Options in the Treatment of Head and Neck Cancer
Content
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❖
Options in the Treatment of
Head and Neck Cancer
Edited by
Marshall R. Posner, MD
Medical Director
Head and Neck Oncology Program
Dana-Farber Cancer Institute
Boston, Massachusetts
Publishers of
ONCOLOGY
Oncology News International
Cancer Management: A Multidisciplinary Approach
www.cancernetwork.com
Posner.bk Page ii Friday, October 20, 2006 11:41 AM
COAB
Clinical Oncology Advisory Board
Note to the reader
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Cover image: X-ray of the skull, side view, showing the upper respiratory tract,
including the larynx, pharynx, and nasal passages. (c) Alain Pol. Copyright (c) ISM/
Phototake – All rights reserved.
Publishers of
ONCOLOGY
Oncology News International
Cancer Management: A Multidisciplinary Approach
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Preface
When I asked coauthors to contribute chapters for this book, I wanted
them to write a brief, up-to-date review of the options for therapy and the
therapeutic decisions we all face in treating patients with head and neck
cancer. This field is rapidly changing, and care for these patients is
extremely challenging. The authors of each of the chapters are active in
clinical care and clinical research and are leading cutting edge trials in this
field. They are thinking every day about how to make the care and treatment better for our patients, and their chapters individually reflect the
most current data and insightful concepts about each topic, the therapy,
and the technology available. I think each chapter will surprise the reader
by its immediate relevance. What I also found when I read the chapters
was something for both experienced and new care givers.
Each chapter covers an important area of therapy in head and neck
cancer and gives background for practitioners and caregivers in different
disciplines. Dr. Gregory Chronowski and Dr. David Rosenthal give a very
thoughtful and logical discussion of the assessment of a patient for chemoradiotherapy and some of the very tough issues surrounding who should
be treated and how much treatment they should recieve. Decision-making
in this population is very hard, and the authors give clarity by identifying
treatment and patient factors that guide the final choice of therapy. In
Chapter 2, I give an overview of induction chemotherapy and a review of
the newest data supporting both induction therapy and sequential treatment for patients with advanced disease. This incorporates data from the
most recently reported trials in 2006. A reader would understand the practical and biologic rationale and support for a sequential treatment
approach. In her chapter, Dr. Barbara Murphy defines the issues of toxicity, quality-of-life, and management of the sequeallae of increasingly
aggressive and effective therapy. Toxicity has become a major factor in the
lives of our patients, and Dr. Murphy is a leader in articulating the biology
and the management of acute and late toxicities of chemoradiotherapy.
This chapter promotes thinking about consequences and long-term life
issues. The chapter by Dr. Ezra Cohen and Dr. Oyewale Abidoye gives a
good review and timely discussion of treatment of recurrent disease.
Although there are many new agents available, they also review data supiii
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iv
Preface
porting an expanded role for re-irradiation and the use of more standard
agents, and they address when and how to make decisions concerning
patients with recurrent cancer. Dr. David Adelstein provides a very detailed
discussion of who is an appropriate organ preservation candidate, decision-making around functional organ preservation, and the data supporting organ preservation strategies in his chapter. As this field changes and
improves, organ preservation strategies have become increasingly important in therapy decisions. Finally, Dr. Gregory Russo and Dr. Mitchell
Machtay write about the basic technology and the common questions surrounding the newest important radiation innovation, intensity-modulated
radiotherapy in their chapter. This last chapter lays an important knowledge foundation to help practitioners understand both the value and the
deficiencies of IMRT, now a standard practice for head and neck cancer.
As the reader can see, the chapters were selected to represent most of
the disciplines in head and neck cancer therapy and reflect the importance
of cross-education and multi-disciplinary care so essential to the management and success of therapy for these difficult patients. We hope readers
find this book and the topics helpful, informative, and interesting.
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Contents
CME
3
Preface
iii
Contributing Authors
vi
Continuing Medical Education Pages
Introduction
viii
xi
Chemoradiation for Head and Neck Cancer
Gregory M. Chronowski, MD, and David I. Rosenthal, MD
Evolving Role of Induction Chemotherapy and Sequential
Therapy in the Treatment of Locally Advanced Squamous
Cell Cancer of the Head and Neck
Marshall R. Posner, MD
1
23
Increasing Cure—Increasing Toxicity: Symptom Management
and Chemoradiotherapy
Barbara A. Murphy, MD
41
Management of Recurrent Disease: Current Treatments
and New Therapies
Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD
61
Integration of Chemotherapy into Organ Preservation Strategies
for Squamous Cell Head and Neck Cancer
David J. Adelstein, MD
77
Intensity-Modulated Radiation Therapy: Promises and Practice
Gregory A. Russo, MD, and Mitchell Machtay, MD
Index
91
115
To earn CME credit, go to www.cancernetwork.com/cme and look for
Earn CME section on our site
v
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Contributing Authors
Oyewale Abidoye, MD
Department of Medicine
Section of Hematology/Oncology
University of Chicago Pritzker School of Medicine
Chicago, Illinois
David J. Adelstein, MD
Department of Solid Tumor Oncology
Taussig Cancer Center
Cleveland Clinic
Cleveland, Ohio
Ezra E. W. Cohen, MD
Department of Medicine
Section of Hematology/Oncology
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Gregory M. Chronowski, MD
Department of Radiation Oncology
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas
Mitchell Machtay, MD
Department of Radiation Oncology
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Barbara A. Murphy, MD
Director, Pain and Symptom Management Program
Director, Head and Neck Research Team
Vanderbilt Ingram Cancer Center
Nashville, Tennessee
vi
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Contributing Authors
Marshall R. Posner, MD
Medical Director, Head and Neck Oncology Program
Dana-Farber Cancer Institute
Boston, Massachusetts
David I. Rosenthal, MD
Director, Head and Neck Translational Research
Department of Radiation Oncology
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas
Gregory A. Russo, M.D.
Department of Radiation Oncology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
vii
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Continuing Medical Education
Activity release date: November 1, 2006
Activity expiration date: December 1, 2007
About the Activity
This activity is based on the book, Options in the Treatment of Head and
Neck Cancer. It was developed from an identified educational need for
information about practical management issues in the practice of medical,
surgical, and radiation oncology.
This activity has been developed and approved under the direction of
Beam Institute.
Activity Learning Objectives
After reading Options in the Treatment of Head and Neck Cancer, participants should be able to:
• Summarize the history of head and neck cancer therapy, expounding
upon various chemoradiotherapeutic modalities used, timing of
therapy, and selection of patients, drugs, and dosing schedules.
• Review currently available treatment modalities for head and neck cancer management that may preserve crucial anatomic structures and
allow their function.
• Discuss current surgical, chemotherapeutic, and radiotherapeutic methods to treat squamous cell cancer of the head and neck and recurrence
of the disease and new therapies and treatments currently being tested
against this malignancy.
• Describe the acute and late effects of surgery and/or chemoradiotherapy used for head and neck cancer and how these treatments
affect quality of life and need for supportive care.
• Examine current best practice for surgery and administration of chemoradiotherapy for head and neck cancer and the differences
between various treatment regimens being investigated.
viii
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Continuing Medical Education
ix
Target Audience
This activity targets physicians in the fields of oncology and hematology.
Accreditation
Beam Institute is accredited by the Accreditation Council for Continuing
Medical Education (ACCME) to provide continuing medical education for
physicians.
Continuing Education Credit
Category 1 Credit
Beam Institute designates this educational activity for a maximum of 3
American Medical Association (AMA) Physician’s Recognition Award
(PRA) Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Note: This activity complies with all ACCME, U. S. Food and Drug
Administration (FDA), and Pharmaceutical Research and Manufacturers
Association (PhRMA) guidelines for CME educational activities.
Compliance Statement
This activity is an independent educational activity under the direction of
Beam Institute. The activity was planned and implemented in accordance with
the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the Health and Human Services Office of Inspector General, and the PhRMA Code on Interactions with Healthcare
Professionals, thus assuring the highest degree of independence, fair balance,
scientific rigor, and objectivity. However, Beam Institute, the Grantor, and
CMPMedica shall in no way be liable for the currency of information or for
any errors, omissions, or inaccuracies in the activity. Discussions concerning
drugs, dosages, and procedures may reflect the clinical experience of the
author(s), or they may be derived from the professional literature or other
sources and may suggest uses that are investigational in nature and not
approved labeling or indications. Activity participants are encouraged to refer
to primary references or full prescribing information resources. The opinions
and recommendations presented herein are those of the author(s) and do not
necessarily reflect the views of the provider or producer.
To earn CME credit, go to www.cancernetwork.com/cme and look for
Earn CME section on our site
Posner.bk Page x Friday, October 20, 2006 11:41 AM
x
Continuing Medical Education
Financial Disclosure
Dr. Posner is a consultant for Amgen, Sanofi-Aventis, Medimmune, GSK,
Genentech, NCI, ASCO, and NCCN. Dr. Rosenthal is a consultant and serves
on the speaker’s bureau for BMS, Imclone, and Medimmune. The following
contributors have no significant financial interest or other relationship with
the manufacturers of any products or providers of any service mentioned in
the article: Dr. Abidoye, Dr. Adelstein, Dr. Chronowski, Dr. Cohen, Dr.
Machtay, Dr. Murphy, and Dr. Russo.
Copyright
Copyrights owned by Beam Institute, a division of CME LLC. Copyright
©2006.
Contact Information
We would like to hear your comments regarding this or other activities
provided by Beam Institute. In addition, suggestions for future programming are welcome. Contact us at:
Address:
Phone:
Fax:
e-mail:
Director of Continuing Education
Beam Institute
CME LLC
11 West 19th Street, 3rd Floor
New York, NY 10011
888-618-5781
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[email protected]
Supported by an educational grant by Sanofi-Aventis
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Introduction
Chemotherapy, as part of a multi-disciplinary and multi-modality
approach, has become the standard of care for the treatment of locally
advanced squamous cell cancer of the head and neck. Until recently, chemotherapy has been delivered as either induction chemotherapy, also
known as neoadjuvant therapy, or in combination with radiotherapy as
chemoradiotherapy (CRT). Although induction chemotherapy with cisplatinum and 5-fluorouracil (PF) is effective in improving survival, patients
treated with induction chemotherapy have a high rate of local-regional
failure despite a reduced rate of distant failure. CRT has improved survival
by reducing local-regional failure, with no improvement in control of distant disease.
To optimize therapy, sequential therapy approaches, combining induction chemotherapy, CRT, and surgery have been developed. In addition,
recent advances in induction chemotherapy, namely the demonstration
that a three drug induction chemotherapy regimen with docetaxel, cisplatinum, and 5-fluorouracil (TPF) is significantly more effective than PF, has
increased interest and optimism regarding the potential gains of induction
chemotherapy, as a sequential therapy approach. Preliminary data support
the use of sequential therapy in patients with poor-prognosis head and
neck, and a phase III trial with this schedule shows highly encouraging
improvements in survival, lessened toxicity, and a significant advantage to
TPF in this setting.
The different treatment paradigms of sequential therapy and CRT are
being compared in phase III studies. TPF has replaced PF as the standard
for induction chemotherapy, and sequential therapy represents an acceptable standard of care for patients with curable, locally advanced head and
neck cancer.
xi
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Chemoradiation for Head
and Neck Cancer
Gregory M. Chronowski, MD, and David I. Rosenthal, MD
History of Chemoradiation for
Head and Neck Cancer
Head and neck cancers affect more than 40,000 patients per year in the
United States (1). As a result of their location, these tumors can cause
varying degrees of functional and cosmetic deficits that are often exacerbated by cancer treatment. From the 1960s through the 1980s, surgery
and radiation therapy (RT), often postoperative, remained the primary
modalities used to treat these tumors. With the publication of the Department of Veterans Affairs (VA) larynx preservation trial in 1991 (2), the
concept of non-surgical organ preservation through the use of radiation
and chemotherapy entered the mainstream. Since then, the most significant
advances in the treatment of head and neck tumors have been the development of altered radiation fractionation schedules and concurrent chemotherapy regimens that have documented improvements in local control
and survival, respectively. In addition, the development of intensity-modulated RT has allowed for greater conformality of radiation dose, allowing
for relative sparing of adjacent dose-limiting normal tissues, most notably
the brain stem, optic nerves, spinal cord, and parotid salivary glands.
Initial attempts at concurrent chemotherapy with RT were disappointing due to significant mucosal toxicity secondary to the use of bleomycin,
5-fluorouracil (5-FU), and methotrexate, whereas the activity of many of
these agents in squamous cell carcinomas was probably not optimal. With
CME
1
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2
Chemoradiation for Head and Neck Cancer
the development of highly effective and better tolerated platinum-based
regimens, concurrent chemoradiation regimens moved to the forefront of
investigation. The publication of a number of multi-institutional trials
documenting both improvements in local control and survival has validated concurrent chemoradiation as the standard of care for locally
advanced, non-metastatic head and neck cancers (3,4).
Despite these therapeutic gains, there are still several unanswered questions about chemoradiation. What remains somewhat controversial is the
appropriate selection of patients for concurrent chemotherapy regimens,
as this approach improves survival primarily through improvements in
local control. In earlier stage cancers or in patients with non-bulky primary tumors and/or small-volume lymphadenopathy, locoregional control
with RT alone using standard or altered fractionation regimens can be
excellent, and whether there is incremental benefit from the addition of
concurrent chemotherapy is an area of debate. Despite a general consensus
that platinum-containing regimens are optimal, the actual dose schedule
and types of agents to add to platinum remain open questions, with various cooperative groups and institutions advocating different drug combinations. In particular, the role of neoadjuvant chemotherapy remains an
active area of discussion.
Neoadjuvant or “Induction” Chemoradiation
Neoadjuvant, or “induction,” chemotherapy is a term commonly used to
describe the administration of chemotherapy followed by RT (or surgery)
alone. Advocates for neoadjuvant chemotherapy approaches in head and
neck cancers cite the fact that there is better compliance, and therefore
greater potential benefit from induction therapy than for concurrent or
adjuvant chemotherapy. Higher doses of chemotherapy drugs can be
given, with fewer unplanned delays and dose reductions, and multiple
agents may be used over multiple cycles as compared to concurrent
chemoradiation approaches that typically include lower doses of single
agents over 6–7 weeks. The higher doses of chemotherapy given with neoadjuvant approaches may have greater potential to address subclinical foci
of systemic micrometastases that occur in up to 20%–40% of patients
receiving curative therapy for locoregionally confined disease. Critics of
this approach cite the potential for tumors to progress during chemotherapy, making it more difficult to obtain local control with curative modalities such as RT or surgery. In addition, some have suggested that treatment
of head and neck tumors with neoadjuvant chemotherapy may select for
more aggressive clonogens that may be less amenable to treatment with
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Chemoradiation for Head and Neck Cancer
3
RT (5). At this time, the weight of the evidence in the medical literature
supports concurrent chemoradiation over neoadjuvant chemotherapy
approaches. A recent large meta-analysis (6) has confirmed the superiority
of concurrent chemoradiation over neoadjuvant chemotherapy; nevertheless, there appears to be some greater benefit from platinum-containing
neoadjuvant regimens (7). Although most trials have not shown a survival
benefit for neoadjuvant approaches, two trials have documented a survival
advantage over RT alone (8,9), but the concept is not universally accepted.
One of the earliest trials of neoadjuvant chemotherapy is the so-called
“VA Larynx Preservation Trial” (2). Published in 1991, this trial randomized patients with stage III or IV larynx cancer to either (a) three cycles of
neoadjuvant chemotherapy with cisplatin and 5-FU followed by definitive
RT or (b) laryngectomy followed by postoperative RT. This trial showed
equivalent 2-year survival (68%) between the nonsurgical and surgical
arms. It is important to note that this trial did not appropriately test the
role of neoadjuvant chemotherapy, as the study did not include an RTalone arm. This shortcoming was addressed in the Radiation Therapy
Oncology Group (RTOG) 91-11 trial (10). This three-arm trial randomized patients with advanced laryngeal cancer to either RT alone, neoadjuvant cisplatin and 5-FU followed by RT, or concurrent cisplatin and RT.
An update of this trial was presented in 2006 (11). At 5 years, both concurrent cisplatin/RT and induction chemotherapy followed by RT had
superior laryngectomy-free survival (47% and 45%, respectively) compared to RT alone (34%). Concurrent cisplatin and RT had superior
locoregional control (69%) compared to neoadjuvant chemotherapy followed by RT (55%) or RT alone (51%). Overall survival at 5 years was
statistically similar between all three arms at approximately 55%.
Concurrent Chemoradiation
The administration of chemotherapy during RT is commonly referred to
as concurrent chemoradiation or simply chemoradiation. This approach is
now the standard of care in most locally advanced cancers of the head and
neck based on the results of multiple randomized trials that have documented a survival benefit (Table 1). Chemoradiation appears to confer a
survival benefit over RT alone in both the “unresectable” setting as well as
the postoperative setting.
The first large head and neck cancer trial documenting a survival benefit to concurrent chemoradiation was the Intergroup 0099 nasopharynx
cancer trial (12). This trial randomized patients to 70 Gy of RT alone with
or without three cycles of concurrent cisplatin followed by three cycles of
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Chemoradiation for Head and Neck Cancer
Table 1. Selected Randomized Chemoradiation versus Radiation Alone
Trials for Head and Neck Squamous Cancer
Trial
(Reference) Agents
ChemoNo. of
therapy
Patients Schedule
Definitive chemoradiation trials
Adelstein et Cisplatin
295
al. (15)
Site
Radiation
Therapy
3×
Multiple
qd
Al-Sarraf et
al. (12)
Cisplatin
193
3×
Nasopharynx
qd
Brizel et al.
(20)
Cisplatin +
5-FU
116
2×
Multiple
bid
Oropharynx
qd
Larynx
qd
Multiple
bid
Postoperative
qd
Multiple
qd
Postoperative
qd
Carbopla226
3×
tin + 5FU
Forastiere et Cisplatin
547
3×
al. (RTOG
91-11)
(10)
Jeremic et
Cisplatin or 159
Daily
al. (27)
carboplatin
Postoperative chemoradiation trials
Cooper et
Cisplatin
495
3×
al. (17)
(RTOG
95-01)
Bachaud et Cisplatin
83
Weekly
al. (28)
Denis et al.
(14)
Bernier et
al. (16)
(EORTC
22931)
Cisplatin
334
3×
bid, twice daily; 5-FU, 5-fluorouracil; qd, once daily.
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Chemoradiation for Head and Neck Cancer
5
Table 1. Selected Randomized Chemoradiation versus Radiation Alone
Trials for Head and Neck Squamous Cancer (Continued)
Follow- Local
Resectable Up
Control
DiseaseFree
Survival
Definitive chemoradiation trials
No
3y
—
—
24% vs.
69%;
P <.001
—
Overall
Survival
Distant
Metastases
23% vs.
37%;
P = .014
47% vs.
78%;
P <.005
34% vs.
55%;
P = .07
16% vs.
22%;
P = .05
No difference
18% vs. 22%;
not significant
10% vs. 2%;
P not given
—
3y
—
Both
3y
44% vs.
70%
—
5y
Yes
2y
15% vs.
25% vs.
48%;
27%;
P = .002
P = .01
70% vs.
—
88%;
P <.001
No
5y
—
Yes
5y
Yes
3y
59% vs.
23% vs.
13% vs.
30% vs. 26%;
77%;
45%;
36%;
not signifiP = .08
P <.02
P <.01
cant
69% vs.
41% vs.
41% vs.
25% vs. 21%;
82%;
59%;
65%;
not signifiP = .007
P = .0014
P = .0096
cant
18% vs. 27%;
P not given
11% vs. 11%;
not significant
16% vs. 8%;
P = .03
27% vs.
25% vs.
43% vs. 14%;
51%;
46%;
P = .0013
P = .018
P = .007
Postoperative chemoradiation trials
Yes
3.8 y
72% vs.
—
No differ- 23% vs. 20%;
82%;
ence
not signifiP = .01
cant
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Chemoradiation for Head and Neck Cancer
adjuvant cisplatin and 5-FU. The addition of chemotherapy led to significant improvements in local control, reduction in distant metastases, and
improved 3-year overall survival (78% vs. 47%, P = .005).
In regard to oropharynx cancer, Calais et al. (13) and Denis et al. (14)
randomized 226 patients to 70 Gy of RT with or without three cycles of
concurrent cisplatin and 5-FU. Five-year local control (48% vs. 25%), disease-free survival (27% vs. 15%), and overall survival (22% vs. 16%)
were significantly improved with the addition of chemotherapy. Rates of
grade 3 and 4 mucositis were increased in the chemotherapy arm (71% vs.
39%) primarily due to the addition of 5-FU, a potent potentiator of radiation mucositis. The publication of this trial in 1999 was particularly
important because an accompanying editorial suggested that chemoradiation should become an accepted standard of care for patients with locally
advanced non-metastatic head and neck cancer (3).
Adelstein and colleagues (15) randomized 295 patients in an intergroup
study with non-nasopharyngeal head and neck squamous cell carcinomas,
primarily cancers of the oropharynx, to either 70 Gy continuous daily RT
alone, 70 Gy continuous daily RT with three cycles of concurrent cisplatin
chemotherapy, or 70 Gy split-course RT with three cycles of concurrent cisplatin. Split-course RT has long been known to be an inferior fractionation
schedule for head and neck cancers due to the repopulation of tumor during
the treatment break, although it does result in less toxicity, primarily mucositis. Nevertheless, a hypothesis of this trial was that the loss of efficacy of
split-course RT could be overcome with the addition of concurrent chemotherapy, and the time of break allowed for surgical evaluation of patients
whose tumors were previously considered “unresectable.” At 3 years, overall survival was significantly improved with continuous once-daily RT and
concurrent cisplatin (37%) compared to RT alone (23%), whereas the overall survivals between the split-course RT/chemotherapy arm and the RTalone arm were not statistically different at 27% and 23%, respectively.
The RTOG 91-11 trial (10,11) has already been discussed in the preceding section, but it also documented a local control and larynx preservation benefit to concurrent chemoradiation in larynx cancer. The lack of a
significant survival benefit to concurrent chemotherapy and induction chemotherapy in larynx cancer is noteworthy and may be related to the fact
that local failures are more readily salvaged with laryngectomy as opposed
to other head and neck sites.
In the postoperative setting, it is important to note that the European
Organisation for Research and Treatment of Cancer (EORTC) 22931 trial
(16) documented significant improvements in local control, disease-free
survival, and overall survival with chemoradiation over RT alone. The
RTOG 95-01 trial (17) documented improvements in local control and
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Chemoradiation for Head and Neck Cancer
7
disease-free survival but was not powered to demonstrate, nor did it show,
a significant difference in overall survival. A pooled analysis of EORTC
22931 and RTOG 95-01 was performed (18) and found that the addition
of cisplatin to postoperative RT improved outcomes for patients with
microscopically involved resection margins or extracapsular spread of
tumor from neck nodes. Concurrent chemoradiation should be considered
the standard of care in patients with these characteristics in the postoperative setting.
Cisplatin-based chemotherapy regimens have been used in all concurrent chemotherapy protocols to date and have found favor due to cisplatin’s activity, the ability to deliver it as a single agent in full dose with
RT, and because it adds relatively little to stomatitis and radiation mucositis compared to other agents (19).
Compared to concurrent chemoradiation, there does not appear to be
an effect on overall survival with radiation dose escalation alone in head
and neck cancer. Brizel et al. (20) showed no difference in overall survival
with higher-dose hyperfractionated RT alone to 75 Gy versus similarly
fractionated RT to 70 Gy but with concurrent cisplatin and 5-FU. In fact,
local control remained improved with the chemoradiation regimen (70%)
versus the radiation dose-escalation regimen (44%). This is similar to the
esophageal cancer literature. The RTOG 85-01 trial (21) randomized
patients with esophageal cancer to 50 Gy of RT with two cycles of concurrent cisplatin/5-FU versus RT alone to a higher dose of 64 Gy. The 5-year
overall survival favored the chemotherapy arm at 26% versus 0% for the
RT-alone arm.
There remains little consensus regarding the optimal RT fractionation
regimen when concurrent chemoradiation is used. To date, most concurrent chemoradiation protocols have used once-daily fractionation regimens using 2 Gy per day to doses of approximately 70 Gy. There have
been documented improvements in local control with altered fractionation regimens using RT alone. The RTOG 90-03 trial (22) showed
improved local control with hyperfractionation (1.2 Gy bid to 81.6 Gy)
and accelerated fractionation with concomitant boost (1.8 Gy once daily,
with a second daily fraction of 1.5 Gy administered toward the end of
RT as a “boost” to 72 Gy) compared to standard 2-Gy fractions per day
to 70 Gy.
Nevertheless, it is unclear as to whether there is a benefit to altered
fractionation in the setting of concurrent chemoradiation. The RTOG 9914 trial (23) addressed this question in a phase II trial that used the concomitant boost fractionation schedule (72 Gy/6 weeks) with two cycles of
concurrent cisplatin. Outcomes were favorable with acceptable toxicity;
local control was 65%, which compares favorably to a local control rate
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8
Chemoradiation for Head and Neck Cancer
of 54% found in the concomitant boost RT-alone arm of RTOG 90-03
(22). Overall survival in RTOG 99-14 was 71.6%, which also compares
favorably to the 50.9% overall survival seen in RTOG 90-03 with concomitant boost RT alone. Obviously, a direct comparison of outcome
between these two trials is inappropriate from a statistical standpoint;
however, the RTOG completed accrual in the summer of 2005 for a phase
III trial comparing standard fractionation chemoradiation with altered
fractionation (concomitant boost) chemoradiation (RTOG H01-29). Both
arms are to receive concurrent cisplatin chemotherapy; two cycles for the
altered fractionation arm due to the shortened treatment time and three
cycles for the standard fractionation treatment arm. The goal of this trial is
to determine a fractionation standard for all subsequent concurrent chemoradiation trials.
It is clear that aggressive altered fractionation regimens combined with
certain chemotherapy agents can result in unacceptable toxicity. A trial by
Staar and colleagues (24) randomized patients to accelerated concomitant
boost RT to 69.9 Gy with or without two cycles of carboplatin and 5-FU.
There was no difference between the two groups in regard to local control
or overall survival. However, there was significantly more grade 3 and 4
mucositis in the chemoradiation arm (68% vs. 52%) and significantly
higher rates of gastrostomy tube dependence due to dysphagia (51% vs.
25%). RTOG 90-03 documented higher rates of acute and late toxicity
with altered fractionation, and these appear to have been exacerbated by
the administration of concurrent cisplatin and 5-FU.
In general, most trials of concurrent chemoradiation have not documented reductions in the rates of distant metastases with the addition of
concurrent chemotherapy to RT (see Table 1). As a result, the survival benefit imparted by chemotherapy is primarily due to improvements in local
control.
Induction Chemotherapy Followed
by Chemoradiation
An intriguing approach to the integration of neoadjuvant chemotherapy in
the treatment of head and neck cancer is the use of induction chemotherapy followed by concurrent chemoradiation; an approach that has not
been tested in prior randomized trials. This approach addresses the risk of
systemic micrometastases with the neoadjuvant portion of treatment,
whereas the issue of local control is addressed directly with the concurrent
portion of treatment. A recent study comparing two different induction
regimens (docetaxel plus cisplatin and 5-FU [TPF] vs. PF) followed by sim-
Posner.bk Page 9 Friday, October 20, 2006 11:41 AM
Chemoradiation for Head and Neck Cancer
9
ilar concurrent chemoradiation, did show an improvement in overall survival favoring the TPF arm (25). Although this suggests that more active
induction regimens can affect survival, the incremental benefit of the use of
induction chemotherapy before chemoradiation is still unknown and
under investigation. This approach has been piloted in several phase II trials, and there are now at least three ongoing phase III trials comparing
chemoradiation alone to the addition of induction therapy.
Chemoradiation Regimens
It is clear that chemoradiation imparts an increase in both early and late
toxicities compared with RT alone. In particular, mucositis and long-term
gastrostomy tube dependence secondary to dysphagia have emerged as
major dose-limiting toxicities for chemoradiation (26). It is also clear that
single-agent cisplatin (100 mg/m2 every 3 weeks) appears to be relatively
well tolerated and has demonstrated improvements in overall survival during rigorous testing in multiple phase III trials conducted by various academic and community practices. This regimen has, therefore, been adopted
by the RTOG as their standard reference regimen.
Most trials of concurrent chemoradiation have used high-dose cisplatin
(100 mg/m2 every 3 weeks). This approach achieves a relatively high systemic dose exposure that may address subclinical micrometastases while
still providing some radiosensitization. Alternatively, some trials have used
low-dose weekly regimens due to the understanding that survival benefits
with chemoradiation are primarily due to improvements in local control.
Low-dose weekly regimens provide more opportunity for tumor radiosensitization on this basis. In addition, toxicity may be more easily managed
with weekly regimens through the use of short chemotherapy breaks without RT breaks, and weekly regimens may also result in less systemic toxicity for some patients. Jeremic et al. (27) used cisplatin at a dose of 6 mg/m2
daily (total, 30 mg/m2/week) and did document a survival benefit and, surprisingly, a reduction in distant metastases, leading many to favor a weekly
dose of 30 mg/m2. In the postoperative setting, Bauchaud et al. (28) gave a
fixed dose of 50 mg weekly, which also translates to approximately 30 mg/
m2/week and offers further support for this dose as a reasonable choice for
weekly cisplatin regimens, though it has not been confirmed in additional
prospective trials. Nonetheless, the RTOG has accepted its use in at least
one postoperative trial currently under way and also when combined with
cetuximab (RTOG 0234). Single-agent carboplatin with a weekly area
under the curve (AUC) dose of 1.5–2.0 was also used by Jeremic et al. (27)
and found to be well tolerated with no difference in efficacy compared to
Posner.bk Page 10 Friday, October 20, 2006 11:41 AM
10
Chemoradiation for Head and Neck Cancer
cisplatin at 6 mg/m2/day. A randomized phase II trial from Japan (29)
compared daily cisplatin at 4 mg/m2/day and carboplatin at 100 mg/m2
and found that outcomes were improved in the carboplatin arm; however,
the authors acknowledged that this may have been due to the low doses of
cisplatin used in the trial.
Concurrent chemoradiation with platinum agents and 5-FU was used
by Calais et al. (13) and Brizel et al. (20) with good results. The dose of 5FU in both of these trials was 600 mg/m2 every 3 weeks given with either
carboplatin or cisplatin, respectively. This regimen is highly active when
used in the neoadjuvant and metastatic setting; however, the overlapping
toxicities of stomatitis and mucositis with concurrent RT are substantial
(30,31). Based on the preceding efficacy data, the RTOG has selected concurrent cisplatin at 100 mg/m2 every 3 weeks as a standard arm because
this regimen is thought to provide the best balance of efficacy and tolerability. It is realized, however, that selected institutions are proficient in
stewarding patients through the increased toxicity of concurrent cisplatin
and 5-FU regimens.
There is increased interest in using taxanes in concurrent chemoradiation regimens; however, this approach is still being investigated in the
phase III setting. The greatest experience is with paclitaxel. Doses of 30
mg/m2/week can be delivered without necessitating unscheduled treatment
interruptions or dose reductions (32,33). Doses of paclitaxel can be escalated further; however, unscheduled treatment interruptions and dose
reductions are necessary (34). It also appears that cisplatin at an AUC of 2/
week (35) can be added to paclitaxel without significant additional toxicity. The combination of concurrent weekly cisplatin (20 mg/m2) and
weekly paclitaxel (30 mg/m2) was tested by the RTOG in a randomized
phase II trial (97-03) (36) that compared the preceding regimen to two
other arms consisting of 5-FU/cisplatin and 5-FU/hydroxyurea given on
somewhat nontraditional schedules. The best 2-year disease-free survival
and overall survival rates (51% and 67%, respectively) were found for the
cisplatin/paclitaxel arm, although all three arms had superior outcomes
when compared to historical controls treated with concurrent cisplatin
and RT alone. Docetaxel is also highly active in head and neck cancers
(37). There are no randomized trials investigating this agent administered
concurrently with RT, but docetaxel (15 mg/m2/week) and cisplatin (20
mg/m2/week) have been combined with accelerated concomitant boost RT
in a clinical trial (38). In the neoadjuvant setting, three trials were presented in 2006 documenting a benefit to adding docetaxel to cisplatin and
5-FU (Table 2).
Other than the preceding, no other agents or drug schedules have been
sufficiently investigated to be considered reasonable options for combination
220
501
5-FU, 5-fluorouracil; RT, radiation therapy.
GORTEC
2000–01
(61)
Tax 324
(25)
Multiple
Site
Induction fol- Multiple
lowed by
concurrent
chemotherapy/RT
Induction
Larynx and
followed
hypoby RT
pharynx
alone
Induction
followed
by RT
alone
385
Vermoken
(EORTC
24971)
(60)
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
No. of
Patients Schedule
Trial
(Reference) Schema
70 Gy conventional
70–74 Gy conventional
or hyperfractionated
70 Gy conventional
RT
Table 2. Selected Randomized Trials of Taxanes in Neoadjuvant Chemotherapy
3y
3y
3y
Laryngectomy-free
survival:
80% vs.
58%
Median, 32
mo: 8.2
mo vs. 11
mo; P =
.0071
49% vs.
37%; P =
.004
DiseaseFollow- Free
Up
Survival
—
Median, 51
mo: 14.2
mo vs.
18.6 mo;
P = .0052
62% vs. 48%;
P = .0058
Overall
Survival
Posner.bk Page 11 Friday, October 20, 2006 11:41 AM
11
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12
Chemoradiation for Head and Neck Cancer
with RT in the noninvestigational setting. Gemcitabine is a potent radiosensitizer but induces significant mucositis, dysphagia, and aspiration (39).
Appropriate Selection of Patients for
Chemoradiation in Head and Neck Cancer
Locoregional control of advanced head and neck cancer can exceed 70% with
concurrent chemoradiation approaches (6,10,11,13,16,18,20,28). However,
with the reduction in mortality associated with improved control of locoregional disease above the clavicles, reduction of the competing risk of death
from distant metastases becomes increasingly relevant. The overall rate of distant metastases may exceed 40% in patients with N3 lymphadenopathy (40).
Vokes and colleagues (41) have referred to this phenomenon of an increase in
distant failure in patients who achieve locoregional control of disease as a
“reversal of the historical pattern of failure” in which, historically, local failure
at the primary tumor site exceeded the incidence of distant metastases.
Therapeutic approaches currently available for patients with locally
advanced head and neck cancers include the following:
1.
2.
3.
Surgical resection followed by postoperative RT with or without
chemotherapy, depending on the presence of high risk factors
(primarily extracapsular spread of nodal disease or microscopically
positive margins) (18)
Concurrent chemoradiation with surgical salvage if necessary
Altered fractionation RT alone with surgical salvage if necessary
With these three options in mind, it is important to remember that the
goal of the multidisciplinary team in assigning patients to appropriate
therapy should be to maximize the projected tumor control probability
while preserving function, structure, and cosmesis.
Patients with locoregionally confined head and neck cancer can be roughly
divided into three groups from least to most aggressive:
Early stage:
T1 or favorable T2 primary tumors
N0–N1 lymphadenopathy
M0
Intermediate stage:
Unfavorable (infiltrative) T2 or favorable (exophytic) T3 primary
tumors
N0–N1 lymphadenopathy
M0
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13
Advanced stage:
Unfavorable (infiltrative) T3 primary tumors
T4 primary tumors
N2 or N3 lymphadenopathy
M0
The boundaries between these groups are obviously vague, but nevertheless
do provide some framework for assigning patients to appropriate therapy. The
terms “favorable” and “unfavorable” are traditional terms used to describe
the appearance and behavior of primary head and neck tumors. Favorable
tumors appear exophytic with lower tumor volume and clearly demarcated
boundaries on physical examination, whereas unfavorable tumors appear
infiltrative and ulcerated with higher tumor volume and vague demarcation on
examination. This distinction has been shown to be relevant to tumor
response in clinical trials in which exophytic tumors responded more favorably to RT than those that were ulcerative or endophytic (42). Patients with
early stage disease have a risk of distant metastases of generally less than 10%,
and locoregional control with RT alone (either standard fractionation or
altered fraction) is often in excess of 80%. As a result, the use of chemoradiation in this subset of patients may not be required and is not presently supported by the literature. Patients with advanced stage disease have local
control rates of only 40%–60% when treated with RT alone and rates of distant metastases of 30%–40%. Chemoradiation improves overall survival by
approximately 10%–15% or more in this subset of patients, and as a result
should be considered the standard of care.
The greatest area of controversy in regard to selection of therapy lies, not
surprisingly, with the intermediate stage patients and in patients who are not
easily classified into the above categories. Most chemoradiation protocols in
head and neck cancer that have documented a benefit to concurrent chemoradiation have included patients with American Joint Committee on Cancer
(AJCC) stage III or IV disease. However, this is a heterogeneous group of
patients that includes patients with small T1/T2 N1 tumors, as well as those
with large T3/ T4 N2/ N3 tumors. Mendenhall and colleagues (43) used the
preceding criteria to describe a favorable subset of patients with AJCC stage
IV laryngeal cancer who had excellent outcomes with altered fractionation RT
alone. These patients in general had advanced primary tumors but limited
nodal disease.
In particular, there is controversy as to whether patients with small (T1/
T2) primary tumors but advanced nodal disease derive a benefit from the
more toxic chemoradiation approaches, despite being technically classified
as stage III or IV. A recent retrospective review by Garden et al. (44) analyzed 299 patients with oropharyngeal Tx, T1, or T2 primary disease and
N1, N2, or N3 nodal disease (i.e., patients with small primary tumors who
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Chemoradiation for Head and Neck Cancer
are classified as AJCC stage III or IV due to nodal disease and not due to
advanced primary disease) treated at the University of Texas M.D. Anderson Cancer Center. All patients received RT alone, either conventionally
fractionated or via altered fractionation regimens, without chemotherapy.
This study found that locoregional control with RT alone was 95% for
patients with Tx–T1 tumors, regardless of nodal stage, and 79% for
patients with T2 tumors, regardless of nodal stage. The 5-year rate of distant metastases for patients with N1/2a disease was 11%, compared with
28% for patients with N2b/N2c/N3 disease. The 5-year actuarial disease
recurrence–free survival rate for patients with T1/Tx disease was 80%,
compared with 67% for patients with T2 disease. The 5-year overall survival rate for the entire cohort was 64%. These results compare quite
favorably with the results of the numerous phase III trials of chemoradiation (see Table 1), and the authors conclude that local treatment intensification by the addition of concurrent chemotherapy to RT would not
significantly benefit this subset of patients. Nevertheless, these patients are
still at risk for the development of distant metastatic disease; however, the
role of neoadjuvant or adjuvant chemotherapy or biotherapy approaches
that address this risk is still unclear and is being evaluated in clinical trials.
It is important to remember that definitive concurrent chemoradiation
in head and neck cancer primarily improves survival through improvements in locoregional control. As a result, advanced T stage is a more accurate predictor of which patients are at high risk for local failure and will
thus benefit most from concurrent chemoradiation approaches. The presence of advanced nodal disease is a more accurate predictor for the risk of
neck failure and distant metastases and should be used in determining
which patients should receive therapy directed at reducing such. Also, concurrent chemoradiation has been beneficial for postoperative patients with
advanced nodal disease—namely, those with extracapsular spread. The
preceding discussion highlights the need for treatment decisions to move
beyond simple tumor/node/metastasis stage groupings and evaluate individual tumor, patient, and treatment factors.
Selection Factors for Chemoradiation
There can be great heterogeneity in prognosis between different tumor
sites and subsites in the head and neck that is not adequately reflected by
the present AJCC staging system. Stage for stage, tumors of different sites
can have widely differing prognoses. For example, 5-year overall survival
with RT alone for T2 cancers of the glottic larynx is in excess of 90% (45),
whereas it is only 52% for patients with T1–T2 hypopharyngeal cancers
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Chemoradiation for Head and Neck Cancer
15
(46). Even among tumors arising in the same site, there can be significant
variability among tumors of the same stage according to growth pattern.
For tumors of the base of the tongue, as noted, Weber and colleagues (47)
reported a 2-year rate of local control of 84% for exophytic tumors and
58% for ulcerative/infiltrative tumors. Impairment of function also predicted poorer outcome in this report. In general, patients with non-bulky
T1/T2 tumors or T3 tumors with “favorable” growth patterns can be successfully managed with RT alone, either standard or altered fractionation,
as appropriate. Chemoradiation should be considered as standard for
more advanced tumors. At the present time, tumor-related selection factors for the treatment of head and neck cancers rely primarily on clinical
evaluation of tumor size, growth pattern, and organ compromise. In the
future, biologic and molecular tumor markers that predict for outcome
with various therapies will be developed (48).
Although the preceding discussion has concentrated on the use of RT as
the primary modality to achieve local control in head and neck cancers, it
is important to acknowledge that in some cases surgical resection may be
preferable to definitive RT. For patients with early stage head and neck
cancers, RT or surgery results in similar rates of local control, but with very
different functional-, cosmetic-, and treatment-related morbidities. For
example, many patients with early stage oral cavity cancers are preferentially treated with surgery to avoid the morbidity of RT-induced xerostomia and the increased risk of soft tissue and bone injury (49). In particular,
early (T1/T2) cancers of the oral cavity can achieve excellent local control
with surgery alone while preserving function if techniques such as hemiglossectomy are used. Patients with larger oral cavity tumors or patients
with adverse pathologic findings, such as perineural invasion, positive
margins, or more than one involved cervical lymph node, benefit from the
addition of adjuvant RT to improve local control (50,51).
In laryngeal cancer as well, surgical resection may be preferable in
selected cases. Adequate baseline organ function is a prerequisite for functional organ preservation. For instance, the use of chemoradiation in the
case of a locally advanced T3 or T4 laryngeal tumor in a patient with compromised swallowing function and significant evidence of aspiration on
baseline examination is probably an exercise in futility, as the patient
would have a high likelihood of requiring toilet laryngectomy for progressive aspiration post-therapy (52) as well as a high likelihood of gastrostomy tube dependence due to progressive dysphagia post-therapy. These
patients are better served with laryngectomy, as there is little baseline function to preserve. With the publication of the pooled analysis of RTOG
9501 and EORTC 22931 (18), there appears to be a benefit to the addition
of concurrent chemotherapy to RT in the postoperative setting for patients
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Chemoradiation for Head and Neck Cancer
with adverse pathologic features. The blind adherence to organ-preserving
approaches in head and neck cancer without full recognition of the baseline and post-therapy function is not in the patient’s long-term best interest. It is important to remember that tumor-related dysfunction and
treatment-imposed dysfunction both contribute equally to long-term functional outcome. Adequate baseline organ function is a prerequisite for
functional organ preservation with chemoradiation.
