotherapy is considered costeffective,99 by virtue of lung cancer’s high incidence,
the cost of treating all advanced stage patients with
chemotherapy adds significantly to health-care budgets and manpower requirements.
Oncologists are still fairly conservative in their
management of advanced lung cancer.108 As well,
many patients are not candidates for systemic therapy because of biologic age, performance status, or
co-morbid conditions. Therefore, the actual impact
of a new treatment for lung cancer on national health
budgets is likely to be less than projected based on
total number of cases.
CONCLUSION
Because of its high incidence, lung cancer is a significant burden on health-care systems. Studies indicate that strategies to minimize hospitalization are
likely to have the greatest impact on these expenditures.53 Despite common perceptions to the contrary,
supportive care for advanced lung cancer is associated with significant cost, and many chemotherapeutic treatments are cost-effective relative to other
commonly accepted medical interventions. However,
decision-makers sometimes have trouble seeing past
the price of these interventions. Therefore, it is important to understand how to assess these technologies
in the broader context of the costs and consequences
associated with their use. Providing decision-makers
with useful information from methodologically sound
studies will help optimize use of health-care resources,
and ensure continuing access to care for lung cancer
patients in the future.
Despite evidence of the cost-effectiveness of lung
cancer treatment, there remains reluctance in the
medical community, even in North America, to adopt
some of these new approaches in the management of
lung cancer. Concern has been expressed about the
quality of life that accompanies such treatments.
However, even when this has been factored into the
economic evaluations, the quality-adjusted life years
gained remain in the range that is considered
acceptable for health-care interventions in Canada.42
The reluctance of some institutions to provide
260 Textbook of Lung Cancer
combined-modality therapy for locally advanced disease or chemotherapy for metastatic disease may relate
to the absolute cost of introducing these new treatments. Since there are a large number of patients who
potentially could receive these treatments, the total
fiscal burden could be quite large. In developing
countries, where there is a need to prioritize healthcare expenditures even more carefully, the absolute
cost of care for lung cancer patients may become a
significant factor in determining health policy. Choices
will need to be made between the introduction of
these new strategies and the withdrawal of previously
existing treatments for cancer or the treatment of
other illnesses. Before such decisions are taken, however, economic data derived from the cost of care in
that particular environment need to be determined.
Evaluations in North America have dispelled the myth
that the treatment of lung cancer is costly and not
cost-effective in this health-care environment.
Although caution must be exercised in extrapolating
this to other health-care jurisdictions, economic factors should probably not be a barrier to the delivery
of current best treatment practices. The comparative
cost-effectiveness data presented in this review may
be useful to those who must make the decisions
about which regimens or strategies to choose.
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18 The future
Giovanni Selvaggi, Giorgio Vittorio Scagliotti
Contents Introduction • Screening • Molecular profiling • New imaging techniques
• Staging • Prognostic factors • Radiotherapy • Pharmacogenomics • Targeted therapies
• Vaccines • Conclusions
INTRODUCTION
The global burden of lung cancer will undergo dramatic
changes in the near future, from the developed to the
developing world, with an impressive contribution of
the over 300 million new smokers in China, almost
exclusively males.1 War against tobacco is the answer to
stop lung cancer epidemics. The identification of predisposed individuals is the next step.
Trends in the prevalence of cigarette smoking strongly
predict lung cancer incidence and mortality rates, which
closely parallel incidence because of the high case fatality of lung cancer. In the United States, the prevalence
of cigarette smoking in males and females declined consistently until approximately 1990, establishing a plateau at 25%. The patterns of smoking prevalence
indicate that lung cancer mortality rates will continue
to decrease until approximately 2020, assuming a
30-year lag between smoking patterns and subsequent
lung cancer incidence. By 2030, lung cancer cases will
no longer have a predominance of gender.2
In the 1990s adenocarcinoma became more frequent
than squamous cell carcinoma.3 Hypotheses concerning
such histologic shift focused on changes in the characteristics of cigarettes and in the inhaled doses of carcinogens.
An increased puff volume might lead to higher deposition
of tobacco smoke in the alveoli of the lung. Higher nitrate
levels in tobacco smoke would lead to enhanced doses of
NNK, a tobacco-specific nitrosamine believed to be
responsible for adenocarcinoma’s higher incidence.4
Understanding the potential links between ethnicity
(e.g. Caucasian vs African Americans vs Asians), low
socioeconomic status, and lung cancer risk is essential
to modify the impact of lung cancer incidence in a vast
part of the population worldwide and to design effective prevention projects. Hints of a higher susceptibility
to lung cancer in women are also a major concern, with
immediate consequences on therapeutic chances offered
by newer targeted therapies.5
There is a need for predictive models to quantify the
risk of developing lung cancer in coming years. A simulation model was constructed in Finland on the basis of
how changes in smoking habits could impact directly
on lung cancer incidence in the future.6 A delay of
10 years in starting age of smoking had the same effect
on lung cancer incidence as cutting the number of
those starting by 50%. Postponement of the starting age
by 20 years would eliminate most of the lung cancer
cases caused by smoking. Persuading youths not to
start smoking represents a socio-economic priority.
Lung cancer has always been viewed as a smoker’s disease. However, the epidemiologic burden of non-smokers
with lung cancer is significant, especially in Asiatic countries. The recent descriptions of epidermal growth factor
receptor (EGFR) mutations being more common among
lung tumors of non-smokers suggest that this selected
group of patients should be examined further. Evidence
exists that lung cancer among non-smokers may be biologically different from that of smokers. Genetic and/or
environmental factors, other than smoking, could possibly
predispose to lung cancer. In the near future lung cancer
in non-smokers may be treated differently from lung cancer arising in smokers. Is it really a different disease?
In a study testing 265 lung cancer specimens the
likelihood of EGFR mutations in exons 19 and 21
decreased as the number of pack-years increased.7
Mutations were less common in people who smoked
for more than 15 pack-years or who stopped smoking
cigarettes less than 25 years ago. Such data could help
clinicians in assessing the likelihood of EGFR mutations on exons 19 and 21 in patients with lung adenocarcinoma when mutational analysis is not available.
SCREENING
The detection of lung cancer at an early stage must be
pursued to cut the mortality from this deadly disease,
The future 265
given the five-year survival of stage I patients in the
range of 65–70%.8 The best tool for detecting early lung
cancer has still to be defined. Studies failed to show the
utility of chest radiography alone or in addition to sputum cytology for lung cancer screening.9
Significant improvements in technology have facilitated the generation of low-resolution images of the
entire chest using low radiation exposure and within a
single breath hold, by the use of low-dose spiral computed tomography (CT). Low-dose CT improved the
likelihood of detecting lung cancer at an earlier stage,
with an estimated five-year survival rate of 60–80% in
the Early Lung Cancer Action Project (ELCAP) study,10
followed by other larger studies from Japan,11 USA, and
Europe.12 In these studies most screening-detected cancers were in stage I. Data from the I-ELCAP study on
over 30 000 volunteers13 showed that lung cancer
detected by annual spiral CT screening is largely curable. Screening resulted in a diagnosis of clinical stage I
lung cancer in 85% of cases, with an estimated 10-year
survival rate of 88%, reaching 92% in those cases who
underwent surgical resection within one month after
diagnosis.
The question of the real impact on lung cancer mortality by CT screening programs will be answered
through the National Lung Cancer Screening Trial from
the National Cancer Institute (NCI) on 25 000 volunteers, using multi-detector-row scanners.
Overdiagnosis could represent a potential drawback
of screening without a true stage shift: an increase in
early stage disease associated with a corresponding
decrease in late stage disease. It was reported that the
gene-expression profile of screen-detected lung carcinomas showed no difference from that of a matched
population with symptomatic lung cancer, suggesting
that the biologic aggressiveness of screening-detected
lung cancer does not differ from the ‘real’ lung cancer,
thus eliminating a source of bias against screening.14
Other issues to be addressed include false-positive rate,
the cost-effectiveness of these projects, and the risk of
radiation exposure with low-dose CT scans.
The rapid advances in imaging technology make it
very difficult to complete a randomized study, sufficiently powered to address the issue of decreased mortality with lung cancer screening, before new devices
come on the market. The CT scan remains the optimal
tool for detection of lung nodules. Current 64-slice
scanners provide images of structures and acquire data
so quickly that motion artifacts and volume-averaging
effects are generally negligible. Computer-aided detection (CAD) CT systems are commercially available and
will provide markedly improved detection of lung nodules. One recently published trial found that the mean
sensitivity for the detection of lung nodules on CT rose
significantly with the addition of CAD.15
Positron emission tomography (PET) might improve
diagnostic accuracy if it is introduced into a screening
program. No data are available yet and prospective
studies are ongoing. Size limitation (lesions below 7 mm)
and false-positive/negative rates have to be defined
when implementing PET as a screening tool for lung
cancer. The limitations of PET with regard to lesion size
have improved with the introduction of combined
PET-CT scanners; the ‘multislice’ CT component
improves the spatial resolution of PET images to a lower
limit of 6–7 mm. False negatives are known to occur
with well-differentiated tumors such as bronchioloalveolar carcinomas (which may produce ‘ground-glass’
opacities on CT scans) and adenocarcinomas.16
On the biologic side, genomics and proteomics are
opening new horizons in both early and advanced lung
cancer management. Mutations, microsatellite alterations, and methylation of promoter regions of specific
cancer-related genes can be detected in the serum of
patients with lung cancer, while genomic instability can
be seen in the bronchoalveolar lavage fluid.17,18 The
measurement of DNA changes in the serum holds great
potential for the development of serum markers for the
early detection of lung cancer.
Proteomics relies on the detection of antibodies
directed at known proteins considered to be involved
in lung carcinogenesis. A monoclonal antibody, HNRNP
A2/B1, showed an accuracy of 90% in predicting
patients who would eventually develop lung cancer
over the next few years.19 The introduction of matrixassisted laser desorption ionization (MALDI) mass spectroscopy allows the generation of a protein ‘profile’
based on the molecular weights and relative quantity of
all proteins in a sample. The proteins that are differentially expressed can then be identified and tested as
potential biomarkers to select patients likely to respond
to targeted therapies.20
MOLECULAR PROFILING
The model of carcinogenesis for lung cancer favors the
hypothesis of a step-wise progression of genetic and epigenetic abnormalities that eventually leads to the loss of
normal control mechanisms of cellular growth. Multiple
genetic and epigenetic hits influence oncogenes, tumor
suppressor genes, growth factors, and DNA repair genes,
266 Textbook of Lung Cancer
resulting in uncontrolled cell growth. Based on these
assumptions, a subcategory for smoke-damaged bronchial mucosa as an intermediate step in the pathway
from normal bronchial mucosa to squamous cell lung
cancer emerges by the finding of early molecular
changes. Epidemiology and early diagnosis could derive
benefit from such studies. One of the earliest changes is
the loss or inactivation of genetic material on the short
arm of chromosome 3 (3p). In lung cancer patients
with 3p changes in the tumor, 3p changes were also
detectable in non-malignant bronchial epithelium. The
loss of large portions of chromosomal material on 3p
gives way to inactivation of tumor suppressor genes,
including RARβ (retinoic acid receptor beta), RASSF1A
(Ras association domain family I), and FHIT (fragile histidine triad) gene (3p14.2).21 Another inactivation pathway occurs via epigenetic silencing by DNA promoter
hypermethylation. All these epigenetic and somatic
changes are progressively caused by smoking.22 Another
early alteration associated with increasing pack-years of
smoking is inactivation of tumor suppressor gene p16,
with consequent phosphorylation of the retinoblastoma
(Rb) protein and uncontrolled proliferation.23
Preneoplastic lesions of adenocarcinoma remain undefined. Based on morphologic findings, some adenocarcinomas might occur as a result of progression from
atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma.24 DNA histogram patterns of AAH are
intermediate between reactive hyperplasia of type II
pneumocytes and small-sized well-differentiated adenocarcinomas.25 Therefore, AAH could represent a
clonal cellular proliferation closely related to adenocarcinoma. Several genetic analyses revealed that up to
39% of AAH had k-ras mutations.26 However, none of
the tumors with EGFR mutations showed k-ras mutation simultaneously.27 EGFR mutation might be the
hallmark of malignant progression of AAH to invasive
adenocarcinoma. EGFR protein expression increased
significantly as lesions progressed from AAH to
BAC.28 The accumulation of multiple allelic losses as
well as p53, k-ras, and EGFR mutations may play
important roles in the multistage carcinogenesis of
adenocarcinoma.29
NEW IMAGING TECHNIQUES
PET with 18F-fluorodeoxyglucose (FDG) has recently
gained a top spot in the staging of lung cancer.30 PET
registered a superior performance in overall TNM
staging compared to magnetic resonance imaging
(MRI)31 in solid tumors. PET diagnostic accuracy will
increase dramatically with progress in gating techniques
and the development of new tracers. New tracers are
continually being tested, but a substitute for 18F-FDG is
far from clinical routine use. A new molecular imaging
probe, 18F-deoxyfluorothymidine (FLT), has been
developed. This is retained in proliferating tissues
through the enzyme thymidine kinase 1 (TK1), that
phosphorylates FLT to FLT-5 phosphate, which is
essentially trapped in tumor cells. However, compared
to FDG-PET, detection of primary and metastatic
NSCLC by FLT-PET is limited by the relatively low FLT
uptake of the tumor tissue.32 FLT-PET is unlikely to
provide more accurate staging information than FDGPET. Future studies should evaluate the use of FLT-PET
for monitoring the cellular apoptotic index in response
to chemotherapy. An FLT-PET scan acquired after the
first course of chemotherapy was useful for predicting
the efficacy of chemotherapy in advanced breast cancer.33
New receptor systems such as those using gastrin
and bombesin are being developed in the field of singlephoton tracers of SPET (single photon emission tomography). Also (99m)Tc-based agents might be useful to
identify hypoxia in cancer, angiogenesis, and apoptosis.
Dual-modality integrated imaging systems (SPET-CT
and PT-CT) allow us to improve the spatial definition
of areas of uptake, thus generating fusion images with
CT scanning data.
A newly developed high-energy probe (positron
emission probe, PEP), optimized for localizing PET
tracers in vivo, was tested successfully for preoperative
planning of the extent of neck dissection in patients with
head and neck cancer.34 With use of the PEP probe,
nodal metastases were identified in 20/21 patients with
a sensitivity of 95%.
An intriguing idea is to implement tracers aimed at
biologic targets such as EGFR and VEGFR. PET with
EGFR kinase-specific radiolabeled tracers could provide the means for imaging the heterogeneity of EGFR
expression and signaling activity in tumors before and
during therapy with EGFR TKIs.35
New gating techniques could help in detecting smaller
lung nodules with PET-CT imaging, especially in
patients with lung nodules detected during CT screening programs.
Another field of interest for PET is radiation therapy.
In the era of image-guided radiation therapy (IGRT),
target delineation could maximize efficacy while simultaneously decreasing toxicity by limiting radiation doses
The future 267
to the surrounding normal tissues. PET-CT has an
innovative potential in the evaluation of disease stage,
in target delineation for treatment planning, and in the
assessment of response to therapy.36
the execution of transbronchial biopsies (TBBs) with a
high diagnostic yield, almost twice that of flexible fiberoptic bronchoscopy under fluoroscopic guidance for small
peripheral pulmonary lesions beyond the optical reach
of the bronchoscope.40
STAGING
PROGNOSTIC FACTORS
The next revision of the current version of the TNM
staging system for lung cancer is under evaluation by a
special committee of the International Association for
the Study of Lung Cancer (IASLC). This will be a joint
effort with the American Joint Committee on Cancer
(AJCC) and the International Union Against Cancer
(UICC). A database with nearly 100 000 lung cancer
cases (both NSCLC and SCLC) originating from all over
the world, with a European predominance, is undergoing evaluation by a panel of experts. Final approval
from the UICC is expected to be effective in 2009.
Current American Thoracic Society (ATS) guidelines
for the staging of lung cancer suggest that contrast-enhanced CT should be considered the standard imaging
technique for the evaluation of the mediastinum.37
Lymph nodes with the short-axis diameter >1 cm on
CT must be considered malignant. However, CT is neither sensitive nor specific for detecting metastasis in the
mediastinum, since some benign nodes may be larger and
small lymph nodes may be malignant. A meta-analysis
showed that PET is more accurate than CT for mediastinal staging.38 Tissue proof of PET-positive mediastinal
nodes by mediastinoscopy is still recommended before
denying surgical resection. Less invasive procedures
such as bronchoscopic transbronchial needle aspiration
(TBNA) will be implemented in the future. A comparison of CT, PET, and direct real-time endobronchial
ultrasound (EBUS)-guided TBNA for detection of mediastinal lymph node metastases in 102 patients with
lung cancer39 showed a diagnostic accuracy of 60%,
72%, and 98%, respectively. EBUS-TBNA did not cause
any complications.
Standard flexible bronchoscopes used for diagnostic
or minimally invasive procedures cannot reach most
peripheral lung lesions due to the progressive narrowing branches of the bronchial tree. An ideal tool would
provide navigational information with real-time positioning of the tip of the forceps to reach for invisible
peripheral lesions. Electromagnetic navigation based on
virtual bronchoscopy and real-time three-dimensional
(3D) CT images allows an approach to the peripheral
lung masses. The SDBS (superDimension/Bronchus
system – superDimension, Hertzliya, Israel) safely allowed
So far the clinical staging system represents the standard for determining lung cancer prognosis. It is also
clear to every medical oncologist how, especially in the
adjuvant setting, there is a wide variety in prognosis on
an individual basis even within the same stage. Other
clinical and biochemical markers with more reliable
prognostic significance are badly needed. In stage I
NSCLC nearly 30% of patients will relapse after radical
surgical resection, and the ability to identify such subgroups of patients at higher risk for relapse may improve
health outcomes across the spectrum of disease.
Microarray technologies used to profile human cancers at the DNA, RNA, and protein levels have led to the
discovery of disease susceptibility genes, therapeutic
targets, and expression profiles predicting disease outcome and sensitivity or resistance to a given drug.
Genomics can be applied to lung cancer results from
gene expression arrays, single-nucleotide polymorphism (SNP) arrays, and high-throughput capillary
sequencing. Gene expression arrays offer the possibility
of simultaneous analysis of the transcription of several
thousands of genes in a semiquantitative manner, either
as cDNA or oligonucleotide arrays. Some profiling
scores are more accurate than others in defining lung
cancer based on the gene expression profiles.41–43 Pattern recognition software and clustering algorithms allow
identification of different groups of genes or tumor specimens with similar repertoires of expressed genes. Novel
histologic subtypes could be delineated with a direct
impact on prognosis and selection of the best treatment
options. Additionally, high-density SNP arrays allow
the detection of loss of heterozygosity (LOH), as well as
copy number changes and homozygous deletions.44
Mutations in the EGFR gene have been found using highthroughput sequencing. A consensus on such matters is
far from being reached.
The Lung Metagene Model predicted recurrence for
individual patients and was consistent across all early
stages of NSCLC, with an overall predictive accuracy of
almost 80%.45 Such predictive power could be of particular benefit in stage IA patients, actually excluded
from adjuvant protocols. If the risk for recurrence based
268 Textbook of Lung Cancer
on the genomic profile is believed to be high, adjuvant
chemotherapy could be proposed in a randomized
fashion to check for its real impact on survival.
In another model, microRNA expression analysis identified unique profiles, which could discriminate lung
cancer from non-malignant lung tissues. MicroRNA
expression profiles correlated with survival, including
stage I adenocarcinomas, hence they could be used as
diagnostic and prognostic markers of lung cancer.46
Genomic tools, as a strategy to refine prognosis and
to precisely select patients, should be utilized across all
stages. Data should be extensively collected and pooled
in a common database. It is of basic importance that the
results of all gene expression studies in lung cancer
should translate into a widely applicable clinical test to
facilitate early identification of patients at high risk in
routine daily practice. A new direction of research is to
identify the effects of mutations on gene expression patterns to clarify the molecular basis of oncogenic signaling and to develop drugs targeting these biomolecular
steps. Expression array data from a KRAS-mutant mouse
model of lung adenocarcinoma identified a KRAS mutation signature.47 Transferring that signature to human
adenocarcinomas correctly identified KRAS-mutant
lung tumors. Given the current lack of a potent, clinically available KRAS inhibitor, one intriguing possibility would be to find inhibitors against key mediators of
mutant KRAS function.
Cancer-specific copy number alterations and LOH
represent important changes found in lung cancer cells.
Amplified regions of the genome may include oncogenes, whereas deletions and regions of LOH may harbor
tumor suppressor genes. Techniques such as comparative genomic hybridization (CGH) and array-CGH are
rapidly evolving. Millions of SNP loci have now been
identified, making them good markers for studying
cancer genetics: arrays of 500 000 SNP loci are in progress. SNP arrays have been used successfully in genomewide screens for detecting LOH in lung cancer.48 The
use of SNP arrays has allowed the selection of regions
of copy number change, amplification (chromosomal
regions 12p11 and 22q11, Myc family) and homozygous deletion (CDKN2A and PTEN, chromosomes
3q25 and 9p23, containing arylacetamide deacetylase,
AADAC), succinate receptor 1 (SUCNR1), and protein
tyrosine phosphatase, receptor type D (PTPRD). It is a
fundamental aim to refine technologies so as to better
understand key molecular changes in NSCLC, to test
whether a gene that is overexpressed is also amplified
and/or mutated, and to define all the complex networks
of signaling pathways on which lung cancer cells rely to
proliferate. Both in vitro and in vivo models will facilitate the testing of specific targeted drugs in the different
subgroups of lung cancer created according to a molecular profile. Clinical trials should be planned to select
patients prospectively.
Protein microarrays may provide a map of known
cell signaling proteins. Identification of critical nodes,
or interactions, within the network is a potential starting point for drug development and, at the same time,
the design of individual therapy regimens.49 The availability of high-quality, specific antibodies or suitable
protein-binding ligands is the limiting factor for reliability of this technology. Post-translational modifications or protein–protein interactions of an individual
protein cannot be explained merely by measuring its
total concentration.
Circulating total DNA levels seem to correlate with
NSCLC stage; this strategy has the potential to assess
responses more accurately and quickly than radiologic
tests, and to confirm the prognosis of surgical resection
and therefore select patients for adjuvant therapy.50 Correlation of both total DNA baseline levels and temporal
trends during treatment with response to therapy and
overall survival is to be investigated in future studies.
RADIOTHERAPY
Stereotactic radiotherapy is a new and promising
approach to the treatment of early NSCLC or single
lung metastases. The consistency of the results, with
high local control rates of 80–100% and a very slight
incidence of symptomatic side-effects, is noteworthy.
Several authors who carried out hypofractionated stereotactic irradiation applied three to ten fractions, with
doses per fraction varying from 6 to 20 Gy.51,52 A recent
study used non-fractionated, single-dose irradiation (more
convenient for the patient) and obtained local control
rates of 90% with negligible side-effects. Two-year and
four-year survival rates were 63% and 39%, respectively,
with a median survival of 20 months. Stereotactic singledose irradiation could become an effective, non-invasive
alternative to conventional surgery in peripheral stage I
NSCLC.53
PHARMACOGENOMICS
It is quite evident in everyday practice how survival can
vary significantly between individual patients at the
same stage of disease. Thus there is an urgent need for
The future 269
factors to predict response to anticancer therapies.
These factors could be used prospectively to identify
subgroups of patients who would show a dramatic
response when treated with either standard chemotherapy regimens or targeted therapies, or a combination of
the two. Protocols designed to test the impact of a treatment driven by a tumor’s genetic profile represent the
next step of integration of clinical and basic research.
Increased expression of the ERCC1 (excision repair
cross-complementation group 1) gene is associated with
cisplatin resistance in a variety of human cancers including NSCLC.54 Therefore, low expression of ERCC1 by
the tumor could predict a benefit from cisplatin-based
chemotherapy. ERCC1 also seems to carry a prognostic
role per se, regardless of platinum therapy. In resected
patients with NSCLC, high ERCC1 expression predicts
a better survival; an intact DNA repair mechanism may
reduce the accumulation of genetic aberrations contributing to the malignant potential of cells. Future adjuvant
and neoadjuvant chemotherapy trials in NSCLC should
stratify patients according to their ERCC1 expression
levels. In advanced NSCLC patients treated with cisplatin plus gemcitabine, a response rate of 52% was seen in
tumors with low ERCC1 mRNA levels, while in those
with high ERCC1 levels the response rate was 36%. The
difference was not statistically significant; however, median
survival was 15 months for patients with low levels of
ERCC1 and only 5 months for those with high levels
(p <0.001).55 In a phase III trial 264 patients were randomized based on the ERCC1 levels: in the control arm
patients received docetaxel plus cisplatin, in the experimental arm they received either docetaxel plus cisplatin
if ERCC1 mRNA levels were low or docetaxel plus gemcitabine if ERCC1 levels were high. The response rate
for patients with low ERCC1 levels was 56% versus 40%
in the control arm (p = 0.02). When patients in the control arm were split according to the ERCC1 levels, those
with low ERCC1 levels had a response rate of 47% versus 26% in those with high ERCC1 levels. Time to progression and survival were significantly in favor of the
group with low ERCC1 levels.56
A recent retrospective report from 761 patients
within the adjuvant IALT trial showed that benefit from
cisplatin-based chemotherapy was associated with lack
of ERCC1, measured by immunohistochemistry (IHC)
as protein level in the tumor. On the other hand, among
patients who did not receive adjuvant chemotherapy,
high expression of ERCC1 was a positive predictive factor for survival.57
The ribonucleotide reductase M1 (RRM1) gene encodes
the regulatory subunits of RR, the molecular target of
gemcitabine. Lower expression of RRM1 predicted longer survival in gemcitabine-treated NSCLC patients.58
Moreover, low levels of RRM1 improved the prognosis
in NSCLC, especially if coupled with low ERCC1 levels.
The ERCC1 and RRM1 genes should be looked at as
reliable candidates for customized chemotherapy in
NSCLC patients treated with cisplatin/gemcitabine.59
Tumoral RRM1, as well as ERCC1 expression, is a major
predictor of response to cisplatin/gemcitabine.60
BRCA1 is a component of multiple DNA repair
pathways and functions as a differential regulator of
chemotherapy-induced apoptosis. BRCA1 abrogates
the apoptotic phenotype induced by a range of DNAdamaging agents, including cisplatin and etoposide, while
inducing dramatic responses to a range of antimicrotubule agents, including paclitaxel and vinorelbine.61 BRCA1
mRNA expression closely correlates with ERCC1 mRNA
expression, and predicts a more favorable outcome in
locally advanced NSCLC patients treated with cisplatin/
gemcitabine followed by surgery; median survival has
not been reached in patients with the lowest BRCA1
mRNA levels.62 Elevation of ERCC1 and BRCA1 is closely
related to high levels of RRM1, which is one of the principal mechanisms of resistance to gemcitabine.
Pooled data indicate that K-ras mutations could be
found in 20% of NSCLC, mainly in adenocarcinoma,
and predicted a poorer prognosis. Adjuvant chemotherapy with vinorelbine plus cisplatin, however, did not
confer any survival advantage in patients whose tumors
had K-ras mutations.63 K-ras mutations also have a role
in predicting lower response to EGFR tyrosine kinase
inhibitors (TKIs), such as erlotinib.64 Time to progression and survival were shorter for patients with K-ras
mutations receiving erlotinib than for those receiving
chemotherapy alone.
A proportion of NSCLCs shows overexpression of
estrogen and progesterone receptors; cross-talk between
estrogen receptors and EGFR pathways is another new
field of research. In NSCLC, EGFR expression is downregulated in response to estrogen and upregulated in
response to fulvestrant (an estrogen receptor antagonist), suggesting that the EGFR pathway is activated as
a consequence of estrogen depletion.65 Expression of
progesterone receptors was more frequently seen in
males, stage I disease, and adenocarcinomas, and had a
favorable prognostic impact.66
Thymidilate synthase (TS) is an enzyme involved in
DNA synthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine
monophosphate (dTMP).67 High TS levels are associated with poor prognosis or progression of disease stage
270 Textbook of Lung Cancer
in gastrointestinal, breast, and non-small cell lung carcinomas.68–70 TS is the target enzyme of 5-fluorouracil
(5-FU) and its expression is significantly related to the
response to 5-FU-based chemotherapy in gastric, colorectal, and breast carcinomas.71 Pemetrexed is a potent
inhibitor of TS, with a lower inhibitory potential for
glycinamide ribonucleotide formyltransferase (GARFT).
Pemetrexed is approved as a second-line chemotherapy
in advanced NSCLC and is currently undergoing phase
III clinical trials to be introduced as a first-line, platinumbased combination. Developments in the understanding of the mechanisms of resistance to pemetrexed and
the role of TS will likely improve its efficacy in selected
patients.
In vitro drug sensitivity data, coupled with Affymetrix microarray data, facilitated the development of gene
expression signatures that predicted sensitivity to individual chemotherapeutic agents. Each signature was
validated with response data from an independent set
of cell lines and was also able to predict sensitivity to
multidrug regimens.72 The development of gene
expression profiles that can predict response to commonly used cytotoxic agents is the key to maximizing
the efficacy of these agents and to finding the right way
to use them in combination with existing targeted
therapies.
Prospective clinical trials are still necessary to assess
whether the expression of RRM1, ERCC1, TS, and other
markers remains the same through all stages of disease.
Other key issues for the near future include better definitions of cut-off levels for such markers, the feasibility
of taking and immediately freezing core needle biopsies
for gene expression analysis, and research into new
molecular pathways that modulate response to anticancer agents.
TARGETED THERAPIES
Continuous progress in the understanding of tumor
biology has led to the identification of molecular pathways that drive tumor growth. Each step in the abnormal
signaling pathways represents a unique target for new
anticancer therapies. Future strategies will require the
selection of patients based on molecular targets peculiar
to each tumor and to each individual subject.
Agents targeting the EGFR family and the angiogenesis
process are the most promising options. The next
step forward will be achieved by successfully combining
such targeted therapies or by finding the most active
sequencing with chemotherapy regimens. Agents are
available which are able to block different growth pathways.
Investigations in several laboratories have demonstrated evidence of negative interactions between chemotherapeutic agents and EGFR TKIs in vitro and in
vivo. A schedule-dependent interaction between erlotinib and other chemotherapeutic agents active in the
G2/M phase (paclitaxel, vinblastine, and bortezomib) in
human NSCLC cell lines (H322 and A549) has been
demonstrated. In fact, pretreatment with erlotinib
caused G1 arrest and abrogated the action of chemotherapy, resulting in decreased cytotoxicity and decreased
apoptosis.73 Based on these results and those discussed
above, a model of sequence-specific interaction should
be evaluated. Intermittent dosing of chemotherapy and
EGFR TKIs was found to be superior to a continuous
concurrent dosing schedule.74
Data from interactions of chemotherapy and monoclonal antibodies are less clear, although there seems to
be an addictive effect. In the first-line treatment of
advanced stage NSCLC new clinical trials must be
designed with sequential schedules, such as administering chemotherapy for four cycles, followed by randomization to either an EGFR TKI or observation/
chemotherapy. One such study is a large phase III trial
in which patients with advanced stage NSCLC achieving disease control after platinum-based chemotherapy
are then randomized to erlotinib or placebo as maintenance therapy. A second trial will compare erlotinib
with pemetrexed or docetaxel in the second-line setting, and a third trial will compare erlotinib plus bevacizumab (a monoclonal antibody to vascular endothelial
growth factor, antiVEGF) with bevacizumab alone in
the first line as maintenance therapy after chemotherapy. Importantly, however, none of these trials will
select patients based on EGFR mutational status or
FISH copy number.
An interesting newer approach considers the combination of bevacizumab with other targeted therapies.
Results from a phase I/II study of bevacizumab plus
erlotinib in previously treated stage IIIB/IV NSCLC patients
showed encouraging median survival prolongation.75
VEGF can also play an important role in the response
to radiotherapy by enhancing endothelial cell survival,
a critical factor determining tumor radiation response.
Inhibition of VEGF impacts on tumor oxygenation and
proliferation. Preclinical studies of ZD6474 and other
antiangiogenic agents plus radiation therapy demonstrated the potential synergistic effect of the two modalities, pending the optimization of scheduling of these
combinations.76
The future 271
Identifying optimal dosing and scheduling of targeted therapies is another key issue. The availability of
surrogate markers of treatment effect could therefore
help in finding the right dosing and schedule. Plasma
VEGF level is one such marker. Increases in plasma
VEGF after administration of antibodies to VEGF receptors seem to be specific to antibodies, and were not
observed following VEGFR TKIs.77 Circulating endothelial progenitor cells (CEPCs), as well as markers released
by damaged endothelial cells (E-selectin and VCAM),
could be investigated.78 The normalization of elevated
CEPC levels after thalidomide treatment indicates the
importance of CEPC as a surrogate marker of response
to antiangiogenic therapy. In NSCLC patients, pretreatment circulating CEPC levels were significantly higher
compared with healthy controls, and a single measurement of CEPC by flow cytometry could be a useful tool
to predict the outcome of chemotherapy.79 Patients
with lower pretreatment CEPC levels respond better to
chemotherapy, presumably due to more ‘normal’ tumor
vessels. Patients with high pretreatment CEPC levels
could be treated with anti-VEGF therapy to lower CEPC
(i.e. ‘normalizing’ the vasculature) before shifting to
chemotherapy.
Protein kinases regulate almost all cellular processes
and represent key enzymes in the vascular endothelial
growth factor signaling cascade that can ultimately
induce tumor angiogenesis. The type C family of protein kinases (PKC) might become an important molecular target for cancer chemotherapy. PKC activation can
trigger signaling through the ras/extracellular signalregulated kinase (ERK) pathway, which may be involved
in the control of cellular proliferation and apoptosis.
PKC might regulate the phosphatidylinositol 3-kinase
(PI3K)/AKT pathway: cross-talk between PKC and the
PI3K/AKT pathway may be an attractive mechanism by
which PKC influences the apoptotic response. Enzastaurin, a potent novel PKC inhibitor, disrupts the
intrinsic phosphotransferase activity of PKC-β,80 and it
has been tested in human tumor xenografts, where it
decreased microvessel density and VEGF expression.81
Additionally, enzastaurin directly suppresses phosphorylation of GSK3β, ribosomal protein S6, and AKT,
thus supporting the notion that enzastaurin elicits an
antitumor effect by suppressing signaling through the
AKT pathway, directly inducing tumor cell death and
suppressing tumor cell proliferation. Data from a phase
I study indicate that enzastaurin 525 mg once daily is
the recommended phase II dose: evidence of early activity was seen with significant stable disease in a variety
of heavily pretreated solid cancers, including NSCLC.82
Given the distinct toxicity profile and molecular targets,
enzastaurin has the potential to be used in combination
with cytotoxic agents to enhance tumor cell killing.
VACCINES
NSCLC is a non-immunogenic cancer.83 However, preliminary results of recent vaccine studies designed
to enhance tumor antigen recognition have demonstrated encouraging efficacy in subsets of patients.84,85
Belagenpumatucel-L is a non-viral gene-based allogeneic tumor cell vaccine that demonstrates enhancement
of tumor antigen recognition as a result of transforming
growth factor beta-2 inhibition. In advanced NSCLC
patients at dose levels of 2.5 × 107 cells/injection, it
produced a surprising estimated two-year survival rate
of 47%. A correlation of positive clinical outcome with
induction of immune enhancement of tumor antigen
was observed.86
CONCLUSIONS
Targeted therapies offer a unique chance to strike cancer cells in a selective way. Targeting multiple pathways
simultaneously will be a way to overcome tumor growth
through alternate mechanisms. It is not clear which
agents should be combined in multitarget regimens. A
combination of COX-2 inhibitors (celecoxib) and gefitinib
in an unselected population of chemotherapy-naive
patients with advanced NSCLC had a lower response
rate and overall efficacy compared with historical controls of chemotherapy.87 An innovative strategy could
be to design an induction treatment with TKIs and
check for efficacy in a three to four week span to look
for sensitive patients. The correlation of EGFR mutations with responsiveness to small-molecule inhibitors of
EGFR further supports this idea. However, testing availability in everyday practice and costs of both genetic
tests and newer targeted therapies are an open issue.
Approaches that can measure early changes in the tumor,
such as functional imaging studies like PET, may be one
effective way to predict a response to therapy.
Novel therapeutic strategies should include maintenance treatment with targeted therapies and implementation of pharmacogenomic profiles in chemotherapy
clinical trials. Functional maps depicting the state of
key pathways within each patient’s tumor cells will
become the starting point to engineer individualized
therapies.
272 Textbook of Lung Cancer
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Appendix: Chemotherapy
Cristiana Sessa, Heine H Hansen
Contents • Glossary • Abbreviations • Alkylating agents • Platinum compounds • Antitumor
antibiotics • Antimicrotubule agents: Vinca alkaloids and taxanes • Topoisomerase II inhibitors:
Anthracyclines, anthracenediones, and epipodophyllotoxins • Topoisomerase I inhibitors:
Camptothecines • Antimetabolites: Antifolates and pyrimidine analogs • Miscellaneous agents
• Targeted therapy • Radiochemoprotectants • Growth factors and supportive treatment
GLOSSARY OF TERMINOLOGY USED IN CLINICAL
PHARMACOKINETICS
Absolute bioavailability is the fraction of drug
absorbed upon extravascular administration in comparison with the dose administered.
Area under the curve (AUC•) is a measure of the
quantity of unchanged drug absorbed and in the body,
calculated as the integral of drug plasma or blood levels
over time from zero to infinity.
Bioavailability (F) is the fraction of drug systematically
available, defined as both the fraction of the administered dose absorbed and the fraction of absorbed
dose reaching systemic circulation in the presence of a
first-pass effect.
Central compartment is the sum of all body regions
(organs and tissues) in which the drug concentration
is in instantaneous equilibrium with that in blood or
plasma. Blood or plasma is always part of the central
compartment.
Compartment is a mathematical entity that can be
described by a definite volume and a concentration of
drug contained in it. In pharmacokinetics, experimental data are explained by fitting them to compartmental
models.
Cumulative urinary excretion curves are plots of the
actual cumulative amounts of drug and/or its metabolites
excreted into urine versus time after administration.
Disposition is the loss of drug from the central compartment due to distribution into other compartments
and/or elimination and metabolism.
Dose or concentration dependence refers to a change
of one or more of the pharmacokinetic processes of
absorption, distribution, metabolism and excretion with
increasing dose or concentration.
Elimination (biological) half-life (t1/2) of a drug is
the time required for the drug levels (in blood,
plasma or serum) to decline by 50% after equilibrium
(between plasma and tissue) is reached. Loss of drug
from the body, as described by the biological half-life,
means the elimination of the administered parent drug
molecule (not its metabolites) by urinary excretion
(renal clearance), metabolism (metabolic clearance) or
other pathways of elimination (lung, skin, etc.). It
includes t1/2α (distribution) and t1/2β (terminal). For
drugs with a high tissue distribution (anthracyclines, platinum compounds), t1/2 also includes t1/2γ, which reflects
accumulation and slow release from third spare compartment. t1/2 may be influenced by dose, variation in
urinary excretion (pH), intersubject variation, age, protein binding, concomitant drugs, and liver and renal
functions.
Enzyme induction is an increase in enzyme content or
rate of enzymatic processes resulting in faster metabolism of a compound. It may increase clearance and
decrease biological half-life.
Enzyme inhibition is a decrease in the rate of metabolism of a compound, usually by competition for an
enzyme system. It may increase biological half-life and
decrease clearance of a drug.
First-pass effect is the phenomenon in which some
drugs are already metabolized (not chemically degraded)
between the site of absorption and reaching systemic
circulation. It may occur in the gut wall, mesenteric
blood and/or the liver, upon oral and deep rectal
administration.
*Adapted from Sessa C, Anticancer agents. In: Textbook of Medical Oncology, 2nd edn (Cavalli F, Hansen HH,
Kaye SB, eds). Martin Dunitz: London, 2000.
276
Textbook of Lung Cancer
Hepatic clearance (CLH) is the hypothetical volume of
distribution in liters of the unmetabolized drug that is
cleared in one minute via the liver. It depends upon
intrinsic hepatic clearance and liver blood flow.
Loading dose, Priming dose or Initial dose is the dose
used in initiating therapy so as to rapidly achieve therapeutic concentrations. The need for a loading dose
depends upon biological half-life, dosing interval and
therapeutic concentration to be achieved.
Mean residence time (MRT) is the average time that
the drug stays in the body or plasma.
Non-linear kinetics or Saturation kinetics refers to a
change in one or more of the pharmacokinetic parameters during absorption, distribution, metabolism or
excretion caused by saturation or overloading because
of increasing doses.
Peak concentration (Cmax) is the maximum concentration of a drug achieved in plasma or in blood after drug
administration.
Peripheral compartment is the sum of all body regions
(i.e. organs, tissues or parts of them) to which a drug is
eventually distributed, but is not in instantaneous equilibrium with the central compartment.
Plasma clearance (CL) can be defined as the volume of
plasma that is completely cleared of drug per unit time.
Protein binding is the phenomenon that occurs when a
drug combines with plasma protein to form a reversible
complex. Some drugs can be displaced from protein
binding by other compounds of higher affinity for the
protein-binding sites. Protein binding is of clinical significance (e.g. with regard to displacement, volume of
distribution and metabolism) when it exceeds 80–90%.
It is the unbound drug that is in equilibrium with the
biophase (FF).
Renal clearance (CLR) is the hypothetical plasma volume in liters (volume of distribution) of the unmetabolized drug that is cleared per unit time via the kidney.
Renal clearance is affected by renal blood flow, urinary
pH, and the net effects of tubular reabsorption and
secretion.
Steady-state concentration (Css) is the concentration
of drug in blood and tissue upon multiple dosing when
input and output are at equilibrium or during a constant-rate intravenous infusion.
Time to peak concentration (Tmax) is the time until
Cmax is reached from drug administration.
Total body clearance (CLb) is an overall measure of
the body’s drug removal rate. CLb is the result of all drug
removal processes, including renal clearance of the
unchanged drug and metabolic clearance. CLb is the
hypothetical volume of distribution in liters of the unmetabolized drug that is cleared per unit of time (l/min or
l/h) by any pathway of drug removal (renal, hepatic and
other pathways of elimination); it is a proportionality
constant relating absorbed dose and steady-state blood,
plasma and serum concentration.
Volume of distribution (Vd) is the hypothetical volume
of body fluid that would be required to dissolve the total
amount of drug at the same concentration as that found
in blood or plasma. It is a proportionality constant that
relates the amount of drug in the body to the serum or
plasma concentration.
ABBREVIATIONS
Drugs
5-CHO-FH4: 5-formyltetrahydrofolate (leucovorin)
5-FU: 5-fluorouracil
Ara-C: cytarabine
ATRA: all-trans-retinoic acid
BLM: bleomycin
CCNU: lomustine
CPT-11: irinotecan
CTX: cyclophosphamide
dFdC: difluorodeoxycytidine (gemcitabine)
DHAD: mitoxantrone
EPI: epirubicin
FT: ftorafur
HMM: hexamethylmelamine
HN2: mechlorethamine
HU: hydroxyurea
IFO: ifosfamide
LV: leucovorin
MGA: megestrol acetate
MMC: mitomycin C
MPA: medroxyprogesterone acetate
MTX: methotrexate
VCR: vincristine
VLB: vinblastine
VM-26: teniposide
VP-16: etoposide
Other abbreviations
ADA: adenosine deaminase
ADCC: antibody-dependent cell-mediated cytotoxicity
Appendix: Chemotherapy
AICAR: aminoimidazole carboxamide ribonucleotide
transformylase
ANC: absolute neutrophil count
AP: alkaline phosphatase
AR: androgen receptor
Ara-CTP: cytarabine triphosphate
Ara-U: uracil arabinoside
AST: aspartate transarinase
AUC: area under the curve, concentration X time
BM: bone marrow
CDC: complement-dependent cytotoxicity
CdR kinase: deoxycytidine kinase
CH2-FH4: reduced-folate cofactor
CHF: cardiac heart failure
CI: continuous infusion
CL: clearance
CNS: central nervous system
COPD: chronic obstructive pulmonary disease
Cr: creatinine
CR: complete remission
CSF: cerebrospinal fluid
Css: steady-state concentration
Cyd deaminase: cytidine deaminase
CYP450: cytochrome P450
dATP: deoxyadenosine triphosphate
dCTP: deoxycytidine-5′-triphosphate
dFdCTP: difluorodeoxycytidine triphosphate
dFdU: difluorodeoxyuridine
DHFR: dihydrofolate reductase
DL: dose-limiting
dNTP: deoxynucleotide triphosphate
DPD: dihydropyrimidine dehydrogenase
dTTP: deoxythymidine triphosphate
DVT: deep venous thrombosis
F-DHU: 5-fluorodihydrouracil
FdUMP: 5-fluoro-2′-deoxyuridine 5′-monophosphate
FH4: reduced folates
FPGS: folylpolyglutamate synthethase
FUMP: 5-fluorouridine 5′-monophosphate
FUTP: 5-fluorouridine 5′-triphosphate
GAR: glycinamide ribonucleotide transformylase
G-CSF: granulocyte colony-stimulating factor
GFR: glomerular filtration rate
GM-CSF: granulocyte–macrophage colony-stimulating
factor
H2O2: hydrogen peroxide
HAI: intrahepatic arterial infusion
277
HGPRTase: hypoxanthine–guanine phosphoribosyl
transferase
HSR: hypersensitivity reaction
HZ: herpes zoster
IFN: interferon
IL: interleukin
i.t.: intrathecal
LFTs: liver function tests
LVEF: left ventricular ejection fraction
MDR: multidrug resistance
mFBP: membrane folate-binding protein
MMR: mismatch repair
MTD: maximum tolerated dose
MTIC: 5-(3-methyl-1-triazeno)-imidazole-4-carboxamide
NAD: nicotinamide adenine dinucleotide
N&V: nausea and vomiting
NSAID: non-steroidal anti-inflammatory drug
NV: normal value
O−2: superoxide
O6-AT: DNA-O6-alkylguanine-DNA alkyltransferase
OH: hydroxyl radical
PALA: N-phosphonocetyl-l-aspartate
PB: premature beats
PBSC: peripheral blood stem cell support
PDGF: platelet-derived growth factor
PE: pulmonary embolism
PEG: polyethylene glycol
P-gp: P-glycoprotein
PK: pharmacokinetics
PKC: protein kinase C
plt: platelets
PRPP: phosphoribosyl pyrophosphate
PS: performance status
PT: prothrombin time
pts: patients
PTT: partial thromboplastin time
RAR: retinoic acid receptor
RBC: red blood cells
RIA: radioimmunoassay
RNR: ribonucleotide reductase
RT: radiotherapy
TE: thromboembolic
Topo: topoisomerase
TS: thymidylate synthase
VOD: veno-occlusive disease
WBC: white blood cells
PO well absorbed;
biphasic plasma disappearance with T1/2β of
4–6.5 h after 6–80 mg/
kg; renal excretion of
metabolites; high degree
of interpt. Variation in
metabolism; only CTX
measured in CSF.
Hepatic CYP450
activation to highly
reactive metabolites
(acrolein: bladder
irritant; phosphoramide mustard:
alkylating moiety)
causing DNA-interstrand cross-links.
Cyclophosphamide
(CTX) Endoxana®
Cyclic phosphamide
ester of HN2.
Special populations
Renal impairment
Cr CL <20 ml/min: ↓
dose 50–75%.
Chemical transformation
into highly reactive
compounds, rapidly
bound to tissues; degradation by spontaneous
hydrolysis; PK not
studied.
Pharmacology and dose
modifications
Prototype of bifunctional alkylating
agent: covalent bond
of the alkyl group to
N7 of guanine with
formation of DNAinterstrand crosslinks between two
guanines located in
the opposite strands.
Mechanism of action
Meclorethamine (HN2)
Mustargen®
Nitrogen mustard
Name, chemistry, relevant
features
ALKYLATING AGENTS
With CYP450
inducers: potential but of
unknown clinical
relevance (barbiturates) or
blockers (glucocorticoids);
detoxification
with MESNA.
Drug interactions
Toxicity
IV HD: 7000 mg/m2
(MTD) (IV hydration +
MESNA).
Thrombocytopenia;
SIADH (more common
at > 50 mg/kg); cardiotoxicity (↑ incidence in
case of prior anthracyclines, large single
infusions, glutathionedepleting agents).
Local vesicant on
Neutropenia and
extravasation.
thrombocytopenia
In case of leakage:
(after about 8 days,
infiltration of the area
for 10–20 days); acute
with sterile isotonic Na severe prolonged N &
thiosulfate (1/6 molar)
V; phlebitis; rare
and application of ice
severe allergic reaccompresses for 6–12 h. tions; maculopapular
IV: 0.4 mg/kg (10–12
rash.
2
mg/m ) every 4–6
weeks; 6 mg/m2 days 1
and 8 every 4 weeks
(MOPP).
PO: 50–100 mg/m2
DL neutropenia after
8–14 days, recovering
daily
within 10 days; N & V
2
(delayed with IV
IV: 1000–1500 mg/m
therapy); alopecia;
every 3 weeks
hemorrhagic cystitis
(prevented by adequate
pre- and
posthydration).
Route, schedule, and
recommendations
278
Ifosfamide (IFO)
Mitoxana®
Analogue of CTX;
oxazophosphorine HN2.
In comparison with
CTX, slower hepatic
activation to acrolein
and active ifosforamide mustard
(which causes
DNA-interstrand
cross-links) and
higher proportion of
inactive dechloroethylated metabolites.
Special populations
Renal impairment
Cr CL < 20 ml/min ↓
dose 50–75%.
High degree of interpt.
intrapt. variability of PK
and metabolism. T1/2
15 h, 60% of dose as
unchanged drug in urine
after single doses of 5 g/
m2.
Induction of IFO metabolism after 3 days of IV
bolus or CI treatment
with increase of CL due
to production of dechloroethylated species;
decreased urinary
fraction (12–18% of
dose) of unchanged IFO
after repeated doses.
Comparable serum AUCs
and urinary fractions of
IFO and metabolites after
IV bolus and CI administration; no effect of DXM
on IFO metabolism.
see CTX
With nephrotoxic
drugs: (DDP) ↑
renal damage
With CNS active
agents: (including
narcotics, some
antiemetics): ↑
CNS toxicities,
methylene-blue to
reverse and
prevent CNS
toxicities.
IV HD (CI): 3–4 g/m2
on days 1–4 (MTD).
Adequate hydration
before, up to 72 h
after to avoid hemorrhagic cystitis.
IV: short (1–3 h inf.)
or CI: 1.2–1.5 g/m2
days 1–3 or days 1–5
every 3–4 weeks; 24 h
CI: 5 g/m2.