Patients bring a multitude of preferences and preconceptions to the
table when selecting cancer treatment. These preferences are influenced,
among other things, by level of education, socioeconomic status, social
support, religious views, and experience with the health care system. It is
important that all members of the treatment team establish a partnership
with the patient that takes all of the preceding factors into account when
selecting a mutually agreeable treatment plan. Nevertheless, it is incumbent on physicians to provide a balanced view during the education of
patients regarding the benefits of intensive curative therapy and its attendant risks and toxicities. Obviously, patient preference after a discussion
of the preceding ultimately forms the basis of the mutually agreed on treatment plan.
In addition to reliability, social support, and the means to comply with
therapy and follow-up, patients must have adequate performance status
and functional reserve, as well as the psychological make-up to tolerate
aggressive cancer therapies. Different chemoradiation regimens have a
spectrum of toxicities. A specific regimen may be appropriate for a robust,
high-performance status patient with significant physiological reserve, but
not for one more physiologically compromised. It is, therefore, critical that
physicians are familiar with the acute and chronic treatment-related toxicities for specific therapeutic regimens so that informed recommendations
are based on expected patient tolerance.
The experience of individual physicians with the treatment of head and
neck cancers is important when selecting patients for chemoradiation.
Chemoradiation requires close collaboration and communication among
all members of the multidisciplinary team that should include physicians
from head and neck surgery, radiation oncology, medical oncology, radiology, pathology, and dental oncology. In addition, input from allied health
providers from nutrition and speech and swallowing therapy is also necessary if outcomes are to be optimized in these complex patients. The lack of
any of the above components can significantly hinder the optimal treatment of the head and neck cancer patient, and, as a result, facilities without the necessary expertise in the preceding disciplines should probably
consider referral of head and neck cancer patients to a tertiary facility with
the necessary expertise.
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17
The importance of expertise in every component of the multidisciplinary care team is exemplified in a study conducted at a tertiary care
institution evaluating the reinterpretation of computed tomography and
magnetic resonance imaging by an expert head and neck radiologist on
patients referred with head and neck cancer. This showed a change in
interpretation in approximately one-half of cases that resulted in changes
in treatment recommendation for nearly all patients in this group (53).
Even within disciplines, the collaborative review of patient treatment
plans can improve the quality of care in patients with head and neck cancer. At the University of Texas M.D. Anderson Cancer Center, the RT
treatment plans are reviewed in a biweekly intradisciplinary conference
attended by all radiation oncologists who treat head and neck cancers,
during which patients are physically present and examined by all physicians in attendance. A review of the recommendations of 134 patients presented at this conference found that peer review led to changes in
treatment plans for 66% of patients. Most changes were minor, but 11%
of changes were major and thought to be of a magnitude that could potentially affect therapeutic outcome or normal tissue toxicity. Most changes
involved target delineation based on physical findings (54).
Conclusion
Chemoradiation for locally advanced head and neck cancer has been extensively investigated since the 1980s. The randomized data clearly document
improvements in both locoregional control and overall survival with concurrent chemoradiation compared to identical RT regimens given without chemotherapy for appropriately selected patients. However, improvements in
outcome with concurrent chemoradiation are achieved at the expense of
increased acute and late toxicities, including dysphagia and aspiration (55).
Despite hundreds of clinical trials involving thousands of patients on the subject, there remains no definitive standard regarding patient selection for
chemoradiation approaches, the appropriate radiation fractionation schedule,
which chemotherapy agents to use, or the optimal chemotherapy schedule.
Nevertheless, based on a thorough review of the literature, we propose
the following general guidelines for the use of concurrent chemoradiation
in head and neck cancers:
• Patients with T1 and favorable T2 tumors with N0 or N1 lymphadenopathy achieve excellent local control with once-daily RT alone.
• Patients with unfavorable T2 or exophytic T3 tumors with N0 or
N1 lymphadenopathy are well served with altered fractionation
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Chemoradiation for Head and Neck Cancer
schedules of RT alone based on the consistent finding that locoregional control is improved without appreciable increase in late toxicity for this group of patients. Survival in these patients is primarily
dependent on achieving locoregional control, as there is minimal
risk for distant micrometastases.
• Although contentious, patients with T1 or T2 tumors with N2 or N3
lymphadenopathy achieve excellent control with RT alone, with neck
dissection for residual neck disease or consideration for planned neck
dissection, especially in non-oropharynx cancer patients (56–59).
Given the rather high risk of distant metastases in these patients, this
population is ideally suited for testing the efficacy of sequential (adjuvant or neoadjuvant) chemoradiation, with the goal of improving
survival.
• Patients with unfavorable T3 and T4 tumors with N2 or N3 lymphadenopathy are ideally suited for treatment with concurrent
chemoradiation.
• Patients with stage III or IV head and neck cancer treated with surgery
who have evidence of extracapsular spread of tumor from lymph nodes
or microscopically involved resection margins have improved survival
with adjuvant concurrent chemoradiation approaches based on the
results of a pooled analysis of two adjuvant chemoradiation trials (18).
In regard to the specifics of chemoradiation schedules, we suggest the
following:
• Neoadjuvant, or induction, chemotherapy is no longer considered
standard treatment for larynx cancer.
• For non-laryngeal, locally advanced primary tumors of the head and
neck (primarily oropharynx and nasopharynx), concurrent cisplatinum (100 mg/m2 every 3 weeks) and conventionally fractionated
RT (70 Gy at 2 Gy per fraction) has been shown to improve overall
survival in multiple randomized trials and is the most commonly
accepted, but not exclusive, standard of care.
• In the non-investigational setting, the role of altered fractionation
regimens (twice-daily RT or accelerated concomitant boost RT) combined with concurrent chemotherapy remains unclear. The results of
the now closed RTOG H-0129 trial are maturing and should help
answer this question.
• Lower-dose, weekly concurrent chemotherapy regimens provide
radiosensitization and improve locoregional control, but in general
have less effect in preventing distant metastases. Emerging regimens
include carboplatin alone (AUC = 1.5–2.0), paclitaxel alone (30 mg/
m2/week) or combined paclitaxel (30 mg/m2/week) with either cis-
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19
platin (20 mg/m2/week) or carboplatin (AUC = 1.5–2.0). The preceding regimens have been tested in phase II, but have not been
validated in the phase III setting.
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28. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative
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29. Homma A, Shirato H, Furuta Y, et al. Randomized phase II trial of concomitant
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30. Lo TC, Wiley AL, Jr., Ansfield FJ, et al. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. AJR Am J Roentgenol 1976;126(2):229–235.
31. Abitbol AA, Sridhar KS, Lewin AA, et al. Hyperfractionated radiation therapy
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carcinoma. Cancer 1997;80(2):266–276.
32. Flood W, Lee DJ, Trotti A, et al. Multimodality therapy of patients with locally
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33. Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapy
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34. Suntharalingam M. The role of concurrent chemotherapy and radiation in the
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37. Glisson BS, Murphy BA, Frenette G, et al. Phase II trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of
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38. Glisson BS, Garden AS, Kies MS, et al. Phase I study of docetaxel (D), cisplatin
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39. Eisbruch A, Shewach DS, Bradford CR, et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 2001;19(3):792–799.
40. Brockstein B, Haraf DJ, Kies MS, et al. Distant metastases (DM) after concomitant
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pretreatment lymph node (LN) stage. Proc Am Soc Clin Oncol 2000;19:abstr 1635.
41. Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol
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42. Ang KK, Peters LJ, Weber RS, et al. Concomitant boost radiotherapy schedules
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43. Mendenhall WM, Parsons JT, Million RR, et al. A favorable subset of AJCC
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45. Mendenhall WM, Parsons JT, Stringer SP, et al. T1–T2 vocal cord carcinoma: a
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46. Garden AS, Morrison WH, Clayman GL, et al. Early squamous cell carcinoma
of the hypopharynx: outcomes of treatment with radiation alone to the primary disease. Head Neck 1996;18(4):317–322.
47. Weber RS, Gidley P, Morrison WH, et al. Treatment selection for carcinoma of
the base of the tongue. Am J Surg 1990;160(4):415–419.
48. Lydiatt WM, Schantz SP. Biological staging of head and neck cancer and its
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49. Fein DA, Mendenhall WM, Parsons JT, et al. Carcinoma of the oral tongue: a
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50. Whitehurst JO, Droulias CA. Surgical treatment of squamous cell carcinoma of
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51. Rodgers LW, Jr., Stringer SP, Mendenhall WM, et al. Management of squamous
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53. Loevner LA, Sonners AI, Schulman BJ, et al. Reinterpretation of cross-sectional
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54. Rosenthal DI, Asper JA, Barker JL, et al. Importance of patient examination to
clinical quality assurance in head and neck radiation oncology. Sixth International Conference on Head and Neck Cancer, 2004.
55. Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia
and aspiration after chemoradiation for head and neck cancer. J Clin Oncol
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56. Clayman GL, Johnson CJ, 2nd, Morrison W, et al. The role of neck dissection
after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease. Arch Otolaryngol Head Neck Surg 2001;127(2):135–139.
57. Lavertu P, Adelstein DJ, Saxton JP, et al. Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck
cancer. Head Neck 1997;19(7):559–566.
58. McHam SA, Adelstein DJ, Rybicki LA, et al. Who merits a neck dissection
after definitive chemoradiotherapy for N2–N3 squamous cell head and neck
cancer? Head Neck 2003;25(10):791–798.
59. Peters LJ, Weber RS, Morrison WH, et al. Neck surgery in patients with primary
oropharyngeal cancer treated by radiotherapy. Head Neck 1996;18(6):552–559.
60. Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus
neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971. 2006
ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18s):abstr.
61. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing
induction chemotherapy using cisplatin (P) fluorouracil (F) with or without
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❖
Evolving Role of Induction
Chemotherapy and Sequential
Therapy in the Treatment of
Locally Advanced Squamous Cell
Cancer of the Head and Neck
Marshall R. Posner, MD
Treatment Options
The curative treatment of patients with locally advanced squamous cell
carcinoma of the head and neck (HNC) is extremely difficult for the general oncology clinician and is best met by a multimodality team of physicians with specific expertise. HNC patients frequently present to their
physicians with advanced but still regionally localized disease. The intensity of therapy and the prognosis are governed both by the site and the volume of disease. Advanced disease can be defined as either intermediate
stage disease of a moderate prognosis with a 50%–75% 3-year survival or
as advanced disease with a poor prognosis and an expected 20%–45% 3year survival. Intermediate disease is usually stage III: T3/N0/M0 or T1–3/
N1/M0, although stage II patients with large T2/N0 primary cancers also
fall into this prognostic category. More advanced patients present with
stage IV disease: T4/N0–1/M0 or T1–4/N2–3/M0, which may or may not
be surgically resected but frequently are large (1).
CME 23
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24
Evolving Role of Induction Chemotherapy
Even the experienced clinician is faced with significant clinical challenges in
making decisions regarding therapy. The treatment options are subject to considerable debate and differences of opinion. There is site-specific heterogeneity
in biology, prognosis, and therapy; functional deficits from therapeutic choices
can be considerable and are part of the therapeutic assessment; and selection
of an appropriate treatment plan that suits the needs and condition of an individual patient can be difficult. Finally, increasingly aggressive nonsurgical
therapy results in substantial acute and long-term toxicity that requires considerable physician management and experience. Nonetheless, treatment of
HNC is associated with increasing rates of cure, functional organ preservation, and a changing demographic of younger, healthier patients, all of which
have resulted in substantial improvements in outcome and clinical benefit.
History of Treatment
Therapeutic options have evolved slowly and incrementally since the 1970s.
Initial enthusiasm for chemotherapy based on the amazing responsiveness and
spectacular regressions of large tumors to induction chemotherapy was
replaced by disappointment when cure and survival did not meet expectations. Locoregional failure remained high, and research shifted to enhancing
locoregional control through optimizing radiation therapy and experimenting
with chemoradiotherapy. There have been small but important gains in outcomes as a result of these efforts. Improved radiation scheduling and the integration of chemotherapy into radiation therapy have significantly improved
locoregional control. However, the improvement in locoregional control has
been limited, and distant metastases have become an increasing sign of failure.
Survival has improved, but gains have been modest.
Thus, despite several decades of progress and significant improvements in
treatment and supportive care, the prognosis and disease-free survival for
patients with locally advanced HNC has remained poor. Since the 1990s,
cisplatin-based combined modality treatment with chemoradiotherapy (CRT)
has been the sole accepted standard of care for unresectable, locally advanced
disease and for organ preservation, although induction therapy is still accepted
and used by many physicians in North America and remains a standard in
Europe (2,3). At 3 years after standard CRT, only approximately 55% and
35% of patients with intermediate and advanced disease, respectively, will
be alive and disease free (2,4,5). Between 30% and 40% of patients will
develop locoregional recurrences, and 20%–30% will develop distant
metastases. This continues to be a dismal outcome. Failure to control HNC
occurs via two biologically distinct pathways: local recurrence and metastatic spread.
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Evolving Role of Induction Chemotherapy
25
Combined Modality Therapy
The debate regarding the optimal delivery of combined modality therapy
has continued unabated with regard to the scheduling and content of therapy. Three major approaches have been investigated: (a) primary induction
chemotherapy, or neoadjuvant therapy before definitive surgery and/or
radiotherapy; (b) concomitant treatment with chemotherapy and radiotherapy (CRT); and (c) a new synthesis of induction chemotherapy and
CRT, sequential chemotherapy (ST), consisting of induction chemotherapy
followed by CRT (6).
Induction Chemotherapy
Metaanalysis of Results
A reassessment of results from induction chemotherapy trials has been
provided by metaanalysis, by recently reported updates and re-analysis of
older trials with longer follow-up, and by the results of several recently
reported phase III trials. Metaanalysis allows a broad review of diverse
and heterogeneous trials that may not by themselves be sufficiently powered to show an effect or may suffer from defects in performance that
reduce efficacy modestly and obscure significant differences. Metaanalysis
reveals that although the general class of induction trials did not improve
survival in patients with HNC compared to standard therapy, the subset of
induction chemotherapy trials that used cisplatin/5-fluorouracil (PF) chemotherapy resulted in a 5% improvement in 5-year survival compared to
standard therapy (7). This difference was less substantial than the 8%
improvement observed with CRT but was significant at P = .01. The interpretation of the results of metaanalysis of induction trials in general is confounded by combining of non-PF and PF regimens, which are ineffective
compared to PF, and by the substitution of carboplatin for cisplatin, which
is an inferior agent in the treatment of HNC (8,9).
Platinum/5-Fluorouracil Chemotherapy
PF-based induction therapy was developed in the late 1970s and has been
studied ever since. The notion that induction therapy could enhance cure
rates and functional organ preservation is rationally based on observations
that PF chemotherapy resulted in marked shrinkage of tumors in patients
with advanced HNC. In organ preservation trials, PF therapy resulted in a
significant fraction of pathologically negative resections (10–12). Induction chemotherapy is better tolerated than adjuvant therapy given postop-
Posner.bk Page 26 Friday, October 20, 2006 11:41 AM
26
Evolving Role of Induction Chemotherapy
eratively or to irradiated patients. Hence, higher doses and systemically
active treatment can be delivered to the treatment-naïve patient, which can
enhance local responses and eradicate micrometastatic disease with less
toxicity and acute morbidity. Furthermore, drug delivery is better in
untreated, well-vascularized tumors (13). The standard PF regimen combined bolus cisplatin and continuous infusion 5-fluorouracil (5-FU) over 5
days. This was the most effective induction chemotherapy regimen and has
remained the gold standard in advanced HNC (14). Improved organ preservation, reduced distant metastases, and significant improvements in survival in PF-treated patients compared to control populations treated solely
with surgery and/or radiotherapy have been reported in four randomized
trials (Table 1) (3,15–17). PF is highly effective in obtaining responses, and
reported response rates have averaged 60%–80%, with complete responses
in 20%–30% of patients (3,15–20). Survival advantages, however, were
hard to discern in the heterogeneous and complex trials associated with
induction chemotherapy.
Many of the studies with PF-based induction chemotherapy were performed in the early 1990s. Many trials also included resectable patients and
unresectable patients and interposed surgery between induction therapy and
radiotherapy. Although surgery could be avoided in larynx and hypopharynx
patients and a functional larynx preserved, local and regional failure remained
considerable, and survival in resectable patients was not enhanced. Thus, PFbased induction therapy has not been widely or formally accepted by the
cooperative groups as a standard of care, although many practitioners in the
community and in academic centers continued to use PF in patients with very
advanced cancers and as a means of organ preservation.
As mentioned, many early PF trials included resectable patients. Before
organ preservation was established as a standard of care, induction chemotherapy trials frequently had surgery timed to occur between induction chemotherapy and radiotherapy. Performing definitive surgery or nodal or
primary site “salvage” surgery after induction chemotherapy but before
radiotherapy negatively impacted on survival and diminished the impact of
induction chemotherapy on survival in early induction chemotherapy studies (6). After induction chemotherapy, the identification of the margins
becomes difficult if not impossible. In addition, if the primary site is preserved and the neck addressed separately, then residual, partially resistant
tumor cells can repopulate the site, making subsequent radiotherapy less
effective. Finally, in the majority of cases the surgical bed also contains residual tumor cells scattered in the lymphatics that are partially resistant to therapy and can repopulate the region in an enhanced growth environment
while regional treatment with radiotherapy is delayed. This is evident in the
Studio Trial in which patients were randomized to standard care or induc-
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Evolving Role of Induction Chemotherapy
27
Table 1. Phase III Cisplatin/5-Fluorouracil (PF) Induction Trials
Study
Treatment
Organ preservation
Veterans Affairs
PF, three cycles;
radiotherapy
Larynx Trial
EORTC
Hypopharynx
Survival
Studio Trial
GETTEC Oropharynx Trial
Follow-Up
Results
12 y
Larynx preserved in
60% of survivors;
no difference in
survival; reduced
distant metastases with PF
Larynx preserved
in 30% of survivors; survival
equivalent;
reduced distant
metastases
PF, three cycles;
radiotherapy
10 y
PF, four cycles;
surgery and/or
radiotherapy
10 y
PF, three cycles;
surgery and/or
radiotherapy
5y
Significant
improvement in
survival in unresectable
patients;
reduced distant
metastases
Significant
improvement in
survival
EORTC, European Organisation for Research and Treatment of Cancer; GETTEC,
Groupe d’Etudes des Tumeurs de la Tête et du Cou.
tion chemotherapy (21,22). Unresectable patients started radiotherapy immediately after induction PF, but resectable patients had surgery between PF
and radiotherapy. Survival in the resectable patients was slightly worse after
PF and surgery than after surgery alone. On the other hand, PF led to a significant improvement in the survival of unresectable patients compared to
radiotherapy, and the survival advantage was maintained for more than 10
years (22). Thus, the proper sequencing of induction chemotherapy in the
combined modality therapy of HNC remains a major issue and obfuscates
the value of induction chemotherapy. A second large trial by the Groupe
d’Etudes des Tumeurs de la Tête et du Cou (GETTEC), reported by Domenge
et al. (3), confirmed these positive results for PF chemotherapy.
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28
Evolving Role of Induction Chemotherapy
Induction Chemotherapy in Resectable Patients
Induction chemotherapy does have a role in resectable patients, particularly
for organ preservation and in patients with poor prognosis. Organ preservation should be considered in the oropharynx, larynx, and hypopharynx to
preserve swallowing and speech. In a phase III larynx preservation study, the
Veterans Affairs Larynx Cancer Trial, larynx preservation was achieved in
approximately two-thirds of patients treated with PF, and the rate of distant
metastasis was decreased (17) compared to surgery. A study of pyriform
sinus cancer performed by the European Organisation for Research and
Treatment of Cancer (EORTC) also demonstrated an equivalent survival
between the chemotherapy and surgical arms, with organ preservation
achieved in one-third of the patients (15). Both studies included primarily
patients with intermediate stage disease, and updates confirmed that the
results were maintained for 10 years or more.
Several studies attempted to replicate these data, but they were unsuccessful; most notably, a GETTEC trial that studied laryngeal cancer (23). This trial
is difficult to interpret because it included few patients and had significant
early morbidity, which suggests poor patient selection and treatment monitoring. The study highlights a problem encountered with many early trials in
HNC: the inclusion of patients with significant comorbidities who were inappropriate for inclusion in clinical trials of aggressive treatments. Inclusion of
these patients impedes the study of new therapies and impairs the treatment of
healthier patients who would benefit from more intensive therapies.
Chemoradiotherapy
Comparisons with Induction Chemotherapy
More recently, induction chemotherapy for organ preservation has been compared to radiotherapy and to cisplatin-based CRT in the Intergroup 91-11
trial (24,25). In the original study, CRT with bolus cisplatin led to greater
laryngectomy-free survival than radiotherapy alone, without a significant loss
of survival, and induction chemotherapy had an intermediate and nonsignificant impact, compared to radiotherapy. Patients were predominantly of an
intermediate stage, and advanced patients and hypopharynx sites were not
entered. Thus, in this intermediate population in the initial report, CRT
appeared to be a more efficient and potentially effective therapy than radiotherapy alone or induction chemotherapy. This study was recently updated
with a 5-year follow-up (25). Laryngectomy-free survival was identical in the
PF and the CRT arms, and both were significantly better than the radiotherapy arm (Table 2). Significantly more patients survived with an intact larynx
in the PF and CRT arms than when treated with radiotherapy alone. Further-
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Evolving Role of Induction Chemotherapy
29
Table 2. Revised Outcomes for Intergroup 91-11
Treatment
Outcome Parameter
Laryngectomy-free survival
Locoregional control
Overall survival
Disease-free survival
Distant metastases
PF (%)
45
55
59
39
14
CRT (%)
XRT (%)
47
69
55
39
13
34a
51b
54
27a
22
CRT, chemoradiotherapy; PF, cisplatin/5-fluorouracil; XRT, external beam radiation
therapy.
aP <.01 for both comparisons with XRT.
bP <.01 for CRT versus XRT and PF.
more, although as might be expected, CRT resulted in better locoregional control. Disease-free survival was equivalent between the CRT and PF arms. Also,
overall survival was 5% better in the PF arm compared to the CRT arm; both
were better than radiotherapy alone. Although not significant, the overall survival benefit suggests that induction chemotherapy might have had a more
positive impact on this outcome than CRT. This latter result may have become
evident because patients treated with induction therapy may have a better
functional outcome when they begin radiotherapy with reduced tumor size
and normal speech and swallowing structures than patients treated at the start
with large intact tumors. Thus, the Intergroup 91-11 study demonstrates that
PF-based induction chemotherapy is at least equivalent to CRT for laryngectomy-free survival and may have an advantage in overall survival.
Addition of Taxanes
Many studies have attempted to improve PF by adding a third agent to the
combination. Taxanes have been shown to have considerable activity in
recurrent disease and have a different spectrum of activity. Combination
regimens of docetaxel or paclitaxel plus PF have been studied extensively
in phase II trials with good outcomes (26–28). Multiple phase III trials
have been reported that show that three-drug, docetaxel-based PF (TPF)
regimens have improved survival or organ preservation compared to the
older two-drug PF standard (Table 3) (29–32). These results document a
substantial improvement in survival or organ preservation and less toxicity
than was observed with PF induction chemotherapy.
In a trial of resectable and unresectable patients, Hitt et al. (30)
reported an improvement in response and in overall survival in patients
30
Unresectable
Unresectable,
resectable with
poor outcome,
organ preservation
Larynx and oropharynx, organ
preservation
Resectable and
unresectable
TAX 323 (32)
TAX 324 (31)
mg/m2;
T: 75 mg/m2; P: 75 mg/m2;
F: 750 mg/m2 IV CI × 5
days; three cycles
Tp: 175 mg/m2; P: 100 mg/
m2; F: 500 mg/m2 IV CI ×
days 2–6; three cycles
P: 75
T: 75
F: 750 mg/m2 IV CI × 5
days; four cycles
T: 75 mg/m2; P: 100 mg/
m2; F: 1,000 mg/m2 IV CI
× 4 days; three cycles
mg/m2;
TPF Treatment
CI, continuous infusion; F, 5-fluorouracil; P, cisplatin; T, docetaxel; Tp, paclitaxel.
Hitt et al., 2005
(30)
GORTEC 2000-01
(29)
Patients
Study (Reference)
Table 3. Completed Phase III Trials of TPF versus PF
Better organ preservation for TPF
Better survival in
unresectable
patients for TpPF
Chemoradiotherapy:
bolus cisplatin, 100 mg/
m2 every 3 weeks × 3
Improved survival
for TPF
Chemoradiotherapy:
carboplatin area
under the curve, 1.5
weekly
Standard radiotherapy
for responders
Improved survival
for TPF
Outcome
Standard radiotherapy
Radiation Therapy
Posner.bk Page 30 Friday, October 20, 2006 11:41 AM
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Evolving Role of Induction Chemotherapy
31
treated with paclitaxel-based TPF, followed by cisplatin-based CRT. In the
Hitt trial, which compares TPF as part of an ST regimen, survival was not
the primary end point, and therapy in resectable patients included nodal
surgery for some patients before CRT. TPF significantly improved survival
in the unresectable patients but not in the resectable patients. It could be
argued that, by incorporating nodal surgery between induction chemotherapy and CRT, the locoregional control and survival might have been
reduced in the resectable patients. As pointed out regarding the Studio
Trial, the failure to see improved survival in the resectable patients may
have been the result of the delay before radiotherapy, inadequate surgery,
or inadequate pretherapy surgical mapping. This was in contrast to the
results achieved in unresectable patients who went immediately from
induction chemotherapy to radiotherapy. Notably, toxicity in the TPF was
less than that observed in the PF arm, and this was mostly due to reduced
mucositis.
In a second phase III trial, TAX 323, performed by the EORTC and
updated by Remenar et al. in 2006 (32), patients with unresectable HNC
were treated with either TPF or PF followed by radiotherapy. The Remenar et al. study population consisted of patients with advanced disease.
More than 70% of patients had T4 cancers, and more than 70% had N2
or N3 nodal disease. More than 300 patients were entered on this study.
The majority of cancers arose in the oropharynx. Survival was significantly
better with TPF compared to PF. At 3 years, 37% of the TPF patients were
alive compared to 24% of the PF patients. Overall, there was a 29%
reduction in mortality with TPF compared to PF in this unresectable population. Also noteworthy, mucositis in the TPF arm was less than that
obtained in the PF arm, and treatment-related mortality was reduced by
50%.
A second phase III trial comparing TPF to PF was presented in 2006, the
TAX 324 trial (31). This trial is an ST trial; patients with locally advanced
disease were treated with three cycles of TPF or PF and then received CRT
with carboplatin weekly at a low area under the curve. After CRT, some
patients received nodal surgery if they presented with an N3 neck or had a
partial response in the neck after the induction phase. More than 500
patients were entered on the trial, which included resectable and unresectable disease. More than one-half of the patients had an oropharyngeal primary, and 80% had stage IV cancers. There was a significant survival
advantage to TPF. Overall mortality was reduced by 30%, and 3-year survival was 62% and 48% in the TPF and PF arms, respectively. Furthermore,
toxicity appeared to be relatively lower in the TPF arm, as dose intensity
was better preserved in patients receiving TPF compared to PF (99% vs.
90%), and there was less toxicity-related mortality in the TPF arm.
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32
Evolving Role of Induction Chemotherapy
Recently, Calais et al. (29) presented the results of a phase III organ preservation trial performed by the GORTEC in patients with larynx and hypopharynx cancer comparing TPF to PF. These patients were treated with three cycles
of TP or PF, and then responders received radiotherapy and nonresponders
underwent laryngectomy. All patients have finished therapy, and follow-up is
ongoing. There were significantly more responders in the TPF arm compared
to the PF arm. Patients who received TPF had better laryngectomy-free survival than patients with PF, approximately 80% versus 60%; however, it is
still too early for a complete analysis. Notably, however, toxicity was again
less in the TPF arm than in the PF arm.
New Standard of Care
The three-drug TPF regimens have been compared to PF in three completed,
randomized trials. Two trials were done for survival, and one for organ preservation. The latter organ preservation trial is still undergoing follow-up, but
the two survival trials are mature, and firm conclusions may be drawn from
those results, although they have not been formally published. The uniform
result in all three trials is that TPF is substantially superior to PF in terms of
survival in patients with locally advanced HNC. In addition, this improvement in survival is accompanied by a reduction in treatment-related mortality
and mucositis. Thus, it can be said with confidence that TPF is the standard
for induction chemotherapy. There are differences between the European TPF
and the North American TPF. The North American TPF is delivered over 4
days compared to 5 days for the Europeans, but the doses of cisplatin and 5FU are slightly higher (see Table 3). In addition, in the European TAX 323
trial, TPF is delivered for four cycles, whereas the North American TPF regimen is delivered for only three cycles. It is unlikely that these differences will
be resolved in the short term, and they should not obscure the basic and
important facts, which are that TPF is more effective and less toxic than PF
and represents the new standard of care for induction chemotherapy.
Sequential Therapy
An Alternative for Unresectable Disease
Despite the improvements recently reported in unresectable disease and organ
preservation, survival in unresectable disease treated with either TPF-based
induction chemotherapy followed by radiotherapy or solely with cisplatinbased CRT remains poor at approximately 40%. There are advantages and
disadvantages to both induction chemotherapy and CRT. Induction chemotherapy provides systemic therapy, treats distant disease, and reduces local and
regional disease before the start of radiotherapy (33). The latter effect can lead
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Evolving Role of Induction Chemotherapy
33
to a better functional outcome as may have been shown in the Intergroup 9111 study. With induction chemotherapy, toxicity is usually transient and is
substantially less than that observed with CRT and aggressive radiotherapy,
but induction chemotherapy is associated with prolongation of treatment.
After induction chemotherapy, an assessment of response can be used to
adjust the intensity of subsequent therapy. Induction therapy results in good
systemic control, but there are frequent locoregional failures. An analysis of
failure among TPF studies performed at the Dana Farber Cancer Institute
demonstrated a 37% locoregional failure rate among patients treated with different TPF regimens followed by hyperfractionated radiotherapy (34). Five of
these patients (6%) had locoregional failure and distant metastases. There
were no patients with only distant failure.
CRT increases locoregional dose intensity, is ineffective systemic therapy,
and is associated with considerable systemic and local toxicity. There is no
method to assess prognosis and adjust intensity once CRT has started. However, CRT is associated with improved local and regional control and survival.
Distant metastases are unaffected, except in larynx cancer. Cisplatin-based
CRT in unresectable patients, oropharynx cancer, and in the postoperative setting show no impact on distant metastases. In some studies, distant metastases
occurred more frequently than locoregional failures.
Combining induction chemotherapy with CRT and surgery as ST makes
good biologic sense (33,35–39). This paradigm may optimize therapy for
HNC based on an analysis of the sites of failure of both therapies. In addition to providing a systemic therapy, induction therapy may better prepare
the local and regional area by reducing tumor bulk, normalizing vasculature, and improving local function. Furthermore, the immediate period after
completion of induction chemotherapy is a biologically critical time period
when tumor cells in the primary site and region are proliferating rapidly and
have some partial resistance to therapy. In a theoretical modeling of tumor
proliferation and growth, tumor cells proliferate more rapidly when tumor
volume is decreased. This model predicts that the addition of a non–crossresistant therapy with minimal delay (i.e., CRT after induction chemotherapy) should improve locoregional control (40). Tumor cells may well retain
increased sensitivity to radiation therapy and chemotherapy-induced sensitization at this point in treatment.
Therapy Comparisons
Several sequential treatment plans have been reported in phase II trials, and
there are several phase III trials comparing TPF-based ST to cisplatin-based
CRT. The University of Pennsylvania (39) reported a sequential program
trial that included two cycles of very high-dose carboplatin and paclitaxel
followed by single-agent weekly CRT with paclitaxel. Survival was more
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34
Evolving Role of Induction Chemotherapy
than 60% at 3 years. The University of Chicago (38) gave an induction regimen of six weekly cycles of intensive carboplatin/paclitaxel (CP) chemotherapy followed by aggressive split-course CRT, THFX. The 3-year overall
survival rate in this phase II study was 70%. The original Chicago induction
regimen of weekly carboplatin and paclitaxel has been modified by the Eastern Cooperative Oncology Group by the addition of weekly cetuximab in a
phase II trial for resectable patients. After induction therapy, patients are
treated with CRT with weekly carboplatin, paclitaxel, and cetuximab. There
is a provision to perform surgery midway through radiotherapy if there is
persistent disease based on an interim positive biopsy. The Minnie Pearl
Cancer Research Network Trial performed a study of high-dose CP for two
cycles with 6-week continuous infusion of 5-FU (41). This induction regimen was followed by CP weekly with radiotherapy. There was a 51%
3-year survival in this advanced group of patients. Vanderbilt University
Medical Center completed a trial similar to the University of Pennsylvania
trial (42). Results are early but suggest a 66% 3-year survival, with a median
follow-up of 31 months.
The University of Michigan has taken a different approach (43). They
have used PF-induction chemotherapy to select patients for organ preservation or surgery. Patients are assessed after one cycle for response.
Responders receive CRT with bolus cisplatin, and two cycles of adjuvant
PF are then given to complete responders. Nonresponders to one cycle
undergo laryngectomy. Survival is 80% at 3 years, and organ preservation
rates are excellent. This population is primarily intermediate stage larynx
cancer and is not directly comparable to the more advanced patients
treated in the other sequential studies. Furthermore, with the update of the
91-11 trial and the superiority of TPF, this concept should be reexamined.
TAX 324 is a phase III trial; however, both arms were ST based. For this
trial, TPF and PF were followed by CRT with weekly carboplatin, a less-intensive CRT regimen than CRT regimens that use bolus cisplatin, or therapy with
cisplatin and another drug such as 5-FU or paclitaxel. The TAX 324 trial
accrued more than 500 patients and demonstrated that ST with TPF and carboplatin-based CRT was a tolerable therapy and that this treatment represented a reasonable standard of care. There are a number of important,
ongoing phase III trials comparing CRT with TPF-based ST. The University of
Chicago is leading a phase III trial comparing docetaxel/hydoxyurea/5-FU/bid
radiation therapy (THFX) CRT to ST with TPF plus THFX (Figure 1A). The
Italian trial compares TPF followed by CRT with cisplatin and 5-FU to CRT
alone (Figure 1B). The Spanish trial is comparing three arms: TPF or PF plus
cisplatin-based CRT to CRT alone (Figure 1C). The Paradigm trial is comparing TPF followed by carboplatin to cisplatin plus aggressive radiotherapy
(Figure 1D). The Southwest Oncology Group organ preservation study in
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Evolving Role of Induction Chemotherapy
T
R
A
N
D
O
M
I
Z
E
P
35
T
Two cycles of
chemotherapy
H
F
F
Six cycles of every
other week
chemoradiotherapy
X
T
H
F
Six cycles of every
other week
chemoradiotherapy
X
A
T
R
A
N
D
O
M
I
Z
E
B
P
P
F
F
Daily radiotherapy
P
F
CRT
Daily radiotherapy
Figure 1. Active phase III trials comparing sequential therapy with docetaxelbased cisplatin/5-fluorouracil (TPF) chemotherapy and chemoradiotherapy
(CRT). A: Schema for the University of Chicago sequential trial. B: Schema for
the Italian trial. TPF: docetaxel, 75 mg/m2 day 1 + cisplatin, 80 mg/m2 day 1 +
5-fluorouracil (5-FU), 800 mg/m2 continuous infusion (CI) days 1–4 for 3
weeks ×3. CRT PF: cisplatin, 20 mg/m2 days 1–4 + 5-FU, 800 mg/m2 CI days 1–
4 weeks 1 and 6. (continued)
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36
Evolving Role of Induction Chemotherapy
T
P
R
A
N
D
O
M
I
Z
E
Cisplatin, 100 mg/m2
F
Salvage
surgery
Daily radiotherapy
P
F
C
ACB
T
R
A
N
D
O
M
I
Z
E
P
Three
cycles of
NR
chemotherapy
T*
Surgery
F
C
PR, CR
Daily radiotherapy
P
Q 3 weeks
Surgery
XRT
ACB radiotherapy
Figure 1. (Continued) C: Schema for the Spanish combined modality therapy trial. TPF versus PF followed by CRT versus CRT alone. TPF: docetaxel, 75
mg/m2 day 1 + cisplatin, 75 mg/m2 day 1 + 5-FU, 750 mg/m2 CI days 1–5 for
3 weeks ×3. PF: cisplatin, 100 mg/m2 day 1 + 5-FU, 1,000 mg/m2 CI days 1–5
for 3 weeks ×3. CRT: cisplatin, 100 mg/m2 days 1, 22, and 42. D: The North
American Paradigm trial. *T + accelerated concomittant boost for nonresponders. (continued)
D
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Evolving Role of Induction Chemotherapy
37
<50% Response
Surgery
T
R
A
N
D
O
M
I
Z
E
E
P
P
Q 3 weeks
F
>50% Response
Two cycles
Surgery
Daily radiotherapy
P
Q 3 weeks
XRT
Surgery
Daily radiotherapy
Figure 1. (Continued) E: The Southwest Oncology Group Oropharynx trial.
CR, complete response; H, hydroxyurea; NR, no response; PR, partial response;
X, BID radiation therapy; XRT, external-beam radiation therapy.
resectable oropharynx cancer compares ST with TPF plus CRT to CRT alone
for organ preservation (Figure 1E).
Conclusion
This has been a productive period in the treatment of locally advanced
HNC. After three decades of study, major advances in combined modality
therapy by incorporating three-drug regimens of TPF into treatment are
being seen. TPF has been shown to improve survival and organ preservation and to result in less acute morbidity than the original standard twodrug PF regimen of induction chemotherapy. In addition, studies of ST as a
new treatment paradigm for locally advanced HNC have shown 2- and 3year survival rates in advanced disease that are unprecedented. There are
more than six phase III studies being performed to compare ST to CRT.
Early data from the European trials may be expected in 2007 and 2008.
When the progress in research and the evolution of induction chemotherapy and CRT over the last few years is reviewed, improved chemotherapy,
better survival, and potentially better functional outcome for patients may be
seen. The concept of ST appears to reflect an increasing understanding of the
biology of HNC. ST makes sound biologic sense and appears to be highly
effective, but it still remains experimental. Despite the lack of completed phase
III trials establishing the relative efficacy of this paradigm, the TAX 324 trial
shows that ST with TPF induction therapy and carboplatin-based CRT is an
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38
Evolving Role of Induction Chemotherapy
acceptable treatment and a reasonable alternative for patients with good performance status and locally advanced disease. Phase III trials, however, remain
the final determinant as to whether this is truly an improvement over the current standards of induction chemotherapy or CRT.
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23. Richard J, Sancho-Garnier H, Pessey J, et al. Randomized trial of induction
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24. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and
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25. Forastiere A, Maor M, Weber R, et al. Long term results of Intergroup RTOG
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26. Posner MR, Glisson B, Frenette G, et al. Multicenter phase I–II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with
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27. Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a
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28. Baselga J, Trigo JM, Bourhis J, et al. Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule
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Evolving Role of Induction Chemotherapy
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Scientific Session, 2006.
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Haddad R, Tishler RB, Norris CM, et al. TPF-based induction chemotherapy
for head and neck cancer and the case for sequential, combined modality treatment. Oncologist 2003;8:35–44.
Haddad R, Wirth L, Posner M. The integration of chemotherapy in the curative treatment of locally advanced head and neck cancer. Expert Rev Anticancer Ther 2003;3:331–338.
Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck
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Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapy
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Hainsworth JD, Meluch AA, McClurkan S, et al. Induction paclitaxel, carboplatin
and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: a
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❖
Increasing Cure—Increasing
Toxicity: Symptom Management
and Chemoradiotherapy
Barbara A. Murphy, MD
History of Management
As recently as the mid-1990s, medical oncologists were peripheral members of the head and neck cancer (HNC) treatment team, with their role
being confined to the administration of chemotherapy for metastatic or
recurrent disease. Now, chemotherapy is being incorporated into the primary treatment plan for the majority of patients with locally advanced
HNC. However, the improved treatment outcome resulting from combined modality therapy is at the expense of markedly increased acute and
late toxicities. Thus, medical oncologists are faced with making treatment
decisions as well as managing a complex array of interrelated treatment
toxicities that are often problematic long after therapy is completed (1). To
complicate matters, information to guide physicians in dealing with the
toxicities of therapy has not kept pace with changing practice. Indeed,
information regarding the incidence, severity, and management of treatment-related toxicities is often weak or lacking. Thus, supportive care in
head and neck oncology has become a critical area of study.
It is important for clinicians to understand the management of acute
and late effects of therapy on both an individual and collective basis. From
the standpoint of the individual, assessment of acute and late toxicities is
necessary to minimize the detrimental effects on physical and mental
CME 41
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Increasing Cure—Increasing Toxicity
health. Collectively, oncologists need to understand how various treatment
regimens impact a patient’s quality of life (QOL) and supportive care outcomes to design regimens that minimize late effects.
Measuring Effects of Treatment: Quality
of Life versus Symptom Control
In evaluating the late effects of therapy, it is important to recognize two
related, but distinct, outcome measures: the first is QOL. QOL is a global construct that attempts to quantify a patient’s sense of general well-being (2). It is
influenced by numerous factors, including beliefs, life experiences, and expectations (3). A number of tools have been developed to measure QOL; the most
commonly used in the HNC patient population are the Functional Assessment
of Cancer Therapy (4) and the European Organisation of Research and Treatment of Cancer systems (5,6). Both systems have well-described general
questionnaires that address important domains, such as physical, functional,
emotional, and social well-being (7), as well as head and neck subscales that
specifically address issues pertinent to HNC patients. A review of the head
and neck QOL literature reveals some important information and insights (8).
However, it can be difficult to translate results from QOL studies into practical recommendations for practicing clinicians.
QOL assessments must be distinguished from symptom assessments. A
symptom is a perceived alteration in a sensation or function. Symptoms may
contribute to alterations in QOL; however, it is important to note that
patients may experience symptoms that fail to significantly impact on QOL.
This does not mean that symptoms are unimportant. Patients with HNC
may have a significant symptom burden that does not affect their QOL but
that does have substantial health implications. For example, a patient may
have moderately impaired swallowing function, which results in maladaptive dietary changes. The patient may not be “bothered” or “distressed” by
the problem, but the long-term implications of diet alterations may be significant. Unlike QOL outcomes, it is easier to translate symptom and function
outcomes into clinical practice.