(Continued)
DL hemorrhagic
cystitis prevented with
hydration and
MESNA; 50% myelosuppression with
cumulative anemia;
>50% N & V; >80%
alopecia; 12% CNS
toxicity with confusion, lethargy, seizures, hallucinations,
possibly due to
inactive metabolites, ↑
CNS toxicity in
elderly/pts with renal
impairment; 60%
nephrotoxicity
(tubular), ↑ risk in
children.
Similar toxicities, but
of ↑ incidence
and degree.
279
Toxicity
PO: N & V if given
undiluted; in case of V
within 1 h, redose IV.
False ↑ of urinary
chetones.
HSR with skin reaction, itching, edema,
rare anaphylaxis.
Route, schedule, and
recommendations
IFO IV short infusion:
60% daily total dose
divided in 3 doses
(each 20%) 15 min
before (always IV), 4
and 8 h later (40%
single dose if given
PO).
IFO CI: same equal
dose (directly mixed),
continue up to 12 h
after the end of IFO.
CTX-HD (>10 mg/kg)
2–3 h infusion: 100%
daily total dose in
repeated doses each
20% total dose, first
dose always IV 15 min
before CTX, then every
6 h from start up to
24 h from end.
Drug interactions
Incompatible in
solution with DDP;
does not affect the
antitumor activity
of other cytotoxic
agents.
Caution
↑ risk of urinary
toxicity in pts with
prior pelvic RT,
urinary infection,
and prior hemorrhagic cystitis.
Pharmacology and dose
modifications
Dimerization in blood to
the inactive disulfide
dimesna, reduced back to
mesna in renal tubules
and excreted in urine;
10% protein bound.
40% and 30% urinary
excretion of free-thiol
mesna after IV and PO
administration; lower but
more prolonged (between
12 and 24 h) urinary
excretion of free-thiol
mesna after PO administration than IV.
Mechanism of action
Selective urinary tract
protectant for oxazophosphorine-type
alkylating agents by
binding of the SH
moiety to acrolein.
Name, chemistry, relevant
features
Mesna
Sodium mercaptoethane
sulfonate
Uromitexan®
IV formulation.
280
Polyfunctional
alkylating agent with
three aziridine
groups. Intracellular
release of aziridine
and generation of
ethylenimonium ions
acting as monofunctional alkylating
agents; the different
functional groups
induce DNA-interstrand cross-links.
Still unknown,
possibly DNA alkylation; structurally
similar to triethylenemelamine.
Thiotepa
N, N′, N″-triethylenethiophosphoramide; can be administered by any parenteral route.
Hexamethylmelamine
Altretamine
Hexalen®
Triazene ring with dimethylamino groups at each of the
three carbons.
Ethylenimines
40% protein bound; rapid
activation by CYP450 to
main metabolite TEPA,
less cytotoxic and with
longer terminal T1/2 (5 h);
24% of dose excreted in
24 h urine. Possible
metabolic saturation at
highest doses studied
(6–7 mg/kg). Advantages
of IT over IV administration still to be verified.
After IV, CSF levels
equivalent to those in
plasma.
Special populations
Liver impairment
No guideline available but
use with caution.
>90% protein bound;
variable PO absorption
with T1/2 of 0.5–3 h. Rapid
demethylation by
microsomal CYP450;
T1/2β 3–10 h; 60–70% of
dose in 24 h urine as
metabolites.
IV bolus: 0.3–0.4
mg/kg every 1–4 weeks
IV HD: 500–1125 mg/m2
(MTD: 1000 mg/m2)
Intrapleural, intrapericardial: 60 mg at ≥1 week
interval.
Intravesical: 30–60 mg/
week ×4.
IT: 15 mg at ≥1 week
interval.
PO: single agent, 260
mg/m2 on days 1–14
every 4 weeks; combination, 150–200
mg/m2 on days 1–14
every 4 weeks (four
divided daily doses).
Inhibition of
pseudocholinesterase
activity with ↑ effect
of succinylcholine.
↑ absorption from
body cavities in
presence of infiltration/inflammation of
mucosa
(radiotherapy).
With CYP450
inducers: (phenobarbitone) with ↓
antitumor effect.
With concomitant
IMAO: severe
orthostatic hypotension.
(Continued)
DL N & V ↓ if
taken after meals;
cumulative CNS
somnolence,
mood disorders,
hallucinations,
dizziness; peripheral neuropathy
mainly sensory;
reversible mild
leukopenia.
Dose related and
cumulative
myelosuppression
with short WBC
and longer Pt
nadir; DL
mucositis,
hyperpigmentation of skin,
hepatotoxicity;
confusion,
somnolence. Rare
myelosuppression.
Lower abdominal
discomfort,
bladder irritability.
281
Glucosamine-1methyl nitrosourea;
water soluble.
Streptozocin
Zanosar®
Chloroethylcyclohexylnitrosourea.
CCNU
Lomustine®
Nitrosoureas
Name, chemistry,
relevant features
DNA methylation;
carbamoylation of
proteins through
isocyanate molecules; inhibition
of O6-AT; inhibition of key
enzymes in gluconeogenesis.
Mechanism of action
Special populations
Renal impairment
Cr CL <25 ml/min: ↓
dose by 50–75%.
Rapid and extensive
metabolism; no intact
drug after 3 h; prolonged
T1/2 of metabolites.20% of
dose in 24 h urine as
metabolites; BBB rapidly
crossed.
Rapid absorption,
decomposition and
metabolism in liver with
parent drug never
detectable; Cmax of
metabolites within 3 h.
50% of dose in 12 h
urine as degradation
products; >30% plasma
levels in CSF.
Pharmacology and dose
modifications
↑ risk of nephrotoxicity with potentially
nephrotoxic drugs; ↑
risk glucose intolerance with corticosteroids;↑ effect of
DNA-reactive anticancer agents through
inactivation of 06-AT;
prolongation of the
T1/2 of DOX requiring
its dose reduction.
Drug interactions
Toxicity
Delayed (after 3–6
weeks) potentially
cumulative myelosuppression; acute N & V;
mild reversible hepatic
toxicity; ↑ risk of second
malignancy after longterm therapy.
Rare, cumulative (after
1100 mg/m2) pulmonary
fibrosis, possible delayed
onset (>10 years after) in
cured children having
received cranial RT.
Local vesicant on
DL cumulative nephroextravasation.
toxicity due to tubular
damage with proteinuria,
IV (30–60 min inf.):
glycosuria, and hyposingle agent: 1 g/m2 every
phosphatemia; acute
week ×4–6 weeks with
severe cumulative
4-week rest; combination;
N & V; occasional
500 mg/m2 on days 1–5
diarrhea and hepatoxicity
every 6 weeks.
with ↑ LFTs and hypoWarning
albuminemia; acute
Adequate hydration
hypoglycemia; burning
before and after each
pain in the vein; mild
course and monitoring of myelosuppression and
renal function (serial
hepatotoxicity.
urinalysis for proteinuria).
PO: 100–130 mg/m2
(single agent) every 6–8
weeks on empty stomach.
Route, schedule, and
recommendations
282
Imidazotetrazine
derivative; analog
of DTIC; methyl
derivative of
mitozolamide.
Temozolomide
Temodal®
Imidazotetrazines
Prodrug; converted
to cytotoxic MTIC
through chemical
process (instead of
metabolic activation
as for DTIC). ↑
induction of
O6-alkylguanine
adducts with
depletion of O6-AT;
schedule-dependent antitumor
activity.
Special populations
Renal impairment
No guideline available but
caution in pts with severe
impairment.
100% F reduced by food,
rapidly absorbed within 1 h;
T1/2β 1.8 h, linear PK. Wide
tissue distribution; crosses BBB
(30% ratio CSF/plasma AUC).
No accumulation with daily
dosing; clearance not affected
by anticonvulsants (with
exception of valproic acid), H2
blockers, barbiturates, DXM but
5% lower in women with
greater myelosuppression.
Possible synergism
with antitumor
agents with similar
mechanism of
action to deplete
O6-AT; possible
synergism with
ionizing radiations.
(Continued)
PO: 150–200 mg/m2 on days DL myelotoxicity
(mainly neutropenia
1–5 every 4 weeks (fasting,
and thrombocytopenia)
single-dose).
with delayed nadir >20
Heavily pretreated pts: 150
days and recovery in
mg/m2 on days 1–5 every 4
7–14 days; 50%
weeks; non-heavily pretreated
N & V (severe 10%);
adult and pediatric pts: 200
30% fatigue and
mg/m2 on days 1–5 every 4
malaise.
weeks. Dose reductions by
50 mg/m2 daily according to
ANC/Pt nadirs, do not
reduce below 100 mg/m2.
283
Special population
Age
↑ risk neurotoxicity
in >65 years due to ↓
renal function.
Renal impairment
Cr CL 50–70 ml/min:
use Mannitol and
increase hydration to ↑
diuresis.
Cr CL <50 ml/min: use
with caution.
Could delay excretion of
drugs eliminated through
kidneys (MTX, BLM,
IFO).
90% protein bound;
active species produced
within the cell by
aquation hydrolysis.
Triphasic disappearance
of total platinum with
T1/2γ of 5.4 days and
high tissue distribution.
90% renal excretion
mainly by glomerular
filtration; 40% of dose
excreted in 24 h urine;
poor CSF penetration.
DNA binding of
aquated species
with formation of
DNA inter-/
intrastrand crosslinks; binding to
SH groups of
critical enzymes.
Mechanisms of
resistance include
↓ cellular drug
accumulation,
cytosolic inactivation by thiol-containing
compounds,
enhancement of
DNA repair,
overexpression of
some proto-oncogenes and loss of
DNA MMR
enzymes.
Cisplatin (DDP)
Cis-diamminedichloroplatinum (II)
Inorganic planar coordination
complex.
IV (30–60 min inf.):
standard dose
50–100 mg/m2 every
3 weeks; 20 mg/m2
on days 1–5 every 3
weeks, with pre-/
posthydration to ↑
diuresis and prevent
renal toxicity.
Route, schedule, and
recommendations
With taxanes: ↑ incidence
of peripheral neuropathy. HD: 120 mg/m2
single day every 3
weeks, 40 mg/m2 on
days 1–5 every 3
weeks (with hypertonic saline; nephroprotective agents).
IP: 90–270 mg/m2
(with pre-/posthydration).
With concomitant
SH-containing agents
(sodium thiosulfate,
amifostine, glutathione):
↓ renal toxicity.
With concomitant
nephrotoxic drugs
(aminoglycosides,
amphotericin B): ↑ renal
toxicity.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant features
PLATINUM COMPOUNDS
Same toxicities but ↑
incidence and
degree; dose-dependent high-frequency
hearing loss and
myelotoxicity
(anemia); rare, focal
encephalopathy and
retinal toxicity.
Dose-dependent,
early (after 1–24 h)
severe and delayed
(after 24–120 h) N
& V; acute tubular
damage with hypomagnesemia; cumulative subclinical
tubular damage with
↓ Cr CL; cumulative
peripheral sensory
neuropathy (paresthesias, sensory
loss) slowly reversible; 30% irreversible.
Toxicity
284
Second-generation platinum
compound; 10-fold more
water soluble than DDP.
Carboplatin (CBDCA)
1,1-Cyclobutanedicarboxylato
(2-)-0, 0-platinum (II).
Carboplatin NP
Paraplatin®
Same as that of
DDP; slower
reactivity with
DNA and lower
potency than
DDP; mechanisms
of resistance
possibly similar to
those of DDP.
Special population
Renal impairment
Doses are based on Cr
CL as estimate of GFR
(Calvert formula).
Lower relative rate of
activation than DDP;
T1/2 of ultrafilterable
platinum of 170 min;
triphasic disappearance
of total platinum with
T1/2β and T1/2γ of 1.5 h
and 5.8 days; 30%
plasma levels in CSF
after IV treatment; 70%
of dose as parent in
24 h urine; plasma
clearance of ultrafilterable species correlated
to GFR.
Dose modifications
Calvert formula
Adults: total dose (mg) =
target AUC × (GFR* +
25); pretreated pts AUC:
4–6 mg/ml/min;
untreated pts AUC: 6–8
mg/ml/min.
Children: total dose: (mg)
= target AUC × (GFR* +
0.36 × BW (kg)).
*GFR as estimated by
51
Cr-EDTA or 24 h urine
collection or CockcroftGault equation).
HD: Single agent,
2000 mg/m2 (MTD)
(with hydration);
combination, AUC
11–20 mg/ml × min.
Standard dose
adult untreated pts/
Calvert formula;
single agent, AUC
6–8 mg/ml/min
every 3–4 weeks;
combination, AUC
4–5 mg/ml/min
every 3–4 weeks
(without hydration)
IV (30–60 min inf):
(Continued)
DL hepatotoxicity,
nephrotoxicity with
loss of serum electrolytes, reversible
vision loss.
DL cumulative
thrombocytopenia
after 2–3 weeks,
recovering within 2
weeks; moderate
N & V after 6–12 h;
myelotoxicity,
cumulative peripheral neuropathy;
allergic reactions
after very high
cumulative doses, no
cross-reactivity with
DDP; transient ↑
hepatic enzymes.
285
Drug interactions
Additive or synergistic
effects in vitro and in vivo
with 5-FU, TS inhibitors,
CPT11.
Incompatible with normal
saline, alkaline solution
(5-FU).
Pharmacology and dose
modifications
95% protein bound; at
the end of inf. 50%
accumulated (nonexchangeable) in RBC
and 50% in plasma
(33% ultrafilterable);
triphasic disappearance
of ultrafilterable
platinum with T1/2β and
T1/2γ of 16.3 h and 273
h; 54% of dose in 48 h
urine. High CL by
tissue binding and renal
CLR (34%) correlated
with GFR. Extensive
non-enzymatic
biotransformation to
cytotoxic/non-cytotoxic
species. ↑ AUC of
ultrafilterable platinum
if Cr CL <60 ml/min.
No need of ↓ dose if Cr
CL > 20 ml/min. No
accumulation of total
plasma platinum with
repeated administrations.
Mechanism of action
Same as that of
DDP with bulkier
DNA adducts;
activity in cancer
cell lines and
murine models
resistant to DDP
because of deficiency of MMR
activity and
enhanced replicative bypass.
Name, chemistry, relevant features
Oxaliplatin
Eloxatin®
Trans-1-diaminocyclohexane
oxalatoplatinum.
Toxicity
DL peripheral
neuropathy (mainly
hands/feet and
perioral) of 2 types:
Type 1: acute early
onset, reversible
within 14 days,
sensory, enhanced
by cold contact;
Type 2: persistent >
14 days paresthesia,
dysesthesia, and
deficit in propioception with functional
impairment, cumulative, reversible at
discontinuation
(complete recovery
only in 41% within
8 months).
Incidence overall
neuropathy single
agent: 82%, persistent 19%, with
functional impair
ment 12%; 10% and
50% of risk of
developing it after 6
and 9 cycles; 65% N
& V (gr 3–4 11%),
30% diarrhea (gr
3–4 4%), 10%
neutropenia. Rare:
HSR.
Route, schedule, and
recommendations
IV (2 h inf.):
single agent,
130 mg/m2 every
3 weeks;
combinations,
85 mg/m2 every
2 weeks.
286
*mg = unit.
IV bolus:
10–20 mg/m2*
per week.
IM, SC: same dose
as IV, with antipyretics/steroids to
prevent fever.
IV CI: 5–10 mg/m2
on days 1–4 every
3 weeks.
Intrapleural:
60–120 U (50% of
dose in the systemic circulation).
Avoid NSAID
against chest pain.
↑ risk of pulmonary toxicity with
hyperoxia, concomitant RT, nephrotoxic drugs with ↓
excretion of BLM.
10% protein bound;
T1/2 of 2–3 h; rapid
tissue inactivation,
lower in skin and
lung with 50% of
dose in 24 h urine,
mainly as inactive
species. Cmax with IM
administration after
30–60 min, 1/3 of
that after IV; 45%
systemic absorption
after intrapleural
administration.
DNA binding with
production of single and
double-strand breaks;
DNA damage affected by
specific repair enzymes,
glutathione, ionizing
radiation. BLM inactivated by BLM hydrolase;
pulmonary toxicity due
to low enzyme concentration and high O2
tension. When used
intrapleurally acts as
sclerosing agent.
Bleomycin sulfate
(BLM)
Mixture of sulfur-containing glycopeptides;
formed by a DNAbinding fragment and
an iron-binding
portion. Activation
through O2 binding.
Special population
Renal impairment
Cr CL ≤30 ml/min:
↓ dose by 50%.
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
ANTITUMOR ANTIBIOTICS
(Continued)
IV: acute DL stomatitis; 50%
fever and chills; 50% cumulative skin hyperpigmentation.
Mild to moderate alopecia.
Rare, HSR (1% of lymphoma
pts) and Raynaud’s phenomenon.
Low-dose hypersensitivity
pneumonitis responsive to
steroids. 10% late chronic
pneumonitis up to irreversible
interstitial fibrosis (dry cough,
dyspnea, rales, basilare infiltrates), ↑ incidence for cumulative dose >250 U, age
>70 years, COPD, thoracic RT,
hyperoxia during surgical
anesthesia; role of steroids
uncertain.
Toxicity
287
Special population
PK unchanged
if liver/renal
impairment.
DNA intercalation of the 5% protein bound; by
Dactinomycin
RIA, biphasic disapplanar multiring phe(DACT)
®
pearance with T1/2 of
noxazone between
Cosmegen Lyovac
guanine-cytosine
base
35 h, longer in case
Phenoxazine pentapeppairs with inhibition of
of liver impairment;
tide antibiotic.
RNA synthesis.
minimally metaboRadiosensitizer.
lized, does not cross
BBB; 30% of dose in
urine and feces as
intact drug within 1
week.
Purple antibiotic
isolated from Streptomyces caespitosus.
Unexpected hepatic
toxicity after
hepatotoxic agents
(halothane, enflurane).
Rapid plasma disap- With concomitant
DOX: ↑ risk of
pearance due to
cardiotoxicity.
tissue distribution
and liver metabolism;
T1/2β: 25–90 min;
<10% of dose in 24 h
urine, 23% hepatic
extraction with HAI
administration.
Activation to bifunctional alkylating agent
with formation of DNA
interstrand cross-links
and oxygen free radicals.
Activation by chemical
reducing agents, enzymatic reduction, exposure to acidic pH.
Possible preferential
activation in hypoxic
environment.
Mitomycin C (MMC)
Mitomycin C Kyowa®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Delayed (after 3–8 weeks)
cumulative leuko- and thrombocytopenia, cumulative
anemia; partial alopecia. Rare:
HUS with thrombocytopenia,
renal and cardiac failure: ↑ risk
for cumulative dose >50 mg,
exacerbated by RBC transfusions, rarely reversible, steroids
ineffective (52% lethal). Rare,
severe interstitial pneumonitis
with lung infiltrates.
Local vesicant on
extravasation.
DL myelotoxicity with leukoand thrombocytopenia in 1
week and nadirs up to 3 weeks.
IV (bolus): single
Severe prolonged (up to 24 h)
agent, 500 µg
N & V; 30% stomatitis and
(max. 15 µg/kg) on
diarrhea; alopecia; late radiadays 1–5 every 4
tion recall toxicity (mainly skin,
weeks; combinabut also GI, liver, lung).
tion, 500 µg on
Immunosuppression.
days 1–2.
Local vesicant on
extravasation.
IV bolus: single
agent, 20 mg/m2
every 6–8 weeks;
combination,
10 mg/m2 every
6–8 weeks.
Intravesical:
20 mg × 3 per
week.
Toxicity
Route, schedule, and
recommendations
288
Mechanism of action
Sulfate salt of a dimeric
alkaloid from Catharantus
rosea.
As VLB with formyl side
chain on vindoline.
Vincristine sulfate (VCR) Same as that of VLB.
Vincristine NP
Oncovin®
vinca alkaloids
Vinblastine sulfate (VLB)
Vinblastine NP
Velbe®
Binding to a specific
site on tubulin with
prevention of polymerization, inhibition
of microtubule
Sulfate salt of a dimeric
assembly and mitotic
alkaloid from Vinca rosea;
spindle formation.
formed by two multiringed
Involved in MDR
units (catharanthine and
phenomenon through
vindoline) with methyl side
P-gp overexpression.
chain on vindoline.
Name, chemistry, relevant
features
ANTIMICROTUBULE AGENTS
Special population
Liver impairment
Bilirubin up to 3 mg/ml:
50% ↓ dose.
Special population
Liver impairment
↓ Dose if obstructive liver
disease.
48% protein bound;
rapidly distributed into
tissues with triphasic
disappearance; liver
metabolism with 70% of
dose in 72 h feces.
80% protein bound;
rapidly distributed into
tissues with triphasic
disappearance (T1/2γ 19–25
h); partially metabolized in
liver to deacetyl VLB; 80%
of dose excreted
unchanged in bile.
Pharmacology and dose
modifications
↑ accumulation
of MTX in
tumor cells.
Drug interactions
Toxicity
IV bolus: 0.4–1.4 mg/m2
(maximum 2 mg total
dose) per week.
IV CI: single agent, 0.5
mg/m2 on days 1–5;
combination, 0.4 mg/m2
days 1–4 (VAD regimen) every 3 weeks.
Local vesicant on
extravasation.
(Continued)
DL cumulative neurotoxicity, with peripheral neuropathy
(paresthesias, loss of
deep tendon reflexes);
less frequent, autonomic effects with
abdominal pain and
constipation; ↑ incidence if underlying
neurological problems);
20% alopecia. Rare:
SIADH.
DL leucopenia after
5–10 days, recovering
2
IV (bolus): 4 mg/m for within 7–14 days. Neurotoxicity with constistarting, increased to
pation and abdominal
6 mg/m2 per week.
Prophylaxis of constipa- pain; less frequent,
peripheral neuropathy,
tion: use lactulose.
jaw pain, urinary
retention ↑ incidence if
underlying neurological problems; stomatitis
and mild alopecia.
Local vesicant on
extravasation
Route, schedule, and
recommendations
289
Mechanism of action
Vinorelbine (NVB)
Navelbine®
Same as VLB; ↓
activity on axonal
microtubules with
Semisynthetic derivative of
possibly ↓ neurotoxVLB with structural modifiicity.
cations on the catharanthine ring.
Name, chemistry, relevant
features
Special population
Liver impairment
Bilirubin > 2 × NV: ↓ dose
by 50%.
80–90% protein bound;
rapid tissue distribution
with triphasic disappearance (T1/2γ 27–40 h); high
liver uptake; hepatic
metabolism by CYP3A in 2
metabolites, 1 active
(desacetyl metab.); main
hepatic excretion. PK
unchanged by age; F, mean
27% ± 14; Cmax after 1.5 h
and large first pass effect.
No food effect on os
absorption.
Pharmacology and dose
modifications
Potential
interactions
with inducers/
inhibitors of
CYP3A.
Drug interactions
IV (5–10 min inf.):
single agent, 30 mg/m2
weekly with ↓ dose
according to myelotoxicity; combination, 25
mg/m2 weekly with
cisplatin every 4 weeks.
PO soft-gel capsules: 60
mg/m2 per week per 3
weeks, then ↑ 80 mg/m2
per week if no severe
neutropenia.
Local vesicant an
extravasation.
Route, schedule, and
recommendations
DL non-cumulative
neutropenia (90%;
36% G 4) after 7–10
days, recovering within
7–14 days; 25%
peripheral neuropathy
(paresthesia) with
decreased deep tendon
reflexes; 35% constipation; 40% N & V (2%
severe); 12% alopecia;
10% chemical phlebitis; 27% fatigue.
PO: 50% N & V (15%
severe); >50% diarrhea;
6% G2–4 neutropenia.
Toxicity
290
Promotes microtubule
assembly of tubulin
dimers and stabilizes
microtubule dynamics
Diterpene from
with inhibition of cell
bark and leaves of
proliferation, blockade
Taxus brevifolia;
of mitosis, and inducpoorly water
tion of apoptosis.
soluble, need of
Resistance related to
vehicle with 50%
P-gp overexpression and
polyoxyethylated
mutations of tubulin,
castor oil (Cremoslower rate of microtuphor EL) and
bule assembly, overex50% ethanol.
pression of Bcl-2.
↑ in vitro cytotoxicity
after longer exposure
time.
In vitro sensitizing effect
to ionizing radiation.
Effective in vitro concentrations
(≥0.1 µmol/1)
achieved in humans
at the end of infusion.
Taxanes
Paclitaxel
Taxol®
Special populations
Liver impairment
Liver enzymes >2 <10 × NV
or bilirubin 2–5 × NV: ↓
dose to 90 mg/m2 (3 h inf.).
Renal impairment
no need of dose ↓.
>90% protein bound; rapid
tissue uptake with triphasic
plasma disappearance and
extensive liver metabolism at
the taxane ring through
CYP2C8 and CYP3A4; main
metabolite inactive 6-OH
paclitaxel. High biliary
secretion and low intestinal
absorption of paclitaxel and
metabolites. Non-linear PK
in humans, mainly caused by
Cremophor EL; Cmax and
AUC not proportional to
dose, because of saturable
distribution, metabolism, and
elimination. Neutropenia
related to the time plasma
concentrations of ≥0.05–0.1
µmol/l are maintained. Does
not cross BBB.
After IP treatment: low Vd,
slow peritoneal CL, prolonged significant IP and
plasma concentrations.
In vitro effects on
metabolism of
concomitant
CYP450 isoenzyme substrates
(cyclosporin,
steroids, macrolide antibiotics,
benzodiazepines,
barbiturates,
anticonvulsant
drugs, fluconazole).
With doxorubicin:
↑ incidence of
CHF with paclitaxel (3 h inf.)
and DOX (bolus
>380 mg/m2
cumulative dose).
With cisplatin: ↑
peripheral
neuropathy.
With concomitant
EIAs: ↓ Css and ↓
systemic toxicity
in pts receiving
96 h infusion
paclitaxel.
(Continued)
DL mucositis, onicolysis.
DL abdominal pain.
DL non-cumulative neutropenia (50% G 4) after 7–10
days recovering in 1 week;
total alopecia (within 2–4
weeks); 60% dose-dependent myalgia (8% severe)
after 2–3 days for 3–4
days; 60% dose-dependent
cumulative peripheral
neuropathy (3% severe),
slowly reversible; 41% HSR
(<2% severe); 12%
hypotension; 23% ECG
abnormalities (sinus
HD (+G-CSF): good
bradytachycardia, PB)
risk pts 200–250 mg/
2
usually asymptomatic, not
m every 3 weeks.
requiring interventions;
IV weekly (1–3 h inf.):
radiation recall skin
90–100 mg/m2 per
reaction. Schedule-depenweek.
dent neutropenia and
IV CI (96 h): 140 mg/
m2 (without premedica- mucositis, ↑ with 24 h
infusion.
tion).
DL cumulative peripheral
IP: 82.5–125 mg/m2
neuropathy, onicolysis.
every 3 weeks.
Premedication: steroids,
histamine H1- and
H2-receptors antagonists (day 1; day 1).
IV 3 h inf.: 175 mg/m2
every 3 weeks.
IV 24 h inf.: 135 mg/m2
every 3 weeks.
291
Special population
Liver impairment
AP >2.5 × NV and transaminases >1.5 × NV: ↓ dose by
25%; bilirubin, AP ↑ >6 ×
NV or transaminases >3.5 ×
NV: discontinue.
Weekly: 36 mg/m2 per
week × 3 every 4
weeks.
DL: non-cumulative neutropenia (80% G 3–4, 11%
febrile neutropenia) after 8
days, recovering within 1
week; 76% total alopecia
(within 2–4 weeks), 62%
asthenia (5% severe), 50%
cumulative sensory neuropathy (4% severe), 47%
skin reactions (5% severe),
39% diarrhea (5% severe),
15% acute HSR (2%
severe); 64% fluid retention (6% severe) due to
capillary protein leak
syndrome, after a median
cumulative dose of ≥400
mg/m2.Steroids useful to ↓
severity of skin reactions
and of fluid retention (after
a median dose of 800 mg/
m2), and to avoid severe
HSR. Rare: radiation recall
phenomena, ischemic
colitis.
DL fatigue and asthenia;
rare peripheral edema and
neuropathy; uncommon
mild neutropenia and
onicolysis.
Premedication: DXM 8
mg b.i.d. for 3 days
(from day –1).
IV (1 h inf.):
single agent,
60–100 mg/m2
every 3 weeks;
combination,
75–100 mg/m2
every 3 weeks.
Specific substrates of CYP450
3A isoenzymes
(erythromycin,
ketoconazole,
nifedipine) could
modify CL.
>90% protein bound; linear
PK up to 115 mg/m2 with
triphasic plasma disappearance (T1/2β and T1/2γ 38 min
and 12 h); extensive liver
metabolism with oxidations
of the C 13 side chain and
production of inactive
metabolites; high interpt.
variability of metabolism and
PK. 74% of dose excreted in
feces as metabolites, 5% in
urine; CL ↓ 27% in pts with
↑ transaminases; CL is
independent predictor of
severe and febrile neutropenia in population of PK
study.
Same mechanisms of
action and resistance of
paclitaxel. Scheduleindependent antitumor
activity; in vitro sensitizing effect to ionizing
radiation.
Docetaxel
Taxotere®
Semisynthetic
paclitaxel derivative from needles
of Taxus baccata;
more water
soluble than
paclitaxel; Tween
80 in the
solution.
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
292
Mechanism of action
Hydroxyl daunorubicin; anthracycline antibiotic
constituted by
water-soluble
aminosugar
(daunosamine)
linked to planar
anthraquinone
nucleus (adriamycinone) site of
electron transfer
reactions.
Same structure as
DNR with
hydroxyacetyl
group C8.
Doxorubicin
(DOX)
Doxorubicin Rapid
Dissolution
Cytotoxicity due to: 1.
DNA intercalation of
aglycone between base
pairs with inhibition of
nucleic acid synthesis; 2.
Topo II inhibition; 3.
Generation of hydroxyl
radicals (relevant mainly
for cardiac toxicity)
through (a) redox cycling
of quinone with production of O2−, H2O2, and
OH− which bind to DNA
and cell membrane lipids;
(b) formation of drug–
metal (Fe2+, Cu2+) complexes which catalyze and
bind to DNA and cell
membranes. Cardiomyopathy possibly related to 3
because of destruction of
detoxifying glutathione
peroxidase by DOX and
relative deficiency of
scavenging enzymes in
heart. Involved in MDR
phenomenon through
P-gp overexpression and
Topo II alterations.
Anthracyclines, anthracenediones
Name, chemistry,
relevant features
TOPOISOMERASE II INHIBITORS
Special populations
Liver impairment
Bilirubin >1.25–2.0 × NV:
↓ dose by 50%.
Bilirubin >2.0–4.0 × NV:
↓ dose by 25%.
No verified guidelines for
abnormal transaminases:
caution suggested.
75% protein bound with
rapid tissue distribution;
triphasic plasma disappearance (T1/2γ DOX and
metabolites: 25–28 h).
Main metabolite DOXOL
produced by ubiquitous
(mainly liver) aldoketo
reductase, less active than
DOX; 7-deoxyaglicones,
inactivation species produced mainly in liver,
conjugated and excreted
into bile and urine. 40% of
dose excreted in bile and
5% in 7-day urine.
Pharmacology and dose
modifications
With dexrazoxane: ↓ risk of
cardiotoxicity
(see p.323).
With MMC,
CTX, paclitaxel,
Ca antagonists:
↑ risk of
cardiotoxicity.
With MDR
modulators:
↓ CL through
P-gp inhibition.
With CYP450
inducers: ↑ CL.
Compatible with
IV BLM, VLB,
VCR, CTX;
incompatible
with DXM,
5-FU, heparin.
Drug interactions
IV bolus intermittent:
Cumulative dose: ≤450
mg/m2; 300–100 mg/m2
if cardiac risk factors.
Warning
Recommended maximum
cumulative dose (doseassociated <10% risk of
CHF).
Cardiac risk factors
(combination CT, prior
mediastinal RT, age >70
years, pre-existing heart
disease).
Local vesicant on extravasation.
IV bolus intermittent:
single agent, 60–75 mg/
m2 every 3 weeks; combination, 50–60 mg/m2
every 3 weeks.
IV bolus weekly: 20 mg/m2
per week.
IV CI (72–96 h) (central
IV line): 60 mg/m2 every
3 weeks.
Route, schedule, and
recommendations
(Continued)
Cardiotoxicity:
Dose independent:
reversible, acute (after
hours or days): arrhythmias (with non-specific
ST segment and T-wave
changes, AV blocks, A
tachyarrhythmia; more
rarely, acute pericarditis/
myocarditis.
Dose-related: irreversible
cumulative, delayed,
chronic cardiomyopathy
with CHF responsive to
diuretics, digitalis, ACE
inhibitors. Serial determinations of LVEF by
MUGA/ECHO to
DL neutropenia after
10–14 days recovering in
1 week; acute dose-dependent N & V; total
alopecia within 3 weeks;
hyperpigmentation of
skin and nails; radiation
recall; venous flare
reactions. Rare,
stomatitis.
Toxicity
293
Mechanism of action
Pharmacology and dose
modifications
Drug interactions
Route, schedule, and
recommendations
IV bolus weekly and IV
CI: Cumulative dose:
≤700 mg/m2; 550 mg/m2
if cardiac risk factors.
77% protein bound;
Do not mix hepa- Local vesicant on extravaEpirubicin (EPI) 1 and 2 same as those of
extensive liver metabolism rin or fluoroura- sation.
DOX; 3 less prominent
Pharmorubicin®
with EPI and 13-OH
due to ↑ glucuronides
cyl; do not mix
IV (10–15 min, inf.):
Epimer of DOX
production escaping redox derivative (epirubicinol)
with other drugs
standard dose, single
with 4′-OH on
with formation of inactive in the same
cycling and free radical
agent: 90 mg/m2 every 3
daunosamine in
glucuronides rapidly
formation. Involved in
syringe; avoid
weeks; combination:
equatorial rather
excreted. Triphasic plasMDR phenomenon.
prolonged
60–75 mg/m2 every 3
than axial position;
matic disappearance with
contact with
weeks.
↑ lipophilicity, ↑
T1/2γ of 40 h; 50% of dose alkaline pH
β-glucuronidation
solution because Warning
excreted in the bile in 4
to inactive comRecommended maximum
days and <20% into urine. of hydrolysis.
pounds with ↓
With cimetidine: cumulative dose (doseSpecial populations
cardiotoxicity, ↑
associated <10% risk of
↑ AUC by 50%
Liver impairment
CL and ↓ potency.
CHF).
and ↓ decrease
Bilirubin 1.2–3 mg/dl or
plasma clearance Cardiac risk factors
AST 2–4 × N: ↓ dose by
(combination CT, prior
by 30%; avoid
50%. Bilirubin >3 mg/dl or
concomitant use. mediastinal RT, age >70
AST >4 × NV: ↓ dose by
years, pre-existing heart
75%.
disease).
Name, chemistry,
relevant features
Acute side-effects comparable to those of DOX
with dose ratio of
DOX:EPI of 1:1.2 for
hematological, 1:1.5 for
non-hematological
toxicities, 1:1.8 for
cardiotoxicity.
Dose-related cumulative
delayed cardiotoxicity as
for DOX; serial LVEFS by
MUGA/ECHO (baseline,
300–400 mg/m2, 600–
700 mg/m2, then after
each dose) to minimize
the risk of cardiotoxicity
(4% at ≥950 mg/m2, 15%
at 1000 mg/m2).
More frequent stomatitis.
minimize the risk of
cardiotox (baseline, 300,
450 mg/m2, then after
each dose). Discontinue
treatment if ≥10% ↓ of
baseline to a level below
normal. Endomyocardial
biopsy findings predictive of subsequent CHF.
Toxicity
294
Doxorubicin HCI Longer circulation times;
higher concentrations in
liposome
®
tumor tissues in animal
Caelyx
models than DOX, possiDOX encapsulated
bly due to enhanced
in pegylated
permeability and
(STEALTH®)
retention.
liposomes.
HD (30–60 min. inf.)
days 1–2: total dose
single agent, 120–150
mg/m2; combination, 120
mg/m2 + CSF or 200 mg/
m2 + PBSC.
Linear PK up to 20 mg/m2; No drug interac- Local vesicant on extravation studies. Do sation.
T1/2: 74 h. In comparison
IV: infuse initially at 1
to DOX: higher CL (0.030 not mix with
mg/min to minimize risk
other drugs.
l/h/m2), lower Vd (1.93 l/
of reactions.
m2 equal to plasma volAIDS-KS: 30 min inf. 20
ume), greater AUC, similar
mg/m2 every 3 weeks;
metabolism.
solid tumors: 60 min inf.
Special populations:
50 mg/m2 every 4 weeks.
Age
Warning
No differences.
Cumulative cardiotoxic
Liver impairment
dose not defined: in
At cycle 1: bilirubin 1.2–3
metastatic frontline pts
mg/dl: ↓ dose by 25%; bilimonitor cardiac functions
rubin >3 mg/dl: ↓ dose by
after >600 mg/m2 in
50%.
naive and 450 mg/m2 in
At second cycle if first
DOX-pretreated pts.
cycle well tolerated: ↑ dose
by 25%.
Single agent, combination:
≤900 mg/m2;
≤540 mg/m2 if risk
factors.
(Continued)
Dose-dependent cumulative skin toxicity with
palmar-plantar erythrodysesthesia, possibly due
to preferential accumulation in flexure, pressure
areas, palms (40% at 50
mg/m2, 17% G 3),
usually appearing after
2–3 cycles, recovering in
2–4 weeks, steroids
benefit unknown; ↓
incidence at ≥4 week
intervals and by avoiding
pressure, high temperature for 1 week after
treatment; pyridoxine
possibly useful.
Secondary AML: cumulative risk 0.2 and 0.8% at
3 and 5 years when used
with other DNA-damaging cytotoxics.
DL mucositis; 90% G 4
neutropenia; severe
N & V; total alopecia.
295
Name, chemistry,
relevant features
Mechanism of action
Renal impairment
Cr CL 30–156 ml/min: no
modifications.
Pharmacology and dose
modifications
Drug interactions
Route, schedule, and
recommendations
34% asthenia; 30%
stomatitis (G3–4 9%);
20% alopecia; 10%
infusion reactions
(occasional HSR); 5%
G3–4 N & V; 10% G3
neutropenia (solid
tumors); <10%, cardiacrelated AE, lower risk of
cardiotoxicity compared
to DOX at cumulative
equiactive doses; evaluation of long-term cardiac
effects ongoing.
Toxicity
296
Etoposide (VP16)
Vepesid®
Topo II inhibition
with stabilization of
the DNA–TOPO II
Semisynthetic derivative
complex and
of podophyllotoxin with
production of DNA
epipodophyllotoxin
double-strand
linked to a glucopyranobreaks. Cytotoxicity
side with methyl group;
phase and schedule
made more water-miscidependent; lower
ble by organic solvents
repeated doses more
(Tween 80, polyethylene
effective than higher
glycol).
single.
Involved in MDR
phenomenon
through P-gp
overexpression and
Topo II alterations
(↓ activity, point
mutations).
Epipodophyllotoxins and aminoacridines
Special populations
↓ Cr CL, ↓ albumin, age
>65 years: ↓ dose.
95% protein bound;
biphasic disappearance
with T1/2 of 6–8 h; linear
PK also at high doses. 44%
of dose in feces and 56%
(mainly parent compound)
in urine of 5 days; hepatic
metabolism with production of less active hydroxy
acid metabolites,
glucuronide and/or sulfate
conjugates in urine.
Dose-dependent, variable F
(50–75%) up to 200 mg
total dose; lower
at >200 mg.
Measurable CSF levels of
parent compound and
metabolites after high
doses.
With DDP,
HD-CBDCA,
cyclosporin A:
↓ CL.
With concomitant EIAs:
↑ CL.
IV (30–60 min.
inf.): 100–120 mg/
m2 on days 1–3 or
on days 1–5 every
3–4 weeks.
IV HD (500 mg/h
inf.): single agent,
60 mg/kg (preparatory for BMT), 3000
mg/m2 (MTD);
combination:
400–800 mg/m2 on
days 1–3.
IV (72 h CI): 150
mg/m2 daily.
PO: 100 mg (50 mg
× 2) daily, in
untreated pts, days
1–14; pretreated
pts, days 1–10
every 4 weeks.
(Continued)
DL non-cumulative neutropenia
after 10–12 days, recovering
within 7–10 days; N & V; less
frequent, exacerbation of preexisting VCR neuropathy,
diarrhea. Rare hypotension,
flushing.
High dose: DL myelotoxicity,
mucositis, severe N & V.
PO: DL neutropenia after
3 weeks, recovering in 1 week;
mild to moderate N & V; total
alopecia after repeated cycles.
All schedules: ↑ risk of secondary
monoblastic leukemia with
balanced 11q 23 translocations,
short latency period, no preleukemic phase for cumulative doses
of ≥2 g/m2. High-dose DDP,
alkylating agents, RT as additional risk factors.
297
Same as etoposide with a
thenylidene group on
the glucopyranoside.
Teniposide (VM26)
(Vumon®)
Same as that of
etoposide.
Special populations
Liver impairment
Bilirubin 1–2.5 mg/dl:
↓ dose by 50%.
Bilirubin >2.5 mg/dl:
↓ dose by 75%.
>99% protein bound;
triphasic disappearance
with T1/2γ of 20 h; 86%
eliminated by hepatic
metabolism (metabolites
mostly unknown), 20% of
dose in 24 h urine; ↓ CLR
than etoposide.
Same as that of etoposide.
Same as that of
etoposide.
Etoposide phosphate
Etopophos®
Water-soluble prodrug
of etoposide, completely
converted to etoposide
in vivo.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Same as that
of etoposide.
Drug
interactions
IV (5 min inf.)
(solution of higher
concentration than
for etoposide):
50–100 mg/m2 on
days 1–3 or 1–5.
IV HD: highest safe
dose: 1000 mg/m2
(2 h inf.) on days 1
and 2.
IV (30–60 min.
inf.): single agent,
60 mg/m2 on days
1–5 every 3–4
weeks; combination
(children ALL), 165
mg/m2 × 2 per week
× 4 (with Ara C).
Route, schedule, and
recommendations
DL neutropenia after 7–10 days,
recovering within 1 week;
moderate N & V; alopecia;
mucositis; chemical phlebitis.
Rare type I HSR.
Secondary leukemias as after
etoposide.
Comparable to those expected
from etoposide.
3% HSR (chills, rigors, bronchospasm, and dyspnea); 2% flushing; 3% skin rashes.
Toxicity
298
Hydrochloride trihydrate; semisynthetic
derivative of camptothecin. Water-soluble
precursor of the lypophilic metabolite SN38.
Irinotecan (CPT-11)
(Campto®)
Camptothecines
Name, chemistry, relevant
features
Topo I inhibition
with production of
single-strand DNA
breaks. Antitumor
activity not schedule
dependent.
Converted primarily
in liver to active and
inactive metabolites
by at least 2 known
pathways: 1. By
carboxylesterase to
SN38, 1000-fold
more potent, subsequently inactivated
by glucuronidation
to SN38G. Both
CPT11 and SN38
undergo pH-dependent reversible
hydrolysis from
active form lactone
(closed ring) to
carboxylate (inactive
open ring). 2. By
CYP3A to oxidative
metabolites: APC
Mechanism of action
TOPOISOMERASE I INHIBITORS
High interpt. variability due
to individual variations of
metabolic pathway activity
(see Mechanism) and polymorphism of UGT enzyme
(responsible for SN38
glucuronidation).
Protein binding: 50% CPT11,
95% SN38.
For both, linear PK up to 350
mg/m2, unchanged after
repeated cycles. SN38 AUC
values <10% of CPT; excretion 28% total urinary with
CPT11 and SN38 as main
products; 24% fecal excretion.
Relationship between AUC
(CPT11 and SN38) and % ↓
of ANC.
Special populations
Guidelines for 3-week schedule only
Liver impairment
Bilirubin >1 mg/dl: keep dose
<145 mg/m2; bilirubin NV but
AST >3 × NV: start dose at
225 mg/m2, then ↑ if
Pharmacology and dose
modifications
No PK interactions with
DDP, 5FU, etoposide
and OXA.
In vitro ↓ CYP3A
metabolism with
CYP3A4 substrates
(loperamide, ketoconazole, ondansetron) of
unknown clinical
relevance.
With EIAs: ↑ CL
(phenytoin, carbamazepine, phenobarbital,
pyrimidone, felbamate).
With Valproate: ↓ SN38
glucuronidation.
Drug interactions
Toxicity
(Continued)
Diarrhea principal of
2 types.
Type 1: early-onset
diarrhea-cholinergic
syndrome (EOD-CS)
(during or within
24 h from infusion),
associated with
rhinitis, salivation,
miosis, diaphoresis,
preventable by
atropine (IV or SC
LOD treatment:
0.25–1 mg).
treat at first
Type 2: late-onset
episode of loose
diarrhea (LOD)
stools with
(>24 h) lasting for
loperamide (4 mg
5–7 days.
immediately, then
Single agent G3–4
2 mg every 2 h
toxicity by schedule:
until diarrhea free
Intermittent: 22%
for 12 h), and
LOD, 22% neutropehydrate.
nia, 15% asthenia,
14% N&V, 12%
EOD-CS, 12% CNS
symptoms, 5%
anorexia.
All schedules: IV
90 min inf.
Single agent:
every 3 weeks:
300–350 mg/m2;
weekly: 125 mg/
m2 × 4, every
6 weeks.
Combination:
every 2 weeks:
180 mg/m2
Route, schedule, and
recommendations
299
Mechanism of action
Pharmacology and dose
modifications
(500-fold less potent
than SN38) and
NPC, excreted in
bile
no toxicity.
Gilbert’s syndrome with mutation of UGT1A1
↓ dose to 200 mg/m2 every 3
weeks.
Renal impairment
Cr >1.6–3.5 mg/dl: start at
225 mg/m2, then ↑ if no
toxicity.
50% of drug as carboxylate
Topo I inhibition
Topotecan
(80% after 18 h) at the end of
with production of
(Hycamtin®)
short infusion; wide tissue
single-strand DNA
9-Dimethylaminomethyldistribution; biphasic disapbreaks; pH-depen10-hydroxycamptothecin;
dent hydrolysis with pearance of lactone (T1/2β 3 h)
water-soluble semisynpredominance of
with linear PK highly variable.
thetic derivative of
lactone (active
Main renal excretion (60–70%
camptothecin.
species) at pH <7.0; total drug in 24 h urine);
less active open-ring. 30–40% penetration into CSF
Active N-desmethyl in children; positive correlametabolite in plasma tion between total AUC and
produced by CYP.
% ↓ of ANC.
Higher antitumor
Special population
activity in experiRenal impairment
mental models after
Cr CL 20–39 ml/min: ↓ dose
CI/repeated than
by 50%; no data in case of
single bolus adminisCrCL <20 ml/min.
trations.
Liver impairment
No need of ↓ dose.
Name, chemistry, relevant
features
Same as those of CPT
11.
With cisplatin: ↑ neutropenia if Topotecan
given after DDP.
With EIAs: ↑ CL
(concomitant with
phenytoin).
Warning
Concomitant anticonvulsant therapy: allowed
gabapentin, lamotrigine;
NOT allowed: phenytoin, carbamazepine,
phenobarbital, pyrimidone, felbamate.
Drug interactions
If G-CSF used,
start at least 24 h
from last dose.
IV (30 min inf.):
single agent, 1.5
mg/m2 on days
1–5 every 3
weeks; combination, 0.75 mg/m2
on days 1–5 every
3 weeks.
Route, schedule, and
recommendations
DL neutropenia (78%
G4) after 10–12 days,
recovering in 1 week;
37% severe anemia
after 15 days; 27%
severe thrombocytopenia after 15 days;
32% diarrhea; 54%
cumulative fatigue;
60% mild to moderate N&V; 49%
dose-related cumulative alopecia.
Weekly: 7% EOD-CS;
31% LOD, 31%
neutropenia, 16% N,
14% asthenia, 12% V,
7% anorexia, 2%
CNS symptoms.
Toxicity
300
Special populations
Renal impairment
↓ re-treatment interval to
4 weeks and reduce dose
according to Cr CL ml/
min. Cr CL 55–65: ↓
dose by 25%; Cr CL
25–54: ↓ dose equivalent
to ml/min (e.g. if 30 ml/
min, give 30% full dose);
Cr CL <25: discontinue.
Warning
Avoid concomitant use
of: folates, tubular
secreted drugs (e.g.
NSAIDs), and highly
protein-bound drugs
(e.g. warfarin).
Serial checks of liver
and renal function tests.
IV (15 min. inf.): 3 mg/
m2 every 3 weeks.
93% protein bound;
triphasic disappearance
with T1/2β and T1/2γ of
1.7 h and 198 h; long
T1/2γ due to intracellular
deglutamation and
release from tissues.
Not metabolized.
Excreted unchanged in
urine (40–50%) and 15%
in feces, about 50%
retained in tissues.
Potent and selective inhibitor
of TS, forms polyglutamates,
100-fold more potent than
parent compound and
retained within cells.
Quinazoline
folate analog
With MTX: see also
high-dose MTX.
With 5–FU (short
infusion): 20–200 mg/m2
on days 1–5.
90% absorption after PO
up to <50 mg total dose,
then 75%; Tmax 0.5 h.
Crosses BBB, rescue
delayed for ≥24 h after IT
treatment.
Route, schedule, and
recommendations
Provides cells with FH4
depleted because of DHFR
inhibition by MTX.
Drug interactions
Antifolates
Leucovorin (LV)
5-CHO-FH4;
reduced form of
folic acid (racemic mixture);
active L-LV.
Raltitrexed
Tomudex®
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
ANTIMETABOLITES
(Continued)
DL prolonged diarrhea
(38%, 10% G 3–4) and
neutropenia (13%);
49% asthenia (5% G
3–4); 58%
N & V (9% G 3–4);
16% ↑ LFTs, 12%
mucositis (2% G 3–4);
6% alopecia.
Toxicity
301
60% protein bound;
triphasic plasma disappearance with T1/2γ of
8–10 h, longer if ↓ Cr CL
and third space fluid
collections. 60–100%
urinary excretion after
high-dose MTX through
glomerular and tubular
processes with drug CLR
comparable to Cr CL;
40% of drug in 24 h
urine as 7-hydroxy-MTX,
poorly soluble in acidic
pH. Biliary excretion
<10% drug clearance.
Well absorbed after PO
doses of ≤25 mg/m2,
erratic F at higher doses
and in children. With HD
(8 g/m2) therapeutic
concentrations achieved
in CSF and maintained
much longer than with
IT. After IT administration, T1/2 of 12–18 h with
delayed CL and ↑
myeloneurotoxicity if
active meningeal disease.
HD or IT treatment for
meningeal prophylaxis;
through Ommaya reservoir (therapeutic).
Tight-binding inhibitor of
DHFR with depletion of
intracellular FH4, necessary
for synthesis of purines
(through GAR and AICAR
transformylases) and thymidylate (through TS) with
inhibition of DNA and RNA
synthesis. MTX and FH2
polyglutamated by FPGS,
higher in some tumors than
in normal cells. DHFR, GAR,
AICAR and TS directly
inhibited by polyglutamates.