Because it has been recognized that chemoradiotherapy (CRT) is associated with increased toxicity, symptom and functional outcomes have become
an important correlative component of clinical trials. It is, therefore, important for clinicians to understand the benefits and limitations of different
measures to be able to interpret results. Symptoms can be assessed in a variety of ways. Most clinical trials report symptoms based on toxicity-reporting systems such as the Common Toxicity Criteria. These systems have
inherent limitations, the most important of which is underreporting. Under-
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43
reporting is both systematized (trials rarely report grade 1 and 2 toxicities,
which may be bothersome or distressing to patients) or inadvertent (failure
to assess and document problems). To deal with this issue, self-report measures that address specific symptom control or functional issues can be
appended to clinical trials. The advantage of self-report measures is that
efforts can be directed at collecting desired information, the cost is modest,
and the patient burden is low. Alternatively, objective measures, such as
modified barium swallow to measure swallow function or pedometers to
measure activity, may be used. Objective measures have the advantage of
providing rich, detailed information. However, they tend to be more expensive and are often dependent on the expertise of the operator.
Symptom Control Issues
The remainder of this chapter provides a brief review of critical symptom
control issues in HNC patients undergoing CRT. The reader is referred to
additional materials for a more comprehensive review (1).
Mucositis
Mucositis secondary to CRT remains one of the major complications of
therapy. Classically, the term mucositis has been used to refer to ulcerative
lesions of the mucous membranes. Because the ulcerative lesions of the
upper aerodigestive tract were visible on examination, most clinicians think
of mucositis as confined to the head and neck region. It is often thought of
as a local process with consequences that are confined to the local tissues.
Older toxicity grading systems have propagated this limited concept by confining mucositis grading to measurement of ulcerative lesions.
As the knowledge base has evolved, the concept of mucositis has
changed. It has become clear that mucositis is associated with complicated
local biology and systemic effects. Sonis (9) has developed a model that
explains the underlying biology of mucositis. The first step in the pathogenesis of mucositis is initiation. During this phase, tissue damage from
chemotherapy and radiation induces the production of reactive oxygen
species (ROS). During the second phase, ROS activate a number of biologic pathways, including nuclear factor κB (NF-κB), sphingomyelinase,
and ceramide. NF-κB, a central signaling molecule, upregulates a number
of pathways resulting in, among other things, an increase in proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1b (IL-1b), and
IL-6. After activation, a series of feedback loops result in amplification of
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Increasing Cure—Increasing Toxicity
biologic responses. Although these biologic responses are meant to be protective, prolonged activation of pathways may paradoxically result in tissue injury. Ulcers develop in the damaged mucosa, and an inflammatory
infiltrate may be seen. After the insulting agent is removed, healing may
begin to take place.
Based on this model, it appears that mucositis is best thought of as a complex biologic process that results from damage to the tissues by systemic chemotherapy or radiation. Regardless of whether the tissue damage is due to
chemotherapy or radiation therapy (RT), there are local and systemic manifestations that result from the tissue response to damage. These effects impact on
a broad array of organs and function, and may be long lasting. Of note, there
is no doubt that the use of CRT results in a marked increase in mucositis when
compared to radiation alone. The use of radiation alone results in grade 3 and
4 mucositis rates of between 20% and 30% (10). Aggressive, concurrent CRT
regimens may result in mucositis rates that approach 100%. Thus, it is critical
for the clinician to have a comprehensive management strategy for the identification and palliation of mucositis-related symptoms.
Mucositis-Related Symptoms
Mucositis is a clinically important toxicity. First and foremost, increased
rates of mucositis may be associated with breaks in therapy and compromised tumor control. In addition to treatment breaks, mucositis is associated with a number of acute and late symptom control and functional issues.
The most common symptom associated with mucositis is pain. A recent
study reported on mucositis-related burden in HNC patients undergoing
CRT (11). Seventy-five patients with stage 3 or 4 HNC undergoing radiation
or CRT were enrolled in this prospective trial. At the end of week 6, 85% of
patients were receiving opioid analgesics. Despite the use of opioids, 76% of
patients complained of “quite a lot” or “extreme” mouth soreness. Pain was
demonstrated to impact on swallowing, drinking, eating, and talking.
Acutely, mucositis results in tissue edema and inflammation. After RT is
completed, healing begins. Tissue edema and inflammation may resolve,
leaving the patient with few clinically evident side effects. Conversely, some
patients may experience significant fibrosis and scarring of the mucosa and
soft tissues of the neck. The long-term effects of tissue scarring are substantial, including lymphedema, decrease in compliance of pharyngeal soft tissues, altered swallowing function, and dietary inadequacies.
Dozens of agents in hundreds of trials have been investigated as preventive or treatment agents for oral mucositis. To date, there are no pharmaceutical interventions that have been shown to be effective either in the
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45
treatment or prevention of radiation-induced mucositis. A thorough
review of the mucositis literature was conducted by the Mucositis Committee of the Multinational Association of Supportive Care in Cancer
(MASCC) (12). Based on this review, evidence-based clinical practice
guidelines have been developed. The recently updated version is available
on the MASCC web site (www.mascc.org). The guidelines recommend the
following:
•
•
•
•
Oral care to attempt the reduction of mucositis
Adequate analgesia
Radiation techniques such as midline blocks and conformal radiation
Benzydamine for prevention of mucositis (not available in the United
States)
Of note, the relative effect of intensity-modulated RT (IMRT) on the
severity and duration of mucositis has yet to be clearly determined and
awaits further prospective study.
It is evident that, at this time, care for radiation-induced mucositis is
supportive in nature. It is critical that the HNC team assess the patient
routinely for the sequela of mucositis and that aggressive measures be used
to maintain comfort, hydration, and nutritional status.
Despite the disappointing results of prior investigations, pharmaceutical companies continue to attempt to develop new agents for the prevention and treatment of oral mucositis. A review of ongoing investigations is
beyond the scope of this text. The reader is referred to the June 2006 issue
of Supportive Care in Cancer, which is dedicated exclusively to mucositis.
Data on the systemic effects of mucositis are much more limited. Investigators at Vanderbilt University have investigated the physiologic effects of
CRT-induced tissue damage on physical function and muscle mass (13,14).
Patients who have completed CRT experience a marked loss of muscle mass
and a decrease in physical function. This correlates with an increase in
proinflammatory cytokines and measures of oxidative stress, and a decrease
in antiinflammatory cytokines. Further evaluation of the systemic effects of
mucositis and related tissue damage is urgently needed.
Nutritional Management and Unintentional Weight Loss
At least 50% of HNC patients are malnourished at some point in their
treatment course. Malnutrition is associated with a decrease in both survival and QOL (15–20). Thus, assessment of nutritional status is a key
component in the management of HNC patients throughout the trajectory
of their disease process (21).
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Table 1. Definition of Critical Weight Loss
Time Course
Significant Weight
Loss (%)
Severe Weight
Loss (%)
1 wk
1 mo
3 mo
6 mo
≤2
≤5
≤ 7.5
≤ 10
>2
>5
>7.5
>10
Information compiled from Blackburn GL, Bistrian BR, Miani BS, et al. Nutritional and
metabolic assessment of the hospitalized patient. J Parenter Enteral Nutr 1977;1:11–22.
At the time of diagnosis, all patients should be assessed to determine if
they have had any recent weight loss. If so, the severity and rapidity of
weight loss should be determined. Risk classifications have been developed
to identify high-risk patients for whom nutritional deficits may significantly
impact on outcome (Table 1). Of note, patients with extreme weight loss
have a decreased healing capacity and may fail to tolerate aggressive combined modality treatment regimens. In addition to the severity of weight
loss, the etiology of weight loss should be established. For most patients,
weight loss at the time of diagnosis is associated with tumor-related pain or
obstruction of the alimentary tract. Cancer cachexia, an inflammatory process due to cancer, may also contribute to weight loss, particularly in
patients with advanced disease (22–24). Once the cause of weight loss is
identified, efforts should be made to ameliorate the identified problem. If
this is not possible, patients may require feeding tube placement.
In addition to a weight loss history, it is important to determine whether
patients are using vitamin supplements. Although the HNC population has a
lower rate of complementary alternative medicine therapy use when compared to other cancer diagnoses, the use of high doses of selected vitamins has
become widespread. Antioxidants have been postulated to have a protective
effect against the tissue damage from radiation (25). Preliminary data indicated that some vitamins, such as vitamin E or vitamin C, may decrease the
acute effects of RT (26,27). However, a more recent randomized trial indicated that vitamin E and carotenoid supplementation may have a tumorsparing effect with compromised local control (28). Therefore, patients
should be warned not to take nonphysiologic vitamin supplements without
discussing them with the medical staff.
Weight loss may also be due to the effects of treatment. Surgery may result
in decreased oral intake in the perioperative period. Generally, if patients are
anticipated to have a prolonged period of decreased oral intake postoperatively, a nasogastric or percutaneous feeding tube is placed at the time of sur-
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gery. A more problematic issue is weight loss associated with radiation-based
therapy (29). Compared to radiation alone, patients who receive CRT have a
more profound weight loss, averaging 6%–12% body weight. When using
CRT, clinicians should be prepared to aggressively address nutrition issues.
The most common reason cited for weight loss during CRT is decreased
oral intake due to painful mucositis (11), and mucositis-related pain can be
refractory to medical therapy. Patients usually require frequent and rapid escalation of opioids along with the use of adjunctive medications such as topical
anesthetics. Because patients have difficulty swallowing, transdermal delivery
systems provide a convenient and effective method for providing analgesia.
Other factors that contribute to decreased oral intake during and immediately after RT include tissue edema and inflammation with resultant decrease
in tissue compliance. Noncompliant tissues have decreased mobility that
inhibits normal swallowing function (21,30). There are two major complications of altered swallowing function: (a) nutritional inadequacies and (b) aspiration. Due to decrease in oral intake from swallowing abnormalities, a high
percentage of patients with locally advanced HNC undergo feeding tube
placement. There is considerable debate as to whether a feeding tube should
be placed prophylactically. There is little doubt that the prophylactic placement of a feeding tube will decrease the amount of weight loss. Recently, however, concern has been expressed that patients with feeding tubes stop using
the muscles of deglutition, allowing atrophy and wasting. Atrophy and wasting are thought to lead to higher rates of feeding tube dependence long term. It
has also been recently recognized that the need for feeding tube placement and
the rate of long-term feeding dependence is associated with the treatment regimen. A clear increase in feeding tube placement and long-term feeding tube
dependence is noted when CRT is compared to radiation alone (30). It also
appears that more aggressive regimens may be associated with increased longterm feeding tube dependence (30). Interpretation of these data is complicated
by the heterogeneous patient populations and differences in supportive measures available at institutions. Nonetheless, clinicians must be prepared to deal
with the acute and late swallowing effects of therapy. It is recommended that
patients continue to attempt to swallow even if they have a feeding tube in
place. Patients should be seen by a speech and language pathologist early in
their course so that they may be provided with exercises that may prevent loss
of swallowing function. Early return to swallowing function should be encouraged as long as it is safe.
Aspiration is one of the unrecognized, but potentially fatal, complications
of swallowing abnormalities. Aspiration may lead to pneumonia, which is
particularly problematic during therapy with myelosuppressive chemotherapy
regimens. Patients who have undergone aggressive CRT are often weak and
debilitated. Thus, if they develop an aspiration pneumonia, they have
decreased reserve. The treating clinician should be aware of several scenarios
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that indicate ongoing aspiration. First, patients may complain of coughing
when eating or after eating. Patients may also present with fever of unclear etiology. Chronically, aspiration may present as pulmonary fibrosis and respiratory compromise. If the clinician is concerned about potential aspiration, a
modified barium swallow should be obtained. If patients have significant aspiration, the patient may need to have a feeding tube placed and designated to
receive nothing by mouth. However, it is difficult to determine “how much
aspiration is too much aspiration.” Thus, a consultation with speech and language pathology is helpful.
Xerostomia
Humans produce 1.0–1.5 L of saliva each day. The major components of
saliva are amylase, mucin, and bicarbonate (31). In addition, saliva contains a
mixture of proteins, electrolytes, and nonprotein, nonelectrolytes. This complex secretion has multiple roles: (a) oral cavity lubrication, (b) maintaining
mucous membrane integrity by protecting it from desiccation and environmental factors/toxins, (c) antibacterial, antifungal, antiviral effect (lysozyme,
lactoferrin, peroxidases), (d) maintaining oral pH, (e) maintaining dental
integrity, (f) food bolus formation, and (g) aid in taste sensation (31,32).
Xerostomia is the sensation of oral dryness. It results both in a decrease
in QOL and marked alteration in critical functions. Xerostomia may be
caused by a wide range of processing, including aging, medications, collagen
vascular disease, anxiety or depression, and, finally, RT-induced damage to
the salivary glands. When the major salivary glands are within the radiation
portal, a >50% reduction in unstimulated flow is noted after 1 week and
reaches <10% of basal salivary flow within 2–3 weeks (33). Salivary function may recover partially if the radiation dose is between 30 and 60 Gy;
however, damage may be permanent above 30 Gy (34,35).
Patients with xerostomia complain of a variety of symptoms, including:
pain or discomfort, painful mucosal ulcers, altered voice (36), increased dental
caries, difficulty wearing dentures, decreased taste, difficulty with mastication
(37), and altered oral intake with nutritional deficits (38). On examination,
patients may have fissures and atrophy of the papillae of the tongue; angular
cheilitis; dental decay, especially at the roots; erythematous mucosa; dry or
pale mucosa due to atrophy; oral ulcers; and candidiasis.
Assessment of salivary function can be made using clinical parameters or
by measuring stimulated and unstimulated saliva production. Unstimulated
salivary flow rates are obtained by asking patients to spit into a plastic container for 5 minutes. Stimulated salivary measurements may be done by asking a patient to chew on paraffin or sugar-free gum while saliva is collected.
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Table 2. Common Terminology Criteria for Adverse Events 3.0 Standards
for Xerostomia
Grade
Description
1
Symptomatic (dry or thick saliva); no dietary alterations; unstimulated flow rate of >0.2 mL /minute
Symptomatic and significant dietary intake alterations (requires
copious water, lubricants, soft foods, moist foods); unstimulated flow rate of 0.1–0.2 mL /minute
Symptomatic; significant oral intake alterations leading to inadequate oral alimentation (requires IV, feeding tube, or total parenteral nutrition); unstimulated flow rate of <0.1 mL /minute
2
3
Alternatively, 4% citric acid can be applied every 2 minutes. Normal, unstimulated flow is 0.3–0.5 mL/minute, and stimulated flow is 1–2 mL/minute. Various criteria have been developed for rating xerostomia (32) (Tables 2 and 3).
The most recent criteria (Common Terminology Criteria for Adverse Events
3.0) incorporates the measurement of unstimulated salivary flow.
Once xerostomia has developed, treatment options are limited. If some salivary function is still present, the goal of treatment is to stimulate remaining
function by mechanical, gustatory, or pharmacologic stimulation. Because
there is no substitute for the dental protection afforded by saliva, the importance of stimulation of residual salivary function cannot be underestimated.
Gustatory stimulants include gum, lozenges, and specific tastes such as sweet,
acid, or menthol. Pharmacologic agents include pilocarpine, 5 mg orally (PO)
qid (39), or cevimeline, 30 mg PO tid (40). These agents are modestly effective
in improving salivary flow and comfort.
If no function is present, the goal of therapy is to increase oral comfort by
using salivary substitutes. Most salivary substitutes contain carboxymethylcellulose. Attempts have been made to add enzymes, such as lysozyme, sialoperoxidase, and lactoferrin, to add an antimicrobial effect (41). These agents
Table 3. Radiation Therapy Oncology Group Salivary Gland Morbidity Scale
Grade
Description
1
Mild dryness, slightly thick saliva, slightly altered or metallic
taste
Moderate to complete dryness, thick sticky saliva, and
marked taste alterations
Not defined for xerostomia
Acute salivary gland necrosis
2
3
4
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improve oral comfort, but there are no consistent data to indicate a change in
bacterial colonization (41,42).
Because of the devastating effects of xerostomia, investigators have
attempted to identify methods for preventing loss of salivary gland function.
Three major methods have been used: salivary gland transfer, pharmacologic
agents such as amifostine, and alternative radiation delivery systems such as
IMRT. Salivary gland transfer is a surgical procedure that is done before RT.
The salivary glands are moved anteriorly and out of the radiation port; thus,
the delivery of radiation to the glands is markedly diminished, and function
loss is minimized (43). Preliminary results indicate that this is an effective
strategy; however, its broad applicability is of concern.
Amifostine is an inorganic thiophosphate that is U.S. Food and Drug
Administration approved for the protection of salivary glands during RT. In a
recently published metaanalysis evaluating data on the efficacy of amifostine,
Sasse et al. (44) identified 14 randomized trials containing 1,451 patients.
Only four studies reported the effects on xerostomia for HNC. Of the four
studies that looked at acute xerostomia, amifostine reduced the odds of xerostomia by 76% (odds ratio [OR], 0.24; confidence interval [CI], 0.15–0.36; P
<.00001). Only two of the studies looked at late xerostomia. In those studies,
amifostine reduced the odds of xerostomia by 67% (OR, 0.33; CI, 0.21–0.51;
P <.00001). Despite the positive data, amifostine has not been broadly
accepted. This is due in part to cost considerations and in part to toxicity. In
an attempt to ameliorate the toxicities of intravenous (IV) amifostine, studies
were done to determine whether amifostine could be used subcutaneously to
decrease side effects without decreasing activity. Bardet et al. (45) reported the
results of a randomized trial of 311 HNC patients receiving primary and postoperative CRT who received RT to at least 75% of both glands. Patients were
randomized to amifostine, 500 mg/m2 or 200 mg/m2 IV. Results demonstrated
no difference in acute xerostomia, mucositis, or dermatitis between the IV and
subcutaneous administration. The subcutaneous administration was better
tolerated, with fewer episodes of hypotension, nausea, or vomiting.
An alternative method for prevention of xerostomia is to use conformal
RT techniques that spare normal tissue. As noted, if the radiation dose to the
salivary gland is limited, salivary function can be spared. Several small studies
have reported a positive effect on salivary function in patients treated with
IMRT (46–48). Further evaluation in trials with a larger sample using objective measures of outcome are needed to confirm these results.
Oral Care
Before initiating therapy, patients should undergo a thorough dental evaluation. This should include an examination with radiographs, periodontal
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care, smoothing of rough dental surfaces, and assessment of dentures and
prosthetics. Questionable teeth must be extracted before radiation. Radiation should not be started until 10–14 days after dental extraction to allow
adequate time for healing (49).
The best recognized and perhaps the most profound ramification of
xerostomia is dental caries. Caries may progress rapidly. Thus, patients
receiving RT to the head and neck should be advised that an oral care regimen is critical before, during, and after therapy is completed. The purpose
of oral care is to decrease the impact of xerostomia, prevent infections, and
control treatment-related symptoms. An oral care regimen should include
routine brushing (for as long as possible during therapy), flossing, using oral
rinses (water, baking soda, saline), and mouth moisturizers for comfort.
Patients should use fluoride treatments (either trays or concentrated toothpaste) throughout treatment until mucositis prohibits its use. Treatments
should then be resumed as quickly as possible after mucositis resolves.
Psychological Issues
Patients undergoing stem cell transplant have an extensive pretreatment
workup that includes a psychological assessment to identify issues that may
impair their ability to tolerate the aggressive nature of the treatment and
recovery. The use of aggressive CRT regimens for treatment of HNC is no less
rigorous than some transplant protocols. However, psychological assessment
and counseling are not financially viable nor are they acceptable to many
patients with HNC. Psychological care, therefore, becomes a responsibility of
the HNC treatment team.
Several key issues should be addressed as part of the initial psychiatric
evaluation. First, it is critical to determine whether patients have a history of
substance abuse; in particular, a history of alcohol use should be obtained
(see Table 4 for Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, criteria). Although only a small percentage of patients may
meet criteria for alcohol abuse syndrome, a much higher percentage of
patients may have a history of alcohol dependence. For the small percentage
of patients who are unable to refrain from excessive alcohol intake, treatment even with radiation as a single modality may be beyond the ability of
the staff to deliver and the patient to tolerate. In this situation, involving
rehabilitation services before starting therapy is advisable. For patients who
do not exhibit severe maladaptive behaviors, but have a history of heavy
alcohol intake, there are several concerns. First, the abrupt discontinuation
of alcohol may result in a withdrawal syndrome. In addition, patients may
have unrecognized nutrient deficiencies and medical sequelae such as com-
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Table 4. Pretreatment Evaluation
Symptom assessment
Pain
Voice or speech alterations
Swallowing difficulty
Loss of range of motion in neck or shoulders
Hearing loss
Vision changes
Dental care
Dental evaluation
Examination with radiographs
Evaluate for trismus—if present, initiate range of motion exercises
Restoration work
Periodontal therapy
Smooth, rough, or irregular dental surfaces
Assess dental appliances for fit
Oral surgery for removal of diseased teeth
Dental education
Oral hygiene instructions
Fluoride treatments
Diet counseling
Nutritional/swallowing assessment
Weight loss history
Establish degree and rapidity of weight loss
Nutritional supplements as needed
If patient is at high risk, consider feeding tube
Referral for dietary counseling if needed
Vitamin supplement history
Thiamine supplementation if history of alcohol use
Iron supplementation if indicated (anemia history or chronic bleeding)
Speech and language pathology referral if available
Provide swallowing exercises for ongoing use
Psychosocial evaluation
Determine level of social support
(continued)
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Table 4. Pretreatment Evaluation (Continued)
Identify current or previous history of mood disorders (anxiety and
depression)
Alcohol history (CAGE questionnaire)a
Have you ever felt the need to cut down on drinking?
Have you ever felt annoyed by criticism of your drinking?
Have you ever had guilty feelings about your drinking?
Have you ever taken a morning eye opener?
DSM-IV criteria for alcohol abuseb
Failure to fulfill work, school, or social obligations
Recurrent substance use in physically hazardous situations
Recurrent legal problems related to substance use
Continued use despite alcohol-related social/interpersonal problems
DSM-IV criteria for alcohol dependenceb
Tolerance
Withdrawal
Substance taken in larger quantity than intended
Persistent desire to cut down or control use
Time is spent obtaining, using, or recovering from the substance
Social, occupational, or recreational tasks are sacrificed
Use continues despite physical and psychological problems
aMayfield
D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry 1974;131:1121.
bAmerican Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Washington, DC: American Psychiatric Association, 1994.
promised hepatic function or cognitive impairment. Although these factors
are not in and of themselves contraindications to CRT, they must be taken
into account in selecting a patient’s treatment regimen. A simple and realistic
approach to identifying patients with alcohol-related problems is to use a
brief questionnaire, such as the CAGE questionnaire, as a routine in all
patients (see Table 4). For treatment recommendations or more information
on alcoholism or alcohol-related illness, visit the American Society of Addiction Medicine web site (www.asam.org/publ/detoxification.htm).
The second major psychiatric issue is depression. HNC patients have a
high rate of premorbid depression. As many as 40% of HNC patients
complain of depression either before diagnosis or after diagnosis. Patients
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with advanced stage, a premorbid history of depression, or poor support
networks are more likely to develop depression during or after treatment
(50,51). Depression has been associated with a decrease in post-treatment
QOL (52). More important, recovery from the effects of CRT requires a
highly motivated and compliant patient. Depressed patients may find it
difficult to get out of bed and participate in rehabilitation activities, making recovery more prolonged and difficult. A practical method for screening for depression in the office setting is to use a two-question screen that
addresses depressed mood (53). If patients answer either question in the
affirmative, further evaluation and treatment may be indicated.
During the past month, have you been bothered by feeling down,
depressed, or hopeless?
During the past month, have you been bothered by little interest or
pleasure in doing things?
An under-recognized issue in HNC patients is anxiety. In a recent study,
Haman (Haman K. Social anxiety in head and neck cancer patients,
unpublished data) reported that 20% of patients treated for HNC developed an anxiety disorder during or after treatment. The impact of anxiety
on QOL and function was profound. It is interesting to note that most
patients who developed anxiety during or after therapy do not have a
prior history of anxiety. Issues that are often expressed by patients include
fear of airway obstruction, fear of being immobilized during radiation,
and fear of undergoing magnetic resonance imaging. Patients with severe
problems that impact on function or impact on the patient’s ability to
complete therapy should be referred for psychiatric evaluation so that
appropriate medical therapy and counseling can be initiated. Patients with
severe claustrophobia may need deconditioning therapy to tolerate RT.
Conclusion
Treatment of head HNC with aggressive CRT regimens is associated with
significant comorbidities. Careful patient selection is mandatory to ensure
that patients are physically and mentally capable of tolerating and managing complicated treatment regimens and their associated toxicities. To provide optimal outcomes for patients, it is important for the HNC treatment
team to have a systematic approach for supportive care. Patients should be
assessed in an organized fashion before (see Table 4), during (Table 5), and
after therapy (Table 6) for risk factors and areas in which supportive care
can prevent, improve, or treat symptoms. Supportive care protocols and
regimens should be agreed on by the team. Individuals should be identified
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Table 5. Assessment during Chemoradiotherapy
Symptom assessment (weekly during therapy):
Mucositis
Dermatitis
Taste changes
Xerostomia
Phlegm
Airway compromise
Fatigue
Depression
Anxiety
Cognitive changes
Dental care
Examine oral hygiene
Bland rinses (warm water, bicarbonate, salt rinses) every 3–4 hours
Continue brushing of teeth and flossing until no longer possible due to
mucositis
Discontinue dentures when mucositis begins
Fluoride treatment until discomfort from mucositis becomes too severe
Mucositis
Pain medications—opioids are usually needed for moderate to severe
mucositis
Topical anesthetics: lidocaine, benzocaine, tetracaine
Miracle mouthwash
Avoid mucosal irritants: acid, high temperature, spicy foods, alcohol,
or tobacco
Monitor for the development of concurrent infection (Candida, herpes
simplex virus)
Nutrition
Weigh weekly
Nutritional assessment weekly, with diet adjustments based on degree
of mucosal pain and swallowing abnormalities
Dietary consultation when indicated
Swallowing exercises throughout therapy if at all possible
Encourage continued swallowing if at all possible
Placement of feeding tube when indicated
(continued)
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Table 5. Assessment during Chemoradiotherapy (Continued)
Mucus production
Suction catheter
Sleep with head of bed elevated to avoid pooling of secretions in the
throat
Scopolamine patch (may be too drying for some patients)
Mucolytics
Antihistamines (may be too drying for some patients)
Cough suppressants to avoid irritation of throat
Clear sodas to help break up mucus
Humidification of air
Table 6. Assessment and Treatment after Treatment
Is Completed
Symptom assessment
Patients should be assessed weekly in the early recovery phase to assess
toxicities and optimize rehabilitation.
Nutrition and oral intake
Continue swallowing exercises while mucositis heals.
If patient is tube dependent, initiate swallowing of soft bland foods as
early as possible.
Avoid mucosal irritants—mucosal sensitivity may last for a prolonged
period post-treatment.
Advance diet as tolerated to encourage tube independence.
Speech and language pathologist referral
Should be done early for patients who are unable to swallow
Should include instrumental assessment
Modified barium swallow
Flexible Endoscopic Evaluation of Swallow
Xerostomia
Stimulatory measures
Gustatory
(continued)
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Table 6. Assessment and Treatment after Treatment
Is Completed (Continued)
Pharmacologic
Pilocarpine, 5 mg PO qid
Cevimeline, 30 mg PO tid
Comfort measures
Humidified air
Artificial saliva
Physical therapy
Cardiovascular activity—increase as tolerated
A pedometer can be used to monitor progress
Strength training—to build back lost muscles
Exercise bands can be used to strengthen back/shoulders
Stretching—neck and shoulder range of motion
Dental care
Monitor oral cavity for the development of dental caries
Routine dental evaluation
Continued dental education:
Continued daily oral care
Continued fluoride treatments for patients with persistent xerostomia
who are willing to take responsibility for the routine assessment and treatment of complications and toxicities. With aggressive supportive care measures, patients may tolerate therapy with fewer breaks and will recover
function more rapidly.
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chronic radiation proctitis with antioxidant vitamin E and C. Am J Gastroenterol 2001;96:1080–1084.
28. Bairati I, Meyer F, Gelinas M, et al. Randomized trial of antioxidant vitamins
to prevent acute adverse effects of radiation therapy in head and neck cancer
patients. J Clin Oncol 2005;23:5805–5813.
29. Mekhail T. Enteral nutrition during the treatment of head and neck carcinoma: is a
percutaneous feeding tube preferable to a nasogastric tube? Cancer 2001;91:
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30. Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia
and aspiration after chemoradiation for head and neck cancer. J Clin Oncol
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31. Mandel ID. The role of saliva in maintaining oral homeostasis. J Am Dent
Assoc 1989;119:298–304.
32. Screeny L. Xerostomia. A neglected symptom. Arch Intern Med 1987;147:1333–
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33. Dreizen S, Brown LR, Daly TE, Drane JB. Prevention of xerostomia-related
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34. Frazen L, Funegard U, Ericson T, Henriksson R. Parotid gland function during
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35. Eisbruch A, Ten Haken RK, Kim HM, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of the head and neck cancer. Int J Radiat Oncol Biol Phys
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36. Roh JL, Kim AY, Cho MJ. Xerostomia following radiotherapy of the head and
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37. Hamlet S, Faull J, Klein B, et al. Mastication and swallowing in patients with
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38. Murphy BA, Freidman J, Dowling E, et al. Dietary intake and adaptations in
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39. Johnson JT, Ferretti GA, Nethery WJ, et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993;
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40. Koukourakis MI, Danielidis V. Preventing radiation induced xerostomia. Cancer Treat Rev 2005;31:546–554.
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41. Epstein JB, Emerton S, Le ND, Stevenson-Moore P. A double-blind crossover
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44. Sasse AD, Clark LGO, Sasse EC, Alark ACC. Amifostine reduces side effects
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47. Saarilahti K, Kouri M, Collan J, et al. Sparing of the submandibular glands by
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❖
Management of Recurrent
Disease: Current Treatments
and New Therapies
Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD
Current Approach to Recurrent Disease
Head and neck cancers are a select group of uncommon and diverse malignancies that can be characterized by their pattern of spread and recurrence.
As such, therapeutic approaches to these unique tumors are based not only
on the tumor histology, but also on the site of disease, surrounding anatomy,
as well as regional lymph node involvement. Approximately 95% of these
tumors are squamous cell carcinomas arising primarily from the lip/oral cavity, larynx, oropharynx, hypopharynx, and larynx. Other less common cancers include mucoepidermoid carcinomas, adenoid cystic carcinomas, and
adenocarcinomas, originating from the salivary glands (1).
Despite aggressive primary therapeutic approaches, up to 65% of patients
are treated for locally advanced disease relapse after primary therapy with surgery and/or radiation. Various studies have implicated locoregional control as
a factor in DFS. With improvements in primary therapy, new focus has been
directed toward improving therapy for patients with recurrent disease. This
includes surgical resection and radiation or re-irradiation with or without concomitant chemotherapy for locoregional disease as well as systemic therapy
with chemotherapy and novel targeted agents for metastatic disease (1).
This chapter focuses on squamous cell carcinoma of the head and
neck (SCCHN) and highlights the current perspectives in treatment for
CME
61
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Management of Recurrent Disease
recurrent disease as well as discusses the current investigational concepts
that are leading to the development of newer therapies and treatment
modalities.
Locoregional Therapies for Recurrent
Head and Neck Cancer
Salvage Surgery
Surgical salvage remains the standard of care for treatment of patients with
locally recurrent disease. However, fewer than 30% of patients who present
with locally recurrent disease are actually surgically resectable. The ability to
obtain tumor-free margins is dependent on tumor location, surrounding
anatomy, as well as the surgeon’s expertise. In cases in which extensive resections are required, expected quality of life postoperatively is also a major
consideration (2).
Overall survival (OS) and disease-free survival (DFS) rates after surgery
are variable and associated with individual patient characteristics, tumor
pathology, presence of lymph node involvement, as well as the adequacy of
surgical margins and use of postoperative radiotherapy (2).
Patients with early stage (T1 or T2) recurrent disease who undergo salvage
surgery alone have been reported to have OS rates and DFS rates of 30%–60%
and 44%–88%, respectively (2,3). Ganly et al. (3) investigated the outcome of
43 patients with early stage recurrent SCCHN after prior therapy with radiation alone for first recurrence. This study also compared outcomes between
patients treated with salvage partial laryngectomy (SPL) versus patients treated
with salvage total laryngectomy (STL). Although the study was able to suggest
the feasibility of SPL in a select group of patients with favorable prognostic
indicators, it also reported that up to 50% of patients who received SPL for
organ preservation went on to require an STL after progression of disease, and
this was also associated with poorer survival outcomes.
Gleich et al. (4) conducted a study of 48 patients with locally advanced (T3
or T4) SCCHN undergoing salvage surgery. Twenty-four patients had primary site recurrence, 20 patients had local recurrence in the neck, and 4 had
both local and regional recurrence. Forty-one of these patients were treated
with salvage surgery with or without radiation; the rest received radiation
alone. Of the 48 patients treated, 42 died in less than 2 years. Results from
this study showed a limited potential for long-term survival and DFS in
patients with recurrent disease treated with salvage surgery after initial therapy for advanced primary-site cancer. Careful counseling was recommended
for patients opting to pursue this course of therapy (4).
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63
Complications of salvage surgery are related to extensive surgical resection and manipulation of previously irradiated tissues. These include fistula formation and local wound complications (3,4).
Role of Radiation Therapy in Locally Recurrent Disease
Patterns of recurrence have identified locoregional failure to be a common
cause for recurrent SCCHN, both locally and distally. This has led to an
emphasis on locoregional control both in the primary setting and also in
the setting of locally recurrent disease. One modality of therapy that has
been used to improve locoregional control in recurrent disease after surgical resection is radiation therapy.
Radiation Therapy for Patients Treated with Salvage Surgery
Surgically resectable patients with recurrent disease with a high risk for
locoregional failure due to poor prognostic indicators (including multilevel
lymph node involvement, extranodal tumor extension, or positive surgical
margins) should undergo adjunct therapy with radiation (5,6). Although
there are no absolute contraindications for those groups of patients with
recurrent disease who have not had prior radiotherapy, severe complications
do exist, and patients must therefore be closely monitored during and after
completion of therapy.
Emerging Concept of Re-Irradiation in Patients with
Recurrent Head and Neck Cancer
As previously discussed, patterns of recurrence in SCCHN point to locoregional failure in both locally recurrent and distant metastatic disease (6). This
has led to the development of the concept of re-irradiation treatment in patients
with locally recurrent SCCHN who have had prior radiation therapy (5,6).
The concept of re-irradiation involves the administration of a second
course of radiation therapy for patients with locally recurrent SCCHN who
have had prior therapy with radiation. This course of therapy offers a potential curative option for patients with locally recurrent SCCHN who present
with unresectable disease (5,6). Re-irradiation is commonly administered in
doses of 60–70 Gy with concomitant chemotherapy in radiosensitizing doses.
This is done to increase the antitumor activity in the field of recurrence where
radio-resistant tumor clonogens may exist (5,6).
Although several phase I–II studies have demonstrated severe toxicity
exists with the administration of radiation to previously radiated tissues, the
feasibility of re-irradiation and its potential for long-term survival and DFS is
evident. As such, treatment with re-irradiation for locally recurrent SCCHN
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Management of Recurrent Disease
should only be considered by an experienced team ready to meet the problems
and complications and who know the limits of therapy (5,6). Since the 1970s,
several studies have been conducted to investigate the feasibility of re-irradiation as a treatment modality for patients with locally recurrent disease (6).
Table 1 summarizes some of the largest trials to date involving re-irradiation.
Institut Gustave Roussy (IGR) reported a 16-year series that included 169
patients with locally recurrent, unresectable head and neck cancer (including
non-squamous histology) (7). These patients were assigned to three groups. The
first group consisted of 27 patients receiving treatment from 1980 to 1996 with
radiotherapy alone at a total dose of 65 Gy in 2-Gy fractions as a continuous
course. The second group consisted of 106 patients who received treatment
with a split-course re-irradiation and a concomitant chemotherapy regimen of
5-fluorouracil (5-FU) at 800 mg/m2 and hydroxyurea at 1.5 g per day administered daily in a week on–week off fashion. The third group consisted of 36
patients receiving hyperfractionated radiation (1.5 Gy twice a day) with a concomitant chemotherapy regimen of mitomycin, 5-FU, and cisplatin, also
administered in a week on–week off fashion. The median cumulative dose after
the second course of radiation was 120 Gy (6,7). Results of this study showed
that it was feasible to safely administer a second course of radiation with concomitant chemotherapy. Grade 3 and 4 mucositis was the most common early
toxicity, occurring in 14%–32% of treated patients. Late toxicities, occurring 6
months post-therapy, included cervical fibrosis, trismus, and soft tissue necrosis.
Five patients also died from carotid hemorrhage (7). Despite the significant toxicities observed, the study showed complete response rates in the range of 25%
to 41%. The highest rates were seen with the FHX (5-FU, hydroxyurea, daily
radiation) regimen. This was statistically higher than the response rates of 10%
seen with palliative chemotherapy. Median survival was 10–11 months for all
three groups, with 13 patients achieving long-term DFS (6,7).
The University of Chicago treated 115 patients on seven different protocols
over 15 years and recently reported a retrospective review of the experience.
These studies differed from the IGR study in two key aspects: (a) the strict
selection of patients with squamous cell histology and (b) the use of salvage
surgery for complete resection or optimal debulking before re-irradiation in 49
patients (6,8). All patients were treated with variants of the FHX regimen,
including varying doses of hydroxyurea and 5-FU; the use of daily versus
twice-daily radiation; as well as the addition of cisplatin, paclitaxel, irinotecan,
or gemcitabine to the FHX regimen at varying doses (8). Nineteen patients
died of treatment-related toxicity. Six patients had carotid hemorrhage, and
only one of these survived. Thirteen patients also developed osteoradionecrosis
requiring surgical repair (8). The median cumulative radiation dose was 131
Gy with 3-year OS, progression-free survival, locoregional control, and freedom from distant metastases rates of 22%, 33%, 51%, and 61%, respectively,
27
106
36
81
115
105
240 (to be
accrued)
De Crevoisier et al.
(7)
Horwitz et al.
Wong et al. (6)
(ongoing)
STD fx RT
H, 5-FU/STD fx RT
MMC, 5-FU, CDDP/ HYP fx RT
H, 5-FU/HYP fx RT
STD fx RT, HYP fx RT with
various chemotherapy
regimens
CDDP, paclitaxel/HYP fx RT
CDDP, paclitaxel/HYP fx RT
CT alone
CDDP, 5-FU
CDDP, paclitaxel
CDDP, docetaxel
Treatment
65.4
60 (planned)
65
60
60
60
64.8
Median RT
Dose (Gy)
NA
NA
NA
24 (2 y)
10 (2 y)
NA
51 (3 y)
Locoregional
Control (%)
25.9 (2 y)
NA
16.9 (2 y)
22 (3 y)
25 (2 y)
Overall
Survival (%)
CDDP, cisplatin; CT, chemotherapy; 5-FU, 5-fluorouracil; H; hydroxyurea; HYP fx RT, hyperfractionated radiation; MMC, mitomycin ; NA, not
available; RT, radiotherapy; STD fx RT, standard fractionated radiation.
Spencer et al.
Salama et al. (8)
No. of
Patients
Phase II–III Clinical Trials in Re-Irradiation for Squamous Cell Carcinoma of the Head and Neck
Study
(References)
Table 1.
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65
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Management of Recurrent Disease
which were statistically significant when compared to palliative chemotherapy
alone (6,8). Multivariate analysis identified surgical resection, re-irradiation
dose, and use of triple-agent chemotherapy (i.e., cisplatin, paclitaxel, or irinotecan with FHX) as independent prognostic indicators for response and survival (6,8).
Common toxicities seen with re-irradiation include xerostomia, mucositis,
tissue fibrosis, trismus, osteoradionecrosis, poor healing in soft tissues and
bones, dysphagia, and hypothyroidism. Less common severe life-threatening
complications include vessel rupture (e.g., carotid artery blow-out) (5,6,8).
These two series were followed by three cooperative group trials conducted by the Radiation Therapy Oncology Group (RTOG). Two of these
trials, RTOG 96-10 and RTOG 96-11, have been completed and are summarized in Table 1 (6). A third ongoing phase III trial (RTOG 0421) is
being conducted to compare re-irradiation and concomitant chemotherapy
to chemotherapy alone in patients with locally recurrent or second primary SCCHN who are inoperable with a prior history of radiation (6).
Although the role of radiation (with or without concomitant chemotherapy) in the setting of recurrent SCCHN still remains to be defined, its
role in the setting of palliative care is definitive (9). Patient selection
includes those with a relatively good performance status who experience
significant impairment in their quality of life due to cancer-related causes
(e.g., severe pain and limited mobility due to osseous and spinal metastases). These patients should be referred to a radiation oncologist for consultation regarding palliative radiation (9).
Systemic Therapy for Recurrent
Head and Neck Cancer
Palliative treatment with systemic therapy includes conventional chemotherapy and novel targeted therapy. Response rates with these therapies
are variable, with several phase II–III clinical trials showing overall
response rates to combination chemotherapy in the order of 20%–40%
and single-agent therapy, including non-cytotoxics, in the order of 5%–
15% (10,11).
Although these response rates are clinically significant, it also important to remember that systemic therapy has not been adequately demonstrated to improve OS, and its role in therapy continues to be a palliative
one with the goal of controlling symptoms and improving quality of life
(10,11). This distinction is important to recognize in the selection of patients
for treatment, with consideration given to treatment toxicity and tolerability (10,11).
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67
Evolution of Systemic Chemotherapy
Combination chemotherapy has demonstrated the highest response rates
in systemic therapy for recurrent and metastatic SCCHN, and is currently
the standard of care. Several phase II–III studies comparing combination
chemotherapy versus single-agent therapy have shown statistically significant improvement in tumor response with combination chemotherapy
over single-agent therapy (10,12). Single-agent therapy is currently recommended in cases in which prior combination chemotherapy has failed and
toxicity is of concern (10,13).
Although combination chemotherapy has been shown to have higher
response rates than single-agent therapy, the incidence of high-grade toxicity is
significantly higher. One exception to this has been the combination regimen
of cisplatin and 5-FU. The effective response rates and favorable toxicity profile have led to this combination regimen becoming the most widely recommended as first-line treatment for recurrent or metastatic SCCHN (10,13).
Other agents currently used in the treatment of SCCHN include the platinum agents (cisplatin and carboplatin), the taxanes (paclitaxel and docetaxel),
5-FU, capecitabine, gemcitabine, pemetrexed, as well as bleomycin and
methotrexate (MTX), which were both the most widely used cytotoxic agents
before the advent of the platinum agents (10,13).
Common Chemotherapy Agents Used for Recurrent
Head and Neck Cancer
Platinum Agents
The platinum agents are among the most widely used agents in the treatment
of SCCHN (10,13). These agents act through covalent binding to cell DNA.
Cisplatin has been the most widely used and most favored for systemic therapy in recurrent SCCHN, in large part due to its statistically higher and rapid
response rates when compared to other agents. Response rates for cisplatin in
single-agent therapy and combination chemotherapy are 10%–15% and
25%–40%, respectively, depending on prior therapy. Its derivative compound,
carboplatin, has been tested in phase II–III trials and found to have acceptable,
though arguably lower, response rates. Adverse effects of platinum agents
include nephrotoxicity, neurotoxicity, nausea, and vomiting (which can be
quite severe), as well hypersensitivity reactions (10,13,14).
Taxanes
The taxanes include paclitaxel and docetaxel, which have both found use in
single-agent therapy and as part of combination chemotherapy (10,13,15).
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Management of Recurrent Disease
These agents act through inhibition of microtubule assembly in rapidly
dividing cells. Single-agent responses range between 20% and 40% in
uncontrolled trials (10,15). Both agents are administered on either weekly or
every 21-day schedules, with paclitaxel administered as a 3-hour infusion
and docetaxel as a 1-hour infusion (10,15). Premedication is given with paclitaxel to prevent possible hypersensitivity reaction and with docetaxel to
also prevent edema. Common toxicities include neutropenia, alopecia,
fatigue, gastrointestinal symptoms, and peripheral neuropathy (15).
Methotrexate
MTX was approved by the U.S. Food and Drug Administration (FDA) for
cancer treatment in 1953 (10,14). Before the advent of platinum agents, this
drug was one of the more widely used cytotoxic agents in the treatment of
SCCHN (10,13,14). MTX is a cell cycle–specific analog that is active in the Sphase of the cell cycle and inhibits the activity of dihydrofolate reductase (13).
Single-agent response rates seen in phase II–III studies vary considerably,
depending on prior therapy, but typically range between 5% and 10%, with
higher response observed in patients with no prior treatment (10,13).
Other commonly used agents, such as bleomycin and 5-FU, have singleagent response rates of 5%–10% and 15%, respectively (10).
Clinical Trials Using Combination Chemotherapy
in Recurrent Head and Neck Cancer
Several clinical trials using combination chemotherapy have shown improvement in response rates (10), especially with platinum-containing regimens.
However, no regimen has been shown to be better in improving survival
over another (10,14).
Cisplatin and 5-Fluorouracil
The cisplatin and 5-FU combination regimen has become a reference regimen for doublet therapy in part due to its reasonable response rates and
favorable toxicity profile when compared to other regimens (10,12–14).
Since the regimen emerged in the early 1990s, several clinical trials have
been conducted comparing this regimen with other combination regimens
and single-agent therapies (10,13). The summation of the trials has been
overall response rates for recurrent disease in the range of 30% to 40%
and median OS of 6–8 months (10,13,14).
Two noteworthy trials were published in 1992, one by Jacobs et al. (16)
and another by Forastiere et al. (12). The study by Jacobs et al. involved
249 patients who were randomized to three clinical treatment arms (cis-
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Management of Recurrent Disease
69
platin and 5-FU, cisplatin alone, and 5-FU alone). Results from this study
showed the combination cisplatin and 5-FU regimen was statistically superior in overall response rates (32%) compared to single-agent cisplatin
(17%) or 5-FU alone (13%) (10,16). The second study by Forastiere et al.
compared cisplatin and 5-FU and carboplatin and 5-FU to single-agent
MTX. Results from this randomized control trial of 227 patients also validated the superiority of cisplatin and 5-FU, with response rates to cisplatin
and 5-FU, carboplatin and 5-FU, and MTX being 32%, 21%, and 10%,
respectively. Neither of the two studies demonstrated improvement in survival between the different regimens, though there appeared to be an association between survival and patient performance status (10,12,16).
Taxanes and 5-Fluorouracil
After the introduction of platinum-based combination therapy, studies
were also conducted using the taxanes paclitaxel and docetaxel. To date,
no major studies have demonstrated superior response rates to the combination of cisplatin and 5-FU. One multicenter phase II study of docetaxel
and 5-FU in 63 patients with recurrent and metastatic SCCHN showed an
overall response rate of approximately 20%, with higher response rates
observed in the cohort arm with a history of prior therapy (10,17,18).
Combination Therapy with Platinum Agents and Taxanes
Several promising phase II and phase III trials investigating taxanes in
combination with platinum agents have also been conducted. Gibson et al.
(19) compared cisplatin/paclitaxel to cisplatin/5-FU in a phase III trial that
enrolled 218 patients. The overall response rates (26% and 27% in the
paclitaxel and 5-FU arms, respectively) and median OS (8.1 months and
8.7 months in the paclitaxel and 5-FU arms, respectively) were nearly
identical. Other phase II trials using platinum and taxane combinations
have demonstrated overall and complete response rates of 41%–70% and
27%–52%, respectively (10,19,20).
Triple-Agent Regimens
Treatment with triple-agent regimens has yielded higher response rates,
both overall and complete, but with increasing toxicity (10,21). Three
common regimens have included (a) cisplatin with paclitaxel and 5-FU;
(b) docetaxel, cisplatin, and 5-FU; and (c) paclitaxel, ifosfamide, and cisplatin. Overall response and complete response rates for these regimens
are comparable, 40%–60% and 12%–50% respectively, with the highest
responses and toxicities seen with cisplatin, paclitaxel, and 5-FU; median
survival for patients treated with these regimens ranges between 9 months
and 14 months (10,21).
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Management of Recurrent Disease
Despite the improvements seen in response rates, results from phase III
trials of triple-agent regimens also show increased toxicity, particularly
grade 3–4 myelosuppression. As such, when considering patients for treatment with triple-agent regimens, the observation of increased toxicity
needs to be balanced against modest gains seen in survival (10,21).
Novel Targeted Therapy
Despite an increase in the number of available cytotoxic agents and their new
uses in combination, median survival for these remains relatively unchanged
when compared to single-agent therapy and appears to have reached a plateau. Toxicity, therefore, becomes a major consideration in therapy that is palliative rather than curative. This issue, along with new understanding of
tumorigenesis, has led to the development of novel targeted therapy (10,22).
Epidermal Growth Factor Receptor
As early as the mid-1960s, the epidermal growth factor receptor (EGFR)
and its ligands were identified as playing a critical role in tumor cell proliferation as well as response to therapy. Most recently, in the 1990s it was
observed that 80%–100% of SCCHN had an abnormal level of EGFR
expression (10,22,23). This generated interest in therapy through the inhibition of EGFR expression via antibodies (e.g., cetuximab) and small molecule inhibitors (e.g., gefitinib and erlotinib) (10,11,22–25).
Cetuximab was approved for use in colorectal cancer in 2004 and in 2006
as single-agent therapy for patients with platinum refractory, recurrent, or
metastatic SCCHN. Several phase II clinical trials have been conducted to study
the efficacy of cetuximab in recurrent SCCHN. A European study enrolled 103
patients with recurrent or metastatic SCCHN and progression of disease after
treatment with platinum-based chemotherapy. Subjects were administered
cetuximab at an initial dose of 400 mg/m2 followed by a weekly dose of 250
mg/m2 until disease progression. After disease progression, these patients were
then offered the option of salvage therapy with cetuximab and the addition of
the platinum agent that they previously had been treated with (10,11,22–25).
Interim data from this study were first presented in 2004 by Trigo et al. (24)
and later by Vermoken et al. (25) in 2005, who demonstrated that cetuximab
monotherapy was well tolerated, with a response rate of 13%, disease control
rate of 46%, and a median survival of 5.9 months, results that were comparable to those seen with first-line therapy and that represented a 2.5-month
increase in median survival compared to platinum-refractory historical controls
(10,22–25). Moreover, two phase II studies that each enrolled patients after failure of a platinum-containing doublet regimen to continue platinum in combination with cetuximab revealed an 11% response rate (25–27). In addition, a
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Management of Recurrent Disease
71
phase III trial comparing cisplatin with or without cetuximab in first-line recurrent or metastatic SCCHN observed a significant improvement in the secondary end point of response rate in the experimental arm (26% vs. 10%;
P = .03) (28). The data, thus, suggest that cetuximab is an active agent in recurrent/metastatic SCCHN. Table 2 highlights some of the recent trials involving
cetuximab in the treatment of recurrent or metastatic SCCHN.
Tyrosine kinase inhibitors directed against the EGFR also appear to be
active single agents, with both gefitinib and erlotinib demonstrating objective
responses (11% and 4%, respectively) (11). A phase II study of gefitinib dosing at 250 mg in recurrent or metastatic SCCHN was recently conducted at
the University of Chicago, and results demonstrated gefitinib to be well tolerated at 250 mg, with modest benefit and without significant deterioration in
overall quality of life (29).
Randomized trials testing the role of gefitinib in SCCHN are under way.
Almost every trial administering an EGFR inhibitor in SCCHN has also noted
an association between development of skin toxicity related to the agents and
improved outcome. Whether this association reflects a true biologic phenomenon and the possible mechanisms underlying it remain to be elucidated (11).
Abidoye et al. (30) recently completed a phase II study of lapatinib, a dual
inhibitor of EGFR and erbB2 tyrosine kinases, in patients with recurrent or
metastatic SCCHN. Preliminary data from this study did not indicate a statistically significant survival benefit when compared to best supportive care;
however, further studies are ongoing (11,30).
Other Agents
Other agents under investigation in trials for recurrent or metastatic SCCHN
include sorafenib, an inhibitor of Raf kinase and the vascular endothelial
growth factor (VEGF) receptor, which recently gained FDA approval in the
treatment of renal cell carcinoma. Two phase II trials of sorafenib as singleagent therapy in recurrent or metastatic SCCHN have demonstrated a response
rate of approximately 5% (31,32). Bevacizumab, an anti-VEGF monoclonal
antibody, has been combined with erlotinib in recurrent/metastatic SCCHN,
with a 14% response rate reported, suggesting the possibility of enhancement
of EGFR-inhibitor activity. In addition, a phase I study of gefitinib with celecoxib, a cyclooxygenase-2 inhibitor, demonstrated tolerability of the combination and a promising response rate of 22% (33).
Conclusion
Even though the majority of patients with SCCHN present with local disease
and there have been vast improvements in therapy of locally advanced disease,
the majority of patients will eventually experience recurrent or metastatic
manifestations. The treatment of recurrent or metastatic disease can involve
72
76
117
103
Herbst et al.
(27)
Burtness et
al. (28)
Vermoken et
al. (25)
200 mg/m2 loading;
125 mg/m2 weekly;
cisplatin, 100 mg/
m2 q4wk
400 mg/m2 loading;
250 mg/m2 weekly
1 prior platinumcontaining
regimen
1 prior platinumcontaining
doublet
1 prior platinumcontaining
doublet
No prior chemotherapy
400 mg/m2 loading;
250 mg/m2 weekly
400 mg/m2 loading;
250 mg/m2 weekly
Prior
Therapy a
Cetuximab Dose/
Schedule
bResponse
therapy represents patient eligibility restrictions in these trials.
rate of cisplatin plus cetuximab.
96
Baselga et al.
(26)
aPrior
No. of
Patients
Study
(References)
13
26b
10
10
Response
Rate (%)
2.3
4.2
2.8
2.2
Progression-Free
Survival (mo)
5.9
9.2
6.1
5.2
Overall
Survival (mo)
Table 2. Clinical Trials of Cetuximab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Posner.bk Page 72 Friday, October 20, 2006 11:41 AM
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Management of Recurrent Disease
73
Locally recurrent or distal recurrence/metastatic disease
Locally recurrent
Distal recurrence
Metastatic disease
Is patient surgically resectable or operable?
YES
Consider
salvage surgery
with or without
adjuvant
radiation
NO
Consider treatment with
radiation alone (if no
prior) or with re-irradiation
with concurrent
chemotherapy
OR
Consider clinical trial
or systemic therapy
with chemotherapy
OR
EGFR inhibitor
Progression of disease
Consider clinical trial OR therapy with
single-agent chemotherapy OR EGFR inhibitor
Further progression of disease
Consider clinical trial OR single-agent chemotherapy
Discuss goal of care, consider hospice if progression continues
Figure 1. Treatment approach to patients with recurrent or metastatic
squamous cell carcinoma of the head and neck. EGFR, epidermal growth factor inhibitor.
surgery or re-irradiation if the disease is confined to locoregional recurrence,
whereas systemic therapy is used with palliative intent in most patients. Cytotoxic doublet therapy is active but has reached an efficacy plateau. Novel targeted agents are being intensely studied as monotherapy and in combination
with conventional chemotherapeutic agents in recurrent or metastatic SCCHN
in an effort to improve outcome, with inhibitors of EGFR already approved by
regulatory authorities. Figure 1 displays a recommended treatment approach
to the patient with recurrent or metastatic SCCHN.
References
1. Gibson MK, Forastiere A. Multidisciplinary approaches in the management of
advanced head and neck tumors: state of the art. Curr Opin Oncol 2004;16:220–
224.
Posner.bk Page 74 Friday, October 20, 2006 11:41 AM
74
Management of Recurrent Disease
2. Wong LY, Wei WI, Lam LK, et al. Salvage of recurrent head and neck squamous
cell carcinoma after primary curative surgery. Head Neck 2003;25:953–959.
3. Ganly I, Patel SG, Matsuo J, et al. Results of surgical salvage after failure of
definitive radiation therapy for early stage squamous cell carcinoma of the
glottic larynx. Arch Otolaryngol Head Neck Surg 2006;132:59–66.
4. Gleich LL, Ryzenman J, Gluckman JL, et al. Recurrent advanced (T3 or T4)
head and neck squamous cell carcinoma. Is salvage possible? Arch Otolaryngol
Head Neck Surg 2004;130:35–38.
5. Sadeghi A, McLaren J, Grist WL, et al. Value of radiation therapy in addition to
surgery for cancer of the head and neck. Otolaryngol Head Neck Surg 1986;94:
601–604.
6. Wong SJ, Machtay M, Yi L. Locally recurrent, previously irradiated head and
neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy
alone? J Clin Oncol 2006;24:2653–2658.
7. De Crevoisier R, Bourhis J, Domenge C, et al. Full dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute
in a series of 169 patients. J Clin Oncol 1998;16:3556–3562.
8. Salama JK, Vokes EE, Chmura SJ, et al. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head and neck
squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006;64:382–391.
9. McQuay HJ, Carroll D, Moore RA. Radiotherapy for bone metastases. A systematic review. Clin Oncol 1997;9:150–154.
10. Covelas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2644–2652.
11. Cohen EE. Role of epidermal growth factor receptor pathway-targeted therapy
in patients with recurrent and/or metastatic squamous cell carcinoma of the
head and neck. J Clin Oncol 2006;24:2659–2556.
12. Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate
in squamous cell carcinoma of the head and neck. A Southwest Oncology
Group Study. J Clin Oncol 1992;10:1245–1251.
13. Fanucchi M, Khuri FR. Chemotherapy for recurrent or metastatic squamous
cell carcinoma of the head and neck. Semin Oncol 2004;31:809–815.
14. Browman GP, Cronin L. Standard chemotherapy in squamous cell head and
neck cancer: what we have learned from randomized clinical trials. Semin
Oncol 1994;21:311–319.
15. Schrijvers D, Vermoken JB. Taxanes in the treatment of head and neck cancer.
Curr Opin Oncol 2005;17:218–224.
16. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing
cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–263.
17. Colevas AD, Adak S, Amrein PC, et al. A phase II trial of palliative docetaxel
plus 5-fluorouracil for squamous cell cancer of the head and neck. Ann Oncol
2000;11:535–539.
18. Genet D, Cupissol D, Calais G, et al. Docetaxel plus 5-fluorouracil in locally
recurrent and/or metastatic squamous cell carcinoma of the head and neck. A
phase II multicenter study. Am J Clin Oncol 2004;27:472–476.
19. Adamo V, Ferraro G, Pergolizzi S, et al. Paclitaxel and cisplatin in patients with
recurrent and metastatic head and neck squamous cell carcinoma. Oral Oncol
2004;40:525–531.
20. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and
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Management of Recurrent Disease
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
75
neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology
Group. J Clin Oncol 2005;23:3562–3567.
Glisson BS, Murphy BA, Frenette G, et al. Phase II study of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of
the head and neck. J Clin Oncol 2002;20:1593–1599.
Hitt R, Jimeno A, Millan J, et al. Phase II trial of dose-dense paclitaxel, cisplatin, 5-fluorouracil, and leucovorin with filgrastim support in patients with
squamous cell carcinoma of the head and neck. Cancer 2004;101:768–775.
Cohen EE. Novel therapeutic targets in squamous cell carcinoma of the head
and neck. Semin Oncol 2004;31:755–768.
Trigo J, Hitt R, Koralewski E, et al. Cetuximab monotherapy is active in
patients with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Results of a phase II study. Proc Am Soc
Clin Oncol 2004;22(14S):5502.
Vermoken J, Bourhis J, Trigo J, et al. Cetuximab (Erbitux ®) in recurrent/metastatic
(R&M) squamous cell carcinoma of the head and neck (SCCHN) refractory to first
line platinum based therapies. Proc Am Soc Clin Oncol 2005;23(16S):5505.
Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination
with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin
Oncol 2005;23:5568–5577.
Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent
and refractory squamous cell carcinoma of the head and neck. J Clin Oncol
2005;23:5578–5587.
Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern
Cooperative Oncology Group study. J Clin Oncol 2005;23(34):8646–8654.
Kane MA, Cohen EE, List M, et al. Phase II study of 250-mg gefitinib in
advanced squamous cell carcinoma of the head and neck (SCCHN). Proc Am
Soc Clin Oncol 2004;22(14S):5586.
Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib
(GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the
head and neck (SCCHN). Proc Am Soc Clin Oncol 2006;24(18S):5568.
Williamson SK, Moon J, Huang CH, et al. A phase II trial of BAY 43-9006 in
patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): a Southwest Oncology Group (SWOG) trial. Proc Am Soc
Clin Oncol 2006;24(18S Part I):5550.
Siu LL, Winquist M, Agulnik SF, et al. A phase II study of BAY 43-9006 in
patients with recurrent and/or metastatic head and neck cancer squamous cell
carcinoma (HNSCC) and nasopharyngeal cancer (NPC). Proc Am Soc Clin
Oncol 2005;23(16S):5566.
Wirth LJ, Haddad RI, Lindeman NI, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck.
J Clin Oncol 2005;23:6976–6981.
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❖
Integration of Chemotherapy
into Organ Preservation
Strategies for Squamous Cell
Head and Neck Cancer
David J. Adelstein, MD
Treatment Goals
The appropriate identification of a treatment goal is critical in the management of any malignancy. Cure, when possible, is clearly the end point of greatest importance. However, for patients with cancers of the head and neck,
achievement of that cure often comes with a significant cost. Surgical resection, the historical standard of care, can result in the loss or compromise of
crucial anatomic structures involved in important human functions, including
speech, swallowing, and non-stomal breathing. As such, the concept of organ
preservation has emerged as another important end point in head and neck
cancer management.
It is important, however, that organ preservation be distinguished from
organ function conservation. Although it may seem obvious that preservation
of the organ is a necessary prelude to preservation of its function, this is an
oversimplification. Current reconstruction and rehabilitation techniques often
allow for successful preservation and/or restoration of organ function even
after surgical resection. Conversely, nonoperative management, such as radiation with or without chemotherapy, may obviate primary site resection yet still
result in significant functional disability. Furthermore, aggressive attempts to
preserve one organ function may significantly and adversely affect another, as
CME
77
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78
Integration of Chemotherapy into Organ Preservation
in the patient who retains his or her larynx at the expense of significant interference in swallowing. Attempts to preserve an organ that is destroyed by the
initial tumor extent are, as such, ill advised.
In patients with advanced laryngeal and hypopharyngeal cancers, the
organ at risk is the larynx. Although partial laryngeal surgery is possible in
many patients, larger primary site tumors often mandate a total laryngectomy
for optimal oncologic care. Stomal breathing and loss of normal vocalization
result. For patients with oropharyngeal cancer, the definition of the organ at
risk is less clear. Little functional impairment is expected after resection of an
early tonsil or tongue lesion. Surgery for larger tumors, however, particularly
of the base of tongue or pharyngeal wall, may require significantly morbid
procedures, including total glossectomy and/or laryngectomy, and may produce marked interference with normal speech and swallowing. Efforts to minimize the resultant functional impairments are critical.
It is also critical that we, as oncologists, remember our patients’ charge.
List et al. (1) reported the results of a study examining the relative value
assigned by patients to specific outcomes after treatment of head and neck
cancer. The most important patient-defined treatment goal was cure, with survival prolongation in second place. Symptomatic and functional concerns,
such as freedom from pain, ability to swallow, and retention of a natural
voice, proved less important. Maximizing a patient’s chance for cure, even at
the cost of functional impairment, remains the top priority. Although individual patients may choose to sacrifice curative potential or survival benefit for
functional preservation, this is not the rule, and these issues require careful
exploration when treatment options are reviewed.
Thus, although organ preservation and, more specifically, organ function
conservation are desirable treatment goals, they are secondary end points. The
survival equivalence of a nonoperative organ-preserving intervention and conventional surgical treatment must be established before such an organ-preservation strategy can be considered acceptable. Furthermore, better assessments
of long-term organ function and measurements of overall patient satisfaction
must be designed and implemented. In the absence of these tools, however, the
potential for organ preservation often provides the best measure of organ
function conservation.
Organ-Preservation Strategies
Radiation Therapy and Surgery
Radiation therapy is the original organ-preserving treatment strategy in
squamous cell head and neck cancer, and these malignancies are generally
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Integration of Chemotherapy into Organ Preservation
79
considered to be very radiosensitive. However, organ function–preserving
surgical procedures are now welldefined for many head and neck primary
sites and may be equally, if not more, successful in achieving primary site
control and preserving primary site function (2). Thus, small primary site
tumors (T1–T2) may be approached with either single-modality radiation
therapy or surgery with, in many cases, relatively similar results. In the
absence of definitive studies comparing these two treatment approaches,
the choice is often based on institutional expertise and patient preference.
Treatment of the primary site must also be considered separately from
treatment of the neck. Organ preservation and organ function conservation reflect an approach to the primary site tumor. The presence of clinical
neck node involvement or the possibility of spread to neck nodes must also
be considered in all patients. A neck dissection can be accomplished irrespective of the approach taken for the primary site and is often indicated
even when definitive radiation therapy is chosen as the primary management. Although there can be functional deficits resulting from a neck dissection, these rarely interfere with speech or swallowing.
For patients with larger (T3–T4) primary site tumors, the relative success
of surgical resection and postoperative radiotherapy, compared to definitive
radiation therapy alone (with subsequent surgical salvage if necessary), is
unknown. It is in this group of patients that the addition of systemic chemotherapy to definitive locoregional management has had the greatest impact.
Integration of Systemic Chemotherapy
Systemic chemotherapy, as a single-treatment modality, can produce significant tumor shrinkage in previously untreated patients with squamous cell
head and neck cancer. Response rates of 70%–90% (complete in 30%–
50%) have been reported and led to considerable enthusiasm about the
potential impact of this treatment modality (3). It was disappointing when
the phase III studies that tested chemotherapy given either before definitive
management or as an adjuvant after locoregional treatment were unable to
demonstrate a reproducible survival benefit (3–5). When chemotherapy
and radiation were given concurrently, however, whether as the definitive
nonoperative treatment or in the postoperative adjuvant setting, a clear
improvement in overall survival was demonstrated. As such, concurrent
radiation and systemic chemotherapy became an integral part of the standard care for many patients with locoregionally advanced squamous cell
head and neck cancer (3,4).
Whether systemic chemotherapy can also improve the possibility of organ
preservation can be evaluated in several ways. Optimally, a phase III trial
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80
Integration of Chemotherapy into Organ Preservation
should be performed comparing a nonsurgical, chemotherapy-based, organpreserving approach with a primary operative intervention. The objective of
such a study would be to demonstrate an improvement in organ preservation
(and by inference, organ function conservation) without a reduction in survival. Alternatively, and less definitively, comparative clinical trials of definitive
nonoperative approaches (e.g., radiotherapy versus concurrent chemoradiotherapy) can report the likelihood of local disease control—a reasonable measure of organ preservation in the absence of planned surgical resection.
Although the likelihood of organ preservation in surviving patients has often
been cited as an end point of interest, it reflects a measure of limited importance if significant numbers of patients do not survive. A more meaningful end
point is the likelihood of survival with an intact organ.
The potential for chemotherapy to favorably impact the likelihood of
organ preservation in patients with squamous cell head and neck cancer was
first reported by Jacobs et al. in 1987 (6). Twelve head and neck cancer
patients who had experienced a pathologic complete response at the primary
site after induction chemotherapy with 5-fluorouracil and cisplatin were
treated with definitive radiation therapy alone, rather than the originally
planned laryngectomy, glossectomy, or composite resection. When this experience was reported, 8 of the 12 patients so treated were free of disease, with a
survival rate equivalent to patients who had undergone definitive surgery.
Other investigators repeated this experience, often focusing on larynx cancer
(7–10). Avoidance of a laryngectomy was thought to be a sufficiently compelling reason to justify an organ-preservation strategy, particularly as salvage
laryngectomy, even after failure of definitive radiation, was a well-established
and successful procedure.
This phase II experience led to the design and performance of the large
Department of Veterans Affairs (VA) Laryngeal Cancer Study Group larynx
preservation trial, first reported in 1991 (11). Three-hundred thirty-two
patients with advanced larynx cancer were randomized to receive either induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation
therapy in responders or to a laryngectomy followed by radiation. Chemotherapy nonresponders underwent laryngectomy and postoperative radiation.
Patients on the nonsurgical arm with residual or recurrent disease after definitive radiation were also offered salvage laryngectomy.
The response to induction 5-fluorouracil and cisplatin was equivalent to the
best of the induction chemotherapy regimens previously reported, with an
overall response rate of 85% and a complete response rate of 31%. Similar to
other induction trials being completed at this time, no survival benefit was
identified for those patients who received the induction chemotherapy. However, there was also no loss of survival potential on this treatment arm. Furthermore, for the chemotherapy-treated patients, larynx preservation was possible
in approximately 2/3 of the survivors, and survival with an intact larynx at 3
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Integration of Chemotherapy into Organ Preservation
81
years was 31%. The results of this study supported the contention that chemotherapy might substitute for surgical resection in responsive patients, perhaps
by enhancing the benefit achieved from the radiation therapy. Alternatively, it
was suggested that a response to induction chemotherapy might have only
served to identify those patients likely to experience a good response after
definitive radiation therapy. Chemotherapy (and therefore radiotherapy) nonresponders were thus identified early and better served by an immediate surgical resection. Regardless, the absence of a clear survival difference between
these two treatment arms justified a nonoperative, organ-preserving approach
for patients with advanced resectable larynx cancer and legitimized the concept
of organ preservation as an appropriate end point in the management of this
disease.
The potential for organ preservation has been supplemented by long-term
functional assessments that have been reported from this study (12,13). Most
patients undergoing laryngectomy were able to re-establish some kind of vocal
communication, whether by esophageal speech, a tracheoesophageal puncture,
or an artificial larynx. Objective evaluation, however, demonstrated significantly better speech intelligibility in patients randomized to the nonoperative
treatment. Swallowing assessments, as reported by the patient, were equivalent
between the two treatment arms, but overall quality of life was better in the
larynx-preservation arm.
A similar study was reported by the European Organisation for Research
and Treatment of Cancer (EORTC) in patients with primary hypopharyngeal tumors using a nearly identical study design (14). Survival again proved
statistically equivalent between the two treatment arms, and the 3-year survival with a functional larynx was 28% in the patients treated with chemotherapy. A third, smaller trial, reported in 1998 by the French Groupe
d’Etudes des Tumeurs de la Tête et du Cou also used the same study design
in previously untreated patients with T3 disease, all presenting with a fixed
vocal cord (15). This study was terminated prematurely because of patient
refusal to be randomized to the surgical arm. Despite this early closure, survival and disease-free survival proved significantly worse in the group given
induction chemotherapy, a result discordant with the other two, larger studies (Table 1). A metaanalysis of updated individual patient data from these
three randomized trials noted a nonsignificant trend suggesting a survival benefit in those patients randomized to laryngectomy despite the clear improvement in organ preservation on the chemotherapy arm (Table 2) (16).
A closer look at this study design, however, leads one to conclude that the
impact of the chemotherapy is not clear. Indeed, the survival equivalence
between the two treatment arms seen in the VA and EORTC trials may only
reflect the equivalence of a primary surgical and a primary radiotherapeutic
approach in patients with advanced laryngeal and hypopharyngeal cancers.
This observation led to the development and performance of a second-
82
F, 5-fluorouracil; P, cisplatin.
Department of Veterans
Affairs Laryngeal Cancer Study Group (11)
European Organisation
for Research and Treatment of Cancer (14)
Groupe d’Etudes des
Tumeurs de la Tête et
du Cou (15)
Group
(Reference)
Larynx
Hypopharynx
Larynx
1996
1998
Primary Site
1991
Year
68
202
332
No. of
Patients
PF
PF
PF
Chemotherapy
Advantage:
surgery
No difference
No difference
Survival
Table 1. Randomized Organ Preservation Trials of Induction Chemotherapy and Radiation
versus Surgical Resection and Radiation
—
28% (3 y)
31% (3 y)
Alive/Organ
Preserved
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Integration of Chemotherapy into Organ Preservation
83
Table 2. Metaanalysis: Larynx Preservation Trials of
Neoadjuvant Chemotherapy
Overall
survival
Diseasefree
survival
Response Rate
(95% Confidence
Interval)
Chemotherapy
(%)
No Chemotherapy
(%)
1.19 (0.97–1.46)
39
45;
P = .1
1.18 (0.97–1.44)
34
40;
P = .1
Note: Survivors with functional larynx at 5 years = 58%.
Information compiled from Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy
added to locoregional treatment for head and neck squamous-cell carcinoma: three
meta-analyses of updated individual data. Lancet 2000;355:949–955.
generation Head and Neck Intergroup larynx preservation trial (Radiation
Therapy Oncology Group 91-11) (17,18). In this trial, the successful experimental arm from the VA laryngeal cancer study (induction chemotherapy followed
by radiation in responders) was compared to radiation therapy alone and to a
third arm of radiation therapy with concurrent single-agent, high-dose cisplatin
in patients with resectable stage III and IV larynx cancer. A laryngectomy arm
was not included in this study, and laryngectomy was reserved for persistent or
relapsed disease or for nonresponders to induction chemotherapy. A neck dissection was planned for all patients with N2 or N3 disease at the time of diagnosis. The results of this study demonstrated no significant difference in larynx
preservation or in locoregional control when the induction chemotherapy arm
was compared to the radiation therapy–alone arm. The concurrent radiation
and single-agent cisplatin treatment arm, however, proved superior for both end
points. It should be noted, however, that in the most recent update of this study,
reported at the 2006 meeting of the American Society of Clinical Oncology, the
combined end point of laryngectomy-free survival was equivalent for the induction and the concurrent arms and was superior to radiation therapy alone (18).
Survival remained the same between all three treatment arms, an observation
attributed at least in part to the success of salvage laryngectomy.
A similar observation was made in a smaller trial reported from the Cleveland Clinic (19). This study randomized non–site-specific patients with resectable stage III and IV head and neck cancer to either definitive radiation
therapy or definitive radiation and concurrent chemotherapy. The concurrent
chemoradiotherapy regimen consisted of radiation, cisplatin, and 5-fluorouracil. Provisions for salvage surgery were incorporated into the study for
patients with no clinical response after 50–55 Gy of radiation, with persistent
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84
Integration of Chemotherapy into Organ Preservation
disease after the completion of a full course of radiation, or with a subsequent
locoregional recurrence. Recurrence-free interval, local control without surgical resection, and overall survival with primary site preservation proved statistically superior in the concurrent chemoradiotherapy arm. An unplanned
subset analysis demonstrated an improvement in overall survival with primary
site preservation for both the patients with laryngeal cancer and hypopharyngeal cancer when treated with concurrent chemoradiotherapy. When required,
salvage surgery proved successful in between 63% and 73% of patients, and,
as a result, there was no difference in overall survival between the two treatment arms.
The results from these two studies in patients with resectable head and
neck cancer are, therefore, consistent (Table 3). The addition of concurrent
chemotherapy to definitive radiation therapy can improve the potential for
organ preservation. Appropriate integration of surgical salvage appears to
blur any overall survival differences between these two treatment approaches,
although a survival benefit has been observed from concurrent chemoradiotherapy (compared to radiotherapy alone) in unresectable patients (20) and in
the postoperative setting (21,22).
It should again be noted, however, that the results after concurrent chemoradiotherapy in these two trials were not compared to definitive surgery-based
approaches. The survival equivalence (or superiority) of concurrent chemoradiotherapy and conventional surgery has not been established. There has been
only one reported study that has compared these two treatment approaches.
This study, from Singapore, compared concurrent 5-fluorouracil, cisplatin,
and radiation therapy with surgery and postoperative radiation in 119 randomized patients (23). Although there was significant difficulty in patient
compliance with both treatment regimens, no overall survival difference was
identified between the two treatment arms. Organ preservation was possible
in 42% of the entire patient cohort treated with chemoradiotherapy and in
62% of those patients with larynx or hypopharyngeal primaries.
The data for oropharynx cancer is considerably less clear. Phase II trials of
both induction and concurrent chemoradiotherapy programs have been
reported, and the possibility of avoiding surgical resection has been described
(24,25). Phase III trials of concurrent chemotherapy and radiation therapy
have suggested both a survival benefit and an improvement in locoregional
control when concurrent chemoradiotherapy is compared to radiation therapy alone (26,27). Once again, however, in the absence of conclusive randomized data, the survival equivalence of primary surgery and these nonoperative
approaches has not been proven. Furthermore, equivalence in long-term
organ function conservation can also not be assumed, and assessments of both
objective measurements of speech and swallowing as well as subjective measures of overall quality of life are required.
End Pointa
Radiation (%)
Chemoradiation (%)
estimates.
N.S., not statistically significant.
aFive-year
Intergroup (Radiation Therapy Oncology Group 91-11) (18)
Laryngeal preserva66
84
tion
Laryngectomy-free
34
47
survival
Locoregional control 51
69
Overall survival
54
55
Cleveland Clinic (19)
Survival with organ
34
42
preservation
45
77
Local control without surgery
Overall survival
48
50
Study
(Reference)
Table 3. Phase III Trials of Concurrent Chemoradiotherapy for Organ Preservation
<.01
.011
<.01
N.S.
.004
<.001
N.S.
45
55
59
—
—
—
Probability
71
Induction (%)
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85
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86
Integration of Chemotherapy into Organ Preservation
Identification of Optimal Treatment
An important question arises from these nonoperative, organ-preserving
treatment strategies. Can patients likely to do well with nonoperative intervention be identified early in their treatment course? If so, such patients could
more confidently be given definitive nonoperative therapy with the goal of
organ preservation. Patients not deemed likely to benefit from this approach
could undergo initial surgical resection. There are currently several clinical disease features that can identify patients less likely to do well with radiation therapy and more appropriate for surgical resection. Certainly, those patients
presenting with a destroyed organ will not experience any benefit from an
attempt to preserve this organ. Similarly, patients with advanced larynx or
hypopharynx cancer with subglottic extension or tumor directly invading into
neck, thyroid, or cricoid cartilage do not do well with primary radiation therapy–based approaches. In addition, comorbid illness or limited social supports
may actually mandate surgical resection as the less morbid of treatment
approaches, given the considerable toxicity associated with chemotherapy and
radiation.
In recognition of the observation that a response to induction chemotherapy is predictive of a subsequent response to radiation therapy (28), it has
been suggested that chemotherapy responsiveness may be useful in prospectively identifying those likely to benefit from nonoperative approaches. Investigators in Michigan have reported their results from a trial in stage III and IV
larynx cancer using this approach (29). After an initial course of chemotherapy, nonresponders proceeded to immediate laryngectomy while those achieving a response were treated with definitive concurrent chemoradiotherapy.
Larynx preservation proved possible in 70% of the patients in this series, with
a 3-year projected overall survival of 85%.
A similar approach has been incorporated into the current Intergroup
phase III trial for resectable oropharynx cancer (Figure 1). Patients entered on
this trial are randomized between definitive concurrent chemoradiotherapy
alone and induction chemotherapy followed by concurrent chemoradiotherapy in responders. Patients not responding to induction chemotherapy
undergo early surgical salvage. This study will hopefully shed light on both the
potential improvement in survival to be gained from adding induction chemotherapy to concurrent treatment, as well as the possibility that a failure to
respond to chemotherapy can identify those patients who will benefit from
early surgical salvage. Critical in the evaluation of results from this study will
be a careful assessment of both late toxicities and quality of life.
It must be pointed out that the use of induction chemotherapy should still
be considered an experimental intervention. This is important when interpreting the recent reports of randomized trials comparing the well-tested cisplatin
and fluorouracil induction regimen with the three-drug combination of cis-
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87
Nonresponders: Surgery*
R
A
N
D
O
M
I
Z
E
Induction:
Docetaxel (T), 75 mg/m2
Cisplatin (P), 75 mg/m2
5 FU (F), 1,000 mg/m2/d × 4
– one course –
Concurrent:
RT: 70 Gy at 2 Gy/d
Cisplatin, 100 mg/m2
q21d × 3
Responders: TPF × 2 (3 total)
Concurrent:
RT: 70 Gy at 2 Gy/d
Cisplatin, 100 mg/m2
q21d × 3
Figure 1. Treatment schema for the current Intergroup phase III trial of concurrent chemoradiotherapy, with or without induction chemotherapy for
resectable squamous cell carcinoma of the oropharynx. *Unresectable patients
or those refusing surgery proceed to concurrent chemoradiotherapy. 5-FU,
5-fluorouracil; RT, radiation therapy.
platin, fluorouracil, and a taxane (3,30). Although the three-drug induction
regimens have consistently produced a superior response rate, the impact of
these induction regimens on the results achieved after optimal concurrent chemoradiotherapy is unknown and is the question being asked by several ongoing phase III trials such as the Intergroup study previously discussed (see
Figure 1). Indeed, Calais and colleagues (31) have recently reported their
results comparing induction cisplatin and fluorouracil with or without docetaxel followed by radiation therapy for larynx preservation. Although radiation therapy alone, as definitive management, must be considered a suboptimal
choice, both the response rate and the laryngeal preservation rate were superior in the docetaxel arm. These results are intriguing and certainly confirm
greater activity for this three-drug chemotherapy combination. Although such
an induction regimen may ultimately prove of benefit in conjunction with
optimal concurrent treatment, induction chemotherapy is currently only
appropriate within the context of a clinical trial.
Recent results from a large phase III trial comparing radiation therapy with
radiation therapy and cetuximab have been reported (32). An improvement in
both overall survival and locoregional control was found in those patients
treated with cetuximab, although this benefit appeared to be confined to
patients with oropharynx cancer treated with the concomitant boost radiotherapy schedule. No impact on distant metastases was seen from the addition
of cetuximab. Incorporation of this kind of targeted intervention into current
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chemotherapy and radiation therapy schedules is being intensively explored
with the hope that an improvement in both organ preservation and survival
will result.
Conclusion
An agenda for clinical investigation has emerged. Although it is unlikely that
any additional true organ-preservation trials with a surgery-based control
arm will be conducted in the future, investigation will continue to focus on
the optimal integration of chemotherapy, radiation therapy, and the newer
targeted agents. An improvement in survival remains the most important
treatment goal, but attention to not just organ preservation but to a careful
assessment of organ function and quality of life is mandatory. These answers
will only come through continued close cooperation between all professionals involved in the care of these patients and continued entry of these
patients onto well-designed and carefully conducted clinical trials.
References
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2. Weinstein GS. Surgical approach to organ preservation in the treatment of cancer of the larynx. Oncology 2001;15:785–796.
3. Adelstein DJ, LeBlanc M. Does induction chemotherapy have a role in the
management of locoregionally advanced squamous cell head and neck cancer?
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4. Cohen EEW, Lingen MW, Vokes EE. The expanding role of systemic therapy in
head and neck cancer. J Clin Oncol 2004;22:1743–1752.
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6. Jacobs C, Goffinet DR, Goffinet L, et al. Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer. A report
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7. Demard F, Chauvel P, Santini J, et al. Response to chemotherapy as justification for modification of the therapeutic strategy for pharyngolaryngeal carcinomas. Head and Neck 1990;12:225–231.
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10. Price LA, Shaw HJ, Hill BT. Larynx preservation after initial non-cisplatin containing combination chemotherapy plus radiotherapy, as opposed to surgical
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for laryngeal cancer. Arch Otol Head Neck Surg 1998;124:964–974.
Hillman RE, Walsh M, Wolf GT, et al. Functional outcomes following treatment for advanced laryngeal cancer. Ann Otol Rhinol Laryngol 1998;107
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sinus cancer: preliminary results of a European Organization for Research and
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Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of induction
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Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional
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Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and
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Forastiere AA, Maor M, Weber RS, et al. Long-term results of Intergroup
RTOG 91-11: a phase III trial to preserve the larynx—induction cisplatin/5-FU
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Oncol 2006;24(abstract):284s.
Adelstein DJ, Lavertu P, Saxton JP, et al. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy
alone in patients with stage III and IV squamous cell carcinoma of the head
and neck. Cancer 2000;88:876–883.
Adelstein DJ, Li Y, Adams GL, et al. An Intergroup phase III comparison of
standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin
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Urba SG, Moon J, Shankar Giri PG, et al. Organ preservation for advanced
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Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated
radiotherapy limits the additional benefit of simultaneous chemotherapyresults of a multicentric randomized German trial in advanced head and neck
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27. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and
Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69–76.
28. Ensley JF, Jacobs JR, Weaver A, et al. Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously
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Cancer 1984;54:811–814.
29. Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects
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30. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing
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31. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing
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567–578.
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❖
Intensity-Modulated
Radiation Therapy:
Promises and Practice
Gregory Russo, MD, and Mitchell Machtay, MD
Introduction of a New Treatment Approach
Intensity-modulated radiation therapy (IMRT) is a relatively new way of
delivering three-dimensional conformal radiation therapy (3D CRT). Ideally,
IMRT allows for delivery of high doses of highly conformal radiation therapy
to clinical target volumes while preserving critical normal structures. Since its
introduction into clinical use in the late 1990s, it has resulted in a flurry of
activity in research and clinical practice to identify the ideal clinical situations
to which it should be applied, how to safely and effectively implement a treatment program, and how to develop the necessary complementary technologies to take full advantage of its capabilities.