MTX enters cells through
reduced folate carrier and
mFBP, with higher affinity for
FH4 than for MTX. Mechanisms of resistance to MTX
include impaired membrane
transport, defective polyglutamation, and alteration of
DHFR due to ↑ expression or
↓ binding affinity. High-dose
therapy based on different
distribution of transport
carrier systems between
tumor and normal cells, with
passive diffusion of MTX into
tumor cells and selective
rescue of normal cells by LV.
LV intracellularly converted
to 10-CHO-FH4, which
Methotrexate
(MTX)
Folic acid analogue; 4-amino,
10-methyl analog
of aminopterin.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Standard dose
IV (bolus): 30–50 mg/m2
per week.
HD
↑ toxicity with
salicylates, sulfonamides, phenytoin
due to protein
binding displacement; with
probenecid,
penicillins, cephalosporins, aspirin,
NSAIDs due to
inhibition of
tubular secretion.
With antitumor
agents: ↓ toxicity of
asparaginase if
MTX given first; ↑
therapeutic activity
of 5FU, VCR or
AraC if MTX given
first; ↑ levels of
6-MP if MTX given
first.
With RT: ↑ risk of
soft tissue necrosis
and osteonecrosis.
Warning
Implement: (1) IV fluids
and urinary alkalinization: keep urinary pH >7;
↑ diuresis at least 12 h
before and up to ≥48 h
after, monitor Cr CL
(must be ≥60 ml/min).
(2) MTX plasma levels
monitoring to guide
duration and amount of
(3). (3) LV rescue: start
2–24 h after MTX until
MTX levels are <5 × 10−8
M.
Jaffe regimen
Dose: 50–250 mg/kg 6 h
inf
Rescue: Start 2 h from the
end of MTX with LV 15
mg/m2 IM every 6 h × 7,
then according to MTX
level at 48 h for 8 doses.
MTX level LV mg/m2
at 48 h
≥5 × 10−7 M
15
≥1 × 10−6 M 100
≥2 × 10−6 M 200.
Repeat after 48 h and
Route, schedule, and
recommendations
Drug interactions
PO: chronic toxicities,
hepatic fibrosis,
interstitial infiltrates.
IT: acute chemical
arachnoiditis; 10%
subacute neurotoxicity
(motor paralysis,
cranial nerve palsies);
chronic demyelinating
encephalopathy
(dementia, limb
HD: Acute: reversible
nephrotoxicity; N & V;
maculopapular rash
(up to 5 days after);
oral stomatitis (after
3–7 days) preceding
myelotoxicity, both
reversible within 2
weeks; ↑ LFTs reversible within 2 weeks;
fever. Transient
encephalopathy with
paresis, aphasia, and
seizures within 6 days,
recovering in 72 h.
Leukothrombocytopenia after 4–14 days;
stomatitis; diarrhea; ↑
toxicity in dehydrated,
malnourished pts.
Toxicity
302
L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4
-oxo-1Hpyrrolo[2,3-d]
pyrimidin-5-yl)
ethyl]benzoyl]
disodium salt.
Pemetrexed
(Alimta®)
Linear PK; ↓ CrCL results
in ↓ CLp and ↑ AUC. Not
metabolized to an appreciable extent, 70–90%
excreted unchanged in
24 h urine.
T1/2β 3.5 h, small Vd, CL
not affected by PO folic
acid, IM vitamin B12 or
concomitant DDP.
Inverse relationship
between severity of
neutropenia and AUC; ↓
ANC nadir also occurring
in presence of baseline ↑
cystathionine and ↑
homocysteine levels
(markers of vitamin B12
and folate deficiency);
vitamin supplementation
effective in ↓ toxicity.
Simultaneous inhibition of TS
(primary target), DHFR and
GARFT (secondary targets)
reverted by thymidine and
hypoxanthine in combination; enters cells through
mainly reduced folate carrier
and mFBP; polyglutamated
by FPGS, with >100-fold
greater affinity for TS than
monoglutamate. In mice
dietary folic acid protects
from toxicity without ↓
efficacy.
Special population
Renal impairment CrCL
≥45 ml/min: no dose
adjustment;
CrCL <45 ml/min: no
data available but caution.
Special populations
Age
↑ sensitivity in elderly
due to ↓ renal function.
Renal impairment
Cr CL ≤80 ml/min: ↓
dose; Cr CL <50 ml/min:
discontinue.
Liver impairment
No need of ↓ dose.
competes with polyglutamated species for DHFR; the
dose of LV to rescue normal
cells depends on MTX
concentration; MTX cytotoxicity depends on drug
concentration and duration of
exposure.
Therapeutic concentrations:
1 × 10−6 mol/l.
Warning
Do not use preservativecontaining solutions.
No interaction
IV (10 min inf) every 3
with aspirin, or
weeks: 500 mg/m2 with
DDP.
vitamin supplementaWith NSAID: ↓ CL tion (vitamin B12 IM
(20%) and ↑ AUC 1000 µg, 1–3 weeks
(20%) with ibubefore and every 9
profen.
weeks during study;
folic acid PO 350–1000
Caution
µg starting 1–3 weeks
Concomitant
NSAID use in renal before and continuing
impairment (CrCL until 30 days after
discontinuation).
45–79 ml/min);
avoid NSAIDs with Skin rash prophylaxis:
short T1/2 for 2 days PO DXM 4 mg b.i.d.
before, the day of, days 1 to 2.
and 2 days following pemetrexed
administration. No
information for
long-acting
NSAIDs; avoid
NSAIDs with long
T1/2 for 5 days
before, the day of,
and 2 days following pemetrexed
administration.
continue up to
<5 × 10−8 M.
PO: 15–20 mg/m2 × 2
per week.
IT: >3 years old: 12 mg
total dose every 2–7
days.
(Continued)
G3–4 toxicities in with
NSCLC pts receiving
vitamin supplementation: 5% neutropenia,
4% anemia, 2%
thrombocytopenia, 2%
ALT elevation, 5%
fatigue, 3% nausea, 2%
febrile neutropenia, 1%
stomatitis, 1% rash,
0.5% diarrhea.
spasticity; ↑ with
concomitant
cerebral RT).
303
Uracil analog with fluorine atom substituted for
H at C5 of the pyrimidine
ring.
5-Fluorouracil (5-FU)
Pyrimidine analogs
Name, chemistry, relevant
features
Intracellular activation to: 1. FdUMP
with inhibition of TS
(ternary complex
with CH2-FH4) and
inhibition of DNA
synthesis and repair;
2. FUMP, metabolized to FUTP, with
incorporation into
RNA, altering RNA
functions; 3. FdUMP
phosphorylated to
FdUTP with incorporation into DNA.
1. Is probably the
principal mechanism
with long T1/2 (6 h) of
ternary complex.
Resistance due to
deletion of activating
enzymes, relative
deficiency of CH2FH4, alterations in
TS, ↑ activity of
catabolic enzymes.
Pattern of 5FU
metabolism different
in different normal
tissues and tumor
types; mechanism of
Mechanism of action
Erratic F, also because of
first-pass effect. After IV
bolus T1/2β 6–20 min
with <1 µM (cytotoxic)
within few hours; nonlinear PK at higher doses,
with ↓ non-renal CL due
to saturation of catabolism. Crosses BBB; Tmax 30
min. Rapid catabolism
(50% of dose) in liver and
in tissues to F-DHU by
DPD; main biliary excretion of 5FU and catabolites; extensive catabolism
also extrahepatic. 50% of
dose cleared through liver
first-pass after HAI or IV
portal infusion. After i.p.
treatment 300:1 gradient
between i.p.:IV concentrations due to slow
peritoneal absorption and
rapid liver metabolism
with low systemic
toxicity.
Improvement of therapeutic index by adapting
5FU dose to AUC in H &
N pts receiving 5FU (96 h
inf.) and DDP in a
Pharmacology and dose
modifications
Incompatible in
solution with any
acidic agent; incompatible with diazepam, AraC, DOX,
MTX.
With LV: stabilization
of the FdUMP-TSfolate ternary complex; with
dipyridamole (inhibitor of thymidine
uptake): ↓ dTTP and
↑ FdUMP; with MTX
(if given before 5FU):
↑ FUMP and FUTP;
with IFN and with
cisplatin: mechanism
of synergism still
uncertain; with
allopurinol (300 mg
t.i.d.): (selective
inhibition of 5FU
anabolism in normal
tissues), to prevent
toxicity; with delayed
high-dose uridine to
prevent myelosuppression.
Drug interactions
HD
IV (bolus): 375 mg/m2
on days 1–5, 1 h after
LV (30 min inf.) 500
mg/m2 on days 1–5
every 3 weeks.
IV (CI) 1000 mg/m2 on
days 1–5 every
3–4 weeks.
Combination with LV
Low dose
IV (bolus): 425 mg/m2
on days 1–5 immediately after LV (bolus)
20 mg/m2 on days 1–5
every 4–5 weeks.
Protect from light
IV (bolus) single
agent: 400–500 mg/m2
(12 mg/kg) on days
1–5 every 3–4 weeks;
500 mg/m2 per week
(15 mg/kg).
Maximum recommended daily dose =
800 mg.
Route, schedule, and
recommendations
Toxicity and clinical
efficacy partly related to
schedule of administration.
DL neutropenia (31% G
3–4) after 9–14 days; 7%
stomatitis; 6% diarrhea
(IV fluids and ↓ dose at
subsequent cycles if >3
discharge/day), excessive
lacrimation. Less frequent, skin hyperpigmentaton, radiation recall
with erythema, moderate
alopecia; transient
blurring of vision, eye
ocular toxicity with
lacrimation, nasal discharge. Rare, neurologic
disturbances with somnolence and cerebellar
ataxia (more frequent
after high-dose and LV
combination); cardiac
toxicity with chest pain,
ECG changes consistent
with myocardial ischemia, ↑ serum enzymes,
(↑ risk in pts with
pre-existing heart disease).
Toxicity
304
Tegafur (FT) and uracil in
a molar ratio of 1:4. FT is
5-FU linked to furan ring
(dehydroxylated ribose
sugar), to be administered
with LV.
UFT
Uftoral®
FT activated to 5-FU
in liver, inactivated to
F-DHU by DPD;
uracil supposed to
inhibit subsequent
catabolism in liver
with possibly higher
concentrations in
tumor than in blood
or normal tissues.
cytotoxicity also
related to drug
concentration and
time of exposure.
FT: 52% protein bound.
Rapid variable absorption;
Tmax 0.3–3 h; after 5 days
AUC and Css of 5-FU
after UFT equivalent to
those achieved with CI of
5-FU; no accumulation
after repeated doses;
<20% FT excreted in
urine.
Special populations
Liver impairment
Omit if bilirubin >4 ( NV
Pharmacogenomic
↑ risk of life-threatening
toxicities at standard
doses in DPD-deficient
persons; present in some
degrees in 3% of patients.
multicentric randomized
study.
With halogenated
antiviral agents:
severe myelosuppression and CNS toxicity.
DL GI toxicity (2%
diarrhea, 3% N & V, 5%
anorexia, mucositis);
3.5% asthenia; fatigue;
leukopenia.
PO: 300 mg/m2 daily
on days 1–28 plus LV
90 mg daily on days
1–28 every 5 weeks
(daily doses of both
drugs divided into 3
doses given every 8 h)
1 h before or 1 h after
meals.
(Continued)
IV + LV: ↑ frequency of
myelosuppression, stomatitis and neurological
disturbances. CI: DL
stomatitis and diarrhea;
slowly reversible handfoot syndrome (34% G
3–4) incidence related to
duration of infusion,
pyridoxine (50–150 mg
per day) possibly useful;
20% epigastric pain and
gastric ulcerations; ↑
frequency of cardiac
toxicity.
HAI or IV portal: mild
mucositis and GI symptoms; biliary sclerosis
with cholestatic jaundice;
catheter-related complications (thrombosis of the
gastroduodenal artery
with necrosis of intestinal
epithelium, hemorrhage,
perforation).
Prolonged CI: 200 mg/
m2 per day until
toxicity (×4–5 weeks).
HAI or IV portal
infusion i.p. 500 mg/l
PO not recommended.
305
Prodrug of 5-FU;
transformed to 5-FU
or to FdUMP. Similar
mechanism of action
as that of 5-FU.
Floxuridine (FUDR)
2-Deoxy-5-fluorodeoxyuridine; deoxyribonucleoside of 5–FU.
Mechanism of action
Name, chemistry, relevant
features
Drug interactions
Special population
↓ dose in pts with liver
impairment, prior pelvic
RT, prior alkylators.
Guidelines not available.
Narrow margin of
Given by HAI, higher
first-pass extraction (90%) safety CI.
than 5-FU (40%) with ↓
systemic toxicity; PK data
not available.
Special population
PK in liver/renal
impairment not
studied.
Undergo microsomal
oxidation by CYP2A6.
Pharmacology and dose
modifications
Toxicity
Catheter-related complications and drug-related
hepatic toxicity as those
of HAI and IV portal
Warning
5-FU: N & V, diarrhea,
Contraindications
stomatitis, localized
Poor nutritional state, ↓
erythema, ↑ LFTs,
BM function, potengastritis, cramps, abdomitially serious infections.
nal pain, intra-/extraheCaution
patic sclerosis, BM
Possibility of severe
depression,
toxic reaction: deliver
GI ulceration.
first course as inpatient. Discontinue therapy
promptly in case of first
signs of cardiac ischemia,
stomatitis, initial leucopenia, intractable vomiting,
and diarrhea.
Caution
In pts with history of
heart disease. In pts
receiving drugs affecting
CYP2A6 activity.
CI HAI: 0.2 mg/kg
on days 1–14 every
4 weeks.
Warning
Give the highest dose
of UFT in the morning
and lower doses in the
afternoon or evening if
the total number of
UFT capsules cannot
be evenly divided.
Route, schedule, and
recommendations
306
Xeloda®
5-Deoxy-5-fluoro-N[(pentyloxy) carbonyl]cytidine; rationally
designed oral fluoropyrimidine carbamate.
Capecitabine
Same as that of 5FU;
tumor-selective agent
with ↓ risk of toxicity
than with systemic
5FU. 5′-DFUR in
tumor converted by
Thd Pase to 5-FU,
further catabolized by
DPD; efficacy in
xenografts correlated
with ratio of Thd
Pase to DPD; tissue
distribution of
activating enzymes in
monkeys, but not in
rodents, comparable
to humans.
In xenografts, 5FU
concentrations in
tumor > than in
plasma and healthy
tissues and > than
after equitoxic doses
of 5FU. Antitumor
activity correlated
with total dose given.
Special populations
Age
No impact on PK, but
monitor >80 years for ↑
risk of diarrhea.
Renal impairment
Cr CL 30–50 ml/min: ↓
dose by 25%; Cr CL
<30 ml/min: discontinue.
Liver impairment
Unknown.
Pharmacogenomic
As with 5FU ↑ risk of G4
toxicities at standard
doses in persons with
DPD deficiency (3%
incidence).
<60% protein binding;
rapid (Tmax 1–2 h); rapid
and almost complete
absorption of unchanged
drug in fasting conditions,
70% with food. Selectively metabolized in liver
to 5′-DFCR by carboxylesterase then converted
to 5′-DFCR by cytidine
deaminase in liver and
tumor. 5′-DFCR is then
activated to 5FU mainly
in liver and at tumor site
(see mechanism). 84% of
dose in urine 24 h, 96%
over 7 days. In xenografts
↑ antitumor activity of
combinations of capecitabine than of combinations of 5FU.
Warning
Do not use in pts with
known hypersensitivity
to 5FU.
PO intermittent schedule, single agent and
combination same dose:
2500 mg/m2 daily in
2 divided doses for
2 weeks, followed by 1
week rest, every 3
weeks. Each dose taken
with water
12 h apart within
30 min from end of
meal.
(Continued)
DL 50% diarrhea (severe
15%), 54% hand-foot
syndrome (severe 17%),
48% hyperbilirubinemia
(severe 23%), 43% N
(severe 4%), 41% fatigue
(severe 8%), 35% abdominal pain (severe 10%),
27% V (severe 4%); 25%
stomatitis (severe 3%),
13% neutropenia (severe
3%), neurological
(<10%).
307
Synergism with
antitumor agents
producing DNA
breaks because of
inhibition of DNA
repair (alkylating
agents, DDP, VP16,
AMSA); synergism
with RNR inhibitors
(thymidine, HU,
fludarabine) because
of ↓ dCTP pools.
Incompatible with
heparin, insulin,
MTX, 5FU, penicillin,
and methylprednisolone.
13% protein bound; after
IV bolus Cmax 10 µM after
100 mg/m2, proportionally higher up to 3 g/m2
(2 h inf.) (>100 µM).
Rapid plasma elimination
with T1/2α of 10–15 min
and T1/2β of 30–150 min;
70–80% of dose in urine
as Ara-U; Ara-U predominates in plasma with T1/2β
of 3–6 h. After CI of
0.1–2 g/m2 daily proportional increase of Css up
to 5 µM; rapid increase of
plasma levels with toxicity
at higher doses due to
saturation of deamination.
After SC or CI, >2-fold
higher AUC than after IV
bolus. Crosses BBB with
Css CSF 20–40% of those
in plasma within 24 h of
CI.
After 50 mg/m2 IT, Cmax
of 1 mM with >0.1 µM
for 24 h, T1/2β of 3 h.
Drug concentration and
duration of exposure
primary determinants of
toxicity.
Activated to Ara-CTP
in tumor cells by
sequential kinase
activity; degraded to
inactive Ara-U by
widely distributed
deaminases. Ara-CTP
acts by inhibiting
DNA polymerase and
DNA repair and by
incorporation into
DNA; possible
differentiating effects
on leukemic cells at
lower doses. Cytotoxicity dependent on
duration of exposure
and rate of DNA
synthesis. Enters cells
by facilitated nucleoside transport system
at standard doses, by
passive diffusion at ↑
doses. Resistance due
to deficiency of CdR
kinase, ↑ of dCTP
pools, ↑ cytidine
deaminase activity, ↓
nucleoside transport
sites, ↓ intracellular
retention of Ara CTP.
Cytarabine (cytosine
arabinoside; Ara-C)
Cytosar®
Deoxycytidine antagonist
with arabinose instead of
deoxyribose.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
Toxicity
High-dose
IV (3 h inf.
>200 mg/m2): 2–3 g/m2
b.i.d. days 1–6.
HD: 20% neurotoxicity
with reversible cerebellar
(10%) and cerebral
dysfunction (somnolence,
confusion); ↑ risk if >36
g/m2 total dose, >50 years
old, ↑ creatinine; repeat
neurological examination
daily; ↓ incidence with
longer infusion. Severe
myelotoxicity; mucositis;
total alopecia; diarrhea;
typhlitis and necrotizing
colitis. Conjunctivitis
(prophylactic steroids
drops up to 48 h after last
dose), sometimes hemorrhagic, with slowly
reversible visual acuity
Standard dose
SD: DL myelosuppresIV (12 h inf.): 100 mg/ sion with biphasic
m2 b.i.d. days 1–5 or 7. leukopenia; initial nadir
after 7–9 days, second
nadir after 12–15 days,
recovering within 2–3
weeks. Frequent acute GI
toxicity (N & V, abdominal pain, diarrhea);
stomatitis and intrahepatic cholestasis. Flu-like
syndrome with rashes,
myalgia, fever, appearing
6–12 h post-treatment.
Route, schedule, and
recommendations
308
Cytarabine liposome
DepoCyt®
As cytarabine;
sustained-release
formulation, direct
Cytarabine encapsulated
administration into
into spherical multivesicuCSF.
lar lipid-based particles
(Depo Foam) for IT
administration only.
Depo Foam particles
release drug by erosion
and are biodegradable and
metabolized.
In AML or ALL pts,
Ara-C uptake,
Ara-CTP formation
and retention in
blasts are determinant
of response.
After 50 mg IT, CSF peak
levels of free cytarabine
within 5 h; T1/2α ∼ 10 h,
T1/2β ∼ 141 h; free
cytarabine concentration
>0.02 µg/ml for >14 days;
negligible systemic
exposure due to rapid
Ara-U conversion in
plasma.
Special po]pulations
Renal impairment
At high dose, ↓ dose if ↑
Cr because of ↑ risk of
neurotoxicity.
Prophylaxis: DXM b.i.d.
4 mg days 1–5, 2 mg
day 6, 1 mg day 7.
Maintenance: every 4
weeks.
Induction and
consolidation: every
2 weeks.
IT (1–5 min bolus): 50
mg.
Low dose
SC or IV (bolus or CI):
5–20 mg/m2 daily ×
2–3 weeks.
IT: 30 mg/m2 × 2 per
week until CR, then
one additional dose.
(Continued)
IT: fever, headache,
chemical arachnoiditis
with vomiting, seizures
with transient paraplegia.
Rare: myelopathic
syndrome.
Acute neurotoxicity
within 5 days from
treatment: 25% headache;
18% chemical arachnoiditis (neck rigidity or
pain, meningism), ↓ with
steroids prophylaxis, ↑
with concomitant RT/CT;
19% nausea, 17% vomiting, fever, back pain;
transient ↑ of CSF
proteins and WBC after
administration.
DL myelosuppression.
problems. Rare: pulmonary toxicity with noncardiogenic edema.
309
Mechanism of action
Gemcitabine (d FdC)
Gemzar®
Intracellularly activated to dFdCTP by
CdR kinase with
2′2′-Difluorodeoxycytidine;
accumulation and
fluorine-substituted Ara-C
prolonged retention.
analogue.
Inhibition of DNA
synthesis through
incorporation into
DNA (masked chain
termination) and
inhibition of RNR
with depletion of
dNTP which compete
with dFdCTP for
incorporation into
DNA (self-potentiating mechanism).
Depletion of dNTP
lead also to: 1. ↑ rate
of dFdC phosphorylation; 2. ↓ activity of
cytidine deaminase,
self-potentiating
mechanisms.
Name, chemistry, relevant
features
Special populations
Renal impairment
↑ risk of HUS, monitor
closely.
Cytotoxicity reversed
by exogenous deoxycytidine; synergistic
effect in vitro/in vivo
of concomitant DDP
and RT.
Low protein binding;
linear PK; for 30 min inf.,
biphasic disappearance
with T1/2 of 8 min due to
tissue inactivation by
cytidine deaminase
(mainly liver and kidney)
to dFdU; 77% of dose as
dFdU in urine. Saturable
accumulation process of
dFd CTP; ↑ intracellular
concentrations possibly
achieved by longer drug
exposure; longer infusion
associated with ↑ Vd and
longer T1/2.
With warfarin: ↑
anticoagulant effect of
warfarin.
With radiosensitizer:
no available guidelines but ↓ dose if
concomitant RT and
avoid concomitant
use in NSCLC.
Drug interactions
Pharmacology and dose
modifications
IV (30 min inf): single
agent, 1000 mg/m2 per
week × 7 followed by 1
week rest, then weekly
× 3 every 4 weeks;
1000 mg/m2 per week
× 3 every 4 weeks;
combination with DDP,
1250 mg/m2 days 1, 8
every 3 weeks or 1000
mg/m2 days 1, 8, 15
every 4 weeks.
Route, schedule, and
recommendations
DL non-cumulative
myelotoxicity (25% G3–4
neutropenia, 5% thrombocytopenia); 75% ↑
LFTs, 10% G3–4; 65%
mild to moderate N & V;
40% mild ‘flu-like
syndrome’, 1.5% severe;
30% maculopapular rash;
30% peripheral edema.
15% alopecia; 8%
diarrhea; 7% stomatitis; ↑
non-hematological
side-effects after more
frequent administrations.
Rare: severe pulmonary
effects including edema,
interstitial pneumonitis
(1%), or ARDS: discontinue drug, steroids might
be effective; HUS in
presence of anemia with
evidence of microangiopathic hemolysis, elevation of bilirubin or LDH,
severe thrombocytopenia
and/or ↑ Cr.
Toxicity
310
Special populations
Renal impairment
According to GFR ml/
min: GFR >50: 100% of
dose; GFR 10–50: ↓ dose
by 50%; GFR <10:
discontinue.
(Continued)
DL leukopenia, after a
median of 10 days,
recovering at discontinuation; maculopapular
rash and facial erythema;
LFTs abnormalities;
drowsiness; transient
renal function abnormalities.
CML
PO: 20–30 mg/kg daily;
discontinue if WBC
<2.5 × 109/1 or Pt <100
× 109/1.
Radiosensitizer: 80 mg/
kg as a single dose,
every 3 days from at
least 7 days before
radiation.
With RT: radiation
recall reactions
independent from
timing of RT (may be
before, concomitant
or even after HU
administration).
With didanosine: ↑
incidence of pancreatitis and neurotoxicity.
With Ara-C: modulation of Ara-C activity,
with ↑ production of
Ara-CTP and incorporation into DNA.
With 5FU: antagonist
effect, with ↓ FdUMP
due to inhibition of
RNR.
Additive effect with
5FU and LV because
of ↓ dUMP pool
competing with
FdUMP for binding
to TS.
Well absorbed; Tmax 1 h,
50% of dose transformed
in liver and excreted in
urine and as respiratory
CO. T1/2 3.5–4 h.
Degraded by urease of
intestinal bacteria; metabolism unknown; 55%
excreted by renal route.
Crosses BBB and third
space fluids with peaks in
3 h.
Enters cells by
passive diffusion;
inhibits RNR with
depletion of ribonucleotides and
inhibition of DNA
synthesis and repair.