Since the 1990s, IMRT has become standard practice in the treatment of
selected types of head and neck cancers at many academic and private centers.
Recently, preliminary reports of the first prospective randomized trial of
IMRT versus traditional radiation therapy were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2005 that
showed the benefits in the preservation of salivary gland function (1).
As with any new technology, there is a learning curve associated with
IMRT that appears to be very large. As institutional experiences are reviewed,
the benefits of IMRT in the preservation of normal critical structures and
improvement of target coverage come at a cost of increased resources and, in
some cases, increased treatment-related toxicity. In this chapter, we provide an
CME 91
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overview of the differences between IMRT and traditional radiation therapy,
the potential benefits and stumbling blocks associated with this technology,
and the selection of patients for whom IMRT is an appropriate treatment.
Intensity-Modulated Radiation Therapy—
Definition and Historical Perspective
Before the introduction of IMRT into clinical practice, most head and neck
cancers were treated with a combination of large opposed lateral (right and left
laterally directed) radiation fields to encompass the primary tumor and
regional lymphatics in the upper and mid-neck, plus an anteriorly directed radiation field to encompass the lower neck and supraclavicular fossa (Figure 1).
Through the use of custom blocking, some critical structures peripherally or
centrally located can be partly or wholly shielded from radiation exposure to
decrease acute and/or long-term toxicity. Within the entire treatment field, the
dose of radiation measured in centigrays was homogeneous. This provided
good assurance that the target(s) was/were being irradiated appropriately, but
it also meant that large volumes of normal tissues were receiving very high
doses of radiation. For example, in the treatment of pharyngeal carcinomas
(especially nasopharynx cancer), the dose received by almost the entirety of
both parotid glands was equal to the dose received by the tumor. Consequently,
the rate of late grade ≥2 xerostomia in large prospective clinical trials was at
least 35%–50% with standard radiation therapy alone. The introduction the
radioprotectant drug amifostine has shown some improvement in rates of
xerostomia with radiation treatment (2,3). However, amifostine protection is
incomplete, and the drug is often poorly tolerated due to its side effects.
Figure 1. Three-field plan for radiation treatment of patient with locally
advanced larynx cancer status-post total laryngectomy—right and left lateral
portals to treat the primary tumor and regional lymphatics in the upper and
mid-cervical region (A and B) and anterior portal to treat lower cervical and
supraclavicular lymph nodes (C).
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Figure 2. A–F: Radiation treatment portals for six-field intensity-modulated
radiation therapy plan to treat a patient with locally advanced oropharynx cancer.
Within each portal, the varying degrees of red color indicate increasing (white =
low dose, red = high dose) intensity of radiation delivered at that location.
In contrast to conventional 3D CRT, IMRT allows the delivery of high
doses of radiation to the same targets and differentially decreased doses of
radiation to critical normal structures even when they are relatively close to
one another. This is accomplished by delivering radiation from multiple angles
and with multiple beam segments of variable intensity (Figure 2) (hence the
use of the term intensity-modulated); the summation of these beams results in
a highly variable, heterogeneous dose distribution within the patient. This
becomes obvious when reviewing the set of slices from the radiation therapy
treatment planning computed tomography (CT) scan (Figures 3–5). It is
important to note that the radiation being delivered is physically the same as
with conventional radiation therapy; it is simply delivered in a different way.
Most modern linear accelerators can be used for either conventional radiation
therapy or IMRT.
The user (radiation oncologist) dictates the complexity of any IMRT plan
with regard to number of beams and beam segments, size of beam segments,
and a set of dose constraints for targets and normal tissues. Increasing the
number of allowed beams and beam segments, decreasing the size of beam
segments, and demanding more highly conformal dose constraints can produce a plan with better conformality and steeper dose gradients. This is done
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Figure 3. Axial (A and B) and coronal (C and D) images from intensitymodulated radiation therapy treatment plan. Red color indicates high-dose
regions, and blue indicates low-dose regions. White marks indicate location
of the parotid glands. The left parotid gland is receiving a lower radiation
dose in an attempt to spare parotid function, whereas a higher dose is being
given to the gross tumor volume and clinical target volume.
at the expense of a longer treatment planning time (potentially delaying the
patient from starting radiation therapy), longer actual patient treatment time
(potentially 20–40 minutes per day), and increased exposure of the patient to
moderate levels of background radiation (4). There has been much focus on
developing treatment-planning algorithms that reach an acceptable balance
between quality of treatment plan and increased treatment time. However,
there are currently no universally accepted standards of care for IMRT planning and delivery; the closest such series of guidelines are those set forth in
several actively accruing Radiation Therapy Oncology Group (RTOG) clinical
trials (e.g., RTOG 0522).
There are essentially two ways of planning IMRT: forward planning and
inverse planning. In both situations, the treating radiation oncologist defines
targets and normal structures. Dose constraints are then assigned for each
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Figure 4. Axial (A and B) and coronal (C and D) images from intensity-modulated radiation therapy treatment plan showing coverage of the parapharyngeal tissues and posterior cervical lymph nodes while delivering a differentially
lower dose of radiation to the spinal cord and posterior neck tissues.
individual structure. For forward-planned IMRT (FP-IMRT), the gantry
angles and beam segments are defined by the radiation oncologist; a series of
manual iterations to optimize the intensity of each segment is then performed
until a satisfactory plan is achieved (5). In contrast, for inverse-planned IMRT
(IP-IMRT), the gantry angles are defined by the treatment team, but the treatment planning software determines the exact number and shape of segments
as well as the dose intensity to be delivered through each segment within predefined constraints. This process is done automatically, based on a preprogrammed series of treatment planning algorithms plus the dose constraints
prescribed by the radiation oncologist.
Treatment times tend to be shorter with FP-IMRT, although treatment
planning time can be substantial due to the need for manual “trial by
error” technique. Plan quality is probably comparable between the two
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Intensity-Modulated Radiation Therapy
Figure 5. Axial (A), coronal (B), and sagittal (C) images of intensity-modulated
radiation therapy treatment plan for a patient with diffuse squamous cell carcinoma of the paranasal sinuses. High-dose region ends abruptly with sharp dose
gradient to spare the optic chiasm, indicated by the white arrow (A and C); dose
is bent around the eyes to deliver high-dose radiation to the sinuses (C).
types of IMRT planning, although IP-IMRT potentially offers improved
ability to achieve extremely sharp radiation dose gradients adjacent to or
wrapping around critical structures (e.g., spinal cord).
Volume Definition for Intensity-Modulated
Radiation Therapy Treatment Planning
One of the most critical steps in formulating an effective IMRT treatment plan
for patients with head and neck cancer is the accurate definition of the target
volumes and normal tissue structure volumes. These volumes include (a) the
gross tumor volume (GTV), representing a region(s) with proven cancer;
(b) the clinical target volume(s) (CTVs), one or more identifiable regions at
risk for microscopic spread of disease; (c) the critical normal structures,
referred to as organs at risk (OAR); and (d) planning volumes, which represent the other types of volume plus a “safety margin” to account for various
uncertainties such as changes in target volume size and shape over time. Errors
in target and/or OAR delineation cannot be easily rectified through the course
of the patient’s treatment and can have a large impact on the actual administered doses to the tumor and OAR. These errors can potentially affect the
probability of tumor control and/or normal tissue complications.
Gross Tumor Volume
The GTV is defined by using information from physical examinations, anatomic imaging, invasive staging (e.g., panendoscopy) and, more recently, func-
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tional imaging. The radiation treatment planning CT scan provides the critical
information for the IMRT treatment plan, including the geometry of the
patient with respect to the incident radiation beams, the relative positions of
targets and critical structures, and the relative density of tissues within the
region of interest. CT scans have also proved to be superior to other imaging
modalities in evaluating for bony invasion that can be present, particularly
with tumors of the nasopharynx and oral cavity (6). Through the use of image
fusion software, magnetic resonance imaging (MRI) and positron emission
tomography (PET) scans can be fused to the treatment planning CT scan and
used as adjuncts to CT image information.
Several groups have shown that MRI can provide critical information
with regard to invasion of soft tissues, particularly in the parapharyngeal
spaces and retropharyngeal lymph nodes (7). In addition, PET has been
investigated for radiation treatment planning and has been shown to
increase or decrease the size of the GTV by up to 49% in selected patients
(8). Other groups have shown that PET fusion has proved instrumental in
defining the extent of the primary tumor and regional nodal metastases in
patients thought to have N0 cancer by other means of evaluation (9,10).
Organs at Risk
OARs include those structures that can be irreparably damaged by exposure to high doses of radiation and cause permanent morbidity or mortality. In the region of the head and neck, OARs can include the spinal cord,
brain stem, optic apparatus (chiasm, optic nerves, retina, cornea, lens),
parotid glands, organs of speech and swallowing, temporal lobes, and the
cerebellum. These structures should be defined anatomically using information from the treatment planning CT scan.
Clinical Target Volume(s)
The definition of the CTV(s) for patients receiving IMRT for head and
neck cancer has proved to be a difficult task. There are two important
components of the CTV as it applies to IMRT planning: (a) areas at risk
for direct invasion by tumor and (b) lymph nodes at risk for micrometastases. The former is defined with knowledge of the pathologic features of the
tumor, its location, and the natural history of the disease entity being
treated. The latter has required a fair amount of adaptation from previous
techniques and is based on knowledge of the natural history of the disease
entity, including studies dating back more than 30 years (11).
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Figure 6. Axial computed tomography images (A–C) of a patient with
locally advanced larynx cancer status post-laryngectomy and bilateral neck
dissections. Clinical target volume 58 (CTV58) and planning target volume 58
(PTV58) in right side of neck indicated by inner and outer lines, respectively.
CTV66, CTV60, and PTV60 in left side of neck. CTV66 is boost to the operative
bed innermost green contour, CTV63 inner purple is the region of removed
cervical lymph nodes containing metastatic cancer, and PTV63 is the outermost purple contour. Note the distortion of the anatomic planes.
Whereas bony landmarks previously served to separate different lymph
nodal levels at risk, an exact anatomic delineation is now necessary. Several
groups have published atlases of cross-sectional anatomy to define the different nodal stations in the head and neck (12–15). A consensus conference
was convened for the purpose of developing an atlas of neck lymph nodes
and is available on the RTOG’s web site (www.rtog.org) (16). Once defined,
different doses of radiation therapy can be assigned to different nodal levels
based on knowledge of patterns of metastatic spread.
The task of CTV definition can be further complicated in patients who have
had either the primary tumor or regional lymphatics removed before radiation
therapy. Surgical manipulation distorts the boundaries of natural tissue planes
and introduces more uncertainty into the process of target definition (Figure 6).
Planning Volumes
For several reasons, before starting IMRT planning, it is necessary to add a
“safety margin” around the GTV, CTV, and at least the most critical OARs.
The volume defined by a target volume plus this safety margin is called a planning target volume (PTV). The volume defined by a critical OAR plus this
safety margin is called a planning at-risk volume (PRV). The reason for adding
these safety margins and thus creating PTV/PRVs is to account for various
uncertainties (errors) in treatment planning and delivery. These potential
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errors may include uncertainties in volume definitions (as discussed in the section “Volume Definition for Intensity-Modulated Radiation Therapy Treatment Planning”), changes in volume size/shape during a course of radiation
therapy or even during an individual radiation treatment (organ motion and/
or deformation), and systematic and/or random setup errors that may occur
on a day-to-day basis.
Determining the size of the safety margin (CTV-to-PTV margin) is complex, controversial, and may require a great deal of individualization. Factors that influence the size of this margin include reproducibility of setup
and availability of adequate patient immobilization. Several groups have
done dosimetric analyses to simulate random setup errors, evaluate their
influence on target coverage, and identify the appropriate CTV-to-PTV
margin to minimize target under-dosing (17–20).
Ultimately, the size of the PTV margin should be customized to each individual clinic and be based on an analysis of daily setup reproducibility. Most
clinics have adopted a CTV-to-PTV margin size of between 3 mm and 8 mm. A
large margin will result in extensive overlap between the target volume(s) and
one or more OARs; this situation can result in the IMRT computer planning
system “failing” to achieve a satisfactory treatment plan. Similarly, the use of a
PRV margin has been shown to decrease the likelihood of delivering unacceptably high doses of radiation to critical normal structures, but can cause further
overlap with adjacent PTVs. Overlapping structures ultimately complicates the
treatment planning process and the ability to interpret treatment plans. In contrast, a small margin affords the potential for an improved computer-generated
IMRT plan but, theoretically, a greater risk of tumor recurrence/progression if
there are clinically relevant errors/uncertainties in treatment planning.
To combat these issues, proper patient immobilization and positioning
verification that eliminates setup variability can help to minimize possible
errors while allowing a modest-sized PTV margin. Consequently, the doses
to surrounding normal structures and resultant probabilities for long-term
morbidity can be reduced (21). To accomplish this, some centers have implemented daily positioning verification protocols with two-dimensional orthogonal portal imaging or three-dimensional imaging with accelerator-mounted
cone beam CT scanners. This is referred to as daily image-guided IMRT (IGIMRT) and is quickly gaining popularity.
Intensity-Modulated Radiation Therapy
Treatment Planning and Evaluation
Once the targets and OARs are defined, specific dose constraints must be
applied to each structure. Typically a goal, maximum, and minimum dose as
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Table 1. Typical Intensity-Modulated Radiation Therapy Dose Constraints
Used for Organs at Risk in the Head and Neck Region
Organ
Maximum Dose
Whole Organ Dose
Spinal cord
Brain stem
Optic nerves
Optic chiasm
Parotid/submandibular glands
Temporal lobes
Mandible/temporomandibular joint
Oral cavity/lips
1% of PTV not to exceed 50 Gy
1% of PTV not to exceed 60 Gy
1% of PTV not to exceed 60 Gy
1% of PTV not to exceed 60 Gy
At least 50% of organ <30 Gy
45 Gy
54 Gy
54 Gy
54 Gy
Mean dose, 26 Gy
<1% PTV to receive >65 Gy
1 cc of PTV not to exceed 75 Gy
60 Gy
70 Gy
As low as possible (typically
20–30 Gy)
1% not to exceed 65 Gy
—
—
Tongue
Larynx/pharynx
55 Gy
Mean dose, 45 Gy
PTV, planning target volume.
well as the volumetric percentage of each structure allowed to receive dose
above and below the goal are defined; this process attempts to dictate the
degree of allowable heterogeneity to minimize hot and cold areas within the
treatment field. For standard fractionated radiation therapy, the typical dose
for gross disease is 66–72 Gy; for resected disease with a positive surgical margin or for lymph nodes with extracapsular extension, the goal is 63–66 Gy; for
completely resected disease with negative surgical margins, the goal is approximately 60 Gy; and for electively irradiated nodal regions for microscopic disease, the goal is 50–55 Gy. The classic values used for normal tissue toxicity
limits were defined by Emami et al. in 1991 (22) and have been adapted for the
purposes of IMRT (Table 1). After completing the process of defining targets,
OARs, and dose specifications, the radiation oncologist works closely with a
team of radiation physicists and dosimetrists to achieve an optimized computer-generated IMRT plan. This process can require a variable amount of
time—from several hours to several weeks. Once treatment planning is completed, the actual doses to each target and critical normal structure needs to be
compared to the predefined constraints. There are few instances where every
single dose constraint can be met with perfection, and the radiation oncologist
and physics/dosimetry team strive to optimize the plan as best as possible.
A detailed discussion of the processes involved in IMRT planning is
beyond the scope of this chapter, and the reader is referred to a consensus
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report from the American Society of Therapeutic Radiology/Oncology and the
American Association of Physicists in Medicine (23). In general, during the
process of IMRT planning and evaluation of plans, compromises are made,
and this is part of both the art and science of medicine. The highest priorities
are given to achieving adequate coverage of the GTV and strict avoidance of
exceeding maximum tolerated dose limits on the spinal cord and optic apparatus. A somewhat lower level of prioritization is assigned to the CTVs, and
the lowest (albeit still significant) priority is given to normal structures that are
important but not life sustaining (e.g., the parotid glands).
The reliability of any IMRT plan to accomplish its preset goals of delivering highly conformal radiation to target tissues and the sparing of OARs is
dependent on maintaining setup reproducibility, both internally in and externally. External patient setup reproducibility can be accomplished with standard treatment aids and image guidance (for details, see section “Planning
Volumes”). Internal reproducibility can be affected by rapidly responding
tumors and/or patient weight loss, resulting in changes in the patient’s external
contour or relative positions of targets and OARs within the patient. Because
of certain physical properties of ionizing radiation, these changes can alter the
final location of high- and low-dose regions of radiation within the patient,
potentially undertreating portions of the target(s) and delivering higher than
intended doses to critical structures. Mid-treatment repeat CT scanning and
replanning in select patients has shown significant deviations in the intended
doses to the target and critical structures, suggesting that this may need to be
considered routine for similar patients (24).
Intensity-Modulated Radiation Therapy
in Clinical Use—Potential Advantages
The leading rationale for head/neck IMRT has been to achieve excellent radiation therapy coverage of all relevant target volumes while minimizing radiation therapy dose to the parotid glands. In addition, IMRT has proved useful
in other areas that previously presented significant challenges in radiation
treatment planning. These included elimination of uncertainty at match lines,
coverage of deep and midline structures, sparing of optic nerves/chiasm in
treating tumors of the nasal cavity and paranasal sinuses, and sparing of other
structures, such as those responsible for swallowing, to decrease long-term
morbidity related to dysphagia and aspiration.
Since 2000, there have been a number of clinical, retrospective series reporting outcomes with IMRT-based radiation therapy for head and neck cancer.
Although these studies compare current patients to retrospective or concurrent
nonrandomized patient groups and, hence, lack the power and rigor of phase
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III randomized trials, the studies do strongly suggest that locoregional control
is not compromised by IMRT, at least when given at an experienced academic
center that treats a substantial number of head and neck cancer patients with
IMRT (25–28). It is hypothesized that IMRT might actually improve locoregional control over standard radiation therapy because IMRT can yield a
higher mean target volume dose (even if the prescription dose at the edge of the
target volume is numerically the same as that with standard x-ray therapy).
In contrast, there has been a well-documented locoregional control
advantage to altered (hyper- and/or accelerated) fractionation radiation therapy (29,30), at least for stage III–IV nonoperative head and neck cancer.
Altered fractionation radiation therapy has become less commonly used in
the era of concurrent chemoradiation therapy but is still highly relevant. The
use of altered fractionation with IMRT is the subject of ongoing investigation. The currently accruing major RTOG trial (RTOG 0522) allows investigators to use altered fractionation IMRT (6 fractions per week) together
with systemic therapy.
Several investigators are exploring the use of a new type of altered fractionation based on IMRT; specifically, accelerated hypofractionation. Accelerated
hypofractionation refers to the use of one fraction per day at a larger than
normal daily dose (2.2–3.0 Gy), significantly increasing the biologic intensity
of the radiation therapy course. With standard radiation therapy, accelerated
hypofractionation is feasible but requires an attenuation of the cumulative
radiation therapy dose and/or the deletion of concurrent chemotherapy. It is
hypothesized that IMRT can overcome these obstacles by strictly limiting the
volume of tissue irradiated to an ultra-high-dose intensity. This technique has
been labeled the “SMART” (simultaneous modulated accelerated radiotherapy) technique as piloted at Baylor University (31). Phase I–II studies of this
approach appear to show acceptable toxicity for IMRT-based accelerated
hypofractionation alone (32,33), but rigorous data combining this technique
with concurrent chemotherapy are scant (34). As of this writing, patients
receiving IMRT with concurrent chemotherapy are generally prescribed conventional daily dose/fractionation schedules.
Parotid Sparing
One of the most significant long-term toxicities in patients treated with radiation therapy for head and neck cancer is xerostomia caused by excessive doses
delivered to the major salivary glands (see Figure 6). Rates of grade 2 or
higher xerostomia following head and neck irradiation range up to 68% in
large randomized studies (30). Maintenance of good salivary flow is essential
for good oral health (35); grade 2 xerostomia indicates moderately severe dry-
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103
ness with significant functional impact. The potential for IMRT to spare the
parotid glands and decrease late xerostomia has been extensively investigated.
Initial work by investigators at the University of Michigan identified the
threshold dose of radiation to the parotid gland—approximately 26 Gy—
above which permanently decreased salivary flow resulted. In patients treated
with IMRT with limited doses to a single parotid gland (36), improvement in
quality of life with regard to eating, communication, pain, and emotion was
noted (25,37). Subsequently, other studies have been published, illustrating the
ability of IMRT to decrease treatment-related xerostomia when treating head
and neck cancer, particularly nasopharyngeal and oropharyngeal tumors.
There has been one randomized trial comparing IMRT to standard radiation therapy, specifically in early stage nasopharyngeal carcinoma (NPC). This
study has only been reported in abstract form (ASCO 2005), and long-term
results are pending. However, preliminary results showed that patients randomized to IMRT had significantly less xerostomia 1 year after treatment,
with dramatically better parotid function and whole saliva flow compared
with standard radiation therapy. However, quality of life as assessed by questionnaires was not significantly different between the two arms.
In addition to parotid gland sparing, there have been attempts to limit dose
to the submandibular glands. Significant decreases in salivary flow were noted
among patients who did not have submandibular gland sparing versus those
who did. Patients with submandibular gland sparing IMRT reported less
xerostomia and decreased need for saliva substitutes (38).
Of course, salivary gland sparing should not be attempted if there is a
high risk of cancer recurrence in the nodal region directly adjacent to the
parotid gland. In general, parotid sparing is attempted for the contralateral
parotid gland in patients with well-lateralized cancers with clinically or
pathologically cancer-free contralateral neck lymph nodes. Patterns of failure studies in patients receiving parotid-sparing IMRT have shown that the
preponderance of locoregional failures are not in the region adjacent to the
spared parotid gland and are, instead, within the regions that were confirmed to have received high doses of radiation. The failures seem to be more
likely in patients who have clinicopathologic features of their tumors that
are predictive of failure, such as positive surgical margins, extracapsular
extension, multiple positive nodes, and postoperative patients, possibly indicating hypoxic regions portending relative radioresistance (39,40).
Match Line Dosimetry
IMRT also offers other benefits in addition to parotid gland sparing when
treating cancers of the head and neck. As noted in the section “Definition
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and Historical Perspective,” the traditional means of treating the entire
neck, from skull base to supraclavicular fossa, was with lateral fields treating the upper neck matched to a lower neck field (see Figure 1). In patients
with extensive neck nodal disease and/or low-lying primary tumors (larynx/pharynx), where the match line would have to be through very highrisk regions, this can cause an area of underdosing (or overdosing) due to
uncertainty at the match line (41). IMRT allows for the treatment of the
entire neck in one uninterrupted field (see Figures 3C, 3D, 4C, and 4D).
This eliminates the uncertainty at the match line (42) and reduces the possibility of neck failures in selected patients. Treatment of the entire neck in
a single field does increase treatment time and may not be appropriate for
patients with limited neck disease that does not cross the match line. In
such cases, treatment of the primary tumor/surgical bed and the upper
neck lymphatics can be treated with IMRT and a matching anterior lowneck field. Because IMRT treatment plans do not produce sharp dose gradients at the field edge similar to a half-beam blocked static field, there is
also uncertainty inherent in this process. Strategies have been formulated
to eliminate the uncertainty of matching IMRT fields with static fields
(43,44).
Coverage of Nasopharynx/Parapharyngeal Tissues
For cancers of the nasopharynx in which coverage of the parapharyngeal
spaces and retropharyngeal lymph nodes is crucial in achieving local control, IMRT has proved superior to traditional techniques of matching
photon and electron fields where significant cold regions can exist at the
match line (see Figure 4) (45). A study at Princess Margaret Hospital
showed that conventional planning/treatment of NPC resulted in poor
dose coverage of the tumor volume and a relatively high rate of local
recurrence (46). Several modern series of IMRT-based treatment for NPC
suggest that local control rates in excess of 90% are achievable (47).
This compares favorably to the U.S. Intergroup standard experience with
conventional chemoradiotherapy that showed approximately 75% local
control (Table 2) (48).
Several groups have reviewed their experience treating nasopharyngeal
cancer with IMRT. Outcomes indicate excellent locoregional control rates
and survivals at least equivalent to traditional radiation therapy techniques
with decreased rates of toxicity (see Table 2). A recently completed RTOG
phase II (RT 02–25) trial of IMRT for nasopharyngeal cancer will be the
first multi-institutional data showing the utility of IMRT in the treatment of
nasopharyngeal cancer.
I–IV
I–IV
63
67
97
92
91
100 (T1/T2)
83 (T3/T4)
95.7
Local
Control (%)
98
98
93
Regional
Control (%)
66
79
94.2
78
Metastasis-Free
Survival (%)
88
90
92.1
83
Overall
Survival (%)
MSKCC, Memorial Sloan Kettering Cancer Center, New York, NY; PWH, Prince of Wales Hospital, Hong Kong, China; QMH, Queen Mary Hospital, Hong Kong, China; UCSF, University of California, San Francisco, CA.
aKwong DL, Sham JS, Leung LH, Cheng AC, Ng WM, Kwong PW, Lui WM, Yau CC, Wu PM, Wei W, Au G. Preliminary results of radiation dose
escalation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):374–381.
bWolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer:
Update of the memorial sloan-kettering experience. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):57–62.
cKam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60(5):1440–1450.
dLee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53(1):12–22.
31
29
25
III–IV b
50
QMH, Hong
Kongb
PWH, Hong
Kong c
UCSFd
Median
Follow-Up (mo)
35
74
MSKCCa
Stage
I–IV
Patient
Number
Source
Table 2. Reported Results for Treatment of Nasopharyngeal Cancer with Intensity-Modulated Radiation Therapy
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Laryngopharyngeal Sparing
IMRT can also be used to decrease the radiation dose to the pharyngeal
constrictor muscles and the glottic/supraglottic larynx. These structures
are centrally located and often receive large doses of radiation when treating lymph nodes in the neck. When large volumes of these structures
receive radiation doses in excess of 50 Gy (V50) there is a substantial risk
of developing long-term dysphagia and/or aspiration. Contouring the
laryngopharynx, defining it as an OAR, and setting dose constraints to
limit the V50 may theoretically decrease the risk of developing dysphagia
and/or aspiration (49).
Sparing of Optic Structures
IMRT is also used to treat cancers of the nasal cavity and paranasal sinuses
(see Figure 5). Traditional radiation treatment fields resulted in large doses to
the optic apparatus, which puts patients at risk for the development of radiation-induced optic neuritis, a catastrophic side effect of radiation therapy that
can cause complete blindness. Dosimetric analyses have shown good coverage of the CTV with less dose delivered to the optic structures with IMRT
compared to 3D CRT (50), and IMRT to be especially useful when the upper
cervical lymph nodes are included in the treatment volume (51). In one study
of 39 patients treated with postoperative IMRT for T2–T4b ethmoid sinus
cancer, 2-year overall survival and local control rates were 68% and 73%,
respectively; these are comparable to historic controls with decreased rates of
vision impairment and no radiation-induced blindness (52).
Coverage of Midline Structures
IMRT can also produce superior dose profiles and coverage of target volumes
that cross the midline and wrap around central structures such as the spinal
cord. One such organ is the thyroid gland. In the past, treatment of substantial
volumes of the thyroid gland to doses ≥45 Gy was limited by the spinal cord
tolerance. The ability of IMRT treatment plans to wrap dose around central
structures in a horseshoe pattern has made treatment of the much larger volumes of the thyroid with substantially higher doses of external beam radiation
therapy possible (53,54). This has correlated to good clinical outcomes in the
published experience of the Memorial Sloan-Kettering Cancer Center, treating
20 patients with nonanaplastic thyroid carcinoma, showing 85% locoregional
control rates and no increase in toxicity (55).
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Re-Irradiation of Head and Neck Cancer
IMRT has also made re-irradiation of head and neck cancers more feasible,
particularly for patients with local or regionally recurrent nasopharynx cancer.
A Chinese group reported on their initial experience re-irradiating 49 patients
with recurrent nasopharynx cancer. They showed that the treatment was feasible with acceptable toxicity and encouraging response rates and local control
(56). Others have evaluated IMRT for re-irradiation in other subsites of the
head and neck and have shown encouraging response rates, with 50% of
patients showing partial or complete response with acceptable toxicity (57).
Potential Disadvantages of Intensity-Modulated
Radiation Therapy
Risk of Marginal Miss
As the reader can probably discern from the section on IMRT volume definition and treatment planning, IMRT is a technically demanding exercise. There
is little room for error at every stage in this planning process. Theoretically, the
use of small margins around target volumes and irradiation plans with sharp
dose gradients between these target volumes and normal structures could
result in a higher rate of local recurrence. There have been reports of recurrences in areas adjacent to a “spared” parotid gland after IMRT.
Risk of Secondary Malignancy
The increased complexity of IMRT treatment plans requires an increased
amount of time to deliver any single fraction of radiation therapy. Increased
treatment time can create problems with patients being unable to tolerate lying
still in the treatment position for extended periods of time; this may be overcome with the use of sedatives, nursing, and psychosocial support. However,
another theoretical concern is that increased radiation therapy beam-on time
and the use of numerous beam angles and segments exposes patients’ total
body to a low-dose of radiation. This amount of irradiation is difficult to measure and well below the threshold for causing typical radiation therapy-induced
organ damage but may be relevant for radiation carcinogenesis. In vivo measurements show that together these factors result in an increase in total body
radiation dose of from 242 mSv for conventional treatment to 1,969 mSv for
IMRT (58). It has been estimated that the risk for development of secondary
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malignancies could be two- to eightfold higher with IMRT than that for
patients treated with conventional radiation therapy (58,59). In the case of
head and neck cancer in which 6 MeV photons are predominantly used, the
relative risk of fatal second malignancy is 3.0–3.7 (60,61).
To date, there have not been any clinical reports to support or refute
this concern, but because IMRT is an exceptionally new technology and
because clinical studies of radiation carcinogenesis require many years and
large numbers of evaluable patients, these data may not be available until
the mid-2010s. Clinicians should be cognizant of this potential risk when
treating patients in their 50s and 60s and balance this against the potential
risks of conventional radiation therapy that contribute to late morbidity
and mortality: radionecrosis, aspiration, and dental complications.
Increased and/or “New” Toxicity(ies)
Due to the high degree of dose heterogeneity in IMRT plans, there is the
potential for unplanned “hot spots” receiving over 120% of the prescribed
dose. With an ideally optimized IMRT plan, these hot spots are within the
GTV; however, they may also occur in normal tissues. This can cause
increased acute and chronic side effects such as severe mucositis, osteoradionecrosis, trismus, and/or tissue necrosis. Strategies to control hot spot
formation have been used in the planning process and have proved effective, but it is important to note the location and possible consequences of
these hot regions when evaluating treatment plans.
Another drawback of IMRT is the potential to have an increased radiation
dose to the skin, resulting in increased rates of grade 3 and 4 radiation dermatitis, necessitating treatment breaks and resulting in poor compliance with
treatment. Multiple factors have been implicated in this process, including the
bolus effect from immobilization devices (i.e., Aquaplast mask), contouring of
CTV and PTV near to the skin surface, and the use of multiple tangential radiation beams. Strategies to reduce skin toxicity have been suggested, including
use of virtual bolus during treatment planning to allow for adequate build-up
so that the optimizer does not favor tangential beams, assigning dose limits to
the skin as an OAR, or editing PTV contours to be at least 5 mm inside the
skin when it is not a part of the CTV (62,63).
Cost/Resources
To treat a patient with IMRT, there is a significant increase in the necessary
resources, and, hence, the monetary cost of the treatment. The hardware and
software for IMRT planning and delivery are considerably more expensive
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than that for conventional radiation therapy. There is an increase in physician,
dosimetrist, therapist, and physicist time over conventional radiation therapy.
Increased beam on-time translates to a need for more regular maintenance of
linear accelerators and a busier treatment schedule, which can create a need
for increased clinic hours and the subsequent costs of overhead and staffing.
Conclusion
IMRT has come far since its introduction in the clinic. There exists an
expanding wealth of knowledge regarding the potential benefits and pitfalls
of this new technology. It is significantly more labor intensive from planning
to delivery, requiring many more resources. IMRT is likely not appropriate
for all patients. It remains uncertain as to which patients will benefit most
clearly from IMRT. The most likely beneficiaries from IMRT are patients
who would otherwise receive extremely high doses to their parotid glands
and/or unacceptably high irradiation dose to the optic apparatus. This suggests that IMRT may be more useful in cancers of the nasopharynx, oropharynx, and paranasal sinuses than for cancers located in the lower neck.
However, from a technical standpoint, IMRT might decrease some of the
dosimetric problems associated with comprehensive head and neck irradiation for a multitude of types of head and neck cancer, ranging from cancers
of the tongue to the larynx/hypopharynx and cancer to the thyroid.
Taken together, the reports in the peer-reviewed literature convey a tone of
cautious optimism. Longer follow-up and extensive quality control reviews are
necessary to determine if the risk of second malignancies is clinically relevant,
and to determine if “marginal misses” are occurring near structures that have
been intentionally underdosed via IMRT. Larger, multicenter studies of IMRT
are currently lacking; at this time it is unclear if the promising results with
IMRT achieved at several centers of excellence can be duplicated in the general
radiation oncology community. Efforts at standardization and quality assurance across multiple centers have lagged behind the enthusiasm about the use of
IMRT in the community. New technologies in head and neck radiation therapy,
such as IG-IMRT, are constantly evolving, and this or any review on IMRT will
likely be very different in 1, 2, or 5 years. Each investigator using IMRT must
pay close attention to new developments and determine if, when, and how to
adapt his or her treatment algorithms based on the current state of the art.
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49. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and
can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60(5):1425–
1439.
50. Mock U, Georg D, Bogner J, et al. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton
therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004;58
(1):147–154.
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51. Pacholke HD, Amdur RJ, Louis DA, et al. The role of intensity modulated
radiation therapy for favorable stage tumor of the nasal cavity or ethmoid
sinus. Am J Clin Oncol 2005;28(5):474–478.
52. Duthoy W, Boterberg T, Claus F, et al. Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: Clinical results in 39 patients. Cancer 2005;
104(1):71–82.
53. Posner MD, Quivey JM, Akazawa PF, et al. Dose optimization for the treatment of anaplastic thyroid carcinoma: A comparison of treatment planning
techniques. Int J Radiat Oncol Biol Phys 2000;48(2):475–483.
54. Nutting CM, Convery DJ, Cosgrove VP, et al. Improvements in target coverage
and reduced spinal cord irradiation using intensity-modulated radiotherapy
(IMRT) in patients with carcinoma of the thyroid gland. Radiother Oncol
2001;60(2):173–180.
55. Rosenbluth BD, Serrano V, Happersett L, et al. Intensity-modulated radiation
therapy for the treatment of nonanaplastic thyroid cancer. Int J Radiat Oncol
Biol Phys 2005;63(5):1419–1426.
56. Lu TX, Mai WY, Teh BS, et al. Initial experience using intensity-modulated
radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol
Phys 2004;58(3):682–687.
57. Chen YJ, Kuo JV, Ramsinghani NS, et al. Intensity-modulated radiotherapy for
previously irradiated, recurrent head-and-neck cancer. Med Dosim 2002;27(2):
171–176.
58. Verellen D, Vanhavere F. Risk assessment of radiation-induced malignancies
based on whole-body equivalent dose estimates for IMRT treatment in the
head and neck region. Radiother Oncol 1999;53(3):199–203.
59. Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT
and IMRT. Int J Radiat Oncol Biol Phys 2003;56(1):83–88.
60. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second
cancers. Int J Radiat Oncol Biol Phys 2006;65(1):1–7.
61. Kry SF, Salehpour M, Followill DS, et al. The calculated risk of fatal secondary
malignancies from intensity-modulated radiation therapy. Int J Radiat Oncol
Biol Phys 2005;62(4):1195–1203.
62. Lee N, Chuang C, Quivey JM, et al. Skin toxicity due to intensity-modulated
radiotherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2002;
53(3):630–637.
63. Thomas SJ, Hoole AC. The effect of optimization on surface dose in intensity
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Posner.bk Page 114 Friday, October 20, 2006 11:41 AM
Posner.bk Page 115 Friday, October 20, 2006 11:41 AM
❖
Index
Note: Page numbers followed by f refer to figures;
page numbers followed by t refer to tables.
Accelerated hypofractionation,
defined, 102
American Association of Physicists
in Medicine, 101
American Joint Committee on
Cancer (AJCC) stage
III or IV disease, 13–
14
AJCC stage III or IV laryngeal
disease, 13–14
AJCC stage IV laryngeal cancer,
13–14
AJCC staging system, 14
American Society of Addiction
Medicine web site, 53
American Society of Clinical
Oncology (ASCO),
91
American Society of Therapeutic
Radiology/Oncology,
101
ASCO, 91
Aspiration, swallowing abnormalities and, 47–48
Baylor University, 102
Bevacizumab, for recurrent
SCCHN, 71
Cancer(s)
head and neck. See specific
types, sites, and Head
and neck cancer
laryngeal, AJCC stage IV,
13–14
Carboplatin, for head and neck
cancer, 10
Carboplatin/5-FU, for head and
neck cancer, 4t
Cetuximab
for head and neck cancer, 9
for recurrent SCCHN, 70–71,
72t
Chemoradiation
assessment after, 54, 56t–57t, 57
assessment during, 54, 55t–56t,
57
concurrent, 3–8, 4t–5t
docetaxel-based cisplatin/5-FU
chemotherapy vs.,
phase III trials comparing, 33–37, 35f–37f
115
Posner.bk Page 116 Friday, October 20, 2006 11:41 AM
116
Index
for head and neck cancer, 1–22
concurrent chemoradiation,
3–8, 4t–5t
history of, 1–2
induction chemotherapy followed by chemoradiation, 8–9
neoadjuvant or “induction” chemoradiation, 2–3
patient selection for, 12–14
regimens, 9–12, 11t
selection factors for, 14–17
therapeutic approaches, 12–
13
unanswered questions
related to, 2
“induction,” 2–3
in locally advanced SCCHN,
28–32, 29t, 30t
as new standard of care,
32
taxanes with, 29–32, 30t
vs. induction chemotherapy,
28–29, 29t
neoadjuvant, 2–3
radiation alone trials vs., for
SCCHN, 4t–5t
symptom management and,
41–60
history of, 41–42
measuring effects of, 42–43
symptom control issues, 43–
54, 46t, 49t, 52t–53t
Chemoradiotherapy. See Chemoradiation
Chemotherapy
combination, for recurrent
SCCHN, clinical trials
using, 68–70
induction. See Induction chemotherapy
in organ preservation for
SCCHN, 77–90. See
also Squamous cell
carcinoma of head
and neck (SCCHN),
organ preservation
strategies for
systemic
evolution of, 67
in organ preservation for
SCCHN, 79–84, 82t,
83t, 85t
Cisplatin, for head and neck cancer, 3–10, 4t–5t
Cisplatin/5-FU
in locally advanced SCCHN,
25–27, 27t
for recurrent SCCHN, clinical
trials using, 68–69
Clinical target volumes (CTVs), in
IMRT treatment plan,
97–98, 98f
Combined modality therapy, for
locally advanced
SCCHN, 25–37, 27t,
29t, 30t, 35f–37f. See
also specific modality,
e.g., Induction chemotherapy
Common Terminology Criteria for
Adverse Events, 49,
49t
Common Toxicity Criteria, 42–43
Concurrent chemoradiation, 3–8,
4t–5t
Cost(s), IMRT-related, 108–109
CTVs, in IMRT treatment plan,
97–98, 98f
Daily image–guided IMRT (IGIMRT), 99
Dana-Farber Cancer Institute, 33
Posner.bk Page 117 Friday, October 20, 2006 11:41 AM
Index
Department of Veterans Affairs
(VA) Laryngeal Cancer Study Group larynx preservation trial,
1, 3, 28, 80
Docetaxel, for head and neck cancer, 10
Docetaxel-based cisplatin/5-FU,
chemoradiation vs.,
phase III trials comparing, 33–37, 35f–37f
Docetaxel/cisplatin/5-FU, vs. cisplatin/5-FU, for head
and neck cancer, 11t
Dosimetry, match line, IMRT in,
103–104
Eastern Cooperative Oncology
Group, 34
EGFR, for recurrent SCCHN, 70–
71
EORTC, 28, 31
EORTC 22931 trial, 6, 7, 15–16
Epidermal growth factor receptor
(EGFR), for recurrent
SCCHN, 70–71
European Organisation for
Research and Treatment of Cancer
(EORTC), 28, 31
22931 trial of, 6, 7
European Organisation for
Research and Treatment of Cancer
(EORTC) systems, 42
FDA, 50, 68
5-Fluorouracil (5-FU), for head
and neck cancer, 10
5-Fluorouracil (5-FU)/carboplatin, for head and neck
cancer, 4t
117
5-Fluorouracil (5-FU)/cisplatin
for head and neck cancer, 10
for recurrent SCCHN, clinical
trials using, 68–69
5-Fluorouracil (5-FU)/hydroxyurea, for head and
neck cancer, 10
5-Fluorouracil (5-FU)/platinum, in
locally advanced
SCCHN, 25–27, 27t
5-Fluorouracil (5-FU)/taxanes, for
recurrent SCCHN,
clinical trials using, 69
Food and Drug Administration
(FDA), 50, 68
Forward-planned IMRT, 95–96
Functional Assessment of Cancer
Therapy, 42
Gefitinib, for recurrent SCCHN,
71
GETTEC, 27, 28, 81
GORTEC 2000–01 trial, 30t, 32
Gross tumor volume (GTV)
defined, 96–97
in IMRT treatment plan, 96–97
Groupement d’Etudes des
Tumeurs d la Tête et
du Cou (GETTEC),
27, 28, 81
Head and neck cancer. See also
specific types
chemoradiation for, 1–22. See
also Chemoradiation,
for head and neck
cancer
prevalence of, 1
recurrent, management of, 61–
75. See also Recurrent
disease, management
of
Posner.bk Page 118 Friday, October 20, 2006 11:41 AM
118
Index
re-irradiation of, IMRT in, 107
squamous cell carcinoma. See
Squamous cell carcinoma of head and
neck (SCCHN)
Hypofractionation, accelerated,
defined, 102
IG-IMRT, 99
“Induction” chemoradiation, 2–3
Induction chemotherapy
chemoradiation after, 8–9
in locally advanced SCCHN,
25–28, 27t
metaanalysis of results, 25
platinum/5-FU chemotherapy, 25–27, 27t
in resectable patients, 28
vs. chemoradiation, 28–29,
29t
Institut Gustave Roussy, 64
Intensity-modulated radiation
therapy (IMRT), 91–
114
advantages of, 101–102
in coverage of midline structures, 106
in coverage of nasopharynx/
parapharyngeal tissues, 104, 105t
defined, 92
disadvantages of, 107–109
cost/resources, 108–109
increased toxicity, 108
new toxicity, 108
risk of marginal miss, 107
risk of secondary malignancy, 107–108
forward-planned, 95–96
historical perspective of, 92–
96, 92f–96f
introduction of, 91–92
inverse-planned, 95–96
in laryngopharyngeal sparing,
106
in match line dosimetry, 103–
104
in parotid sparing, 102–103
planning of, 94–95
in re-irradiation of head and
neck cancer, 107
in sparing of optic structures,
106
Intensity-modulated radiation
therapy (IMRT) treatment plan
evaluation of, 99–101, 100t
volume definition for, 96–99,
98f. See also Volume
definition, for IMRT
treatment plan
Intergroup 0099 nasopharynx
cancer trial, 3
Inverse-planned IMRT, 95–96
Lapatinib, for recurrent SCCHN,
71
Laryngeal cancer, AJCC stage IV,
13–14
Laryngopharyngeal sparing, IMRT
in, 106
Locoregional therapies
for recurrent head and neck
cancer, 62–66, 65t
salvage surgery, 62–63
for recurrent SCCHN, radiation therapy, 63–66,
65t
Malignancy, secondary, IMRT
and, 107–108
Marginal miss, IMRT and,
107
MASCC, 45
Posner.bk Page 119 Friday, October 20, 2006 11:41 AM
Index
Match line dosimetry, IMRT in,
103–104
Methotrexate, for recurrent
SCCHN, 68
Midline structures, coverage of,
IMRT in, 106
Minnie Pearl Cancer Research
Network Trial, 34
Mucositis, in head and neck cancer patients undergoing
chemoradiation, 43–
44
Mucositis Committee, of MASCC,
45
Mucositis-related symptoms, in
head and neck cancer
patients undergoing
chemoradiation, 44–
45
Multinational Association of Supportive Care in Cancer (MASCC),
Mucositis Committee
of, 45
Nasopharynx/parapharyngeal tissues, coverage of,
IMRT in, 104, 105t
Neck, cancer of. See Head and
neck cancer
Neoadjuvant chemoradiation, 2–3
Nutritional management, in head
and neck cancer
patients undergoing
chemoradiation, 45–
48
OARs, in IMRT treatment plan,
97
Optic structures, sparing of, IMRT
in, 106
119
Oral care, in head and neck cancer
patients undergoing
chemoradiation, 50–
51
Organ preservation, in SCCHN,
strategies for, chemotherapy integration in,
77–90. See also Squamous cell carcinoma
of head and neck
(SCCHN), organ preservation strategies for
Organs at risk (OARs), in IMRT
treatment plan, 97
Paclitaxel, for head and neck cancer, 10
Parotid sparing, IMRT in, 102–
103
Planning at-risk volume (PRV), for
IMRT treatment plan,
98
Planning target volume (PTV), for
IMRT treatment plan,
98–99
Planning volumes, in IMRT treatment plan, 98–99
Platinum agents
for head and neck cancer, 10
for recurrent SCCHN, 67
Platinum agents/taxanes, for recurrent SCCHN, clinical
trials using, 69
Platinum/5-FU, in locally
advanced SCCHN,
25–27, 27t
PRV, for IMRT treatment plan, 98
Psychological issues, in head and
neck cancer patients
undergoing chemoradiation, 51–54, 52t–
53t
Posner.bk Page 120 Friday, October 20, 2006 11:41 AM
120
Index
PTV, for IMRT treatment plan,
98–99
Quality of life (QOL), symptom
control vs., 42–43
Radiation therapy (RT)
chemotherapy during, 3–8, 4t–
5t
chemotherapy with. See
Chemoradiation
intensity-modulated, 91–114.