Radiation sensitizer.
Hydroxyurea (HU)
Hydroxycarbamide/
Hydroxyurea
NP
Hydrea®
CH4N2O2
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
MISCELLANEOUS AGENTS
311
Weak MAOI: avoid
concomitant use of
sympathomimetic
drugs (isoproterenol,
ephedrine), tricyclic
antidepressants,
gingseng, tyraminerich foods (dark beer,
cheese, red wine,
bananas), MOA and
Special populations
COMT inhibitors (↑
Renal and liver impairment
effect with headache,
No guidelines available
hypertensive crisis,
but ↓ dose.
tremor, palpitations).
With alcohol: disulfiram-like reaction
(severe G1 toxicity,
headache).
With antitumor
agents: possible
interaction through
inhibition of CYP450
system and depletion
of O6-AT.
Completely absorbed with
peak concentrations in
plasma and in CSF in 1 h.
Rapidly concentrated and
metabolized (T1/2β 10
min) in liver and kidney
with 75% of dose
excreted as metabolites in
24 h urine.
Prodrug; generates
several reactive free
radicals, with direct
damage to DNA
through autooxidation, chemical
decomposition, and
CYP450-mediated
metabolism; generates
also methyldiazonium
with monofunctional
alkylating activity.
Also DNA methylation mainly at N7-O6
of guanine with
extent of O6 methylation correlated to
O5-AT activity.
Procarbazine
N-methylhydrazine;
structure similar to MAO
inhibitors.
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry, relevant
features
DL delayed myelosuppression (mainly thrombocytopenia after up to 4
weeks); acute GI toxicity
(N & V, diarrhea), with
tolerance after continued
administration; flu-like
syndrome at the beginning of treatment; allergic
reactions with skin rash
and pulmonary infiltrates
(controlled with low-dose
cortisone); CNS disturbances (paresthesia,
headache, insomnia). Late
toxicities: azospermia,
anovulation, ↑ incidence
of second tumors after
MOPP + RT.
PO: 100 mg/m2 daily
days 1–14 every 4
weeks (MOPP regimen).
Warning
Start at low dose and
then escalate daily to
minimize GI toxicity.
Toxicity
Route, schedule, and
recommendations
312
a-(N-phtalimido)
glutarimide.
Thalidomide
Thalomid®
Immunomodulatory
agent with anti-inflammatory activity;
antiangiogenic effects.
Mechanism of action
not fully understood:
in humans ↓ suppression of excessive
TNFα production
and down modulation of selected
adhesion molecules.
Special population
No data available.
Protein binding
None known; avoid
unknown; F not estabconcomitant
lished; Tmax 3–6 h,
sedatives.
dose-proportional AUC,
Cmax less proportional
suggesting PO solubility
in aqueous media may
hinder absorption rate, fat
meals ↑ Tmax to 6 h;
distribution unknown,
crosses BBB; metabolism
unknown, liver metabolism minimal, undergoes
non-enzymatic hydrolysis;
mechanism of excretion
mostly unknown: T1/2 5–7
h, CL 1.1 ml/min, 0.7%
unchanged drug in 48 h
urine.
(Continued)
Most commom: 48%
fatigue, 43% drowsiness
Multiple myeloma: initial
and somnolence, 28%
dose 200 mg, then
dizziness, 22% tremor,
increase after 14 days
22% incoordination, 22%
to 400 mg daily, in
peripheral edema; 25%
absence of severe
generalized skin rash
side-effects.
(pruritic, macular,
Administer at bedtime to
erythematous; not dose
minimize dizziness and
related, reversible, can be
somnolence.
rechallenged at lower
Anticoagulant prophydoses); 22% depression
laxis: PO warfarin 1 mg
GI (59% constipation,
daily, suggested in pts
11% nausea); 15% TE.
receiving concomitant
Most severe: peripheral
CT.
neuropathy (up to 28%)
Warning
can be irreversible after
Do not start if ANC
chronic use (cumulative
>750/mm3.
dose not known) or if
Discontinue at earliest
severe; starts with symsymptoms of peripheral metrical paresthesias of
neuropathy, if clinically hands and feet, progressappropriate.
ing to cramps, postural
tremor, ↓ muscle
Teratogen
reflexes, palmar eryCan cause severe
thema, and brittle nails.
defects in humans,
Rare: hallucinations,
male and female
delayed skin ulcers,
contraception must be
Stevens–Johnson
implemented.
syndrome.
PO daily
313
Mechanism of action
Recombinant,
humanized, IgG1
MAB against the
extracellular
domain of the
erb-B2 receptor
(HER2).
Herceptin
Trastuzumab®
Binds to HER2
with inhibition of
proliferation and
mediation of
ADCC. HER2
protein overexpression tested by ICH
assays (e.g.
HercepTest); HER2
gene amplification
tested by FISH
assays (e.g.
PathVysion).
Monoclonal antibodies
Name, chemistry,
relevant features
TARGETED THERAPY
Dose-dependent PK
with ↑ T1/2 and ↓ CL at
higher doses; at the RD
terminal T1/2 5–8 days,
Vd 44 ml/kg; ↓ serum
concentration in
presence of high levels
of shedded Ag.
Pharmacology and dose
modifications
In vitro, in vivo
synergistic effects
with DDP, VP16,
and docetaxel;
additive with paclitaxel,
anthracyclines,
NVB.
Drug interactions
Toxicity
Most common: mild, less
frequently moderate: 42%
asthenia, 36% fever, 32% chills,
26% ↑ cough, 26% headache,
25% diarrhea, 23% dyspnea,
IV every 3 weeks: loading
20% infections, 18% rash,
dose: 90 min inf. 8 mg/
14% insomnia.
kg; maintenance: 90
Most serious: cardiomyopathy
min inf. 6 mg/kg.
5% severe CHF (responsive to
Warning
cardiac medications) with
Pre-existing cardiac
dyspnea, peripheral edema and
conditions or with prior
↓ LVEF; discontinue treatment
cardiotoxic
in pts with symptomatic CHF;
therapies: baseline
in combination with
cardiac assessment
anthracyclines 19%.
(EKG + Echo or Muga). HSR including anaphylaxis and
pulmonary symptoms mainly
Pre-existing pulmonary during initial infusion, rechalcompromise
lenge with steroids and antihisDo not administer
tamines. Infusion reaction
as an IV push or bolus. during first infusions with
Do not mix or dilute
chills, fever, nausea, vomiting,
with other drugs; do
hypotension (40% mild to
not mix with Dextrose
moderate); pulmonary events
solutions.
most frequent in elderly.
IV weekly: loading dose:
90 min inf. 4 mg/kg;
maintenance: 30 min
inf. 2 mg/kg.
Route, schedule, and
recommendations
314
Recombinant
chimeric
human IgG1
MAB
against the
extracellular
domain of EGFR
Cetuximab
Erbitux®
Specific, high-affinity binding to the
extracellular
portion of EGFR;
competitive antagonist of TGFα
resulting in:
1. Inhibition of
EGFR function
with ↓ cell proliferation, induction
of apoptosis, ↓
tumor angiogenesis, ↓ DNA repair.
2. Internalization
of EGFR with
downregulation.
Cetuximab also
exhibits ADCC. In
vitro additive
effects with cytotoxics, biological
agents, RT.
Synergistic activity
of combination of
Cetuximab plus
CPT11 in CRC
xenografts refractory to single agent
CPT11. Overexpression of EGFR
tested by ICH
assays.
Special populations
Age
No age effect.
Other
Not studied in
children, in pts with
renal and in pts with
moderate to severe liver
impairment
(AST and/or ALT >2.5
NV, or bilirubin
>1.5 × NV).
Linear increase of
Cmax and AUC up to
400 mg/m2;
dose-dependent CL
with plateau at
200 mg/m2 of
0.02 l/h/m2, possibly
due to a saturable
excretion pathway at
low doses; Tmax 1–2 h,
Vss 1.9–2.9 l/m2, T1/2
66–97 h at the RD
400/250 mg/m2; Css
achieved after 3 weeks
of treatment.
No PK interaction
with CPT11, DDP,
Gemcitabine, Paclitaxel, Docetaxel.
(Continued)
Immunogenicity: 4% HACA, not
clinically relevant.
Most common: acne-like rash
(88%, G3–4 14%), correlated
with response to treatment,
occurring mostly during the
Premedication with
first week, lasting for >90 days
antihistamine.
in 50% of pts, resolving in 50%
of pts within 30 days after
Skin reactions: prolong
discontinuation.
retreatment interval, ↓
dose, and symptomatic Other common G 3–4; 11%
asthenia, 10% dyspnea, 7%
topical steroids.
abdominal pain. 4% HSR,
occurring at first infusion in
Warning
Resuscitation equipment 80% of cases, mainly moderate,
with fever, chills, rash, dyspnea,
available. Monitor HR,
BP during the infusion, cough, back pain; controlled by
↓ infusion rate; if severe disconup to 1 h after.
tinue treatment permanently.
IV 2 h inf.: 400 mg/m2
day 1, then IV 1 h inf.
250 mg/m2 weekly.
315
Recombinant
humanized IgG1
MAB anti-VEGF.
With CPT11
(potential): 33% ↑
concentration of
SN-38 in pts
receiving
bevacizumab in
combination with
Special populations
CPT11/LV/5FU and
Age, gender
↑ of G3–4 diarrhea;
No adjustment required
extent and reasons of
for age, gender.
interaction uncerOther
tain.
No information
available in pts with
renal or liver
impairment.
T1/2 20 days; time to
Css 100 days; CL
1.2–2.66 1/day; higher
in males and in pts
with high tumor
burden.
Binds to
VEGF inhibiting
biological activity
in vitro and in vivo
by preventing the
interactions of
VEGF to the cell
surface receptors
Flt-1 and KDR.
Causes ↓ of
microvascular
growth and
metastatic spread
in murine colon
xenograft models.
Bevacizumab
Avastatin®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Toxicity
In combination with:
CPT11/LV/5FU.
IV (90 min infusion)
5 mg/kg once every
14 days until disease
progression. Start
treatment at least 28
days after surgery.
Post-bevacizumab
surgery: at least 20 days
after last administration.
Most common: (NB incidence
refers to the combination): 37%
leukopenia, 34% diarrhea, 10%
asthenia.
Most serious: GI perforation:
2–4% (potentially fatal), 1%
wound healing complications
(15% if surgery after bevacizumab; hemorrhage: 4–31%
G3–4 usually massive
hemoptysis (in NSCLC pts),
rare GI, subarachnoid and
Warning
stroke; TE: possibly ↑; hyperDo not administer as an
tension: 60–67% (placebo
IV push or bolus.
43%), G3–4 7–10% (placebo
Do not freeze; do not
2%); proteinuria: 2–4% G3,
shake.
rare (0.5%) nephrotic synDiscontinue permanently:
drome; CHF: 2%, ↑ risk (14%)
in case of GI perforawith concomitant DOX; HSR <
tion, wound dehiscence,
3%.
serious bleeding,
Immunogenicity: data uncertain
nephritic syndrome,
hypertensive crisis, HSR due to different assays.
(no data on rechallenge).
Temporary suspension:
in case of severe
proteinuria.
Route, schedule, and
recommendations
316
Binds to CD20
(human
B-lymphocyteImmunoradiotherarestricted differenpic agent; murine
tiation Ag, Bp35) a
IgG2a lambda MAB
transmembrane
against CD20,
phospho protein
covalently bound to
expressed on
iodine-131.
pre-B cells, mature
B cells, and in 90%
NHL B cells.
CD20 is not
internalized upon
binding, nor shed
or found in the
blood.
Mechanisms of
action not fully
elucidated, may
include triggering
of apoptosis (with
the contribution of
131
I), CDC and
ADCC. 7 weeks
from end of
treatment no
circulating CD20+
cells.
Tositumomab
Bexxar®
Special populations
Renal impairment
Not studied; 131I CL
might be ↓, leading to
↑ exposure.
After predosing with
unlabeled MAB ↓
splenic targeting and ↑
terminal T1/2. In pts
with high tumor
burden, splenomegaly,
or BM involvement, ↑
CL, Vd, and ↓ terminal
T1/2; elimination by
decay and urinary
excretion (98%).
Vaccines: not studied, but caution.
Anticoagulants and
drugs affecting Pt
function: potential
pharmacological
interaction with ↑ of
bleeding.
Two-step regimen: step
1 dosimetry, then after
7–14 days therapeutic
step.
Dosimetry:
Tositumomab 450 mg
IV (inf. 60 min),
followed by 131I
Tositumomab IV
(inf 20 min), monitor
postinfusion with
SPECT at 1 h, 2–4 and
7–10 days. If acceptable
biodistribution proceed
to therapy (single
course): Tositumomab
450 mg IV (inf. 60 min)
followed by 131I Tositumomab (35 mg Tositumomab) at therapeutic
doses according to Pt
count/mm3.
Do not treat if Pt <
100 000/mm3 Pt.
Maximum dose of 131I
Tositumomab: 75 cGy.
(Continued)
Secondary malignancies: 4.2
and 10.7% AML a/o myelodysplasia at 2 and 4 years, respectively, in patient previously
treated with APC, onset average
27 months; other
malignancies 5%.
Most common: 46% asthenia,
36% N (with V 15%); 29%
infusion-related effects (chills,
fever, rigor, hypotension,
dyspnea, bronchospasm,
sweating), during or within
48 h from therapy; 9–17%
hypothyroidism, 15% abdominal pain, 14% anorexia.
Most serious: pancytopenia
severe (G3–4) prolonged: 63%
neutropenia, 53%
thrombocytopenia, 29%
anemia; nadir 4–7 weeks,
recovering in 30 days (90 days
in 5% of pts); 45% infections,
12% hemorrhage; 6% HSR
(bronchospasm and angioedema), risk ↑ in pts with
HAMA.
317
Name, chemistry,
relevant features
Mechanism of action
Pharmacology and dose
modifications
Drug interactions
Warning
Resuscitation equipment
available.
HSR: discontinue
treatment and treat
appropriately.
Premedication with
acetominophene and
antihistamine suggested
but value not known.
Thyroid protective
therapy: initiate 24 h
before and for 14 days
after. Assess thyroid
status before treatment
and monitor annually.
Route, schedule, and
recommendations
Toxicity
318
Gefitinib
Iressa®
Selective EGFR-TK
inhibitor, which
blocks autophosSynthetic
phorylation of
anilinoquinazoline.
EGFR; EGFR
N-(3-chloroinhibition
4-fluorophenyl)maintained for
7-methoxy-624 h gives need of
(3-morpholinochronic treatment
propoxy)
for antitumor
quinazolin-4-amine. effect. No
correlation between
EGFR expression
and xenograft
sensitivity.
In vitro synergistic
effect with
radiation; at higher
doses proapoptic
effect mainly in
combination with
CT.
Small molecules
Special populations
No relationship with
body weight, age,
gender, ethnicity, renal
function.
Liver impairment
Not observed in pts
with mild to severe
LFTs alteration due to
liver mets. No data
available for noncancer-related
impairment.
90% protein bound. F
60%; slow absorption
with Cmax at 3–7 h.
Plasma Css achieved
within 10 days, with
56% and 30% interpt./
intrapt. variability.
Terminal T1/2 48 h.
Extensively distributed:
Vdss 1400 1 after IV.
Extensively metabolized by CYP, principally by 3A4; excretion
in feces (86%), renal
elimination (parent and
metabolites) <4%.
With CYP3A4
inhibitors or
inducers:
itraconazole
(inhibitor) ↑ 85%
AUC rifampicin
(inducer) ↓ 88%
AUC.
With drugs ↑ gastric
pH: potential reduction of plasma
concentrations.
With warfarin: INR
elevations and/or
bleeding events.
(Continued)
Very common: 48% G1–2
diarrhea, 12% G1–2 V, 56%
G1–2 pustular skin rash, rarely
Interrupt treatment
itchy.
temporarily (maximum
Common: 30% G1–2 ↑ AST/
14 days): for G 3–4:
ALT, 7% anorexia, 6% G1
diarrhea, ↑ LFTs, skin
asthenia, 2% conjunctivitis
rashes; any grade eye
alopecia.
symptoms.
Uncommon (0.1 to <1%):
Discontinue treatment
corneal erosion; G3–4 ILD, fatal
for acute onset or
in 34% of cases, as interstitial
worsening of pulmonary pneumonitis and alveolitis with
symptoms (dyspnea,
cough and fever, acute onset,
cough, fever).
higher mortality in case of
concurrent idiopathic
pulmonary fibrosis. ILD has
occurred in pts with prior RT
(31% of cases), prior CT (57%),
no previous therapy (12%).
PO: 250 mg fixed daily
dose.
319
N-(3-ethynylphenyl)-6,7-bis(2methoxyethoxy)-4quinazolinamine,
monohydrochloride.
With CYP3A4
>90% protein bound;
inducers: ↓ plasma
rapid absorption after
concentration.
oral administration
with Tmax 3–4 h; F in
humans not clarified,
T1/2 24 h, Css plasma
concentration
1.20 mg/ml; no drug
accumulation after
daily dosing
150 mg.
Metabolism: predominantly liver through
CYP3A4 and 3A5;
principal active metabolite OSI–420; by other
P450 systems also in
tumor tissues.
Excretion 90% in feces.
Direct and
reversible
inhibition of HER1/
EGFR TK, and
EGFR-dependent
proliferation at
nanomolar
concentrations. In
animals, 0.5 µg/ml
plasma
concentrations
result in EGFR
inhibition
associated with
antiproliferative
activity; after oral
administration,
maximum
inhibition 1 h,
>70% for >12 h.
Erlotinib
Tarceva®
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Toxicity
Possible relationship between
skin toxicity and antitumor
effects, to be confirmed by
phase III analysis.
Most common: DL 39% diarrhea
PO: 150 mg daily
uninterrupted schedule. (≥G3 4%), 61% cutaneous rash
(≥G3 5%), 21% nausea, 21%
Treatment for skin rash:
pulmonary disorders (≥G3 2%),
steroid creams, topical
18% fatigue (≥G3 2%), 13%
antibiotics and systemic
acne, 11% vomiting, 10%
antihistamines have
headache, 8% dry eye, 8%
been tried.
dry mouth.
Route, schedule, and
recommendations
320
Competitive
inhibitor of Bcr-Abl
TK, constitutively
4-[(4-Methyl-1activated in Ph+
piperazinyl)
CML. Inhibits also
methyl]-N-[4-methTK of c-Kit, PDGF,
yl-3-[[4-(3and SCF. Inhibits
pyridinyl)-2-pyrimproliferation and
idinyl]
induces apoptosis
amino]-phenyl]
in vitro and in vivo
benzamide
Ph+ CML cells.
methanesulfonate.
Mechanism of
resistance not fully
elucidated,
includes AAG
binding, mutation
a/o amplification
(resulting in ↑
expression of
Bcr-Abl TK) of the
Bcr-Abl gene.
Imatinib mesylate
Gleevec®
Special populations
Age
Edema more frequent
in elderly; no pediatric
data.
Liver impairment
No guidelines, suggested: bilirubin
>3 × NV and AST 5 ×
NV: withhold, then if
bilirubin <1.5 × NV
and AST <2.5 × NV:
resume at ↓ doses.
95% protein bound; F
98%, Tmax 2–4 h, high
fat meals ↓ absorption;
linear and dose-dependent PK (25–1000 mg).
T1/2 parent and major
active metabolite,
respectively, 18
and 40 h.
Metabolized mainly by
CYP3A4, N-demethylated piperazine
derivative main active
human metabolite;
eliminated 13% in 7
days urine and 68% in
feces (mostly as metabolites); CL 8–14 1/h
with <40% interpt.
variability allowing
fixed dosing.
With CYP3A4
inhibitors
(ketoconazole,
grapefruit juice,
erythromycin, etc.):
↑ plasma
concentration.
With CYP3A4
inducers (DXM, St
John’s wort,
rifampicin,
phenytoin, etc.): ↓
plasma
concentration.
With CYP3A4
substrates
(cyclosporin,
triazolo benzodiazepine, etc.): ↑
plasma concentration
of substrate.
With CYP2D6
substrates (CTX,
beta-blockers,
morphine, etc.): ↑
Plasma concentration
of substrate.
With warfarin: ↑
anticoagulant effects.
With acetaminophen:
potential ↑
hepatotoxicity.
GIST: 400–600 mg
daily.
PO daily.
CML
Chronic phase: 400 mg
daily; accelerated phase:
600 mg daily.
↑ to 600 and 800 (400
× 2) respectively daily,
in absence of severe toxicity, if: disease progression or failure to
achieve hematological
response after 3
months, or failure to
achieve cytogenetic
response after 6–12
months, or loss of
previous hem or cytogenetic response.
(Continued)
Common: 55% fluid retention
(severe 1%), 42% N (15% V),
30% diarrhea, 32% rash, 35%
muscle cramps, 30% headache,
28% arthralgia, 23% abdominal
pain, 15% dyspepsia;
hematological: 19% hemorrhage (G3 1%), 12% ≥G3
neutropenia, 7% thrombocytopenia, 3% liver toxicity.
321
Natural retinoid;
related to retinol
(vitamin A);
differentiating
agent.
86% headache in 50% due to ↑
intracranial pressure
(pseudotumor cerebri, espeIntermittent PO
cially in children), early signs:
schedule (to overcome
papilledema, N & V, visual
metabolic induction);
disturbances; 77% skin and
45 mg/m2 daily, in two
mucosal toxicity (dryness,
divided doses, days
itching, peeling, cheilitis); 70%
1–14 every 3 months.
bone pain, arthralgia; 50% ↑
Administer in fed
LFTs slowly reversible; 25%
conditions.
edema, fatigue, fever and rigors;
17% ocular disorders; 25%
Monitor LFTs:
temporary withdrawal if RA-APL syndrome (usually
during first month) with
>5 × NV.
leukocytosis, fever, hypotenRA-APL syndrome: HD
sion, dyspnea, RX lung infilIV steroids at first
trates, fluid retention, CHF,
suspicion.
DIC-like syndrome (differential
diagnosis with APL). Teratogenic: avoid pregnancy.
Maintenance regimen
only
With CYP450
inducers: ↑ catabolism; unproven
clinical relevance.
With CYP450
inhibitors (e.g.
ketoconazole): ↑
T1/2 of unproven
clinical relevance.
>95% protein bound;
Tmax, 1–2 h; F 50%
affected by biliar pH
and high fat meal; high
interpt. variability of
absorption and plasma
levels. T1/2 <1 h,
undetectable after 10 h;
metabolized by CYP450
to 4-OXO-ATRA then
glucuronidated; 60%
excretion in urine, 30%
in feces.
Induces its own
metabolism: ↑ CL after
2 weeks chronic dosing
due to ↑ catabolism
and ↑ tissue
sequestration.
Differentiating
effect through
binding to cytosolic
and nuclear
receptors (RARs)
with induction of
transcription of
genes involved in
growth inhibition
and differentiation.
ATRA most active
among natural
retinoids in reversing changes of
epithelial-derived
malignancies.
Tretinoin (alltrans-retinoic acid,
ATRA)
Vesanoid®
Toxicity
Route, schedule, and
recommendations
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
322
2% protein bound;
minimal tissue binding;
T1/2α 15 min, T1/2 β 140
min; 42% excreted in
urine.
Cardioprotection
observed in >65 years
old and in pts with
LVEF low normal.
Cleared from plasma in
10 min; retained in
normal tissues; T1/2 9
min; 4% urinary excretion. High
concentration of free
thiol in BM, declining
within 2.5 h.
Cardioprotection:
intracellular hydrolysis to ring-opened
chelating agent with
removal of Fe2+ and
Cu2+ from DOXcomplexes and ↓ of
O2 free radicals
generation.
Dexrazoxane
Zinecar®
Prodrug; selectively
dephosphorylated in
normal tissues by
Cytoprotective
AP to free thiol
thiophosphate
which acts (a) by
compound.
binding to reactive
Indications: (1) to ↓
molecules of DDP
the cumulative renal
and (b) as a free
toxicity associated
radical scavenger of
with repeated
free radicals generadministrations of
ated by DDP and
DDP in pts with
RT.
ovarian and NSCL
Higher uptake and
cancers; (2) to ↓
metabolism in
incidence of modernormal cells due to
ate to severe xerostohigher pH and AP
mia in pts with
concentration.
H&N receiving
postsurgery RT
(1.8–2 Gy) to >75%
of both parotid
glands.
Amifostine
Ethyol®
Indication: continuation of DOX after
≥300 mg/m2 cumulative dose in pts in
whom
continued therapy
is indicated.
Bispiperazinedione;
cyclic derivative of
EDTA.
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
RADIOCHEMOPROTECTANTS
Caution
In pts with preexisting cardiovascular/cerebrovascular
conditions.
With antihypertensives:
hypotension,
to be interrupted at
least 24 h before
Amifostine.
IV (15 min inf.): a
maximum of 30 min
should elapse within the
start of inf. and DOX
administration.
Dosage ratio to DOX:
10:1 (500 mg/m2: 50 mg/
m2).
With DOX: ↓
incidence and severity
of DOX cardiomyopathy. Does not influence PK of DOX.
HSR, severe cutaneous
reaction: discontinue
treatment.
Warning
Incidence of side-effects
↑ with longer infusion.
Antiemetic prophylaxis
with steroids and 5HT3
antagonists.
With CT:
IV (15 min inf.): 910 mg/
m2 30 min before DDP
(≥100 mg/m2) (keep pts
in supine position during
and after treatment).
With RT:
IV (3 min inf.):
200 mg/m2 15–30 min
before RT (keep pts in
supine position during
and after treatment).
Do not mix with other
drugs during infusion.
Warning
Cardiac function must be
monitored serially.
Route, schedule, and
recommendations
Drug interactions
DL toxicities: emesis (92%) and
hypotension (62%) at the end of
infusion, lasting 5 min.
Less frequent: sneezing, warm
flush, mild somnolence,
hypocalcemia (<1%).
Rare: HSR, serious cutaneous
reactions, more frequent in pts
receiving RT.
May add to chemotherapy myelotoxicity: serial CBC monitoring.
Urticaria 2%, pain on injection
site 7%.
Toxicity
323
Recombinant made
by gene-modified
mammalian cells
with human gene.
Glycoprotein
hormone for
erythropoiesis,
produced primarily
in peritubular
interstitial cells of
kidney; ↑ production due to ↑ gene
transcription if
kidney/liver
hypoxia.
Delayed incomplete
Not known.
absorption with sustained levels after SC.
T1/2 3–10 h, detectable
in plasma up to 24 h;
Tmax between 5 and
24 h after SC dosing;
hepatic metabolism
with desialyzation, 10%
excretion in urine.
Binds on specific
receptors on
committed
erythroid
progenitor cells,
stimulates
proliferation and
differentiation of
erythroid cells with
negative feedback
on hypoxic
stimulus. Inverse
correlation between
erythropoietin
plasma levels and
Hb concentration if
normal kidney
function.
Recombinant
human
erythropoietin
(rHuEPO)
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
GROWTH FACTORS AND SUPPORTIVE TREATMENT
Toxicity
Absolute contraindications: uncontrolled
hypertension, severe
cardiac/peripheral
arteriopathies, recent
TIA, DVT.
Warning
EPO likely to be
ineffective if erythropoietin plasma levels
>500 mU/ml.
Check hematocrit (Ht)
weekly, 25% dose
titration up or down,
discontinue if Ht >35%.
Exacerbation of pre-existent
hypertension with need of
CT-associatcd anemia:
weekly monitoring of BP; mild
150–300 mU/kg 3 times
arthralgia, local pain injection,
a week for 8 weeks.
pure red cell aplasia due to
Zidovudine-associated
neutralizing Ab to native
anemia: 100 mU/kg 3
erythropoietin; ↑ incidence of
times a week.
CVC thrombosis; potential
Supplemental iron if
stimulation of growth of some
serum ferritin <100 µg/l tumors.
or serum transferrin
saturation <0%.
SC
Route, schedule, and
recommendations
324
Differs from
rHuEPO for a
5-chain, instead
of a 3-chain
oligosaccharide,
with ↑ molecular
weight.
Darbepoetin alfa
(Aranesp)
Same mechanism
as endogenous
erythropoietin with
↑ Hb within 2–6
weeks after
starting.
Special populations
No age effect.
Linear PK within
Not known.
0.45–4.5 µg/kg with no
accumulation. After SC
administration slow
rate-limiting absorption
with T1/2 49 h (27–89
h), Cmax between 71
and 123 h; 37%
bioavailability in
chronic renal failure
pts.
Absolute
contraindications:
uncontrolled
hypertension, known
hypersensitivity.
Warning
EPO likely to be ineffective if erythropoietin
plasma levels
>500 mU/ml.
Supplemental iron
if serum ferritin <100
µg/l or serum transferrin
saturation <20%.
Keep Hb around 12 g/
dl; ↓ dose for ↑ Hb
>1 g/dl over 2 weeks;
discontinue if Hb
>14 g/dl, then restart at
50% dose.
SC: start with 2.25 µg/
kg once a week; check
Hb weekly, increase to
4.5 µg/kg once a week
for ↑ Hb <1 g/dl after 4
weeks; discontinue after
4 weeks for ↑ Hb still
>1 g/dl.
(Continued)
↑ risk of cardiovascular events,
exacerbation of pre-existing
hypertension with need of
weekly monitoring of BP.
Rare: severe allergic reaction
requiring discontinuation.
Most common: 23% hypertension, 21% myalgia, 16%
headache, 15% diarrhea, 11%
edema, 11% arthralgia, 11%
fluid retention, 10% back pain,
9% fatigue, 9% fever, 8% CNS,
8% rash, 6% TE, 1.3% PE.
325
Recombinant
glycoprotein
hormone necessary
to maintain
adequate numbers
of circulating PMN;
produced by
E. coli-inserted
G-CSF gene.
T1/2β 3.5 h; Tmax 2–8 h; With lithium: ↑
distributed into plasma ANC release, ↑
and BM, metabolized in frequency CBC.
liver and kidney.
By binding on
specific receptors
induces proliferation of granulocyte
progenitor cells, ↑
PMN chemotaxis,
phagocytosis and
intracellular killing.
Filgrastim
Neupogen®
G-CSF
Drug interactions
Pharmacology and dose
modifications
Mechanism of action
Name, chemistry,
relevant features
Paracetamol to control
bone pain.
Autologous or allogenic
BMT and in AML: start
the day of BM infusion,
>24 h after CT, >12 h
after total body irradiation, up to ANC
1500/mm3 for 3 days.
PBPC reinfusion: 5 µg/kg
daily starting up to 5
days after, up to ANC
10 000/mm3.
PBPC mobilization: 10
µg/kg (or 480 µg/day)
daily.
SC
CT-induced neutropenia:
5 µg/kg daily (or 300
µg), starting 1–5 days
after CT for 14 days or
up to ANC
5000–10 000/mm3;
check counts bi-weekly.
Route, schedule, and
recommendations
Exacerbation of pre-existing
inflammatory conditions.
20% bone pain, mainly medullary and iliac, due to ANC
expansion in BM, leg pain,
musculoskeletal pain; transient
↑ AP/LDH.
Rare: HSR, ARDS in neutropenic septic pts; sickle cell
crises in pts with sickle cell
disease.
Toxicity
326
Covalent conjugate
of filgrastim and
monomethoxypolyethylene glycol.
Pegfilgrastim
Neulasta®
Same as filgrastim
Special populations
No age effect.
↓ CL and prolonged
With lithium: ↑
persistence; as comANC release, ↑
pared to filgrastin
frequency CBC.
larger intrapt. variability with T1/2β of 15–80
h. Non-linear PK, ↓ CL
for ↑ dose, serum clearance related to ANC
count and body weight.
Long-lasting effect.
Warning
Must be given: at least
24 h after CT; at least
14 days prior to subsequent CT. Avoid use in
weekly or <3 weeks CT
schedules.
Absolute
contraindication:
known hypersensitivity.
Approved indication: ↓
incidence of infection.
SC
Adults and children ≥45
kg: 6 mg once per cycle.
Children <45 kg: dose
not defined (<6 mg).
(Continued)
26% mild to moderate medullary bone pain, 12% requiring
non-opioid analgesics, 19% ↑
LDH, 9% ↑ AP.
Rare: splenic rupture, ARDS,
sickle cell crises, HSR.
327
Mechanism of action
IL-11 (Oprelvekin) Stimulation of
proliferation of
Neumega®
HSC and
Recombinant
megakaryocyte
polypeptide,
progenitor cells,
thrombopoietic
induction of
growth factor for
megakaryocyte
prevention of severe
maturation.
thrombocytopenia
Stimulation of
and reduction of
osteoclastogenesis.
transfusions need
after
myelosuppressive
CT.
Name, chemistry,
relevant features
Drug interactions
Warning
In pts with CrCL <15
ml/min, doubling of
Cmax AUC and ↑ >20%
mean plasma volume,
with ↓ RBC volume
resulting in dilutional
anemia, prirmirely due
to Na and water
retention (beginning
after 3–5 days,
reversible within
1 week after
discontinuation).
After SC administration No interaction with
80% bioavailability.
filgrastim.
Tmax 3 ± 2 h, T1/2γ 7 h
with no accumulation
after repeated
administrations; low
urinary excretion.
Dose-dependent effect,
beginning 5–9 days
after start, continuing
up to 7 days from end,
recovering to baseline
within 14 days.
Pharmacology and dose
modifications
Absolute
contraindication: prior
hypersensitivity.
Caution in pts with:
pre-existing papilledema, prior/concomitant CHF, aggressive
hydration, atrial
arrhythmias. Safety of
chronic dosing not
established.
Warning
Discontinue at least 2
days before restarting
CT.
Monitor periodically Pt
count, fluid balance,
and electrolytes.
SC daily
Adults: 50 µg/kg, start
6-24 h after completion
of CT, continue up to
postnadir value of
50 000/mm3 Pt (usually
for 10–21 days).
Children: recommended
dose not defined, higher
doses used with ↑
side-effects, mainly
papilledema see toxicity.
Route, schedule, and
recommendations
Adults: 59% peripheral edema
due to fluid retention, 48% dyspnea, 41% headache, 36%
fever; 25% skin rash; cardiac:
dizziness, 14% palpitation, 20%
tachycardia, 15% arrhythmia;
1% papilledema.
Children: ↑ incidence due to ↑
doses up to 125 µg/kg; cardiac:
84% tachycardia, 24%
radiographic evidence of
cardiomegaly; 58% conjunctival
injection, 16% papilledema
after repeated courses, 11%
periosteal changes.
Rare (all pts): HSR including
anaphylaxis, after first or
subsequent doses.
Toxicity
328
Bisphosphonates
Pamidronate
Aredia®
aminohydroxypropylidenebiphosphate
Zoledronic acid
Zometa®
Inhibition of bone
resorption due to:
(1) direct
inhibition of
osteoclastic
activity;
(2) binding to Ca
phosphate crystals
in bone blocking
its dissolution and
bone/cartilage
resorption; (3)
inhibition of tumor
factors activating
osteoclasts and
bone resorption.
If renal impairment
after long-term use,
discontinue treatment
until recovery, repeat
examinations every
3–4 weeks.
Caution
No data in pts with Cr
>3 mg/dl or >245
µmol/l): ↑ inf. time.
Special populations
Renal impairment
Withhold treatment: if
Cr baseline normal and
Cr ↑ by 0.5 mg/dl; if
Cr baseline abnormal
and Cr ↑ by 1 mg/dl.
Re-introduce only if
recovery to 10%
baseline.
Zoledronic acid: 56%
protein bound; 44 ±
18% dose as parent
compound in 24 h
urine; triphasic plasma
disappearance with
T1/2α 0.23 h, T1/2β 1.75 h,
T1/2γ 167 h.
Pamidronate: not
metabolized but
exclusively eliminated
through renal excretion
(46%); CLR closely
correlated to renal
function.
Zoledronic acid
With loop diuretics,
aminoglycosides,
thalidomide: possible
↑ renal damage.
Pamidronate: none
known.
Warning
Do not mix with
Ca-cantaining
solution, administer
through a separate
line.
Zoledronic acid (Z) IV
Osteolytic lesions
15 min inf. 4 mg every
4 weeks.
Hypercalcemia
Hydrate to daily
diuresis 2 1/day. Titrate
dose to serum Ca
values.
Pamidronate (P) IV
Osteolytic lesions 90 mg
every 4 weeks. Inf
duration: 2 h inf.
(diluted in 250 ml NS
0.9%); 4 h inf. (diluted
in 500 ml NS 0.9%).
Hypercalcemia
Hydrate to daily diuresis 2 1/day. Titrate dose
to serum Ca values.
Maximum effect within
3–7 days, at least 7 days
within retreatments if
no activity.
Gr 3–4 (%) P Z
Hypocalcemia 2 1, hypophosphatemia 38 53
Hypomagnesemia 1 0
Renal deterioration <1 <1
Nausea 45 43
Vomiting 30 30
Fatigue 37 36
Diarrhea 25 32
Pyrexia 28 30
Myalgia 24 21
Paresthesia 14 12
Rash 11 11.
Rare: scleritis
within 6 h to 2 days
after P.
329
List of drugs
1. Alkylating agents
1.1 Nitrogen mustard
Meclorethamine
Cyclophosphamide (CTX)
Ifosfamide (IFO)
Mesna
1.3 Ethylenimines
Thiotepa
Hexamethylmelamine
1.4 Nitrosoureas
CCNU
Streptozocin
1.6 Imidazotetrazines
Temozolomide
2. Platinum compounds
Cisplatin (DDP)
Carboplatin (CBDCA)
Oxaliplatin
3. Antitumor antibiotics
Bleomycin sulfate (BLM)
Mitomycin C (MMC)
Dactinomycin (DACT)
4. Antimicrotubule agents
4.1 Vinca alkaloids
Vinblastine sulfate (VLB)
Vincristine sulfate (VCR)
Vinorelbine (NVB)
4.2 Taxanes
Paclitaxel
Docetaxel
5. Enzyme inhibitors: topoisomerase II inhibitors
5.1 Anthracyclines, anthracenediones
Doxorubicin (DOX)
Epirubicin (EPI)
Doxorubicin HCl liposome
5.2 Epipodophyllotoxins
Etoposide (VP16)
Etoposide phosphate
Teniposide (VM26)
6. Enzyme inhibitors: topoisomerase I inhibitors
6.1 Camptothecines
Irinotecan (CPT-11)
Topotecan
8. Antimetabolites
8.1 Antifolates
Leucovorin (LV)
Raltitrexed
Methotrexate (MTX)
Pemetrexed
8.2 Pyrimidine analogues
5-Fluorouracil (5-FU)
UFT
Floxuridine (FUDR)
Capecitabine
Cytarabine (cytosine arabinoside; Ara-C)
Cytarabine liposome
Gemcitabine (d FdC)
9. Miscellaneous agents
Hydroxyurea (HU)
Procarbazine
Thalidomide
10. Targeted therapy
10.1 Monoclonal antibodies
Herceptin
Cetuximab
Bevacizumab
Tositumomab
332 List of drugs
10.2 Small molecules
Gefitinib
Erlotinib
Imatinib mesylate
Tretinoin (all-trans-retinoic acid, ATRA)
11. Radiochemoprotectants
Dexrazoxane
Amifostine
13. Growth factors and supportive treatment
Recombinant human erythropoietin (rHeEPO)
Darbepoetin alfa
Filgrastim
Pegfilgrastim
IL-11 (Oprelvekin)
Biophosphonates
Index
Note: Locators in italics denote tables and illustrations.
18
F-fluoro-2-deoxy-D-glucose positron emission tomography, clinical
diagnosis 88, 89, 90
5-fluorouracil (5-FU) 304–5
abbreviations 276–7
drugs 276
abdominal ultrasound, staging 107
aberrant anti-growth signaling, molecular biology 26–9
acupuncture, smoking cessation 48
adenocarcinoma
BAC 63–5
classification 63
defining 63
histopathology 63–5
molecular profiling 266
pathoradiologic correlations 64
prognostic correlations 64–5
variants 63
adenosquamous carcinoma
defining 68
histopathology 68
adjuvant chemotherapy after surgical resection 147–52
meta-analyses 152
Adjuvant Lung Project Italy (ALPI trial) 148
Adjuvant Navelbine International Trialists Association (ANITA)
trial 152
adrenal metastases, clinical diagnosis 78–9
advanced NSCLC
bevacizumab 165
chemotherapy 158–65
erlotinib 164
first-line therapy 158–9, 161–2
second-line therapy 163–4
targeted therapies 164–5
three-drug combinations 161, 162
air pollution 6–7
alkylating agents 278–83
ALPI trial see Adjuvant Lung Project Italy
altered fractionation radiation therapy, NSCLC 141–2
alternative therapies, smoking cessation 48
amifostine 323
aminoacridines 297–8
anemia 243
angiogenesis, molecular biology 30–1
angiogenic factors, targeting 31
animal models, MM 195–7
ANITA see Adjuvant Navelbine International Trialists Association trial
ANNA-1 see antineuronal nuclear
autoantibodies-1-associated syndromes
ANNA-2 see type 2 antineuronal nuclear autoantibodies
anorexia, symptom management 241
anthracenediones 293–6
anthracyclines 293–6
anti-angiogenic agents, MM 201
anti-Ri antibodies, clinical diagnosis 83
antibiotics, antitumor 287–8
antifolates 301–3
antimetabolites 301–10
antimicrotubule agents 289–92
antineuronal nuclear autoantibodies-1-associated (ANNA-1)
syndromes, clinical diagnosis 83
antitumor antibiotics 287–8
anxiety, symptom management 241
APC see argon plasma coagulation
apoptosis, lung cancer 24–6
apoptotic pathways, targeting 25–6
Ara-C 308–9
argon plasma coagulation (APC), bronchoscopic treatment 211–12
asbestos, MM 191
atypical/typical carcinoid tumors 69–70
availability, tobacco policy 36
BAC see bronchioloalveolar carcinoma
basaloid carcinoma
differential diagnosis 66–8
cf LCNEC 66–7, 68
cf NSCLC 68
cf SCLC 66–7
334 Index
bevacizumab 316
advanced NSCLC 165
biomarkers, MM 198
bisphosphonates 329
bleomycin sulfate (BLM) 287
bone metastases, clinical diagnosis 80
bone scintigraphy, staging 107
bones, clubbing, fingers/toes 83–4
brain metastases
clinical diagnosis 79–80
complications 224–5
bronchioloalveolar carcinoma (BAC) 63–5
bronchoscopic treatment 210–17
advantages 213, 215
APC 211–12
cryotherapy 212
disadvantages 213, 215
EC 211–12
economic aspects 215
endobronchial brachytherapy 212
extraluminal tumors 214–15
indications 210
laser resection 211
mechanical obstruction removal 210–11
palliation of lung tumors 210–17
PDT 212–14
recommendations 215
results 214
stenting 214–15
techniques to remove endobronchial tumors 210–14
bronchoscopy
clinical diagnosis 91
staging 104
bronchus cancer, incidence 13–16
bupropionSR, smoking cessation 47
CALGB 9633 trial see Cancer and Leukemia Group B 9633 trial
camptothecines 299–300
Canada, costs 254–5
Cancer and Leukemia Group B (CALGB) 9633 trial 151–2
capecitabine 307
carbon monoxide
expired air 42
smoking cessation 42
carboplatin (CBDCA) 285
vs cisplatin 160
carcinogenesis 1–5
carcinogens, tobacco smoke 1–5
carcinoid tumors
differential diagnosis 70
histopathology 69–70
immunohistochemistry 69–70
typical/atypical 69–70
carcinosarcoma, histopathology 69
cardiac tamponade, complications 223–4
care, supportive see supportive care
causative agents, lung cancer 1–5
CBA see cost-benefit analysis
CCNU 282
central nervous system metastases, clinical diagnosis 79–80
cervical mediastinoscopy, staging 107–8
cessation, smoking see smoking cessation
cetuximab 315
chemotherapy
adjuvant chemotherapy after surgical resection 147–52
advanced NSCLC 158–65
agents used 184–7
bevacizumab 165
chemotherapy followed by radiotherapy 155
combined-modality therapy 137–41
concurrent chemoradiotherapy 155–7
docetaxel 163–4
elderly patients 163
erlotinib 164
first-line therapy 158–9, 161–2
induction chemoradiotherapy before surgery 154
induction chemotherapy before surgery 152–4
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
induction chemotherapy, restaging after 113–15
locally advanced unresectable (IIIA and IIIB) NSCLC 154–8
MM 199, 200
non-cisplatin-containing 159–61
NSCLC 147–69
platinum-based 158–9
poor performance patients 163
preoperative (neoadjuvant) chemotherapy 152–4
regimens, common 184–7
SCLC 184–9
second-line therapy 163–4, 187
topoisomerase inhibitors 184–7
two drugs vs one drug 161, 162
chest pain 220–1
see also Pancoast’s syndrome
symptom management 239–40
chest radiography
clinical diagnosis 84–5
staging 103–4, 109–13
children, tobacco policy 39
chromosomal abnormalities
3p 28–9
MM 192–3
cigarettes, changing, tobacco policy 38–9
cisplatin (DDP) 284
vs carboplatin 160
non-cisplatin-containing chemotherapy 159–61
classification
adenocarcinoma 63
histopathology 61–3
lung tumors 61–3
MM 194
SCC 61
SCLC 65
staging 97–102
TNM Classification of Malignant Tumors 97–102
clinical approach, smoking cessation 41
clinical diagnosis 75–96
18
F-fluoro-2-deoxy-D-glucose positron emission
tomography 88, 89, 90
adrenal metastases 78–9
ANNA-1 83
ANNA-2 83
anti-Ri antibodies 83
bone metastases 80
brain metastases 79–80
bronchoscopy 91
Index
central nervous system metastases 79–80
chest radiography 84–5
clubbing, fingers/toes 83–4
CT 86–8, 93
Cushing’s syndrome 82
diagnostic techniques 89–92
differential diagnosis 66–8, 70
ECOG 84, 85, 102–3
ectopic adrenocorticotropic hormone syndrome 82
endoscopic ultrasound 91–2
evaluation 75, 92–3
flexible fiberoptic bronchoscopy 91
future developments 93
GGOs 87–8
history 75–84
hypercalcemia 80
imaging 84–9
Karnofsky Performance Scale 84, 85
Lambert–Eaton myasthenic syndrome 82–3
liver metastases 79
local effects 75–6
magnetic resonance imaging 88
metastatic effects 78–80
MM 194, 200
neurologic syndromes 82–3
Pancoast’s syndrome 78, 79
paraneoplastic effects 80–4
physical examination 84, 85
pleural effusion 77
presentation aspects 75–6
regional extension effects 76–8
SIADH 80–2
skeletal metastases 80
SPN 86–7
sputum examination 90–1
superior vena cava syndrome 77–8
surgery, thoracic 92
techniques 89–92
thoracic surgery 92
TTNA 91
ultrasound 91–2
V/Q scans 88–9
clinical history and examination, staging 102–3
clinical presentation, MM 197
clonidine, smoking cessation 48
clubbing, fingers/toes, clinical diagnosis 83–4
combination therapies, MM 201–2
combined-modality therapy
NSCLC 137–41
patient selection 142
toxicity 142
complications 218–35
anemia 243
brain metastases 224–5
cardiac tamponade 223–4
chest pain 220–1
Cushing’s syndrome 228
DIC 232–3
digital clubbing 231–2
ectopic adrenocorticotropic hormone syndrome 228
extrathoracic 224–6
hemoptysis 219–20
HPO 231–2
humoral hypercalcemia 228–30
hypercalcemia 228–30
infections 218–19
Lambert–Eaton myasthenic syndrome 230
marantic endocarditis 233
nausea/vomiting 243
NBTE 233
neurologic syndromes 230–1
neutropenia 242–3
Pancoast’s syndrome 220–1
paraneoplastic cutaneous syndromes 231–2
paraneoplastic endocrine syndromes 226–8
paraneoplastic hematologic syndromes 232–3
paraneoplastic musculoskeletal syndromes 231–2
paraneoplastic neurologic syndromes 230
paraneoplastic syndromes 226–33
paraneoplastic vascular syndromes 232–3
PCD 230
peripheral neuropathy 230–1
pleural effusion 221–2
SCC 225–6
SIADH 226–8
superior sulcus tumors 220–1
SVCS 77–8, 222–3
thrombocytopenia 243
thromboembolic 232–3
tumor embolization 233
complications management, supportive care 241–3
computed tomography (CT)
clinical diagnosis 86–8, 93
future 264–5
future developments 93
GGOs 87–8
screening 53–60, 88
SPN 86–7
staging 104–7, 110
concurrent chemoradiaton, vs sequential
chemoradiation 139–40
cost-benefit analysis (CBA) 249
cost-effectiveness
lung cancer management 247–63
lung cancer treatment 255–9
cost-effectiveness analysis 248–9
cost-minimization analysis 248
cost-utility analysis 249
costs
assessing 250
assessing cost effectiveness 252–3
assessing effectiveness 252
bronchoscopic treatment 215
Canada 254–5
direct non-treatment 250
direct treatment 250
discounting 251–2
economic evaluation types 248–9
health-care policy 259
indirect 250
intangible 250
league tables 252–3
lung cancer economics 259
lung cancer management 247–63
methodologic issues 249–50
NSCLC 253–4
335
336 Index
costs (Continued)
SCLC 254
sensitivity analysis 251
setting 250–1
time horizon 250
transparency 251
uncertainty 251
cough, symptom management 240–1
CPT-11 see irinotecan
cryotherapy, bronchoscopic treatment 212
CT see computed tomography
cultural background, tobacco policy 36–7
Cushing’s syndrome
clinical diagnosis 82
complications 228
cyclophosphamide 278
cytarabine (cytosine arabinoside; Ara-C) 308–9
cytarabine liposome 309
cytology, MM 198
d FdC see gemcitabine
dactinomycin (DACT) 288
darbepoetin alfa 325
DDP see cisplatin
depression, symptom management 241
developing countries, tobacco policy 39
dexrazoxane 323
diagnosis, clinical see clinical diagnosis
diagnostic techniques, clinical diagnosis 89–92
DIC see disseminated intravascular coagulation
differential diagnosis
basaloid carcinoma 66–8
carcinoid tumors 70
LCNEC 66–7
SCLC 66–7
digital clubbing, complications 231–2
direct non-treatment costs 250
direct treatment costs 250
discounting, costs 251–2
disseminated intravascular coagulation (DIC), complications 232–3
docetaxel 292
second-line therapy 163–4
doxorubicin (DOX) 293–4
doxorubicin HCI liposome 295–6
DRR see digitally reconstructed radiograph
drugs, abbreviations 276
duration of smoking 17
dyspnea, symptom management 240
early disease, NSCLC 136–7
Eastern Cooperative Oncology Group (ECOG)
clinical diagnosis 84, 85, 102–3
staging 102–3
EC see electrocautery
ECOG see Eastern Cooperative Oncology Group
economic aspects see costs
ectopic adrenocorticotropic hormone syndrome
clinical diagnosis 82
complications 228
EGFR see epidermal growth factor receptor
elderly patients
chemotherapy 163
treatment, SCLC 187
electrocautery (EC), bronchoscopic treatment 211–12
endobronchial brachytherapy, bronchoscopic treatment 212
endoscopic ultrasound, clinical diagnosis 91–2
environmental agents 6–7
environmental tobacco smoke (ETS) 5–6
EPI see epirubicin
epidemiology 10–19
1930s onwards 10–12
1950s 12–13
1960s onwards 16–18
descriptive 13–16
etiology, 1950s 12–13
MM 190–1, 202
public health success 10–12