See also Intensitymodulated radiation
therapy (IMRT)
for locally recurrent SCCHN,
63–66, 65t
for patients treated with salvage surgery for
SCCHN, 63
surgical resection with, in
organ preservation for
SCCHN, 78–79
Radiation Therapy Oncology
Group (RTOG), 3, 9,
66, 94. See also specific RTOG trials
Radiation Therapy Oncology
Group (RTOG) Salivary Gland Morbidity Scale, 49t
Reactive oxygen species (ROS),
43
Recurrent disease, management of,
61–75
approaches to, 61–62, 73f
locoregional therapies in, 62–
66, 65t
systemic therapy in, 66–71,
72t, 73f
chemotherapeutic agents,
67–68
combination chemotherapy,
clinical trials using,
68–70
EGFR, 70–71
evolution of, 67
methotrexate, 68
novel targeted therapy, 70–
71, 72t
platinum agents, 67
taxanes, 67–68
triple-agent regimens, 69–70
Re-irradiation
of head and neck cancer, IMRT
in, 107
for patients with recurrent head
and neck cancer, 63–
66, 65t
Resource(s), IMRT-related, 108–
109
ROS, 43
RTOG, 3, 9, 66, 94
RTOG 85-01 trial, 7
RTOG 90-03 trial, 7, 8
RTOG 91-11 trial, 3, 6
RTOG 95-01 trial, 6–7, 15
RTOG 99-14 trial, 7–8
RTOG H-0129 trial, 18
Salvage surgery, for recurrent
SCCHN, 62–63
radiation therapy with, 63
Sequential therapy, in locally
advanced SCCHN,
32–37, 35f–37f
compared with other therapies,
33–37, 35f–37f
docetaxel-based cisplatin/5-FU
chemotherapy and
chemoradiation, phase
III trials comparing,
33–37, 35f–37f
for unresectable disease, 32–33
Posner.bk Page 121 Friday, October 20, 2006 11:41 AM
Index
“SMART” technique, 102
Sorafenib, for recurrent SCCHN,
71
Southwest Oncology Group Oropharynx trial, 34, 37,
37f
Squamous cell carcinoma of head
and neck (SCCHN)
chemoradiation vs. radiation
alone trials for, 4t–5t
locally advanced
defined, 23
treatment of, 23–40
chemoradiation in, 28–
32, 29t, 30t
combined modality
therapy in, 25–37,
27t, 29t, 30t, 35f–
37f
history of, 24
induction chemotherapy
in, 25–28. See also
Induction
chemotherapy, in
locally advanced
SCCHN
options in, 23–24
sequential therapy in,
32–37, 35f–37f
management of
approach to, 73f
goals in, 77–78
options in, 77–78
organ preservation strategies
for
best treatment options, early
identification of, 86–
88, 87f
chemotherapy integration
in, 77–90
radiation therapy and surgery, 78–79
121
systemic chemotherapy, 79–
84, 82t, 83t, 85t
recurrent
management of, 61–75. See
also Recurrent disease, management of
systemic therapy in, 66–71,
72t, 73f
re-irradiation for patients
with, 63–66, 65t
Supportive Care in Cancer, 45
Surgical resection, radiation therapy with, in organ
preservation for
SCCHN, 78–79
Swallowing abnormalities, aspiration due to, 47–48
Symptom control, quality of life
vs., 42–43
Symptom control issues, in head
and neck cancer
patients undergoing
chemoradiation, 43–
54, 46t, 49t, 52t–53t
mucositis, 43–44
mucositis-related symptoms,
44–45
nutritional management, 45–
48
oral care, 50–51
pretreatment evaluation, 52t–
53t
psychological issues, 51–54,
52t–53t
unintentional weight loss, 45–
48, 46t
xerostomia, 48–50, 49t
Systemic chemotherapy
evolution of, 6–7
in organ preservation for
SCCHN, 79–84, 82t,
83t, 85t
Posner.bk Page 122 Friday, October 20, 2006 11:41 AM
122
Index
Systemic therapy, for recurrent
SCCHN, 66–71, 72t,
73f. See also Recurrent disease, management of, systemic
therapy in
TAX 323 trial, 30t, 31, 32
TAX 324 trial, 30t, 31, 34, 37
Taxane(s)
chemoradiation and, in locally
advanced SCCHN,
29–32, 30t
for recurrent SCCHN, 67–68
Taxane(s)/5-FU, for recurrent
SCCHN, clinical trials
using, 69
Taxane(s)/platinum agents, for
recurrent SCCHN,
clinical trials using,
69
Toxicity(ies), increased or “new,”
IMRT and, 108
Tyrosine kinase inhibitors, for
recurrent SCCHN,
71
University of Chicago, 34, 35f,
64
University of Michigan, 34, 103
University of Pennsylvania, 33
University of Texas M.D. Anderson Cancer Center,
14, 17
U.S. Food and Drug Administration (FDA), 50, 68
“VA Larynx Preservation Trial,”
1, 3
Vanderbilt University, 45
Vanderbilt University Medical
Center, 34
Volume definition, for IMRT
treatment plan, 96–
99, 98f
CTVs, 97–98, 98f
GTV, 96–97
OARs, 97
planning volumes, 98–99
Weight loss, unintentional, in head
and neck cancer
patients undergoing
chemoradiation, 45–
48, 46t
Xerostomia
adverse events associated with,
48–49, 49t
in head and neck cancer patients
undergoing chemoradiation, 48–50, 49t
Posner.bk Page 123 Friday, October 20, 2006 11:41 AM
Posner.bk Page 124 Friday, October 20, 2006 11:41 AM
❖
Options in the Treatment of
Head and Neck Cancer
Edited by
Marshall R. Posner, MD
Medical Director
Head and Neck Oncology Program
Dana-Farber Cancer Institute
Boston, Massachusetts
Publishers of
ONCOLOGY
Oncology News International
Cancer Management: A Multidisciplinary Approach
www.cancernetwork.com
Posner.bk Page ii Friday, October 20, 2006 11:41 AM
COAB
Clinical Oncology Advisory Board
Note to the reader
The information in this book has been carefully reviewed for accuracy of dosage
and indications. Before prescribing any drug, however, the clinician should consult
the manufacturer’s current package labeling for accepted indications, absolute dosage recommendations, and other information pertinent to the safe and effective use
of the product described. This is especially important when drugs are given in combination or as an adjunct to other forms of therapy. Furthermore, some of the medications described herein, as well as some of the indications mentioned, may not have
been approved by the U.S. Food and Drug administration at the time of publication.
This possibility should be borne in mind before prescribing or recommending any
drug or regimen.
Educational activities in the form of monographs, audio programs, supplements, and
other formats are sent to the readership of ONCOLOGY on a regular basis. All
recipients of the journal can opt out of receiving it and accompanying educational
activities at any time by contacting our circulation department at CMPMedica,
ONCOLOGY, phone: (203) 662-6551 or by e-mail: [email protected].
Copyright ©2006 by CMPMedica, The Oncology Group. All rights reserved. This
book is protected by copyright. No part of it may be reproduced in any manner or by
any means, electronic or mechanical, without the written permission of the publisher.
Library of Congress Catalog Card Number 2006930812
ISBN 978-1-891483-41-7
Single copies of this book are available for $19.95 each. For information on obtaining
additional copies, contact the publisher, CMPMedica, The Oncology Group, 600
Community Drive, Manhasset, New York 11030. Telephone (212) 600-3012, Fax
(212) 600-3050.
Cover image: X-ray of the skull, side view, showing the upper respiratory tract,
including the larynx, pharynx, and nasal passages. (c) Alain Pol. Copyright (c) ISM/
Phototake – All rights reserved.
Publishers of
ONCOLOGY
Oncology News International
Cancer Management: A Multidisciplinary Approach
www.cancernetwork.com
Posner.bk Page iii Friday, October 20, 2006 11:41 AM
❖
Preface
When I asked coauthors to contribute chapters for this book, I wanted
them to write a brief, up-to-date review of the options for therapy and the
therapeutic decisions we all face in treating patients with head and neck
cancer. This field is rapidly changing, and care for these patients is
extremely challenging. The authors of each of the chapters are active in
clinical care and clinical research and are leading cutting edge trials in this
field. They are thinking every day about how to make the care and treatment better for our patients, and their chapters individually reflect the
most current data and insightful concepts about each topic, the therapy,
and the technology available. I think each chapter will surprise the reader
by its immediate relevance. What I also found when I read the chapters
was something for both experienced and new care givers.
Each chapter covers an important area of therapy in head and neck
cancer and gives background for practitioners and caregivers in different
disciplines. Dr. Gregory Chronowski and Dr. David Rosenthal give a very
thoughtful and logical discussion of the assessment of a patient for chemoradiotherapy and some of the very tough issues surrounding who should
be treated and how much treatment they should recieve. Decision-making
in this population is very hard, and the authors give clarity by identifying
treatment and patient factors that guide the final choice of therapy. In
Chapter 2, I give an overview of induction chemotherapy and a review of
the newest data supporting both induction therapy and sequential treatment for patients with advanced disease. This incorporates data from the
most recently reported trials in 2006. A reader would understand the practical and biologic rationale and support for a sequential treatment
approach. In her chapter, Dr. Barbara Murphy defines the issues of toxicity, quality-of-life, and management of the sequeallae of increasingly
aggressive and effective therapy. Toxicity has become a major factor in the
lives of our patients, and Dr. Murphy is a leader in articulating the biology
and the management of acute and late toxicities of chemoradiotherapy.
This chapter promotes thinking about consequences and long-term life
issues. The chapter by Dr. Ezra Cohen and Dr. Oyewale Abidoye gives a
good review and timely discussion of treatment of recurrent disease.
Although there are many new agents available, they also review data supiii
Posner.bk Page iv Friday, October 20, 2006 11:41 AM
iv
Preface
porting an expanded role for re-irradiation and the use of more standard
agents, and they address when and how to make decisions concerning
patients with recurrent cancer. Dr. David Adelstein provides a very detailed
discussion of who is an appropriate organ preservation candidate, decision-making around functional organ preservation, and the data supporting organ preservation strategies in his chapter. As this field changes and
improves, organ preservation strategies have become increasingly important in therapy decisions. Finally, Dr. Gregory Russo and Dr. Mitchell
Machtay write about the basic technology and the common questions surrounding the newest important radiation innovation, intensity-modulated
radiotherapy in their chapter. This last chapter lays an important knowledge foundation to help practitioners understand both the value and the
deficiencies of IMRT, now a standard practice for head and neck cancer.
As the reader can see, the chapters were selected to represent most of
the disciplines in head and neck cancer therapy and reflect the importance
of cross-education and multi-disciplinary care so essential to the management and success of therapy for these difficult patients. We hope readers
find this book and the topics helpful, informative, and interesting.
posFM(i-xii).fm Page v Wednesday, October 25, 2006 3:53 PM
❖
Contents
CME
3
Preface
iii
Contributing Authors
vi
Continuing Medical Education Pages
Introduction
viii
xi
Chemoradiation for Head and Neck Cancer
Gregory M. Chronowski, MD, and David I. Rosenthal, MD
Evolving Role of Induction Chemotherapy and Sequential
Therapy in the Treatment of Locally Advanced Squamous
Cell Cancer of the Head and Neck
Marshall R. Posner, MD
1
23
Increasing Cure—Increasing Toxicity: Symptom Management
and Chemoradiotherapy
Barbara A. Murphy, MD
41
Management of Recurrent Disease: Current Treatments
and New Therapies
Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD
61
Integration of Chemotherapy into Organ Preservation Strategies
for Squamous Cell Head and Neck Cancer
David J. Adelstein, MD
77
Intensity-Modulated Radiation Therapy: Promises and Practice
Gregory A. Russo, MD, and Mitchell Machtay, MD
Index
91
115
To earn CME credit, go to www.cancernetwork.com/cme and look for
Earn CME section on our site
v
Posner.bk Page vi Friday, October 20, 2006 11:41 AM
❖
Contributing Authors
Oyewale Abidoye, MD
Department of Medicine
Section of Hematology/Oncology
University of Chicago Pritzker School of Medicine
Chicago, Illinois
David J. Adelstein, MD
Department of Solid Tumor Oncology
Taussig Cancer Center
Cleveland Clinic
Cleveland, Ohio
Ezra E. W. Cohen, MD
Department of Medicine
Section of Hematology/Oncology
University of Chicago Pritzker School of Medicine
Chicago, Illinois
Gregory M. Chronowski, MD
Department of Radiation Oncology
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas
Mitchell Machtay, MD
Department of Radiation Oncology
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Barbara A. Murphy, MD
Director, Pain and Symptom Management Program
Director, Head and Neck Research Team
Vanderbilt Ingram Cancer Center
Nashville, Tennessee
vi
Posner.bk Page vii Friday, October 20, 2006 11:41 AM
Contributing Authors
Marshall R. Posner, MD
Medical Director, Head and Neck Oncology Program
Dana-Farber Cancer Institute
Boston, Massachusetts
David I. Rosenthal, MD
Director, Head and Neck Translational Research
Department of Radiation Oncology
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas
Gregory A. Russo, M.D.
Department of Radiation Oncology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
vii
Posner.bk Page viii Friday, October 20, 2006 11:41 AM
❖
Continuing Medical Education
Activity release date: November 1, 2006
Activity expiration date: December 1, 2007
About the Activity
This activity is based on the book, Options in the Treatment of Head and
Neck Cancer. It was developed from an identified educational need for
information about practical management issues in the practice of medical,
surgical, and radiation oncology.
This activity has been developed and approved under the direction of
Beam Institute.
Activity Learning Objectives
After reading Options in the Treatment of Head and Neck Cancer, participants should be able to:
• Summarize the history of head and neck cancer therapy, expounding
upon various chemoradiotherapeutic modalities used, timing of
therapy, and selection of patients, drugs, and dosing schedules.
• Review currently available treatment modalities for head and neck cancer management that may preserve crucial anatomic structures and
allow their function.
• Discuss current surgical, chemotherapeutic, and radiotherapeutic methods to treat squamous cell cancer of the head and neck and recurrence
of the disease and new therapies and treatments currently being tested
against this malignancy.
• Describe the acute and late effects of surgery and/or chemoradiotherapy used for head and neck cancer and how these treatments
affect quality of life and need for supportive care.
• Examine current best practice for surgery and administration of chemoradiotherapy for head and neck cancer and the differences
between various treatment regimens being investigated.
viii
posFM(i-xii).fm Page ix Wednesday, October 25, 2006 3:53 PM
Continuing Medical Education
ix
Target Audience
This activity targets physicians in the fields of oncology and hematology.
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Medical Education (ACCME) to provide continuing medical education for
physicians.
Continuing Education Credit
Category 1 Credit
Beam Institute designates this educational activity for a maximum of 3
American Medical Association (AMA) Physician’s Recognition Award
(PRA) Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Note: This activity complies with all ACCME, U. S. Food and Drug
Administration (FDA), and Pharmaceutical Research and Manufacturers
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scientific rigor, and objectivity. However, Beam Institute, the Grantor, and
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any errors, omissions, or inaccuracies in the activity. Discussions concerning
drugs, dosages, and procedures may reflect the clinical experience of the
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sources and may suggest uses that are investigational in nature and not
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to primary references or full prescribing information resources. The opinions
and recommendations presented herein are those of the author(s) and do not
necessarily reflect the views of the provider or producer.
To earn CME credit, go to www.cancernetwork.com/cme and look for
Earn CME section on our site
Posner.bk Page x Friday, October 20, 2006 11:41 AM
x
Continuing Medical Education
Financial Disclosure
Dr. Posner is a consultant for Amgen, Sanofi-Aventis, Medimmune, GSK,
Genentech, NCI, ASCO, and NCCN. Dr. Rosenthal is a consultant and serves
on the speaker’s bureau for BMS, Imclone, and Medimmune. The following
contributors have no significant financial interest or other relationship with
the manufacturers of any products or providers of any service mentioned in
the article: Dr. Abidoye, Dr. Adelstein, Dr. Chronowski, Dr. Cohen, Dr.
Machtay, Dr. Murphy, and Dr. Russo.
Copyright
Copyrights owned by Beam Institute, a division of CME LLC. Copyright
©2006.
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[email protected]
Supported by an educational grant by Sanofi-Aventis
Posner.bk Page xi Friday, October 20, 2006 11:41 AM
❖
Introduction
Chemotherapy, as part of a multi-disciplinary and multi-modality
approach, has become the standard of care for the treatment of locally
advanced squamous cell cancer of the head and neck. Until recently, chemotherapy has been delivered as either induction chemotherapy, also
known as neoadjuvant therapy, or in combination with radiotherapy as
chemoradiotherapy (CRT). Although induction chemotherapy with cisplatinum and 5-fluorouracil (PF) is effective in improving survival, patients
treated with induction chemotherapy have a high rate of local-regional
failure despite a reduced rate of distant failure. CRT has improved survival
by reducing local-regional failure, with no improvement in control of distant disease.
To optimize therapy, sequential therapy approaches, combining induction chemotherapy, CRT, and surgery have been developed. In addition,
recent advances in induction chemotherapy, namely the demonstration
that a three drug induction chemotherapy regimen with docetaxel, cisplatinum, and 5-fluorouracil (TPF) is significantly more effective than PF, has
increased interest and optimism regarding the potential gains of induction
chemotherapy, as a sequential therapy approach. Preliminary data support
the use of sequential therapy in patients with poor-prognosis head and
neck, and a phase III trial with this schedule shows highly encouraging
improvements in survival, lessened toxicity, and a significant advantage to
TPF in this setting.
The different treatment paradigms of sequential therapy and CRT are
being compared in phase III studies. TPF has replaced PF as the standard
for induction chemotherapy, and sequential therapy represents an acceptable standard of care for patients with curable, locally advanced head and
neck cancer.
xi
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Posner.bk Page 1 Friday, October 20, 2006 11:41 AM
❖
Chemoradiation for Head
and Neck Cancer
Gregory M. Chronowski, MD, and David I. Rosenthal, MD
History of Chemoradiation for
Head and Neck Cancer
Head and neck cancers affect more than 40,000 patients per year in the
United States (1). As a result of their location, these tumors can cause
varying degrees of functional and cosmetic deficits that are often exacerbated by cancer treatment. From the 1960s through the 1980s, surgery
and radiation therapy (RT), often postoperative, remained the primary
modalities used to treat these tumors. With the publication of the Department of Veterans Affairs (VA) larynx preservation trial in 1991 (2), the
concept of non-surgical organ preservation through the use of radiation
and chemotherapy entered the mainstream. Since then, the most significant
advances in the treatment of head and neck tumors have been the development of altered radiation fractionation schedules and concurrent chemotherapy regimens that have documented improvements in local control
and survival, respectively. In addition, the development of intensity-modulated RT has allowed for greater conformality of radiation dose, allowing
for relative sparing of adjacent dose-limiting normal tissues, most notably
the brain stem, optic nerves, spinal cord, and parotid salivary glands.
Initial attempts at concurrent chemotherapy with RT were disappointing due to significant mucosal toxicity secondary to the use of bleomycin,
5-fluorouracil (5-FU), and methotrexate, whereas the activity of many of
these agents in squamous cell carcinomas was probably not optimal. With
CME
1
Posner.bk Page 2 Friday, October 20, 2006 11:41 AM
2
Chemoradiation for Head and Neck Cancer
the development of highly effective and better tolerated platinum-based
regimens, concurrent chemoradiation regimens moved to the forefront of
investigation. The publication of a number of multi-institutional trials
documenting both improvements in local control and survival has validated concurrent chemoradiation as the standard of care for locally
advanced, non-metastatic head and neck cancers (3,4).
Despite these therapeutic gains, there are still several unanswered questions about chemoradiation. What remains somewhat controversial is the
appropriate selection of patients for concurrent chemotherapy regimens,
as this approach improves survival primarily through improvements in
local control. In earlier stage cancers or in patients with non-bulky primary tumors and/or small-volume lymphadenopathy, locoregional control
with RT alone using standard or altered fractionation regimens can be
excellent, and whether there is incremental benefit from the addition of
concurrent chemotherapy is an area of debate. Despite a general consensus
that platinum-containing regimens are optimal, the actual dose schedule
and types of agents to add to platinum remain open questions, with various cooperative groups and institutions advocating different drug combinations. In particular, the role of neoadjuvant chemotherapy remains an
active area of discussion.
Neoadjuvant or “Induction” Chemoradiation
Neoadjuvant, or “induction,” chemotherapy is a term commonly used to
describe the administration of chemotherapy followed by RT (or surgery)
alone. Advocates for neoadjuvant chemotherapy approaches in head and
neck cancers cite the fact that there is better compliance, and therefore
greater potential benefit from induction therapy than for concurrent or
adjuvant chemotherapy. Higher doses of chemotherapy drugs can be
given, with fewer unplanned delays and dose reductions, and multiple
agents may be used over multiple cycles as compared to concurrent
chemoradiation approaches that typically include lower doses of single
agents over 6–7 weeks. The higher doses of chemotherapy given with neoadjuvant approaches may have greater potential to address subclinical foci
of systemic micrometastases that occur in up to 20%–40% of patients
receiving curative therapy for locoregionally confined disease. Critics of
this approach cite the potential for tumors to progress during chemotherapy, making it more difficult to obtain local control with curative modalities such as RT or surgery. In addition, some have suggested that treatment
of head and neck tumors with neoadjuvant chemotherapy may select for
more aggressive clonogens that may be less amenable to treatment with
Posner.bk Page 3 Friday, October 20, 2006 11:41 AM
Chemoradiation for Head and Neck Cancer
3
RT (5). At this time, the weight of the evidence in the medical literature
supports concurrent chemoradiation over neoadjuvant chemotherapy
approaches. A recent large meta-analysis (6) has confirmed the superiority
of concurrent chemoradiation over neoadjuvant chemotherapy; nevertheless, there appears to be some greater benefit from platinum-containing
neoadjuvant regimens (7). Although most trials have not shown a survival
benefit for neoadjuvant approaches, two trials have documented a survival
advantage over RT alone (8,9), but the concept is not universally accepted.
One of the earliest trials of neoadjuvant chemotherapy is the so-called
“VA Larynx Preservation Trial” (2). Published in 1991, this trial randomized patients with stage III or IV larynx cancer to either (a) three cycles of
neoadjuvant chemotherapy with cisplatin and 5-FU followed by definitive
RT or (b) laryngectomy followed by postoperative RT. This trial showed
equivalent 2-year survival (68%) between the nonsurgical and surgical
arms. It is important to note that this trial did not appropriately test the
role of neoadjuvant chemotherapy, as the study did not include an RTalone arm. This shortcoming was addressed in the Radiation Therapy
Oncology Group (RTOG) 91-11 trial (10). This three-arm trial randomized patients with advanced laryngeal cancer to either RT alone, neoadjuvant cisplatin and 5-FU followed by RT, or concurrent cisplatin and RT.
An update of this trial was presented in 2006 (11). At 5 years, both concurrent cisplatin/RT and induction chemotherapy followed by RT had
superior laryngectomy-free survival (47% and 45%, respectively) compared to RT alone (34%). Concurrent cisplatin and RT had superior
locoregional control (69%) compared to neoadjuvant chemotherapy followed by RT (55%) or RT alone (51%). Overall survival at 5 years was
statistically similar between all three arms at approximately 55%.
Concurrent Chemoradiation
The administration of chemotherapy during RT is commonly referred to
as concurrent chemoradiation or simply chemoradiation. This approach is
now the standard of care in most locally advanced cancers of the head and
neck based on the results of multiple randomized trials that have documented a survival benefit (Table 1). Chemoradiation appears to confer a
survival benefit over RT alone in both the “unresectable” setting as well as
the postoperative setting.
The first large head and neck cancer trial documenting a survival benefit to concurrent chemoradiation was the Intergroup 0099 nasopharynx
cancer trial (12). This trial randomized patients to 70 Gy of RT alone with
or without three cycles of concurrent cisplatin followed by three cycles of
Posner.bk Page 4 Friday, October 20, 2006 11:41 AM
4
Chemoradiation for Head and Neck Cancer
Table 1. Selected Randomized Chemoradiation versus Radiation Alone
Trials for Head and Neck Squamous Cancer
Trial
(Reference) Agents
ChemoNo. of
therapy
Patients Schedule
Definitive chemoradiation trials
Adelstein et Cisplatin
295
al. (15)
Site
Radiation
Therapy
3×
Multiple
qd
Al-Sarraf et
al. (12)
Cisplatin
193
3×
Nasopharynx
qd
Brizel et al.
(20)
Cisplatin +
5-FU
116
2×
Multiple
bid
Oropharynx
qd
Larynx
qd
Multiple
bid
Postoperative
qd
Multiple
qd
Postoperative
qd
Carbopla226
3×
tin + 5FU
Forastiere et Cisplatin
547
3×
al. (RTOG
91-11)
(10)
Jeremic et
Cisplatin or 159
Daily
al. (27)
carboplatin
Postoperative chemoradiation trials
Cooper et
Cisplatin
495
3×
al. (17)
(RTOG
95-01)
Bachaud et Cisplatin
83
Weekly
al. (28)
Denis et al.
(14)
Bernier et
al. (16)
(EORTC
22931)
Cisplatin
334
3×
bid, twice daily; 5-FU, 5-fluorouracil; qd, once daily.
Posner.bk Page 5 Friday, October 20, 2006 11:41 AM
Chemoradiation for Head and Neck Cancer
5
Table 1. Selected Randomized Chemoradiation versus Radiation Alone
Trials for Head and Neck Squamous Cancer (Continued)
Follow- Local
Resectable Up
Control
DiseaseFree
Survival
Definitive chemoradiation trials
No
3y
—
—
24% vs.
69%;
P <.001
—
Overall
Survival
Distant
Metastases
23% vs.
37%;
P = .014
47% vs.
78%;
P <.005
34% vs.
55%;
P = .07
16% vs.
22%;
P = .05
No difference
18% vs. 22%;
not significant
10% vs. 2%;
P not given
—
3y
—
Both
3y
44% vs.
70%
—
5y
Yes
2y
15% vs.
25% vs.
48%;
27%;
P = .002
P = .01
70% vs.
—
88%;
P <.001
No
5y
—
Yes
5y
Yes
3y
59% vs.
23% vs.
13% vs.
30% vs. 26%;
77%;
45%;
36%;
not signifiP = .08
P <.02
P <.01
cant
69% vs.
41% vs.
41% vs.
25% vs. 21%;
82%;
59%;
65%;
not signifiP = .007
P = .0014
P = .0096
cant
18% vs. 27%;
P not given
11% vs. 11%;
not significant
16% vs. 8%;
P = .03
27% vs.
25% vs.
43% vs. 14%;
51%;
46%;
P = .0013
P = .018
P = .007
Postoperative chemoradiation trials
Yes
3.8 y
72% vs.
—
No differ- 23% vs. 20%;
82%;
ence
not signifiP = .01
cant
Posner.bk Page 6 Friday, October 20, 2006 11:41 AM
6
Chemoradiation for Head and Neck Cancer
adjuvant cisplatin and 5-FU. The addition of chemotherapy led to significant improvements in local control, reduction in distant metastases, and
improved 3-year overall survival (78% vs. 47%, P = .005).
In regard to oropharynx cancer, Calais et al. (13) and Denis et al. (14)
randomized 226 patients to 70 Gy of RT with or without three cycles of
concurrent cisplatin and 5-FU. Five-year local control (48% vs. 25%), disease-free survival (27% vs. 15%), and overall survival (22% vs. 16%)
were significantly improved with the addition of chemotherapy. Rates of
grade 3 and 4 mucositis were increased in the chemotherapy arm (71% vs.
39%) primarily due to the addition of 5-FU, a potent potentiator of radiation mucositis. The publication of this trial in 1999 was particularly
important because an accompanying editorial suggested that chemoradiation should become an accepted standard of care for patients with locally
advanced non-metastatic head and neck cancer (3).
Adelstein and colleagues (15) randomized 295 patients in an intergroup
study with non-nasopharyngeal head and neck squamous cell carcinomas,
primarily cancers of the oropharynx, to either 70 Gy continuous daily RT
alone, 70 Gy continuous daily RT with three cycles of concurrent cisplatin
chemotherapy, or 70 Gy split-course RT with three cycles of concurrent cisplatin. Split-course RT has long been known to be an inferior fractionation
schedule for head and neck cancers due to the repopulation of tumor during
the treatment break, although it does result in less toxicity, primarily mucositis. Nevertheless, a hypothesis of this trial was that the loss of efficacy of
split-course RT could be overcome with the addition of concurrent chemotherapy, and the time of break allowed for surgical evaluation of patients
whose tumors were previously considered “unresectable.” At 3 years, overall survival was significantly improved with continuous once-daily RT and
concurrent cisplatin (37%) compared to RT alone (23%), whereas the overall survivals between the split-course RT/chemotherapy arm and the RTalone arm were not statistically different at 27% and 23%, respectively.
The RTOG 91-11 trial (10,11) has already been discussed in the preceding section, but it also documented a local control and larynx preservation benefit to concurrent chemoradiation in larynx cancer. The lack of a
significant survival benefit to concurrent chemotherapy and induction chemotherapy in larynx cancer is noteworthy and may be related to the fact
that local failures are more readily salvaged with laryngectomy as opposed
to other head and neck sites.
In the postoperative setting, it is important to note that the European
Organisation for Research and Treatment of Cancer (EORTC) 22931 trial
(16) documented significant improvements in local control, disease-free
survival, and overall survival with chemoradiation over RT alone. The
RTOG 95-01 trial (17) documented improvements in local control and
Posner.bk Page 7 Friday, October 20, 2006 11:41 AM
Chemoradiation for Head and Neck Cancer
7
disease-free survival but was not powered to demonstrate, nor did it show,
a significant difference in overall survival. A pooled analysis of EORTC
22931 and RTOG 95-01 was performed (18) and found that the addition
of cisplatin to postoperative RT improved outcomes for patients with
microscopically involved resection margins or extracapsular spread of
tumor from neck nodes. Concurrent chemoradiation should be considered
the standard of care in patients with these characteristics in the postoperative setting.
Cisplatin-based chemotherapy regimens have been used in all concurrent chemotherapy protocols to date and have found favor due to cisplatin’s activity, the ability to deliver it as a single agent in full dose with
RT, and because it adds relatively little to stomatitis and radiation mucositis compared to other agents (19).
Compared to concurrent chemoradiation, there does not appear to be
an effect on overall survival with radiation dose escalation alone in head
and neck cancer. Brizel et al. (20) showed no difference in overall survival
with higher-dose hyperfractionated RT alone to 75 Gy versus similarly
fractionated RT to 70 Gy but with concurrent cisplatin and 5-FU. In fact,
local control remained improved with the chemoradiation regimen (70%)
versus the radiation dose-escalation regimen (44%). This is similar to the
esophageal cancer literature. The RTOG 85-01 trial (21) randomized
patients with esophageal cancer to 50 Gy of RT with two cycles of concurrent cisplatin/5-FU versus RT alone to a higher dose of 64 Gy. The 5-year
overall survival favored the chemotherapy arm at 26% versus 0% for the
RT-alone arm.
There remains little consensus regarding the optimal RT fractionation
regimen when concurrent chemoradiation is used. To date, most concurrent chemoradiation protocols have used once-daily fractionation regimens using 2 Gy per day to doses of approximately 70 Gy. There have
been documented improvements in local control with altered fractionation regimens using RT alone. The RTOG 90-03 trial (22) showed
improved local control with hyperfractionation (1.2 Gy bid to 81.6 Gy)
and accelerated fractionation with concomitant boost (1.8 Gy once daily,
with a second daily fraction of 1.5 Gy administered toward the end of
RT as a “boost” to 72 Gy) compared to standard 2-Gy fractions per day
to 70 Gy.
Nevertheless, it is unclear as to whether there is a benefit to altered
fractionation in the setting of concurrent chemoradiation. The RTOG 9914 trial (23) addressed this question in a phase II trial that used the concomitant boost fractionation schedule (72 Gy/6 weeks) with two cycles of
concurrent cisplatin. Outcomes were favorable with acceptable toxicity;
local control was 65%, which compares favorably to a local control rate
Posner.bk Page 8 Friday, October 20, 2006 11:41 AM
8
Chemoradiation for Head and Neck Cancer
of 54% found in the concomitant boost RT-alone arm of RTOG 90-03
(22). Overall survival in RTOG 99-14 was 71.6%, which also compares
favorably to the 50.9% overall survival seen in RTOG 90-03 with concomitant boost RT alone. Obviously, a direct comparison of outcome
between these two trials is inappropriate from a statistical standpoint;
however, the RTOG completed accrual in the summer of 2005 for a phase
III trial comparing standard fractionation chemoradiation with altered
fractionation (concomitant boost) chemoradiation (RTOG H01-29). Both
arms are to receive concurrent cisplatin chemotherapy; two cycles for the
altered fractionation arm due to the shortened treatment time and three
cycles for the standard fractionation treatment arm. The goal of this trial is
to determine a fractionation standard for all subsequent concurrent chemoradiation trials.
It is clear that aggressive altered fractionation regimens combined with
certain chemotherapy agents can result in unacceptable toxicity. A trial by
Staar and colleagues (24) randomized patients to accelerated concomitant
boost RT to 69.9 Gy with or without two cycles of carboplatin and 5-FU.
There was no difference between the two groups in regard to local control
or overall survival. However, there was significantly more grade 3 and 4
mucositis in the chemoradiation arm (68% vs. 52%) and significantly
higher rates of gastrostomy tube dependence due to dysphagia (51% vs.
25%). RTOG 90-03 documented higher rates of acute and late toxicity
with altered fractionation, and these appear to have been exacerbated by
the administration of concurrent cisplatin and 5-FU.
In general, most trials of concurrent chemoradiation have not documented reductions in the rates of distant metastases with the addition of
concurrent chemotherapy to RT (see Table 1). As a result, the survival benefit imparted by chemotherapy is primarily due to improvements in local
control.
Induction Chemotherapy Followed
by Chemoradiation
An intriguing approach to the integration of neoadjuvant chemotherapy in
the treatment of head and neck cancer is the use of induction chemotherapy followed by concurrent chemoradiation; an approach that has not
been tested in prior randomized trials. This approach addresses the risk of
systemic micrometastases with the neoadjuvant portion of treatment,
whereas the issue of local control is addressed directly with the concurrent
portion of treatment. A recent study comparing two different induction
regimens (docetaxel plus cisplatin and 5-FU [TPF] vs. PF) followed by sim-
Posner.bk Page 9 Friday, October 20, 2006 11:41 AM
Chemoradiation for Head and Neck Cancer
9
ilar concurrent chemoradiation, did show an improvement in overall survival favoring the TPF arm (25). Although this suggests that more active
induction regimens can affect survival, the incremental benefit of the use of
induction chemotherapy before chemoradiation is still unknown and
under investigation. This approach has been piloted in several phase II trials, and there are now at least three ongoing phase III trials comparing
chemoradiation alone to the addition of induction therapy.
Chemoradiation Regimens
It is clear that chemoradiation imparts an increase in both early and late
toxicities compared with RT alone. In particular, mucositis and long-term
gastrostomy tube dependence secondary to dysphagia have emerged as
major dose-limiting toxicities for chemoradiation (26). It is also clear that
single-agent cisplatin (100 mg/m2 every 3 weeks) appears to be relatively
well tolerated and has demonstrated improvements in overall survival during rigorous testing in multiple phase III trials conducted by various academic and community practices. This regimen has, therefore, been adopted
by the RTOG as their standard reference regimen.
Most trials of concurrent chemoradiation have used high-dose cisplatin
(100 mg/m2 every 3 weeks). This approach achieves a relatively high systemic dose exposure that may address subclinical micrometastases while
still providing some radiosensitization. Alternatively, some trials have used
low-dose weekly regimens due to the understanding that survival benefits
with chemoradiation are primarily due to improvements in local control.
Low-dose weekly regimens provide more opportunity for tumor radiosensitization on this basis. In addition, toxicity may be more easily managed
with weekly regimens through the use of short chemotherapy breaks without RT breaks, and weekly regimens may also result in less systemic toxicity for some patients. Jeremic et al. (27) used cisplatin at a dose of 6 mg/m2
daily (total, 30 mg/m2/week) and did document a survival benefit and, surprisingly, a reduction in distant metastases, leading many to favor a weekly
dose of 30 mg/m2. In the postoperative setting, Bauchaud et al. (28) gave a
fixed dose of 50 mg weekly, which also translates to approximately 30 mg/
m2/week and offers further support for this dose as a reasonable choice for
weekly cisplatin regimens, though it has not been confirmed in additional
prospective trials. Nonetheless, the RTOG has accepted its use in at least
one postoperative trial currently under way and also when combined with
cetuximab (RTOG 0234). Single-agent carboplatin with a weekly area
under the curve (AUC) dose of 1.5–2.0 was also used by Jeremic et al. (27)
and found to be well tolerated with no difference in efficacy compared to
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10
Chemoradiation for Head and Neck Cancer
cisplatin at 6 mg/m2/day. A randomized phase II trial from Japan (29)
compared daily cisplatin at 4 mg/m2/day and carboplatin at 100 mg/m2
and found that outcomes were improved in the carboplatin arm; however,
the authors acknowledged that this may have been due to the low doses of
cisplatin used in the trial.
Concurrent chemoradiation with platinum agents and 5-FU was used
by Calais et al. (13) and Brizel et al. (20) with good results. The dose of 5FU in both of these trials was 600 mg/m2 every 3 weeks given with either
carboplatin or cisplatin, respectively. This regimen is highly active when
used in the neoadjuvant and metastatic setting; however, the overlapping
toxicities of stomatitis and mucositis with concurrent RT are substantial
(30,31). Based on the preceding efficacy data, the RTOG has selected concurrent cisplatin at 100 mg/m2 every 3 weeks as a standard arm because
this regimen is thought to provide the best balance of efficacy and tolerability. It is realized, however, that selected institutions are proficient in
stewarding patients through the increased toxicity of concurrent cisplatin
and 5-FU regimens.
There is increased interest in using taxanes in concurrent chemoradiation regimens; however, this approach is still being investigated in the
phase III setting. The greatest experience is with paclitaxel. Doses of 30
mg/m2/week can be delivered without necessitating unscheduled treatment
interruptions or dose reductions (32,33). Doses of paclitaxel can be escalated further; however, unscheduled treatment interruptions and dose
reductions are necessary (34). It also appears that cisplatin at an AUC of 2/
week (35) can be added to paclitaxel without significant additional toxicity. The combination of concurrent weekly cisplatin (20 mg/m2) and
weekly paclitaxel (30 mg/m2) was tested by the RTOG in a randomized
phase II trial (97-03) (36) that compared the preceding regimen to two
other arms consisting of 5-FU/cisplatin and 5-FU/hydroxyurea given on
somewhat nontraditional schedules. The best 2-year disease-free survival
and overall survival rates (51% and 67%, respectively) were found for the
cisplatin/paclitaxel arm, although all three arms had superior outcomes
when compared to historical controls treated with concurrent cisplatin
and RT alone. Docetaxel is also highly active in head and neck cancers
(37). There are no randomized trials investigating this agent administered
concurrently with RT, but docetaxel (15 mg/m2/week) and cisplatin (20
mg/m2/week) have been combined with accelerated concomitant boost RT
in a clinical trial (38). In the neoadjuvant setting, three trials were presented in 2006 documenting a benefit to adding docetaxel to cisplatin and
5-FU (Table 2).
Other than the preceding, no other agents or drug schedules have been
sufficiently investigated to be considered reasonable options for combination
220
501
5-FU, 5-fluorouracil; RT, radiation therapy.
GORTEC
2000–01
(61)
Tax 324
(25)
Multiple
Site
Induction fol- Multiple
lowed by
concurrent
chemotherapy/RT
Induction
Larynx and
followed
hypoby RT
pharynx
alone
Induction
followed
by RT
alone
385
Vermoken
(EORTC
24971)
(60)
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
Docetaxel/
cisplatin/5FU vs.
cisplatin/5FU
No. of
Patients Schedule
Trial
(Reference) Schema
70 Gy conventional
70–74 Gy conventional
or hyperfractionated
70 Gy conventional
RT
Table 2. Selected Randomized Trials of Taxanes in Neoadjuvant Chemotherapy
3y
3y
3y
Laryngectomy-free
survival:
80% vs.
58%
Median, 32
mo: 8.2
mo vs. 11
mo; P =
.0071
49% vs.
37%; P =
.004
DiseaseFollow- Free
Up
Survival
—
Median, 51
mo: 14.2
mo vs.
18.6 mo;
P = .0052
62% vs. 48%;
P = .0058
Overall
Survival
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Chemoradiation for Head and Neck Cancer
with RT in the noninvestigational setting. Gemcitabine is a potent radiosensitizer but induces significant mucositis, dysphagia, and aspiration (39).
Appropriate Selection of Patients for
Chemoradiation in Head and Neck Cancer
Locoregional control of advanced head and neck cancer can exceed 70% with
concurrent chemoradiation approaches (6,10,11,13,16,18,20,28). However,
with the reduction in mortality associated with improved control of locoregional disease above the clavicles, reduction of the competing risk of death
from distant metastases becomes increasingly relevant. The overall rate of distant metastases may exceed 40% in patients with N3 lymphadenopathy (40).
Vokes and colleagues (41) have referred to this phenomenon of an increase in
distant failure in patients who achieve locoregional control of disease as a
“reversal of the historical pattern of failure” in which, historically, local failure
at the primary tumor site exceeded the incidence of distant metastases.
Therapeutic approaches currently available for patients with locally
advanced head and neck cancers include the following:
1.
2.
3.
Surgical resection followed by postoperative RT with or without
chemotherapy, depending on the presence of high risk factors
(primarily extracapsular spread of nodal disease or microscopically
positive margins) (18)
Concurrent chemoradiation with surgical salvage if necessary
Altered fractionation RT alone with surgical salvage if necessary
With these three options in mind, it is important to remember that the
goal of the multidisciplinary team in assigning patients to appropriate
therapy should be to maximize the projected tumor control probability
while preserving function, structure, and cosmesis.
Patients with locoregionally confined head and neck cancer can be roughly
divided into three groups from least to most aggressive:
Early stage:
T1 or favorable T2 primary tumors
N0–N1 lymphadenopathy
M0
Intermediate stage:
Unfavorable (infiltrative) T2 or favorable (exophytic) T3 primary
tumors
N0–N1 lymphadenopathy
M0
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13
Advanced stage:
Unfavorable (infiltrative) T3 primary tumors
T4 primary tumors
N2 or N3 lymphadenopathy
M0
The boundaries between these groups are obviously vague, but nevertheless
do provide some framework for assigning patients to appropriate therapy. The
terms “favorable” and “unfavorable” are traditional terms used to describe
the appearance and behavior of primary head and neck tumors. Favorable
tumors appear exophytic with lower tumor volume and clearly demarcated
boundaries on physical examination, whereas unfavorable tumors appear
infiltrative and ulcerated with higher tumor volume and vague demarcation on
examination. This distinction has been shown to be relevant to tumor
response in clinical trials in which exophytic tumors responded more favorably to RT than those that were ulcerative or endophytic (42). Patients with
early stage disease have a risk of distant metastases of generally less than 10%,
and locoregional control with RT alone (either standard fractionation or
altered fraction) is often in excess of 80%. As a result, the use of chemoradiation in this subset of patients may not be required and is not presently supported by the literature. Patients with advanced stage disease have local
control rates of only 40%–60% when treated with RT alone and rates of distant metastases of 30%–40%. Chemoradiation improves overall survival by
approximately 10%–15% or more in this subset of patients, and as a result
should be considered the standard of care.
The greatest area of controversy in regard to selection of therapy lies, not
surprisingly, with the intermediate stage patients and in patients who are not
easily classified into the above categories. Most chemoradiation protocols in
head and neck cancer that have documented a benefit to concurrent chemoradiation have included patients with American Joint Committee on Cancer
(AJCC) stage III or IV disease. However, this is a heterogeneous group of
patients that includes patients with small T1/T2 N1 tumors, as well as those
with large T3/ T4 N2/ N3 tumors. Mendenhall and colleagues (43) used the
preceding criteria to describe a favorable subset of patients with AJCC stage
IV laryngeal cancer who had excellent outcomes with altered fractionation RT
alone. These patients in general had advanced primary tumors but limited
nodal disease.
In particular, there is controversy as to whether patients with small (T1/
T2) primary tumors but advanced nodal disease derive a benefit from the
more toxic chemoradiation approaches, despite being technically classified
as stage III or IV. A recent retrospective review by Garden et al. (44) analyzed 299 patients with oropharyngeal Tx, T1, or T2 primary disease and
N1, N2, or N3 nodal disease (i.e., patients with small primary tumors who
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Chemoradiation for Head and Neck Cancer
are classified as AJCC stage III or IV due to nodal disease and not due to
advanced primary disease) treated at the University of Texas M.D. Anderson Cancer Center. All patients received RT alone, either conventionally
fractionated or via altered fractionation regimens, without chemotherapy.
This study found that locoregional control with RT alone was 95% for
patients with Tx–T1 tumors, regardless of nodal stage, and 79% for
patients with T2 tumors, regardless of nodal stage. The 5-year rate of distant metastases for patients with N1/2a disease was 11%, compared with
28% for patients with N2b/N2c/N3 disease. The 5-year actuarial disease
recurrence–free survival rate for patients with T1/Tx disease was 80%,
compared with 67% for patients with T2 disease. The 5-year overall survival rate for the entire cohort was 64%. These results compare quite
favorably with the results of the numerous phase III trials of chemoradiation (see Table 1), and the authors conclude that local treatment intensification by the addition of concurrent chemotherapy to RT would not
significantly benefit this subset of patients. Nevertheless, these patients are
still at risk for the development of distant metastatic disease; however, the
role of neoadjuvant or adjuvant chemotherapy or biotherapy approaches
that address this risk is still unclear and is being evaluated in clinical trials.
It is important to remember that definitive concurrent chemoradiation
in head and neck cancer primarily improves survival through improvements in locoregional control. As a result, advanced T stage is a more accurate predictor of which patients are at high risk for local failure and will
thus benefit most from concurrent chemoradiation approaches. The presence of advanced nodal disease is a more accurate predictor for the risk of
neck failure and distant metastases and should be used in determining
which patients should receive therapy directed at reducing such. Also, concurrent chemoradiation has been beneficial for postoperative patients with
advanced nodal disease—namely, those with extracapsular spread. The
preceding discussion highlights the need for treatment decisions to move
beyond simple tumor/node/metastasis stage groupings and evaluate individual tumor, patient, and treatment factors.
Selection Factors for Chemoradiation
There can be great heterogeneity in prognosis between different tumor
sites and subsites in the head and neck that is not adequately reflected by
the present AJCC staging system. Stage for stage, tumors of different sites
can have widely differing prognoses. For example, 5-year overall survival
with RT alone for T2 cancers of the glottic larynx is in excess of 90% (45),
whereas it is only 52% for patients with T1–T2 hypopharyngeal cancers
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15
(46). Even among tumors arising in the same site, there can be significant
variability among tumors of the same stage according to growth pattern.
For tumors of the base of the tongue, as noted, Weber and colleagues (47)
reported a 2-year rate of local control of 84% for exophytic tumors and
58% for ulcerative/infiltrative tumors. Impairment of function also predicted poorer outcome in this report. In general, patients with non-bulky
T1/T2 tumors or T3 tumors with “favorable” growth patterns can be successfully managed with RT alone, either standard or altered fractionation,
as appropriate. Chemoradiation should be considered as standard for
more advanced tumors. At the present time, tumor-related selection factors for the treatment of head and neck cancers rely primarily on clinical
evaluation of tumor size, growth pattern, and organ compromise. In the
future, biologic and molecular tumor markers that predict for outcome
with various therapies will be developed (48).
Although the preceding discussion has concentrated on the use of RT as
the primary modality to achieve local control in head and neck cancers, it
is important to acknowledge that in some cases surgical resection may be
preferable to definitive RT. For patients with early stage head and neck
cancers, RT or surgery results in similar rates of local control, but with very
different functional-, cosmetic-, and treatment-related morbidities. For
example, many patients with early stage oral cavity cancers are preferentially treated with surgery to avoid the morbidity of RT-induced xerostomia and the increased risk of soft tissue and bone injury (49). In particular,
early (T1/T2) cancers of the oral cavity can achieve excellent local control
with surgery alone while preserving function if techniques such as hemiglossectomy are used. Patients with larger oral cavity tumors or patients
with adverse pathologic findings, such as perineural invasion, positive
margins, or more than one involved cervical lymph node, benefit from the
addition of adjuvant RT to improve local control (50,51).
In laryngeal cancer as well, surgical resection may be preferable in
selected cases. Adequate baseline organ function is a prerequisite for functional organ preservation. For instance, the use of chemoradiation in the
case of a locally advanced T3 or T4 laryngeal tumor in a patient with compromised swallowing function and significant evidence of aspiration on
baseline examination is probably an exercise in futility, as the patient
would have a high likelihood of requiring toilet laryngectomy for progressive aspiration post-therapy (52) as well as a high likelihood of gastrostomy tube dependence due to progressive dysphagia post-therapy. These
patients are better served with laryngectomy, as there is little baseline function to preserve. With the publication of the pooled analysis of RTOG
9501 and EORTC 22931 (18), there appears to be a benefit to the addition
of concurrent chemotherapy to RT in the postoperative setting for patients
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Chemoradiation for Head and Neck Cancer
with adverse pathologic features. The blind adherence to organ-preserving
approaches in head and neck cancer without full recognition of the baseline and post-therapy function is not in the patient’s long-term best interest. It is important to remember that tumor-related dysfunction and
treatment-imposed dysfunction both contribute equally to long-term functional outcome. Adequate baseline organ function is a prerequisite for
functional organ preservation with chemoradiation.
Patients bring a multitude of preferences and preconceptions to the
table when selecting cancer treatment. These preferences are influenced,
among other things, by level of education, socioeconomic status, social
support, religious views, and experience with the health care system. It is
important that all members of the treatment team establish a partnership
with the patient that takes all of the preceding factors into account when
selecting a mutually agreeable treatment plan. Nevertheless, it is incumbent on physicians to provide a balanced view during the education of
patients regarding the benefits of intensive curative therapy and its attendant risks and toxicities. Obviously, patient preference after a discussion
of the preceding ultimately forms the basis of the mutually agreed on treatment plan.
In addition to reliability, social support, and the means to comply with
therapy and follow-up, patients must have adequate performance status
and functional reserve, as well as the psychological make-up to tolerate
aggressive cancer therapies. Different chemoradiation regimens have a
spectrum of toxicities. A specific regimen may be appropriate for a robust,
high-performance status patient with significant physiological reserve, but
not for one more physiologically compromised. It is, therefore, critical that
physicians are familiar with the acute and chronic treatment-related toxicities for specific therapeutic regimens so that informed recommendations
are based on expected patient tolerance.
The experience of individual physicians with the treatment of head and
neck cancers is important when selecting patients for chemoradiation.
Chemoradiation requires close collaboration and communication among
all members of the multidisciplinary team that should include physicians
from head and neck surgery, radiation oncology, medical oncology, radiology, pathology, and dental oncology. In addition, input from allied health
providers from nutrition and speech and swallowing therapy is also necessary if outcomes are to be optimized in these complex patients. The lack of
any of the above components can significantly hinder the optimal treatment of the head and neck cancer patient, and, as a result, facilities without the necessary expertise in the preceding disciplines should probably
consider referral of head and neck cancer patients to a tertiary facility with
the necessary expertise.
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The importance of expertise in every component of the multidisciplinary care team is exemplified in a study conducted at a tertiary care
institution evaluating the reinterpretation of computed tomography and
magnetic resonance imaging by an expert head and neck radiologist on
patients referred with head and neck cancer. This showed a change in
interpretation in approximately one-half of cases that resulted in changes
in treatment recommendation for nearly all patients in this group (53).
Even within disciplines, the collaborative review of patient treatment
plans can improve the quality of care in patients with head and neck cancer. At the University of Texas M.D. Anderson Cancer Center, the RT
treatment plans are reviewed in a biweekly intradisciplinary conference
attended by all radiation oncologists who treat head and neck cancers,
during which patients are physically present and examined by all physicians in attendance. A review of the recommendations of 134 patients presented at this conference found that peer review led to changes in
treatment plans for 66% of patients. Most changes were minor, but 11%
of changes were major and thought to be of a magnitude that could potentially affect therapeutic outcome or normal tissue toxicity. Most changes
involved target delineation based on physical findings (54).
Conclusion
Chemoradiation for locally advanced head and neck cancer has been extensively investigated since the 1980s. The randomized data clearly document
improvements in both locoregional control and overall survival with concurrent chemoradiation compared to identical RT regimens given without chemotherapy for appropriately selected patients. However, improvements in
outcome with concurrent chemoradiation are achieved at the expense of
increased acute and late toxicities, including dysphagia and aspiration (55).
Despite hundreds of clinical trials involving thousands of patients on the subject, there remains no definitive standard regarding patient selection for
chemoradiation approaches, the appropriate radiation fractionation schedule,
which chemotherapy agents to use, or the optimal chemotherapy schedule.
Nevertheless, based on a thorough review of the literature, we propose
the following general guidelines for the use of concurrent chemoradiation
in head and neck cancers:
• Patients with T1 and favorable T2 tumors with N0 or N1 lymphadenopathy achieve excellent local control with once-daily RT alone.
• Patients with unfavorable T2 or exophytic T3 tumors with N0 or
N1 lymphadenopathy are well served with altered fractionation
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Chemoradiation for Head and Neck Cancer
schedules of RT alone based on the consistent finding that locoregional control is improved without appreciable increase in late toxicity for this group of patients. Survival in these patients is primarily
dependent on achieving locoregional control, as there is minimal
risk for distant micrometastases.
• Although contentious, patients with T1 or T2 tumors with N2 or N3
lymphadenopathy achieve excellent control with RT alone, with neck
dissection for residual neck disease or consideration for planned neck
dissection, especially in non-oropharynx cancer patients (56–59).
Given the rather high risk of distant metastases in these patients, this
population is ideally suited for testing the efficacy of sequential (adjuvant or neoadjuvant) chemoradiation, with the goal of improving
survival.
• Patients with unfavorable T3 and T4 tumors with N2 or N3 lymphadenopathy are ideally suited for treatment with concurrent
chemoradiation.
• Patients with stage III or IV head and neck cancer treated with surgery
who have evidence of extracapsular spread of tumor from lymph nodes
or microscopically involved resection margins have improved survival
with adjuvant concurrent chemoradiation approaches based on the
results of a pooled analysis of two adjuvant chemoradiation trials (18).
In regard to the specifics of chemoradiation schedules, we suggest the
following:
• Neoadjuvant, or induction, chemotherapy is no longer considered
standard treatment for larynx cancer.
• For non-laryngeal, locally advanced primary tumors of the head and
neck (primarily oropharynx and nasopharynx), concurrent cisplatinum (100 mg/m2 every 3 weeks) and conventionally fractionated
RT (70 Gy at 2 Gy per fraction) has been shown to improve overall
survival in multiple randomized trials and is the most commonly
accepted, but not exclusive, standard of care.
• In the non-investigational setting, the role of altered fractionation
regimens (twice-daily RT or accelerated concomitant boost RT) combined with concurrent chemotherapy remains unclear. The results of
the now closed RTOG H-0129 trial are maturing and should help
answer this question.
• Lower-dose, weekly concurrent chemotherapy regimens provide
radiosensitization and improve locoregional control, but in general
have less effect in preventing distant metastases. Emerging regimens
include carboplatin alone (AUC = 1.5–2.0), paclitaxel alone (30 mg/
m2/week) or combined paclitaxel (30 mg/m2/week) with either cis-
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platin (20 mg/m2/week) or carboplatin (AUC = 1.5–2.0). The preceding regimens have been tested in phase II, but have not been
validated in the phase III setting.
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oropharyngeal cancer treated by radiotherapy. Head Neck 1996;18(6):552–559.
60. Remenar E, Van Herpen C, Germa Lluch J, et al. A randomized phase III multicenter trial of neoadjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF) versus
neoadjuvant PF in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN). Final analysis of EORTC 24971. 2006
ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18s):abstr.
61. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing
induction chemotherapy using cisplatin (P) fluorouracil (F) with or without
docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01. 2006 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18s):abstr.
Posner.bk Page 23 Friday, October 20, 2006 11:41 AM
❖
Evolving Role of Induction
Chemotherapy and Sequential
Therapy in the Treatment of
Locally Advanced Squamous Cell
Cancer of the Head and Neck
Marshall R. Posner, MD
Treatment Options
The curative treatment of patients with locally advanced squamous cell
carcinoma of the head and neck (HNC) is extremely difficult for the general oncology clinician and is best met by a multimodality team of physicians with specific expertise. HNC patients frequently present to their
physicians with advanced but still regionally localized disease. The intensity of therapy and the prognosis are governed both by the site and the volume of disease. Advanced disease can be defined as either intermediate
stage disease of a moderate prognosis with a 50%–75% 3-year survival or
as advanced disease with a poor prognosis and an expected 20%–45% 3year survival. Intermediate disease is usually stage III: T3/N0/M0 or T1–3/
N1/M0, although stage II patients with large T2/N0 primary cancers also
fall into this prognostic category. More advanced patients present with
stage IV disease: T4/N0–1/M0 or T1–4/N2–3/M0, which may or may not
be surgically resected but frequently are large (1).
CME 23
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24
Evolving Role of Induction Chemotherapy
Even the experienced clinician is faced with significant clinical challenges in
making decisions regarding therapy. The treatment options are subject to considerable debate and differences of opinion. There is site-specific heterogeneity
in biology, prognosis, and therapy; functional deficits from therapeutic choices
can be considerable and are part of the therapeutic assessment; and selection
of an appropriate treatment plan that suits the needs and condition of an individual patient can be difficult. Finally, increasingly aggressive nonsurgical
therapy results in substantial acute and long-term toxicity that requires considerable physician management and experience. Nonetheless, treatment of
HNC is associated with increasing rates of cure, functional organ preservation, and a changing demographic of younger, healthier patients, all of which
have resulted in substantial improvements in outcome and clinical benefit.
History of Treatment
Therapeutic options have evolved slowly and incrementally since the 1970s.
Initial enthusiasm for chemotherapy based on the amazing responsiveness and
spectacular regressions of large tumors to induction chemotherapy was
replaced by disappointment when cure and survival did not meet expectations. Locoregional failure remained high, and research shifted to enhancing
locoregional control through optimizing radiation therapy and experimenting
with chemoradiotherapy. There have been small but important gains in outcomes as a result of these efforts. Improved radiation scheduling and the integration of chemotherapy into radiation therapy have significantly improved
locoregional control. However, the improvement in locoregional control has
been limited, and distant metastases have become an increasing sign of failure.
Survival has improved, but gains have been modest.
Thus, despite several decades of progress and significant improvements in
treatment and supportive care, the prognosis and disease-free survival for
patients with locally advanced HNC has remained poor. Since the 1990s,
cisplatin-based combined modality treatment with chemoradiotherapy (CRT)
has been the sole accepted standard of care for unresectable, locally advanced
disease and for organ preservation, although induction therapy is still accepted
and used by many physicians in North America and remains a standard in
Europe (2,3). At 3 years after standard CRT, only approximately 55% and
35% of patients with intermediate and advanced disease, respectively, will
be alive and disease free (2,4,5). Between 30% and 40% of patients will
develop locoregional recurrences, and 20%–30% will develop distant
metastases. This continues to be a dismal outcome. Failure to control HNC
occurs via two biologically distinct pathways: local recurrence and metastatic spread.
Posner.bk Page 25 Friday, October 20, 2006 11:41 AM
Evolving Role of Induction Chemotherapy
25
Combined Modality Therapy
The debate regarding the optimal delivery of combined modality therapy
has continued unabated with regard to the scheduling and content of therapy. Three major approaches have been investigated: (a) primary induction
chemotherapy, or neoadjuvant therapy before definitive surgery and/or
radiotherapy; (b) concomitant treatment with chemotherapy and radiotherapy (CRT); and (c) a new synthesis of induction chemotherapy and
CRT, sequential chemotherapy (ST), consisting of induction chemotherapy
followed by CRT (6).
Induction Chemotherapy
Metaanalysis of Results
A reassessment of results from induction chemotherapy trials has been
provided by metaanalysis, by recently reported updates and re-analysis of
older trials with longer follow-up, and by the results of several recently
reported phase III trials. Metaanalysis allows a broad review of diverse
and heterogeneous trials that may not by themselves be sufficiently powered to show an effect or may suffer from defects in performance that
reduce efficacy modestly and obscure significant differences. Metaanalysis
reveals that although the general class of induction trials did not improve
survival in patients with HNC compared to standard therapy, the subset of
induction chemotherapy trials that used cisplatin/5-fluorouracil (PF) chemotherapy resulted in a 5% improvement in 5-year survival compared to
standard therapy (7). This difference was less substantial than the 8%
improvement observed with CRT but was significant at P = .01. The interpretation of the results of metaanalysis of induction trials in general is confounded by combining of non-PF and PF regimens, which are ineffective
compared to PF, and by the substitution of carboplatin for cisplatin, which
is an inferior agent in the treatment of HNC (8,9).
Platinum/5-Fluorouracil Chemotherapy
PF-based induction therapy was developed in the late 1970s and has been
studied ever since. The notion that induction therapy could enhance cure
rates and functional organ preservation is rationally based on observations
that PF chemotherapy resulted in marked shrinkage of tumors in patients
with advanced HNC. In organ preservation trials, PF therapy resulted in a
significant fraction of pathologically negative resections (10–12). Induction chemotherapy is better tolerated than adjuvant therapy given postop-
Posner.bk Page 26 Friday, October 20, 2006 11:41 AM
26
Evolving Role of Induction Chemotherapy
eratively or to irradiated patients. Hence, higher doses and systemically
active treatment can be delivered to the treatment-naïve patient, which can
enhance local responses and eradicate micrometastatic disease with less
toxicity and acute morbidity. Furthermore, drug delivery is better in
untreated, well-vascularized tumors (13). The standard PF regimen combined bolus cisplatin and continuous infusion 5-fluorouracil (5-FU) over 5
days. This was the most effective induction chemotherapy regimen and has
remained the gold standard in advanced HNC (14). Improved organ preservation, reduced distant metastases, and significant improvements in survival in PF-treated patients compared to control populations treated solely
with surgery and/or radiotherapy have been reported in four randomized
trials (Table 1) (3,15–17). PF is highly effective in obtaining responses, and
reported response rates have averaged 60%–80%, with complete responses
in 20%–30% of patients (3,15–20). Survival advantages, however, were
hard to discern in the heterogeneous and complex trials associated with
induction chemotherapy.
Many of the studies with PF-based induction chemotherapy were performed in the early 1990s. Many trials also included resectable patients and
unresectable patients and interposed surgery between induction therapy and
radiotherapy. Although surgery could be avoided in larynx and hypopharynx
patients and a functional larynx preserved, local and regional failure remained
considerable, and survival in resectable patients was not enhanced. Thus, PFbased induction therapy has not been widely or formally accepted by the
cooperative groups as a standard of care, although many practitioners in the
community and in academic centers continued to use PF in patients with very
advanced cancers and as a means of organ preservation.
As mentioned, many early PF trials included resectable patients. Before
organ preservation was established as a standard of care, induction chemotherapy trials frequently had surgery timed to occur between induction chemotherapy and radiotherapy. Performing definitive surgery or nodal or
primary site “salvage” surgery after induction chemotherapy but before
radiotherapy negatively impacted on survival and diminished the impact of
induction chemotherapy on survival in early induction chemotherapy studies (6). After induction chemotherapy, the identification of the margins
becomes difficult if not impossible. In addition, if the primary site is preserved and the neck addressed separately, then residual, partially resistant
tumor cells can repopulate the site, making subsequent radiotherapy less
effective. Finally, in the majority of cases the surgical bed also contains residual tumor cells scattered in the lymphatics that are partially resistant to therapy and can repopulate the region in an enhanced growth environment
while regional treatment with radiotherapy is delayed. This is evident in the
Studio Trial in which patients were randomized to standard care or induc-
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Evolving Role of Induction Chemotherapy
27
Table 1. Phase III Cisplatin/5-Fluorouracil (PF) Induction Trials
Study
Treatment
Organ preservation
Veterans Affairs
PF, three cycles;
radiotherapy
Larynx Trial
EORTC
Hypopharynx
Survival
Studio Trial
GETTEC Oropharynx Trial
Follow-Up
Results
12 y
Larynx preserved in
60% of survivors;
no difference in
survival; reduced
distant metastases with PF
Larynx preserved
in 30% of survivors; survival
equivalent;
reduced distant
metastases
PF, three cycles;
radiotherapy
10 y
PF, four cycles;
surgery and/or
radiotherapy
10 y
PF, three cycles;
surgery and/or
radiotherapy
5y
Significant
improvement in
survival in unresectable
patients;
reduced distant
metastases
Significant
improvement in
survival
EORTC, European Organisation for Research and Treatment of Cancer; GETTEC,
Groupe d’Etudes des Tumeurs de la Tête et du Cou.
tion chemotherapy (21,22). Unresectable patients started radiotherapy immediately after induction PF, but resectable patients had surgery between PF
and radiotherapy. Survival in the resectable patients was slightly worse after
PF and surgery than after surgery alone. On the other hand, PF led to a significant improvement in the survival of unresectable patients compared to
radiotherapy, and the survival advantage was maintained for more than 10
years (22). Thus, the proper sequencing of induction chemotherapy in the
combined modality therapy of HNC remains a major issue and obfuscates
the value of induction chemotherapy. A second large trial by the Groupe
d’Etudes des Tumeurs de la Tête et du Cou (GETTEC), reported by Domenge
et al. (3), confirmed these positive results for PF chemotherapy.
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28
Evolving Role of Induction Chemotherapy
Induction Chemotherapy in Resectable Patients
Induction chemotherapy does have a role in resectable patients, particularly
for organ preservation and in patients with poor prognosis. Organ preservation should be considered in the oropharynx, larynx, and hypopharynx to
preserve swallowing and speech. In a phase III larynx preservation study, the
Veterans Affairs Larynx Cancer Trial, larynx preservation was achieved in
approximately two-thirds of patients treated with PF, and the rate of distant
metastasis was decreased (17) compared to surgery. A study of pyriform
sinus cancer performed by the European Organisation for Research and
Treatment of Cancer (EORTC) also demonstrated an equivalent survival
between the chemotherapy and surgical arms, with organ preservation
achieved in one-third of the patients (15). Both studies included primarily
patients with intermediate stage disease, and updates confirmed that the
results were maintained for 10 years or more.
Several studies attempted to replicate these data, but they were unsuccessful; most notably, a GETTEC trial that studied laryngeal cancer (23). This trial
is difficult to interpret because it included few patients and had significant
early morbidity, which suggests poor patient selection and treatment monitoring. The study highlights a problem encountered with many early trials in
HNC: the inclusion of patients with significant comorbidities who were inappropriate for inclusion in clinical trials of aggressive treatments. Inclusion of
these patients impedes the study of new therapies and impairs the treatment of
healthier patients who would benefit from more intensive therapies.
Chemoradiotherapy
Comparisons with Induction Chemotherapy
More recently, induction chemotherapy for organ preservation has been compared to radiotherapy and to cisplatin-based CRT in the Intergroup 91-11
trial (24,25). In the original study, CRT with bolus cisplatin led to greater
laryngectomy-free survival than radiotherapy alone, without a significant loss
of survival, and induction chemotherapy had an intermediate and nonsignificant impact, compared to radiotherapy. Patients were predominantly of an
intermediate stage, and advanced patients and hypopharynx sites were not
entered. Thus, in this intermediate population in the initial report, CRT
appeared to be a more efficient and potentially effective therapy than radiotherapy alone or induction chemotherapy. This study was recently updated
with a 5-year follow-up (25). Laryngectomy-free survival was identical in the
PF and the CRT arms, and both were significantly better than the radiotherapy arm (Table 2). Significantly more patients survived with an intact larynx
in the PF and CRT arms than when treated with radiotherapy alone. Further-
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Evolving Role of Induction Chemotherapy
29
Table 2. Revised Outcomes for Intergroup 91-11
Treatment
Outcome Parameter
Laryngectomy-free survival
Locoregional control
Overall survival
Disease-free survival
Distant metastases
PF (%)
45
55
59
39
14
CRT (%)
XRT (%)
47
69
55
39
13
34a
51b
54
27a
22
CRT, chemoradiotherapy; PF, cisplatin/5-fluorouracil; XRT, external beam radiation
therapy.
aP <.01 for both comparisons with XRT.
bP <.01 for CRT versus XRT and PF.
more, although as might be expected, CRT resulted in better locoregional control. Disease-free survival was equivalent between the CRT and PF arms. Also,
overall survival was 5% better in the PF arm compared to the CRT arm; both
were better than radiotherapy alone. Although not significant, the overall survival benefit suggests that induction chemotherapy might have had a more
positive impact on this outcome than CRT. This latter result may have become
evident because patients treated with induction therapy may have a better
functional outcome when they begin radiotherapy with reduced tumor size
and normal speech and swallowing structures than patients treated at the start
with large intact tumors. Thus, the Intergroup 91-11 study demonstrates that
PF-based induction chemotherapy is at least equivalent to CRT for laryngectomy-free survival and may have an advantage in overall survival.
Addition of Taxanes
Many studies have attempted to improve PF by adding a third agent to the
combination. Taxanes have been shown to have considerable activity in
recurrent disease and have a different spectrum of activity. Combination
regimens of docetaxel or paclitaxel plus PF have been studied extensively
in phase II trials with good outcomes (26–28). Multiple phase III trials
have been reported that show that three-drug, docetaxel-based PF (TPF)
regimens have improved survival or organ preservation compared to the
older two-drug PF standard (Table 3) (29–32). These results document a
substantial improvement in survival or organ preservation and less toxicity
than was observed with PF induction chemotherapy.
In a trial of resectable and unresectable patients, Hitt et al. (30)
reported an improvement in response and in overall survival in patients
30
Unresectable
Unresectable,
resectable with
poor outcome,
organ preservation
Larynx and oropharynx, organ
preservation
Resectable and
unresectable
TAX 323 (32)
TAX 324 (31)
mg/m2;
T: 75 mg/m2; P: 75 mg/m2;
F: 750 mg/m2 IV CI × 5
days; three cycles
Tp: 175 mg/m2; P: 100 mg/
m2; F: 500 mg/m2 IV CI ×
days 2–6; three cycles
P: 75
T: 75
F: 750 mg/m2 IV CI × 5
days; four cycles
T: 75 mg/m2; P: 100 mg/
m2; F: 1,000 mg/m2 IV CI
× 4 days; three cycles
mg/m2;
TPF Treatment
CI, continuous infusion; F, 5-fluorouracil; P, cisplatin; T, docetaxel; Tp, paclitaxel.
Hitt et al., 2005
(30)
GORTEC 2000-01
(29)
Patients
Study (Reference)
Table 3. Completed Phase III Trials of TPF versus PF
Better organ preservation for TPF
Better survival in
unresectable
patients for TpPF
Chemoradiotherapy:
bolus cisplatin, 100 mg/
m2 every 3 weeks × 3
Improved survival
for TPF
Chemoradiotherapy:
carboplatin area
under the curve, 1.5
weekly
Standard radiotherapy
for responders
Improved survival
for TPF
Outcome
Standard radiotherapy
Radiation Therapy
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Evolving Role of Induction Chemotherapy
31
treated with paclitaxel-based TPF, followed by cisplatin-based CRT. In the
Hitt trial, which compares TPF as part of an ST regimen, survival was not
the primary end point, and therapy in resectable patients included nodal
surgery for some patients before CRT. TPF significantly improved survival
in the unresectable patients but not in the resectable patients. It could be
argued that, by incorporating nodal surgery between induction chemotherapy and CRT, the locoregional control and survival might have been
reduced in the resectable patients. As pointed out regarding the Studio
Trial, the failure to see improved survival in the resectable patients may
have been the result of the delay before radiotherapy, inadequate surgery,
or inadequate pretherapy surgical mapping. This was in contrast to the
results achieved in unresectable patients who went immediately from
induction chemotherapy to radiotherapy. Notably, toxicity in the TPF was
less than that observed in the PF arm, and this was mostly due to reduced
mucositis.
In a second phase III trial, TAX 323, performed by the EORTC and
updated by Remenar et al. in 2006 (32), patients with unresectable HNC
were treated with either TPF or PF followed by radiotherapy. The Remenar et al. study population consisted of patients with advanced disease.
More than 70% of patients had T4 cancers, and more than 70% had N2
or N3 nodal disease. More than 300 patients were entered on this study.
The majority of cancers arose in the oropharynx. Survival was significantly
better with TPF compared to PF. At 3 years, 37% of the TPF patients were
alive compared to 24% of the PF patients. Overall, there was a 29%
reduction in mortality with TPF compared to PF in this unresectable population. Also noteworthy, mucositis in the TPF arm was less than that
obtained in the PF arm, and treatment-related mortality was reduced by
50%.
A second phase III trial comparing TPF to PF was presented in 2006, the
TAX 324 trial (31). This trial is an ST trial; patients with locally advanced
disease were treated with three cycles of TPF or PF and then received CRT
with carboplatin weekly at a low area under the curve. After CRT, some
patients received nodal surgery if they presented with an N3 neck or had a
partial response in the neck after the induction phase. More than 500
patients were entered on the trial, which included resectable and unresectable disease. More than one-half of the patients had an oropharyngeal primary, and 80% had stage IV cancers. There was a significant survival
advantage to TPF. Overall mortality was reduced by 30%, and 3-year survival was 62% and 48% in the TPF and PF arms, respectively. Furthermore,
toxicity appeared to be relatively lower in the TPF arm, as dose intensity
was better preserved in patients receiving TPF compared to PF (99% vs.
90%), and there was less toxicity-related mortality in the TPF arm.
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32
Evolving Role of Induction Chemotherapy
Recently, Calais et al. (29) presented the results of a phase III organ preservation trial performed by the GORTEC in patients with larynx and hypopharynx cancer comparing TPF to PF. These patients were treated with three cycles
of TP or PF, and then responders received radiotherapy and nonresponders
underwent laryngectomy. All patients have finished therapy, and follow-up is
ongoing. There were significantly more responders in the TPF arm compared
to the PF arm. Patients who received TPF had better laryngectomy-free survival than patients with PF, approximately 80% versus 60%; however, it is
still too early for a complete analysis. Notably, however, toxicity was again
less in the TPF arm than in the PF arm.
New Standard of Care
The three-drug TPF regimens have been compared to PF in three completed,
randomized trials. Two trials were done for survival, and one for organ preservation. The latter organ preservation trial is still undergoing follow-up, but
the two survival trials are mature, and firm conclusions may be drawn from
those results, although they have not been formally published. The uniform
result in all three trials is that TPF is substantially superior to PF in terms of
survival in patients with locally advanced HNC. In addition, this improvement in survival is accompanied by a reduction in treatment-related mortality
and mucositis. Thus, it can be said with confidence that TPF is the standard
for induction chemotherapy. There are differences between the European TPF
and the North American TPF. The North American TPF is delivered over 4
days compared to 5 days for the Europeans, but the doses of cisplatin and 5FU are slightly higher (see Table 3). In addition, in the European TAX 323
trial, TPF is delivered for four cycles, whereas the North American TPF regimen is delivered for only three cycles. It is unlikely that these differences will
be resolved in the short term, and they should not obscure the basic and
important facts, which are that TPF is more effective and less toxic than PF
and represents the new standard of care for induction chemotherapy.
Sequential Therapy
An Alternative for Unresectable Disease
Despite the improvements recently reported in unresectable disease and organ
preservation, survival in unresectable disease treated with either TPF-based
induction chemotherapy followed by radiotherapy or solely with cisplatinbased CRT remains poor at approximately 40%. There are advantages and
disadvantages to both induction chemotherapy and CRT. Induction chemotherapy provides systemic therapy, treats distant disease, and reduces local and
regional disease before the start of radiotherapy (33). The latter effect can lead
Posner.bk Page 33 Friday, October 20, 2006 11:41 AM
Evolving Role of Induction Chemotherapy
33
to a better functional outcome as may have been shown in the Intergroup 9111 study. With induction chemotherapy, toxicity is usually transient and is
substantially less than that observed with CRT and aggressive radiotherapy,
but induction chemotherapy is associated with prolongation of treatment.
After induction chemotherapy, an assessment of response can be used to
adjust the intensity of subsequent therapy. Induction therapy results in good
systemic control, but there are frequent locoregional failures. An analysis of
failure among TPF studies performed at the Dana Farber Cancer Institute
demonstrated a 37% locoregional failure rate among patients treated with different TPF regimens followed by hyperfractionated radiotherapy (34). Five of
these patients (6%) had locoregional failure and distant metastases. There
were no patients with only distant failure.
CRT increases locoregional dose intensity, is ineffective systemic therapy,
and is associated with considerable systemic and local toxicity. There is no
method to assess prognosis and adjust intensity once CRT has started. However, CRT is associated with improved local and regional control and survival.
Distant metastases are unaffected, except in larynx cancer. Cisplatin-based
CRT in unresectable patients, oropharynx cancer, and in the postoperative setting show no impact on distant metastases. In some studies, distant metastases
occurred more frequently than locoregional failures.
Combining induction chemotherapy with CRT and surgery as ST makes
good biologic sense (33,35–39). This paradigm may optimize therapy for
HNC based on an analysis of the sites of failure of both therapies. In addition to providing a systemic therapy, induction therapy may better prepare
the local and regional area by reducing tumor bulk, normalizing vasculature, and improving local function. Furthermore, the immediate period after
completion of induction chemotherapy is a biologically critical time period
when tumor cells in the primary site and region are proliferating rapidly and
have some partial resistance to therapy. In a theoretical modeling of tumor
proliferation and growth, tumor cells proliferate more rapidly when tumor
volume is decreased. This model predicts that the addition of a non–crossresistant therapy with minimal delay (i.e., CRT after induction chemotherapy) should improve locoregional control (40). Tumor cells may well retain
increased sensitivity to radiation therapy and chemotherapy-induced sensitization at this point in treatment.
Therapy Comparisons
Several sequential treatment plans have been reported in phase II trials, and
there are several phase III trials comparing TPF-based ST to cisplatin-based
CRT. The University of Pennsylvania (39) reported a sequential program
trial that included two cycles of very high-dose carboplatin and paclitaxel
followed by single-agent weekly CRT with paclitaxel. Survival was more
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34
Evolving Role of Induction Chemotherapy
than 60% at 3 years. The University of Chicago (38) gave an induction regimen of six weekly cycles of intensive carboplatin/paclitaxel (CP) chemotherapy followed by aggressive split-course CRT, THFX. The 3-year overall
survival rate in this phase II study was 70%. The original Chicago induction
regimen of weekly carboplatin and paclitaxel has been modified by the Eastern Cooperative Oncology Group by the addition of weekly cetuximab in a
phase II trial for resectable patients. After induction therapy, patients are
treated with CRT with weekly carboplatin, paclitaxel, and cetuximab. There
is a provision to perform surgery midway through radiotherapy if there is
persistent disease based on an interim positive biopsy. The Minnie Pearl
Cancer Research Network Trial performed a study of high-dose CP for two
cycles with 6-week continuous infusion of 5-FU (41). This induction regimen was followed by CP weekly with radiotherapy. There was a 51%
3-year survival in this advanced group of patients. Vanderbilt University
Medical Center completed a trial similar to the University of Pennsylvania
trial (42). Results are early but suggest a 66% 3-year survival, with a median
follow-up of 31 months.
The University of Michigan has taken a different approach (43). They
have used PF-induction chemotherapy to select patients for organ preservation or surgery. Patients are assessed after one cycle for response.
Responders receive CRT with bolus cisplatin, and two cycles of adjuvant
PF are then given to complete responders. Nonresponders to one cycle
undergo laryngectomy. Survival is 80% at 3 years, and organ preservation
rates are excellent. This population is primarily intermediate stage larynx
cancer and is not directly comparable to the more advanced patients
treated in the other sequential studies. Furthermore, with the update of the
91-11 trial and the superiority of TPF, this concept should be reexamined.