epidermal growth factor receptor (EGFR)
NSCLC 21–2
overexpression 21–2
signaling 21–2
targeted therapies 270–1
epipodophyllotoxins 297–8
epirubicin (EPI) 294–5
ERCC1 gene see excision repair cross-complementation group 1 gene
erlotinib 320
advanced NSCLC 164
ethylenimines 281
etiology, lung cancer 1–9
1950s 12–13
genetic susceptibility 7
etoposide (VP16) 297
etoposide phosphate 298
ETS see environmental tobacco smoke
evaluation, clinical diagnosis 75, 92–3
excision repair cross-complementation group 1 (ERCC1) gene,
future 269–70
experimental treatments, tumor suppressors 29
extraluminal tumors, bronchoscopic treatment 214–15
febrile neutropenia (FN) 242–3
females
lung cancer susceptibility 7–8
prevalence of smoking 17–18
filgrastim 326
financial aspects see costs
first-line therapy
advanced NSCLC 158–9, 161–2
duration 161–2
timing 161–2
flexible fiberoptic bronchoscopy, clinical diagnosis 91
floxuridine (FUDR) 306
FN see febrile neutropenia
FUDR see floxuridine
future 264–74
CT 264–5
ERCC1 gene 269–70
imaging 266–7
MALDI 266
molecular profiling 265–6
PET 266–7
pharmacogenomics 268–70
prognostic factors 267–8
radiotherapy 266–7, 268
RRM1 gene 269–70
screening 264–5
Index
staging 267
targeted therapies 270–1
tobacco policy 39–40
vaccines 271
future developments
clinical diagnosis 93
CT 93
screening 93
future directions
MM 200–2
radiotherapy 181–2
SCLC 181–2
gefitinib 319
gemcitabine (d FdC) 310
gender differences
incidence, lung cancer 61
lung cancer susceptibility 7–8
prevalence of smoking 17–18
gene therapy, MM 199
genetic susceptibility, lung cancer etiology 7
GGOs see ground-glass opacities
giant cell carcinoma, histopathology 68–9
global transcriptional profiling, MM 194–5
glossary, clinical pharmacokinetics 275–6
ground-glass opacities (GGOs), clinical diagnosis 87–8
growth factor receptors, overexpression 21–3
growth factors
targeting 24
VEGF 270–1
growth factors/supportive treatments 324–9
growth signals
EGFR overexpression 21–2
lung cancer 20–4
health-care policy, costs 259
health warnings, tobacco policy 36
hematologic parameters, staging 104
hemoptysis, complications 219–20
herceptin 314
hexamethylmelamine 281
histopathology
adenocarcinoma 63–5
adenosquamous carcinoma 68
carcinoid tumors 69–70
carcinosarcoma 69
classification, lung tumors 61–3
giant cell carcinoma 68–9
LCNEC 67–8
lung tumors 61–74
MM 198
NSCLC 67–8
pulmonary blastoma 69
sarcomatoid carcinoma 68–9
SCC 61
SCLC 65–7
spindle cell carcinoma 68–9
historical background, epidemiology 10–19
history
clinical diagnosis 75–84
clinical history and examination 102–3
HN2 see meclorethamine
HPO see hypertrophic pulmonary osteoarthropathy
337
HU see hydroxyurea
humoral hypercalcemia, complications 228–30
hydroxyurea (HU) 311
hypercalcemia
clinical diagnosis 80
complications 228–30
hypertrophic pulmonary osteoarthropathy (HPO),
complications 231–2
hypnosis, smoking cessation 48
IALT trial see International Adjuvant Lung Cancer trial
ifosfamide (IFO) 279
IL-11 (oprelvekin) 328
imaging
see also screening
18
F-fluoro-2-deoxy-D-glucose positron emission tomography 88,
89, 90
bone scintigraphy 107
chest radiography 84–5, 103–4, 109–13
clinical diagnosis 84–9
CT 53–60, 86–8, 93, 104–7, 110
future 266–7
MRI 88, 111–13
PET 109–11
scintigraphic scans 107
staging 103–7
V/Q scans 88–9
imatinib mesylate 321
imidazotetrazines 283
immunobiology, MM 195
immunotherapy, MM 199, 201
incidence
bronchus cancer 13–16
gender differences 61
lung cancer 1, 13–16, 61
trachea cancer 13–16
indirect costs 250
induction chemoradiation, NSCLC 140–1
induction chemoradiotherapy before surgery 154
induction chemotherapy
plus adjuvant surgery, SCLC 171–4
restaging after 113–15
before surgery 152–4
infections, complications 218–19
intangible costs 250
intensive care 238–9
International Adjuvant Lung Cancer trial (IALT trial) 148–51
International Staging System (ISS) 97–102
irinotecan (CPT-11) 299–300
ISS see International Staging System
Karnofsky Performance Scale, clinical diagnosis 84, 85
Lambert–Eaton myasthenic syndrome
clinical diagnosis 82–3
complications 230
large cell neuroendocrine carcinoma (LCNEC)
cf basaloid 66–7
cf basaloid carcinoma 68
differential diagnosis 66–7
histopathology 67–8
cf NSCLC 67–8
cf SCLC 66–7
338 Index
laser resection, bronchoscopic treatment 211
LCNEC see large cell neuroendocrine carcinoma
league tables, costs 252–3
legislation, tobacco policy 36–7
leucovorin (LV) 301
liver metastases, clinical diagnosis 79
local effects, clinical diagnosis 75–6
locally advanced disease
see also advanced NSCLC
defining 137
NSCLC 137–41
lung tumors
classification 61–3
histopathology 61–74
LV see leucovorin
magnetic resonance imaging (MRI)
clinical diagnosis 88
staging 111–13, 114
MALDI see matrix assisted laser desorption ionization mass
spectroscopy
malignant mesothelioma (MM) 190–206
animal models 195–7
anti-angiogenic agents 201
asbestos 191
biomarkers 198
chemotherapy 199, 200
chromosomal abnormalities 192–3
classification 194
clinical diagnosis 194, 197–8, 200
clinical presentation 197
combination therapies 201–2
course 197
cytology 198
epidemiology 190–1, 202
etiologic agents 191–2
future directions 200–2
gene therapy 199
global transcriptional profiling 194–5
histopathology 198
immunobiology 195
immunotherapy 199, 201
management 198–200
mesothelial tissues 191
NF2 gene 194
oncogenes 193
p16INK4a 193–4
pathobiology 194
pathogenesis 191–4
radiology 197
radiotherapy 199, 200
surgery 199–200
SV40 virus 191–2, 195–6
therapy, future 200–2
transcription factor p53 193
treatment summary 209
tumor biology 202
tumor suppressor genes 193–4
WT1 194
marantic endocarditis, complications 233
matrix assisted laser desorption ionization (MALDI) mass
spectroscopy, future 266
mechanical obstruction removal, bronchoscopic treatment 210–11
meclorethamine (HN2) 278
mediastinal exploration, staging 107–8
mediastinal needle biopsy, staging 108–9
Medical Expenditure Panel Survey (MEPS) 247–8
mesna 280
mesothelioma, malignant see malignant mesothelioma
metastasis
brain metastases 179–80
molecular biology 31–2
prophylactic cranial irradiation, NSCLC 142–3
prophylactic cranial irradiation, SCLC 179–80
metastatic effects, clinical diagnosis 78–80
metastatic process, targeting 32
methotrexate (MTX) 302–3
mitomycin C (MMC) 288
MM see malignant mesothelioma
MMC see mitomycin C
molecular alterations, lung cancer 20
molecular biology
aberrant anti-growth signaling 26–9
angiogenesis 30–1
apoptosis 24–6
growth signals 20–4
lung cancer 20–34
metastasis 31–2
replicative potential 29–30
telomerases 29–30
tissue invasion 31–2
molecular profiling
adenocarcinoma 266
future 265–6
monoclonal antibodies 314–18
mortality data, lung cancer 61, 75
motivation stages, smoking cessation 41–2
MRI see magnetic resonance imaging
MTX see methotrexate
mutations, Tp53 26–7
Myc amplification 23–4
National Cancer Institute of Canada (NCIC) JBR10 trial 151
nausea/vomiting 243
NBTE see non-bacterial thrombotic endocarditis
NCIC JBR10 trial see National Cancer Institute of Canada JBR10 trial
neurologic syndromes
clinical diagnosis 82–3
complications 230–1
neuropeptides, overexpression 23
neutropenia 242–3
new drugs, smoking cessation 48
NF2 gene, MM 194
nicotine replacement therapy (NRT)
smoking cessation 42–7
tobacco policy 37–8
nitrogen mustard 278–80
nitrosoureas 282
non-bacterial thrombotic endocarditis (NBTE), complications 233
non-cisplatin-containing chemotherapy 159–61
non-platinum doublets, vs platinum 160–1
non-small cell lung cancer (NSCLC)
adjuvant chemotherapy after surgical resection 147–52
advanced NSCLC, chemotherapy 158–65
altered fractionation radiation therapy 141–2
cf basaloid carcinoma 68
Index
chemotherapy 147–69
chemotherapy followed by radiotherapy 155
chemotherapy for advanced NSCLC 158–65
chemotherapy for locally advanced unresectable (IIIA and IIIB)
NSCLC 154–8
combined-modality therapy 137–41
concurrent chemoradiaton 139–40
concurrent chemoradiotherapy 155–7
costs 253–4
differential diagnosis 67–8
early disease 136–7
EGFR overexpression 21–2
first-line therapy 158–9, 161–2
histopathology 67–8
induction chemoradiation 140–1
induction chemoradiotherapy before surgery 154
induction chemotherapy before surgery 152–4
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
inoperable stage III treatment 208
cf LCNEC 67–8
locally advanced disease 137–41
palliative therapy 143
patient selection 142
preoperative (neoadjuvant) chemotherapy 152–4
prognostic indicators 115–17
prophylactic cranial irradiation 142–3
radiotherapy 136–46
second-line therapy 163–4
sequential chemoradiation 138–40
single-modality therapy 137
stage IA treatment 208
stage IB–IIIA treatment 208
stage IV (and IIIB with pleural effusion) treatment 208–9
superior sulcus tumors 141
surgery 123–35
targeted therapies 164–5
toxicity 142
treatment 123–69
treatment summary 208–9
nortriptyline, smoking cessation 47–8
NRT see nicotine replacement therapy
NSCLC see non-small cell lung cancer
NVB see vinorelbine
oncogenes
MM 193
targeting 24
oncogenic viruses 7
oprelvekin (IL-11) 328
outcome factors, lung cancer 75
overexpression
EGFR 21–2
growth factor receptors 21–3
neuropeptides 23
oxaliplatin 286
p16INK4a
MM 193–4
Rb signaling 27–8, 29
packet labeling, tobacco policy 36
paclitaxel 291
pain
see also Pancoast’s syndrome
chest 220–1
symptom management 239–40
palliation of lung tumors, bronchoscopic treatment 210–17
palliative therapy
NSCLC 143
radiotherapy 143, 181
SCLC 181
pamidronate 329
Pancoast’s syndrome 220–1
clinical diagnosis 78, 79
MRI 111
superior sulcus tumors 141, 220–1
paraneoplastic cerebellar degeneration (PCD),
complications 230
paraneoplastic cutaneous syndromes, complications 231–2
paraneoplastic effects, clinical diagnosis 80–4
paraneoplastic endocrine syndromes, complications 226–8
paraneoplastic hematologic syndromes, complications 232–3
paraneoplastic musculoskeletal syndromes,
complications 231–2
paraneoplastic neurologic syndromes, complications 230
paraneoplastic syndromes, complications 226–33
paraneoplastic vascular syndromes, complications 232–3
passive smoking 5–6
pathobiology, MM 194
pathogenesis, MM 191–4
patient selection
combined-modality therapy 142
NSCLC 142
toxicity 142
PCD see paraneoplastic cerebellar degeneration
PDT see photodynamic therapy
pegfilgrastim 327
pemetrexed 303
peripheral neuropathy, complications 230–1
PET see positron emission tomography
pharmacogenomics, future 268–70
photodynamic therapy (PDT), bronchoscopic treatment 212–14
physical examination, clinical diagnosis 84, 85
platinum-based chemotherapy 158–9
platinum compounds 284–6
platinum, vs non-platinum doublets 160–1
pleural effusion
clinical diagnosis 77
complications 221–2
policy, tobacco see tobacco policy
pollution, air 6–7
poor performance patients, chemotherapy 163
poor-prognosis patients, treatment, SCLC 187
positron emission tomography (PET)
future 266–7
staging 109–11
preoperative (neoadjuvant) chemotherapy, NSCLC 152–4
presentation aspects, clinical diagnosis 75–6
prevalence, lung cancer 1, 10
procarbazine 312
prognosis 117
prognostic correlations, adenocarcinoma 64–5
prognostic factors, future 267–8
prognostic indicators 115–17
NSCLC 115–17
promotion abolition, tobacco policy 36
339
340 Index
prophylactic cranial irradiation
NSCLC 142–3
SCLC 179–80
proteases, targeting 32
pulmonary blastoma, histopathology 69
pyrimidine analogs 304–10
quality of life (QoL) 236–46
assessing 236–8
critical care 238–9
intensive care 238–9
supportive care 236–46
radiochemoprotectants 323
radiography see imaging
radiology, MM 197
radiotherapy
altered fractionation radiation therapy 141–2
brain metastases 179–80
chemotherapy followed by radiotherapy 155
combined-modality therapy 137–41
concurrent chemoradiaton 139–40
concurrent chemoradiotherapy 155–7
current recommendations, SCLC 180–1, 182
future 266–7, 268
future directions 181–2
induction chemoradiation 140–1
induction chemotherapy followed by concurrent
chemoradiotherapy 157–8
MM 199, 200
NSCLC 136–46
palliative therapy 143, 181
prophylactic cranial irradiation 142–3, 179–80
SCLC 177–83
sequential chemoradiation 138–40
thoracic irradiation, SCLC 177–9
radon 6
raltitrexed 301
Ras mutations 22, 23
Rb signaling, p16INK4a 27–8, 29
recombinant human erythropoietin (rHuEPO) 324
regimens, common, SCLC 184–7
regional extension effects, clinical diagnosis 76–8
regulation of the product, tobacco policy 37
replicative potential, telomerases 29–30
restaging after induction chemotherapy 113–15
rHuEPO see recombinant human erythropoietin
ribonucleotide reductase M1 (RRM1) gene, future 269–70
rimonabant, smoking cessation 48
RRM1 gene see ribonucleotide reductase M1 gene
salvage surgery, SCLC 174–5
sarcomatoid carcinoma, histopathology 68–9
SCC see spinal cord compression; squamous cell carcinoma
scintigraphic scans, staging 107
SCLC see small cell lung cancer
screening 53–60, 88
CT 53–60, 88, 93
current evidence 53–5
current status 53–60
discussion points 56–7
future 264–5
future developments 93
recent developments 57–8
recommendations, professional societies 56–7
technical innovations 55–6
second-line therapy
advanced NSCLC 163–4
chemotherapy 163–4
SCLC 187
sensitivity analysis, costs 251
sequential chemoradiation
vs concurrent chemoradiaton 139–40
NSCLC 138–40
SIADH see syndrome of inappropriate antidiuretic hormone
single-modality therapy, NSCLC 137
skeletal effects, clubbing, fingers/toes 83–4
skeletal metastases, clinical diagnosis 80
small cell lung cancer (SCLC)
agents used 184–7
cf basaloid carcinoma 66–7
chemotherapy 184–9
classification 65
combined 65–6
costs 254
defining 65
differential diagnosis 66–7
extensive disease treatment 207–8
future directions 181–2
growth factor receptors overexpression 22–3
histopathology 65–7
induction chemotherapy plus adjuvant surgery 171–4
cf LCNEC 66–7
limited disease treatment 207
palliative therapy 181
primary surgery 171, 172
radiotherapy 177–83
recurrent disease treatment 208
regimens, common 184–7
salvage surgery 174–5
second-line therapy 187
surgery 170–6
surgery plus postoperative chemotherapy 171, 172
survivin 25–6
targeted therapies 187
thoracic irradiation 177–9
topoisomerase inhibitors 184–7
treatment 170–89
treatment summary 207–8
small molecules 319–22
smoke-free environments, tobacco policy 36
smokers, changing, tobacco policy 37–8
smoking cessation 41–52
acupuncture 48
alternative therapies 48
bupropionSR 47
cancer patients 49
carbon monoxide 42
clinical approach 41
clonidine 48
hypnosis 48
motivation stages 41–2
new drugs 48
nortriptyline 47–8
NRT 42–7
rimonabant 48
Index
smoking reduction 48–9
vaccines 48
varenicline 47
weight gain 49–50
smoking reduction, smoking cessation 48–9
SND see systematic nodal dissection
solitary pulmonary nodule (SPN), CT 86–7
spinal cord compression (SCC), complications 225–6
spindle cell carcinoma, histopathology 68–9
SPN see solitary pulmonary nodule
sputum examination
clinical diagnosis 90–1
sputum cytology 90
sputum cytometry 90–1
squamous cell carcinoma (SCC)
classification 61
defining 61
histopathology 61
variants 61
staging 97–115
abdominal ultrasound 107
bone scintigraphy 107
bronchoscopy 104
cervical mediastinoscopy 107–8
chest radiography 103–4, 109–13
classification 97–102
clinical history and examination 102–3
CT 104–7, 110
ECOG 102–3
future 267
hematologic parameters 104
imaging 103–7
ISS 97–102
mediastinal exploration 107–8
mediastinal needle biopsy 108–9
MRI 114
PET 109–11
process 99–102
restaging after induction chemotherapy 113–15
scintigraphic scans 107
SND 112–13, 114
system 97–102
TEMLA 108
tests 102–13
TNM Classification of Malignant Tumors 97–102
transesophageal fine needle aspiration 109
ultrasound 107
VAMLA 108
stenting, bronchoscopic treatment 214–15
streptozocin 282
superior sulcus tumors
see also Pancoast’s syndrome
NSCLC 141, 220–1
superior vena cava syndrome (SVCS)
clinical diagnosis 77–8
complications 222–3
supportive care
complications management 241–3
critical care 238–9
intensive care 238–9
QoL 236–46
symptom management 239–41
surgery
adjuvant chemotherapy after surgical resection 147–52
MM 199–200
NSCLC 123–35
SCLC 170–6
thoracic, clinical diagnosis 92
survivin, SCLC 25–6
SV40 virus, MM 191–2, 195–6
SVCS see superior vena cava syndrome
symptom management
anorexia 241
anxiety 241
cough 240–1
depression 241
dyspnea 240
pain 239–40
supportive care 239–41
weight loss 241
syndrome of inappropriate antidiuretic hormone (SIADH)
clinical diagnosis 80–2
complications 226–8
systematic nodal dissection (SND), staging 112–13, 114
targeted therapies
advanced NSCLC 164–5
EGFR 270–1
future 270–1
SCLC 187
VEGF 270–1
targeting
angiogenic factors 31
apoptotic pathways 25–6
growth factors 24
metastatic process 32
oncogenes 24
proteases 32
telomerases 30
tax, tobacco policy 36–7
taxanes 291–2
techniques
clinical diagnosis 89–92
endobronchial tumors removal 210–14
telomerases
replicative potential 29–30
targeting 30
telomere maintenance 30
TEMLA see transcervical extended mediastinal lymphadenectomy
temozolomide 283
teniposide (VM26) 298
TGFβ signaling, aberrant 28
thalidomide 313
thiotepa 281
thoracic irradiation, SCLC 177–9
thoracic surgery, clinical diagnosis 92
three-drug combinations, advanced NSCLC 161, 162
thrombocytopenia 243
thromboembolic complications 232–3
time horizon, costs 250
tissue invasion, molecular biology 31–2
TNM Classification of Malignant Tumors, staging 97–102
tobacco policy 35–40
availability 36
basic policy 36–9
children 39
341
342 Index
cigarettes, changing 38–9
cultural background 36–7
developing countries 39
future 39–40
health warnings 36
legislation 36–7
NRT 37–8
packet labeling 36
promotion abolition 36
regulation of the product 37
smoke-free environments 36
smokers, changing 37–8
tax 36–7
tobacco smoke, carcinogens 1–5
topoisomerase I inhibitors 299–300
topoisomerase II inhibitors 293–8
topoisomerase inhibitors, SCLC 184–7
topotecan 300
tositumomab 317–18
toxicity
combined-modality therapy 142
patient selection 142
Tp53 see transcription factor p53
trachea cancer, incidence 13–16
transcervical extended mediastinal lymphadenectomy (TEMLA ),
staging 108
transcription factor p53 (Tp53)
MM 193
mutations 26–7, 28
transesophageal fine needle aspiration, staging 109
transparency, costs 251
transthoracic needle aspiration (TTNA), clinical diagnosis 91
treatment, cost-effectiveness 255–9
treatment, NSCLC
chemotherapy 147–69
radiotherapy 136–46
summary 208–9
surgery 123–35
treatment, SCLC 170–89
chemotherapy 184–9
elderly patients 187
poor-prognosis patients 187
radiotherapy 177–83
summary 207–8
surgery 170–6
tretinoin 322
triplets, advanced NSCLC 161, 162
TTNA see transthoracic needle aspiration
tumor biology, MM 202
tumor embolization, complications 233
tumor suppressor genes, MM 193–4
tumor suppressors, experimental treatments 29
tumors, lung
classification 61–3
histopathology 61–74
type 2 antineuronal nuclear autoantibodies (ANNA-2), clinical
diagnosis 83
typical/atypical carcinoid tumors 69–70
UFT 305–6
UFT adjuvant trials 151
ultrasound
abdominal 107
clinical diagnosis 91–2
staging 107
uncertainty, costs 251
V/Q scans see ventilation-perfusion scans
vaccines
future 271
smoking cessation 48
VAMLA see video-assisted mediastinoscopic lymphadenectomy,
staging
varenicline, smoking cessation 47
vascular endothelial growth factor (VEGF), targeted
therapies 270–1
VCR see vincristine sulfate
VEGF see vascular endothelial growth factor
ventilation-perfusion (V/Q) scans, clinical diagnosis 88–9
video-assisted mediastinoscopic lymphadenectomy (VAMLA),
staging 108
vinblastine sulfate (VLB) 289
vinca alkaloids 289–90
vincristine sulfate (VCR) 289
vinorelbine (NVB) 290
viruses, oncogenic 7
VLB see vinblastine sulfate
VM26 see teniposide
vomiting see nausea/vomiting
VP16 see etoposide
weight gain, smoking cessation 49–50
weight loss, symptom management 241
Wilms’ tumor gene (WT1), MM 194
workplace exposure 6–7
WT1 see Wilms’ tumor gene
Lung
Hansen
Textbook of
Cancer
Textbook of Lung Cancer, Second Edition, published in association with the European
Society for Medical Oncology, is a comprehensive and multidisciplinary text, which
examines all aspects of this disease, with contributions from a multinational team
of authors on etiology, epidemiology, molecular biology, pathology, smoking,
detection and management, clinical features, staging and prognostic factors, surgery,
radiotherapy and chemotherapy. It provides essential information and guidance for
specialist trainees in oncology, and for the many physicians and specialists involved in
Table of contents
Etiology of lung cancer • Epidemiology of lung cancer • Molecular biology of lung cancer
• Tobacco policy • Smoking cessation programs • Current status of early lung cancer
screening • Histopathology of lung tumors • Clinical diagnosis and basic evaluation
• Staging, classification and prognosis • Treatment of non-small cell lung cancer
• Treatment of small cell lung cancer • Malignant mesothelioma • Summary of treatment
• Therapeutic bronchoscopy for palliation of lung tumors • Complications to lung cancer
• Quality of life and supportive care • The cost and cost-effectiveness of lung cancer
management • The future • Appendix: Chemotherapy
About the editor
Heine Hansen MD FRCP is Professor of Clinical Oncology at the Finsen Center,
National University Hospital, Copenhagen, Denmark.
Also available:
ESMO Handbook of Cancer Prevention
Edited by Schrijvers, Senn, Mellstedt, Zakotnik (ISBN: 9780415390859)
ESMO Handbook of Principles of Translational Research
Edited by Mellstedt, Schrijvers, Bafaloukos & Greil (ISBN: 9780415410915)
Lung Cancer – Translational and Emerging Therapies
Edited by Pandya, Brahmer & Hidalgo (ISBN: 9780849390210)
Image-Guided Radiotherapy of Lung Cancer
Edited by Cox, Chang & Komaki (ISBN: 9780849387838)
Lung Cancer
the field of lung cancer.
Textbook of
Second Edition
Cancer
Second Edition
Edited by
Heine Hansen
Textbook of Surgical Oncology
Edited by Poston, Beauchamp & Ruers (ISBN: 9781841845074)
Lung Cancer Therapy Annual 6
Edited by Hansen (ISBN 9780415465458)
Second
Edition
www.informahealthcare.com
Lung
Textbook of
Published in association with
the European Society for Medical Oncology