TAX 324 is a phase III trial; however, both arms were ST based. For this
trial, TPF and PF were followed by CRT with weekly carboplatin, a less-intensive CRT regimen than CRT regimens that use bolus cisplatin, or therapy with
cisplatin and another drug such as 5-FU or paclitaxel. The TAX 324 trial
accrued more than 500 patients and demonstrated that ST with TPF and carboplatin-based CRT was a tolerable therapy and that this treatment represented a reasonable standard of care. There are a number of important,
ongoing phase III trials comparing CRT with TPF-based ST. The University of
Chicago is leading a phase III trial comparing docetaxel/hydoxyurea/5-FU/bid
radiation therapy (THFX) CRT to ST with TPF plus THFX (Figure 1A). The
Italian trial compares TPF followed by CRT with cisplatin and 5-FU to CRT
alone (Figure 1B). The Spanish trial is comparing three arms: TPF or PF plus
cisplatin-based CRT to CRT alone (Figure 1C). The Paradigm trial is comparing TPF followed by carboplatin to cisplatin plus aggressive radiotherapy
(Figure 1D). The Southwest Oncology Group organ preservation study in
Posner.bk Page 35 Friday, October 20, 2006 11:41 AM
Evolving Role of Induction Chemotherapy
T
R
A
N
D
O
M
I
Z
E
P
35
T
Two cycles of
chemotherapy
H
F
F
Six cycles of every
other week
chemoradiotherapy
X
T
H
F
Six cycles of every
other week
chemoradiotherapy
X
A
T
R
A
N
D
O
M
I
Z
E
B
P
P
F
F
Daily radiotherapy
P
F
CRT
Daily radiotherapy
Figure 1. Active phase III trials comparing sequential therapy with docetaxelbased cisplatin/5-fluorouracil (TPF) chemotherapy and chemoradiotherapy
(CRT). A: Schema for the University of Chicago sequential trial. B: Schema for
the Italian trial. TPF: docetaxel, 75 mg/m2 day 1 + cisplatin, 80 mg/m2 day 1 +
5-fluorouracil (5-FU), 800 mg/m2 continuous infusion (CI) days 1–4 for 3
weeks ×3. CRT PF: cisplatin, 20 mg/m2 days 1–4 + 5-FU, 800 mg/m2 CI days 1–
4 weeks 1 and 6. (continued)
Posner.bk Page 36 Friday, October 20, 2006 11:41 AM
36
Evolving Role of Induction Chemotherapy
T
P
R
A
N
D
O
M
I
Z
E
Cisplatin, 100 mg/m2
F
Salvage
surgery
Daily radiotherapy
P
F
C
ACB
T
R
A
N
D
O
M
I
Z
E
P
Three
cycles of
NR
chemotherapy
T*
Surgery
F
C
PR, CR
Daily radiotherapy
P
Q 3 weeks
Surgery
XRT
ACB radiotherapy
Figure 1. (Continued) C: Schema for the Spanish combined modality therapy trial. TPF versus PF followed by CRT versus CRT alone. TPF: docetaxel, 75
mg/m2 day 1 + cisplatin, 75 mg/m2 day 1 + 5-FU, 750 mg/m2 CI days 1–5 for
3 weeks ×3. PF: cisplatin, 100 mg/m2 day 1 + 5-FU, 1,000 mg/m2 CI days 1–5
for 3 weeks ×3. CRT: cisplatin, 100 mg/m2 days 1, 22, and 42. D: The North
American Paradigm trial. *T + accelerated concomittant boost for nonresponders. (continued)
D
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Evolving Role of Induction Chemotherapy
37
<50% Response
Surgery
T
R
A
N
D
O
M
I
Z
E
E
P
P
Q 3 weeks
F
>50% Response
Two cycles
Surgery
Daily radiotherapy
P
Q 3 weeks
XRT
Surgery
Daily radiotherapy
Figure 1. (Continued) E: The Southwest Oncology Group Oropharynx trial.
CR, complete response; H, hydroxyurea; NR, no response; PR, partial response;
X, BID radiation therapy; XRT, external-beam radiation therapy.
resectable oropharynx cancer compares ST with TPF plus CRT to CRT alone
for organ preservation (Figure 1E).
Conclusion
This has been a productive period in the treatment of locally advanced
HNC. After three decades of study, major advances in combined modality
therapy by incorporating three-drug regimens of TPF into treatment are
being seen. TPF has been shown to improve survival and organ preservation and to result in less acute morbidity than the original standard twodrug PF regimen of induction chemotherapy. In addition, studies of ST as a
new treatment paradigm for locally advanced HNC have shown 2- and 3year survival rates in advanced disease that are unprecedented. There are
more than six phase III studies being performed to compare ST to CRT.
Early data from the European trials may be expected in 2007 and 2008.
When the progress in research and the evolution of induction chemotherapy and CRT over the last few years is reviewed, improved chemotherapy,
better survival, and potentially better functional outcome for patients may be
seen. The concept of ST appears to reflect an increasing understanding of the
biology of HNC. ST makes sound biologic sense and appears to be highly
effective, but it still remains experimental. Despite the lack of completed phase
III trials establishing the relative efficacy of this paradigm, the TAX 324 trial
shows that ST with TPF induction therapy and carboplatin-based CRT is an
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38
Evolving Role of Induction Chemotherapy
acceptable treatment and a reasonable alternative for patients with good performance status and locally advanced disease. Phase III trials, however, remain
the final determinant as to whether this is truly an improvement over the current standards of induction chemotherapy or CRT.
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23. Richard J, Sancho-Garnier H, Pessey J, et al. Randomized trial of induction
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25. Forastiere A, Maor M, Weber R, et al. Long term results of Intergroup RTOG
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26. Posner MR, Glisson B, Frenette G, et al. Multicenter phase I–II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with
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27. Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a
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28. Baselga J, Trigo JM, Bourhis J, et al. Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule
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30. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing
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Scientific Session, 2006.
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Haddad R, Colevas AD, Tishler R, et al. Docetaxel, cisplatin, and 5-fluorouracil–based induction chemotherapy in patients with locally advanced squamous
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Haddad R, Tishler RB, Norris CM, et al. TPF-based induction chemotherapy
for head and neck cancer and the case for sequential, combined modality treatment. Oncologist 2003;8:35–44.
Haddad R, Wirth L, Posner M. The integration of chemotherapy in the curative treatment of locally advanced head and neck cancer. Expert Rev Anticancer Ther 2003;3:331–338.
Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck
cancer. J Clin Oncol 2003;21:320–326.
Machtay M, Rosenthal DI, Hershock D, et al. Organ preservation therapy
using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: a University of Pennsylvania phase II trial. J Clin Oncol
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Takimoto C, Rowinsky E. Dose-intense paclitaxel: deja vu all over again? J
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Hainsworth JD, Meluch AA, McClurkan S, et al. Induction paclitaxel, carboplatin
and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: a
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298–300.
Cmelak A, Murphy BA, Burkey B, et al. Induction chemotherapy (IC) followed by
concurrent chemoradiation (CCR) for organ preservation (OP) in locally advanced
squamous head and neck cancer (SHNC): results of a phase II trial. Proc ASCO
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advanced laryngeal cancer. Proc ASCO 2003;22:497.
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❖
Increasing Cure—Increasing
Toxicity: Symptom Management
and Chemoradiotherapy
Barbara A. Murphy, MD
History of Management
As recently as the mid-1990s, medical oncologists were peripheral members of the head and neck cancer (HNC) treatment team, with their role
being confined to the administration of chemotherapy for metastatic or
recurrent disease. Now, chemotherapy is being incorporated into the primary treatment plan for the majority of patients with locally advanced
HNC. However, the improved treatment outcome resulting from combined modality therapy is at the expense of markedly increased acute and
late toxicities. Thus, medical oncologists are faced with making treatment
decisions as well as managing a complex array of interrelated treatment
toxicities that are often problematic long after therapy is completed (1). To
complicate matters, information to guide physicians in dealing with the
toxicities of therapy has not kept pace with changing practice. Indeed,
information regarding the incidence, severity, and management of treatment-related toxicities is often weak or lacking. Thus, supportive care in
head and neck oncology has become a critical area of study.
It is important for clinicians to understand the management of acute
and late effects of therapy on both an individual and collective basis. From
the standpoint of the individual, assessment of acute and late toxicities is
necessary to minimize the detrimental effects on physical and mental
CME 41
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Increasing Cure—Increasing Toxicity
health. Collectively, oncologists need to understand how various treatment
regimens impact a patient’s quality of life (QOL) and supportive care outcomes to design regimens that minimize late effects.
Measuring Effects of Treatment: Quality
of Life versus Symptom Control
In evaluating the late effects of therapy, it is important to recognize two
related, but distinct, outcome measures: the first is QOL. QOL is a global construct that attempts to quantify a patient’s sense of general well-being (2). It is
influenced by numerous factors, including beliefs, life experiences, and expectations (3). A number of tools have been developed to measure QOL; the most
commonly used in the HNC patient population are the Functional Assessment
of Cancer Therapy (4) and the European Organisation of Research and Treatment of Cancer systems (5,6). Both systems have well-described general
questionnaires that address important domains, such as physical, functional,
emotional, and social well-being (7), as well as head and neck subscales that
specifically address issues pertinent to HNC patients. A review of the head
and neck QOL literature reveals some important information and insights (8).
However, it can be difficult to translate results from QOL studies into practical recommendations for practicing clinicians.
QOL assessments must be distinguished from symptom assessments. A
symptom is a perceived alteration in a sensation or function. Symptoms may
contribute to alterations in QOL; however, it is important to note that
patients may experience symptoms that fail to significantly impact on QOL.
This does not mean that symptoms are unimportant. Patients with HNC
may have a significant symptom burden that does not affect their QOL but
that does have substantial health implications. For example, a patient may
have moderately impaired swallowing function, which results in maladaptive dietary changes. The patient may not be “bothered” or “distressed” by
the problem, but the long-term implications of diet alterations may be significant. Unlike QOL outcomes, it is easier to translate symptom and function
outcomes into clinical practice.
Because it has been recognized that chemoradiotherapy (CRT) is associated with increased toxicity, symptom and functional outcomes have become
an important correlative component of clinical trials. It is, therefore, important for clinicians to understand the benefits and limitations of different
measures to be able to interpret results. Symptoms can be assessed in a variety of ways. Most clinical trials report symptoms based on toxicity-reporting systems such as the Common Toxicity Criteria. These systems have
inherent limitations, the most important of which is underreporting. Under-
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reporting is both systematized (trials rarely report grade 1 and 2 toxicities,
which may be bothersome or distressing to patients) or inadvertent (failure
to assess and document problems). To deal with this issue, self-report measures that address specific symptom control or functional issues can be
appended to clinical trials. The advantage of self-report measures is that
efforts can be directed at collecting desired information, the cost is modest,
and the patient burden is low. Alternatively, objective measures, such as
modified barium swallow to measure swallow function or pedometers to
measure activity, may be used. Objective measures have the advantage of
providing rich, detailed information. However, they tend to be more expensive and are often dependent on the expertise of the operator.
Symptom Control Issues
The remainder of this chapter provides a brief review of critical symptom
control issues in HNC patients undergoing CRT. The reader is referred to
additional materials for a more comprehensive review (1).
Mucositis
Mucositis secondary to CRT remains one of the major complications of
therapy. Classically, the term mucositis has been used to refer to ulcerative
lesions of the mucous membranes. Because the ulcerative lesions of the
upper aerodigestive tract were visible on examination, most clinicians think
of mucositis as confined to the head and neck region. It is often thought of
as a local process with consequences that are confined to the local tissues.
Older toxicity grading systems have propagated this limited concept by confining mucositis grading to measurement of ulcerative lesions.
As the knowledge base has evolved, the concept of mucositis has
changed. It has become clear that mucositis is associated with complicated
local biology and systemic effects. Sonis (9) has developed a model that
explains the underlying biology of mucositis. The first step in the pathogenesis of mucositis is initiation. During this phase, tissue damage from
chemotherapy and radiation induces the production of reactive oxygen
species (ROS). During the second phase, ROS activate a number of biologic pathways, including nuclear factor κB (NF-κB), sphingomyelinase,
and ceramide. NF-κB, a central signaling molecule, upregulates a number
of pathways resulting in, among other things, an increase in proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1b (IL-1b), and
IL-6. After activation, a series of feedback loops result in amplification of
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biologic responses. Although these biologic responses are meant to be protective, prolonged activation of pathways may paradoxically result in tissue injury. Ulcers develop in the damaged mucosa, and an inflammatory
infiltrate may be seen. After the insulting agent is removed, healing may
begin to take place.
Based on this model, it appears that mucositis is best thought of as a complex biologic process that results from damage to the tissues by systemic chemotherapy or radiation. Regardless of whether the tissue damage is due to
chemotherapy or radiation therapy (RT), there are local and systemic manifestations that result from the tissue response to damage. These effects impact on
a broad array of organs and function, and may be long lasting. Of note, there
is no doubt that the use of CRT results in a marked increase in mucositis when
compared to radiation alone. The use of radiation alone results in grade 3 and
4 mucositis rates of between 20% and 30% (10). Aggressive, concurrent CRT
regimens may result in mucositis rates that approach 100%. Thus, it is critical
for the clinician to have a comprehensive management strategy for the identification and palliation of mucositis-related symptoms.
Mucositis-Related Symptoms
Mucositis is a clinically important toxicity. First and foremost, increased
rates of mucositis may be associated with breaks in therapy and compromised tumor control. In addition to treatment breaks, mucositis is associated with a number of acute and late symptom control and functional issues.
The most common symptom associated with mucositis is pain. A recent
study reported on mucositis-related burden in HNC patients undergoing
CRT (11). Seventy-five patients with stage 3 or 4 HNC undergoing radiation
or CRT were enrolled in this prospective trial. At the end of week 6, 85% of
patients were receiving opioid analgesics. Despite the use of opioids, 76% of
patients complained of “quite a lot” or “extreme” mouth soreness. Pain was
demonstrated to impact on swallowing, drinking, eating, and talking.
Acutely, mucositis results in tissue edema and inflammation. After RT is
completed, healing begins. Tissue edema and inflammation may resolve,
leaving the patient with few clinically evident side effects. Conversely, some
patients may experience significant fibrosis and scarring of the mucosa and
soft tissues of the neck. The long-term effects of tissue scarring are substantial, including lymphedema, decrease in compliance of pharyngeal soft tissues, altered swallowing function, and dietary inadequacies.
Dozens of agents in hundreds of trials have been investigated as preventive or treatment agents for oral mucositis. To date, there are no pharmaceutical interventions that have been shown to be effective either in the
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treatment or prevention of radiation-induced mucositis. A thorough
review of the mucositis literature was conducted by the Mucositis Committee of the Multinational Association of Supportive Care in Cancer
(MASCC) (12). Based on this review, evidence-based clinical practice
guidelines have been developed. The recently updated version is available
on the MASCC web site (www.mascc.org). The guidelines recommend the
following:
•
•
•
•
Oral care to attempt the reduction of mucositis
Adequate analgesia
Radiation techniques such as midline blocks and conformal radiation
Benzydamine for prevention of mucositis (not available in the United
States)
Of note, the relative effect of intensity-modulated RT (IMRT) on the
severity and duration of mucositis has yet to be clearly determined and
awaits further prospective study.
It is evident that, at this time, care for radiation-induced mucositis is
supportive in nature. It is critical that the HNC team assess the patient
routinely for the sequela of mucositis and that aggressive measures be used
to maintain comfort, hydration, and nutritional status.
Despite the disappointing results of prior investigations, pharmaceutical companies continue to attempt to develop new agents for the prevention and treatment of oral mucositis. A review of ongoing investigations is
beyond the scope of this text. The reader is referred to the June 2006 issue
of Supportive Care in Cancer, which is dedicated exclusively to mucositis.
Data on the systemic effects of mucositis are much more limited. Investigators at Vanderbilt University have investigated the physiologic effects of
CRT-induced tissue damage on physical function and muscle mass (13,14).
Patients who have completed CRT experience a marked loss of muscle mass
and a decrease in physical function. This correlates with an increase in
proinflammatory cytokines and measures of oxidative stress, and a decrease
in antiinflammatory cytokines. Further evaluation of the systemic effects of
mucositis and related tissue damage is urgently needed.
Nutritional Management and Unintentional Weight Loss
At least 50% of HNC patients are malnourished at some point in their
treatment course. Malnutrition is associated with a decrease in both survival and QOL (15–20). Thus, assessment of nutritional status is a key
component in the management of HNC patients throughout the trajectory
of their disease process (21).
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Table 1. Definition of Critical Weight Loss
Time Course
Significant Weight
Loss (%)
Severe Weight
Loss (%)
1 wk
1 mo
3 mo
6 mo
≤2
≤5
≤ 7.5
≤ 10
>2
>5
>7.5
>10
Information compiled from Blackburn GL, Bistrian BR, Miani BS, et al. Nutritional and
metabolic assessment of the hospitalized patient. J Parenter Enteral Nutr 1977;1:11–22.
At the time of diagnosis, all patients should be assessed to determine if
they have had any recent weight loss. If so, the severity and rapidity of
weight loss should be determined. Risk classifications have been developed
to identify high-risk patients for whom nutritional deficits may significantly
impact on outcome (Table 1). Of note, patients with extreme weight loss
have a decreased healing capacity and may fail to tolerate aggressive combined modality treatment regimens. In addition to the severity of weight
loss, the etiology of weight loss should be established. For most patients,
weight loss at the time of diagnosis is associated with tumor-related pain or
obstruction of the alimentary tract. Cancer cachexia, an inflammatory process due to cancer, may also contribute to weight loss, particularly in
patients with advanced disease (22–24). Once the cause of weight loss is
identified, efforts should be made to ameliorate the identified problem. If
this is not possible, patients may require feeding tube placement.
In addition to a weight loss history, it is important to determine whether
patients are using vitamin supplements. Although the HNC population has a
lower rate of complementary alternative medicine therapy use when compared to other cancer diagnoses, the use of high doses of selected vitamins has
become widespread. Antioxidants have been postulated to have a protective
effect against the tissue damage from radiation (25). Preliminary data indicated that some vitamins, such as vitamin E or vitamin C, may decrease the
acute effects of RT (26,27). However, a more recent randomized trial indicated that vitamin E and carotenoid supplementation may have a tumorsparing effect with compromised local control (28). Therefore, patients
should be warned not to take nonphysiologic vitamin supplements without
discussing them with the medical staff.
Weight loss may also be due to the effects of treatment. Surgery may result
in decreased oral intake in the perioperative period. Generally, if patients are
anticipated to have a prolonged period of decreased oral intake postoperatively, a nasogastric or percutaneous feeding tube is placed at the time of sur-
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gery. A more problematic issue is weight loss associated with radiation-based
therapy (29). Compared to radiation alone, patients who receive CRT have a
more profound weight loss, averaging 6%–12% body weight. When using
CRT, clinicians should be prepared to aggressively address nutrition issues.
The most common reason cited for weight loss during CRT is decreased
oral intake due to painful mucositis (11), and mucositis-related pain can be
refractory to medical therapy. Patients usually require frequent and rapid escalation of opioids along with the use of adjunctive medications such as topical
anesthetics. Because patients have difficulty swallowing, transdermal delivery
systems provide a convenient and effective method for providing analgesia.
Other factors that contribute to decreased oral intake during and immediately after RT include tissue edema and inflammation with resultant decrease
in tissue compliance. Noncompliant tissues have decreased mobility that
inhibits normal swallowing function (21,30). There are two major complications of altered swallowing function: (a) nutritional inadequacies and (b) aspiration. Due to decrease in oral intake from swallowing abnormalities, a high
percentage of patients with locally advanced HNC undergo feeding tube
placement. There is considerable debate as to whether a feeding tube should
be placed prophylactically. There is little doubt that the prophylactic placement of a feeding tube will decrease the amount of weight loss. Recently, however, concern has been expressed that patients with feeding tubes stop using
the muscles of deglutition, allowing atrophy and wasting. Atrophy and wasting are thought to lead to higher rates of feeding tube dependence long term. It
has also been recently recognized that the need for feeding tube placement and
the rate of long-term feeding dependence is associated with the treatment regimen. A clear increase in feeding tube placement and long-term feeding tube
dependence is noted when CRT is compared to radiation alone (30). It also
appears that more aggressive regimens may be associated with increased longterm feeding tube dependence (30). Interpretation of these data is complicated
by the heterogeneous patient populations and differences in supportive measures available at institutions. Nonetheless, clinicians must be prepared to deal
with the acute and late swallowing effects of therapy. It is recommended that
patients continue to attempt to swallow even if they have a feeding tube in
place. Patients should be seen by a speech and language pathologist early in
their course so that they may be provided with exercises that may prevent loss
of swallowing function. Early return to swallowing function should be encouraged as long as it is safe.
Aspiration is one of the unrecognized, but potentially fatal, complications
of swallowing abnormalities. Aspiration may lead to pneumonia, which is
particularly problematic during therapy with myelosuppressive chemotherapy
regimens. Patients who have undergone aggressive CRT are often weak and
debilitated. Thus, if they develop an aspiration pneumonia, they have
decreased reserve. The treating clinician should be aware of several scenarios
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that indicate ongoing aspiration. First, patients may complain of coughing
when eating or after eating. Patients may also present with fever of unclear etiology. Chronically, aspiration may present as pulmonary fibrosis and respiratory compromise. If the clinician is concerned about potential aspiration, a
modified barium swallow should be obtained. If patients have significant aspiration, the patient may need to have a feeding tube placed and designated to
receive nothing by mouth. However, it is difficult to determine “how much
aspiration is too much aspiration.” Thus, a consultation with speech and language pathology is helpful.
Xerostomia
Humans produce 1.0–1.5 L of saliva each day. The major components of
saliva are amylase, mucin, and bicarbonate (31). In addition, saliva contains a
mixture of proteins, electrolytes, and nonprotein, nonelectrolytes. This complex secretion has multiple roles: (a) oral cavity lubrication, (b) maintaining
mucous membrane integrity by protecting it from desiccation and environmental factors/toxins, (c) antibacterial, antifungal, antiviral effect (lysozyme,
lactoferrin, peroxidases), (d) maintaining oral pH, (e) maintaining dental
integrity, (f) food bolus formation, and (g) aid in taste sensation (31,32).
Xerostomia is the sensation of oral dryness. It results both in a decrease
in QOL and marked alteration in critical functions. Xerostomia may be
caused by a wide range of processing, including aging, medications, collagen
vascular disease, anxiety or depression, and, finally, RT-induced damage to
the salivary glands. When the major salivary glands are within the radiation
portal, a >50% reduction in unstimulated flow is noted after 1 week and
reaches <10% of basal salivary flow within 2–3 weeks (33). Salivary function may recover partially if the radiation dose is between 30 and 60 Gy;
however, damage may be permanent above 30 Gy (34,35).
Patients with xerostomia complain of a variety of symptoms, including:
pain or discomfort, painful mucosal ulcers, altered voice (36), increased dental
caries, difficulty wearing dentures, decreased taste, difficulty with mastication
(37), and altered oral intake with nutritional deficits (38). On examination,
patients may have fissures and atrophy of the papillae of the tongue; angular
cheilitis; dental decay, especially at the roots; erythematous mucosa; dry or
pale mucosa due to atrophy; oral ulcers; and candidiasis.
Assessment of salivary function can be made using clinical parameters or
by measuring stimulated and unstimulated saliva production. Unstimulated
salivary flow rates are obtained by asking patients to spit into a plastic container for 5 minutes. Stimulated salivary measurements may be done by asking a patient to chew on paraffin or sugar-free gum while saliva is collected.
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49
Table 2. Common Terminology Criteria for Adverse Events 3.0 Standards
for Xerostomia
Grade
Description
1
Symptomatic (dry or thick saliva); no dietary alterations; unstimulated flow rate of >0.2 mL /minute
Symptomatic and significant dietary intake alterations (requires
copious water, lubricants, soft foods, moist foods); unstimulated flow rate of 0.1–0.2 mL /minute
Symptomatic; significant oral intake alterations leading to inadequate oral alimentation (requires IV, feeding tube, or total parenteral nutrition); unstimulated flow rate of <0.1 mL /minute
2
3
Alternatively, 4% citric acid can be applied every 2 minutes. Normal, unstimulated flow is 0.3–0.5 mL/minute, and stimulated flow is 1–2 mL/minute. Various criteria have been developed for rating xerostomia (32) (Tables 2 and 3).
The most recent criteria (Common Terminology Criteria for Adverse Events
3.0) incorporates the measurement of unstimulated salivary flow.
Once xerostomia has developed, treatment options are limited. If some salivary function is still present, the goal of treatment is to stimulate remaining
function by mechanical, gustatory, or pharmacologic stimulation. Because
there is no substitute for the dental protection afforded by saliva, the importance of stimulation of residual salivary function cannot be underestimated.
Gustatory stimulants include gum, lozenges, and specific tastes such as sweet,
acid, or menthol. Pharmacologic agents include pilocarpine, 5 mg orally (PO)
qid (39), or cevimeline, 30 mg PO tid (40). These agents are modestly effective
in improving salivary flow and comfort.
If no function is present, the goal of therapy is to increase oral comfort by
using salivary substitutes. Most salivary substitutes contain carboxymethylcellulose. Attempts have been made to add enzymes, such as lysozyme, sialoperoxidase, and lactoferrin, to add an antimicrobial effect (41). These agents
Table 3. Radiation Therapy Oncology Group Salivary Gland Morbidity Scale
Grade
Description
1
Mild dryness, slightly thick saliva, slightly altered or metallic
taste
Moderate to complete dryness, thick sticky saliva, and
marked taste alterations
Not defined for xerostomia
Acute salivary gland necrosis
2
3
4
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improve oral comfort, but there are no consistent data to indicate a change in
bacterial colonization (41,42).
Because of the devastating effects of xerostomia, investigators have
attempted to identify methods for preventing loss of salivary gland function.
Three major methods have been used: salivary gland transfer, pharmacologic
agents such as amifostine, and alternative radiation delivery systems such as
IMRT. Salivary gland transfer is a surgical procedure that is done before RT.
The salivary glands are moved anteriorly and out of the radiation port; thus,
the delivery of radiation to the glands is markedly diminished, and function
loss is minimized (43). Preliminary results indicate that this is an effective
strategy; however, its broad applicability is of concern.
Amifostine is an inorganic thiophosphate that is U.S. Food and Drug
Administration approved for the protection of salivary glands during RT. In a
recently published metaanalysis evaluating data on the efficacy of amifostine,
Sasse et al. (44) identified 14 randomized trials containing 1,451 patients.
Only four studies reported the effects on xerostomia for HNC. Of the four
studies that looked at acute xerostomia, amifostine reduced the odds of xerostomia by 76% (odds ratio [OR], 0.24; confidence interval [CI], 0.15–0.36; P
<.00001). Only two of the studies looked at late xerostomia. In those studies,
amifostine reduced the odds of xerostomia by 67% (OR, 0.33; CI, 0.21–0.51;
P <.00001). Despite the positive data, amifostine has not been broadly
accepted. This is due in part to cost considerations and in part to toxicity. In
an attempt to ameliorate the toxicities of intravenous (IV) amifostine, studies
were done to determine whether amifostine could be used subcutaneously to
decrease side effects without decreasing activity. Bardet et al. (45) reported the
results of a randomized trial of 311 HNC patients receiving primary and postoperative CRT who received RT to at least 75% of both glands. Patients were
randomized to amifostine, 500 mg/m2 or 200 mg/m2 IV. Results demonstrated
no difference in acute xerostomia, mucositis, or dermatitis between the IV and
subcutaneous administration. The subcutaneous administration was better
tolerated, with fewer episodes of hypotension, nausea, or vomiting.
An alternative method for prevention of xerostomia is to use conformal
RT techniques that spare normal tissue. As noted, if the radiation dose to the
salivary gland is limited, salivary function can be spared. Several small studies
have reported a positive effect on salivary function in patients treated with
IMRT (46–48). Further evaluation in trials with a larger sample using objective measures of outcome are needed to confirm these results.
Oral Care
Before initiating therapy, patients should undergo a thorough dental evaluation. This should include an examination with radiographs, periodontal
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51
care, smoothing of rough dental surfaces, and assessment of dentures and
prosthetics. Questionable teeth must be extracted before radiation. Radiation should not be started until 10–14 days after dental extraction to allow
adequate time for healing (49).
The best recognized and perhaps the most profound ramification of
xerostomia is dental caries. Caries may progress rapidly. Thus, patients
receiving RT to the head and neck should be advised that an oral care regimen is critical before, during, and after therapy is completed. The purpose
of oral care is to decrease the impact of xerostomia, prevent infections, and
control treatment-related symptoms. An oral care regimen should include
routine brushing (for as long as possible during therapy), flossing, using oral
rinses (water, baking soda, saline), and mouth moisturizers for comfort.
Patients should use fluoride treatments (either trays or concentrated toothpaste) throughout treatment until mucositis prohibits its use. Treatments
should then be resumed as quickly as possible after mucositis resolves.
Psychological Issues
Patients undergoing stem cell transplant have an extensive pretreatment
workup that includes a psychological assessment to identify issues that may
impair their ability to tolerate the aggressive nature of the treatment and
recovery. The use of aggressive CRT regimens for treatment of HNC is no less
rigorous than some transplant protocols. However, psychological assessment
and counseling are not financially viable nor are they acceptable to many
patients with HNC. Psychological care, therefore, becomes a responsibility of
the HNC treatment team.
Several key issues should be addressed as part of the initial psychiatric
evaluation. First, it is critical to determine whether patients have a history of
substance abuse; in particular, a history of alcohol use should be obtained
(see Table 4 for Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, criteria). Although only a small percentage of patients may
meet criteria for alcohol abuse syndrome, a much higher percentage of
patients may have a history of alcohol dependence. For the small percentage
of patients who are unable to refrain from excessive alcohol intake, treatment even with radiation as a single modality may be beyond the ability of
the staff to deliver and the patient to tolerate. In this situation, involving
rehabilitation services before starting therapy is advisable. For patients who
do not exhibit severe maladaptive behaviors, but have a history of heavy
alcohol intake, there are several concerns. First, the abrupt discontinuation
of alcohol may result in a withdrawal syndrome. In addition, patients may
have unrecognized nutrient deficiencies and medical sequelae such as com-
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Table 4. Pretreatment Evaluation
Symptom assessment
Pain
Voice or speech alterations
Swallowing difficulty
Loss of range of motion in neck or shoulders
Hearing loss
Vision changes
Dental care
Dental evaluation
Examination with radiographs
Evaluate for trismus—if present, initiate range of motion exercises
Restoration work
Periodontal therapy
Smooth, rough, or irregular dental surfaces
Assess dental appliances for fit
Oral surgery for removal of diseased teeth
Dental education
Oral hygiene instructions
Fluoride treatments
Diet counseling
Nutritional/swallowing assessment
Weight loss history
Establish degree and rapidity of weight loss
Nutritional supplements as needed
If patient is at high risk, consider feeding tube
Referral for dietary counseling if needed
Vitamin supplement history
Thiamine supplementation if history of alcohol use
Iron supplementation if indicated (anemia history or chronic bleeding)
Speech and language pathology referral if available
Provide swallowing exercises for ongoing use
Psychosocial evaluation
Determine level of social support
(continued)
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Table 4. Pretreatment Evaluation (Continued)
Identify current or previous history of mood disorders (anxiety and
depression)
Alcohol history (CAGE questionnaire)a
Have you ever felt the need to cut down on drinking?
Have you ever felt annoyed by criticism of your drinking?
Have you ever had guilty feelings about your drinking?
Have you ever taken a morning eye opener?
DSM-IV criteria for alcohol abuseb
Failure to fulfill work, school, or social obligations
Recurrent substance use in physically hazardous situations
Recurrent legal problems related to substance use
Continued use despite alcohol-related social/interpersonal problems
DSM-IV criteria for alcohol dependenceb
Tolerance
Withdrawal
Substance taken in larger quantity than intended
Persistent desire to cut down or control use
Time is spent obtaining, using, or recovering from the substance
Social, occupational, or recreational tasks are sacrificed
Use continues despite physical and psychological problems
aMayfield
D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry 1974;131:1121.
bAmerican Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Washington, DC: American Psychiatric Association, 1994.
promised hepatic function or cognitive impairment. Although these factors
are not in and of themselves contraindications to CRT, they must be taken
into account in selecting a patient’s treatment regimen. A simple and realistic
approach to identifying patients with alcohol-related problems is to use a
brief questionnaire, such as the CAGE questionnaire, as a routine in all
patients (see Table 4). For treatment recommendations or more information
on alcoholism or alcohol-related illness, visit the American Society of Addiction Medicine web site (www.asam.org/publ/detoxification.htm).
The second major psychiatric issue is depression. HNC patients have a
high rate of premorbid depression. As many as 40% of HNC patients
complain of depression either before diagnosis or after diagnosis. Patients
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with advanced stage, a premorbid history of depression, or poor support
networks are more likely to develop depression during or after treatment
(50,51). Depression has been associated with a decrease in post-treatment
QOL (52). More important, recovery from the effects of CRT requires a
highly motivated and compliant patient. Depressed patients may find it
difficult to get out of bed and participate in rehabilitation activities, making recovery more prolonged and difficult. A practical method for screening for depression in the office setting is to use a two-question screen that
addresses depressed mood (53). If patients answer either question in the
affirmative, further evaluation and treatment may be indicated.
During the past month, have you been bothered by feeling down,
depressed, or hopeless?
During the past month, have you been bothered by little interest or
pleasure in doing things?
An under-recognized issue in HNC patients is anxiety. In a recent study,
Haman (Haman K. Social anxiety in head and neck cancer patients,
unpublished data) reported that 20% of patients treated for HNC developed an anxiety disorder during or after treatment. The impact of anxiety
on QOL and function was profound. It is interesting to note that most
patients who developed anxiety during or after therapy do not have a
prior history of anxiety. Issues that are often expressed by patients include
fear of airway obstruction, fear of being immobilized during radiation,
and fear of undergoing magnetic resonance imaging. Patients with severe
problems that impact on function or impact on the patient’s ability to
complete therapy should be referred for psychiatric evaluation so that
appropriate medical therapy and counseling can be initiated. Patients with
severe claustrophobia may need deconditioning therapy to tolerate RT.
Conclusion
Treatment of head HNC with aggressive CRT regimens is associated with
significant comorbidities. Careful patient selection is mandatory to ensure
that patients are physically and mentally capable of tolerating and managing complicated treatment regimens and their associated toxicities. To provide optimal outcomes for patients, it is important for the HNC treatment
team to have a systematic approach for supportive care. Patients should be
assessed in an organized fashion before (see Table 4), during (Table 5), and
after therapy (Table 6) for risk factors and areas in which supportive care
can prevent, improve, or treat symptoms. Supportive care protocols and
regimens should be agreed on by the team. Individuals should be identified
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Table 5. Assessment during Chemoradiotherapy
Symptom assessment (weekly during therapy):
Mucositis
Dermatitis
Taste changes
Xerostomia
Phlegm
Airway compromise
Fatigue
Depression
Anxiety
Cognitive changes
Dental care
Examine oral hygiene
Bland rinses (warm water, bicarbonate, salt rinses) every 3–4 hours
Continue brushing of teeth and flossing until no longer possible due to
mucositis
Discontinue dentures when mucositis begins
Fluoride treatment until discomfort from mucositis becomes too severe
Mucositis
Pain medications—opioids are usually needed for moderate to severe
mucositis
Topical anesthetics: lidocaine, benzocaine, tetracaine
Miracle mouthwash
Avoid mucosal irritants: acid, high temperature, spicy foods, alcohol,
or tobacco
Monitor for the development of concurrent infection (Candida, herpes
simplex virus)
Nutrition
Weigh weekly
Nutritional assessment weekly, with diet adjustments based on degree
of mucosal pain and swallowing abnormalities
Dietary consultation when indicated
Swallowing exercises throughout therapy if at all possible
Encourage continued swallowing if at all possible
Placement of feeding tube when indicated
(continued)
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Table 5. Assessment during Chemoradiotherapy (Continued)
Mucus production
Suction catheter
Sleep with head of bed elevated to avoid pooling of secretions in the
throat
Scopolamine patch (may be too drying for some patients)
Mucolytics
Antihistamines (may be too drying for some patients)
Cough suppressants to avoid irritation of throat
Clear sodas to help break up mucus
Humidification of air
Table 6. Assessment and Treatment after Treatment
Is Completed
Symptom assessment
Patients should be assessed weekly in the early recovery phase to assess
toxicities and optimize rehabilitation.
Nutrition and oral intake
Continue swallowing exercises while mucositis heals.
If patient is tube dependent, initiate swallowing of soft bland foods as
early as possible.
Avoid mucosal irritants—mucosal sensitivity may last for a prolonged
period post-treatment.
Advance diet as tolerated to encourage tube independence.
Speech and language pathologist referral
Should be done early for patients who are unable to swallow
Should include instrumental assessment
Modified barium swallow
Flexible Endoscopic Evaluation of Swallow
Xerostomia
Stimulatory measures
Gustatory
(continued)
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Table 6. Assessment and Treatment after Treatment
Is Completed (Continued)
Pharmacologic
Pilocarpine, 5 mg PO qid
Cevimeline, 30 mg PO tid
Comfort measures
Humidified air
Artificial saliva
Physical therapy
Cardiovascular activity—increase as tolerated
A pedometer can be used to monitor progress
Strength training—to build back lost muscles
Exercise bands can be used to strengthen back/shoulders
Stretching—neck and shoulder range of motion
Dental care
Monitor oral cavity for the development of dental caries
Routine dental evaluation
Continued dental education:
Continued daily oral care
Continued fluoride treatments for patients with persistent xerostomia
who are willing to take responsibility for the routine assessment and treatment of complications and toxicities. With aggressive supportive care measures, patients may tolerate therapy with fewer breaks and will recover
function more rapidly.
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❖
Management of Recurrent
Disease: Current Treatments
and New Therapies
Ezra E. W. Cohen, MD, and Oyewale Abidoye, MD
Current Approach to Recurrent Disease
Head and neck cancers are a select group of uncommon and diverse malignancies that can be characterized by their pattern of spread and recurrence.
As such, therapeutic approaches to these unique tumors are based not only
on the tumor histology, but also on the site of disease, surrounding anatomy,
as well as regional lymph node involvement. Approximately 95% of these
tumors are squamous cell carcinomas arising primarily from the lip/oral cavity, larynx, oropharynx, hypopharynx, and larynx. Other less common cancers include mucoepidermoid carcinomas, adenoid cystic carcinomas, and
adenocarcinomas, originating from the salivary glands (1).
Despite aggressive primary therapeutic approaches, up to 65% of patients
are treated for locally advanced disease relapse after primary therapy with surgery and/or radiation. Various studies have implicated locoregional control as
a factor in DFS. With improvements in primary therapy, new focus has been
directed toward improving therapy for patients with recurrent disease. This
includes surgical resection and radiation or re-irradiation with or without concomitant chemotherapy for locoregional disease as well as systemic therapy
with chemotherapy and novel targeted agents for metastatic disease (1).
This chapter focuses on squamous cell carcinoma of the head and
neck (SCCHN) and highlights the current perspectives in treatment for
CME
61
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Management of Recurrent Disease
recurrent disease as well as discusses the current investigational concepts
that are leading to the development of newer therapies and treatment
modalities.
Locoregional Therapies for Recurrent
Head and Neck Cancer
Salvage Surgery
Surgical salvage remains the standard of care for treatment of patients with
locally recurrent disease. However, fewer than 30% of patients who present
with locally recurrent disease are actually surgically resectable. The ability to
obtain tumor-free margins is dependent on tumor location, surrounding
anatomy, as well as the surgeon’s expertise. In cases in which extensive resections are required, expected quality of life postoperatively is also a major
consideration (2).
Overall survival (OS) and disease-free survival (DFS) rates after surgery
are variable and associated with individual patient characteristics, tumor
pathology, presence of lymph node involvement, as well as the adequacy of
surgical margins and use of postoperative radiotherapy (2).
Patients with early stage (T1 or T2) recurrent disease who undergo salvage
surgery alone have been reported to have OS rates and DFS rates of 30%–60%
and 44%–88%, respectively (2,3). Ganly et al. (3) investigated the outcome of
43 patients with early stage recurrent SCCHN after prior therapy with radiation alone for first recurrence. This study also compared outcomes between
patients treated with salvage partial laryngectomy (SPL) versus patients treated
with salvage total laryngectomy (STL). Although the study was able to suggest
the feasibility of SPL in a select group of patients with favorable prognostic
indicators, it also reported that up to 50% of patients who received SPL for
organ preservation went on to require an STL after progression of disease, and
this was also associated with poorer survival outcomes.
Gleich et al. (4) conducted a study of 48 patients with locally advanced (T3
or T4) SCCHN undergoing salvage surgery. Twenty-four patients had primary site recurrence, 20 patients had local recurrence in the neck, and 4 had
both local and regional recurrence. Forty-one of these patients were treated
with salvage surgery with or without radiation; the rest received radiation
alone. Of the 48 patients treated, 42 died in less than 2 years. Results from
this study showed a limited potential for long-term survival and DFS in
patients with recurrent disease treated with salvage surgery after initial therapy for advanced primary-site cancer. Careful counseling was recommended
for patients opting to pursue this course of therapy (4).
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Management of Recurrent Disease
63
Complications of salvage surgery are related to extensive surgical resection and manipulation of previously irradiated tissues. These include fistula formation and local wound complications (3,4).
Role of Radiation Therapy in Locally Recurrent Disease
Patterns of recurrence have identified locoregional failure to be a common
cause for recurrent SCCHN, both locally and distally. This has led to an
emphasis on locoregional control both in the primary setting and also in
the setting of locally recurrent disease. One modality of therapy that has
been used to improve locoregional control in recurrent disease after surgical resection is radiation therapy.
Radiation Therapy for Patients Treated with Salvage Surgery
Surgically resectable patients with recurrent disease with a high risk for
locoregional failure due to poor prognostic indicators (including multilevel
lymph node involvement, extranodal tumor extension, or positive surgical
margins) should undergo adjunct therapy with radiation (5,6). Although
there are no absolute contraindications for those groups of patients with
recurrent disease who have not had prior radiotherapy, severe complications
do exist, and patients must therefore be closely monitored during and after
completion of therapy.
Emerging Concept of Re-Irradiation in Patients with
Recurrent Head and Neck Cancer
As previously discussed, patterns of recurrence in SCCHN point to locoregional failure in both locally recurrent and distant metastatic disease (6). This
has led to the development of the concept of re-irradiation treatment in patients
with locally recurrent SCCHN who have had prior radiation therapy (5,6).
The concept of re-irradiation involves the administration of a second
course of radiation therapy for patients with locally recurrent SCCHN who
have had prior therapy with radiation. This course of therapy offers a potential curative option for patients with locally recurrent SCCHN who present
with unresectable disease (5,6). Re-irradiation is commonly administered in
doses of 60–70 Gy with concomitant chemotherapy in radiosensitizing doses.
This is done to increase the antitumor activity in the field of recurrence where
radio-resistant tumor clonogens may exist (5,6).
Although several phase I–II studies have demonstrated severe toxicity
exists with the administration of radiation to previously radiated tissues, the
feasibility of re-irradiation and its potential for long-term survival and DFS is
evident. As such, treatment with re-irradiation for locally recurrent SCCHN
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64
Management of Recurrent Disease
should only be considered by an experienced team ready to meet the problems
and complications and who know the limits of therapy (5,6). Since the 1970s,
several studies have been conducted to investigate the feasibility of re-irradiation as a treatment modality for patients with locally recurrent disease (6).
Table 1 summarizes some of the largest trials to date involving re-irradiation.
Institut Gustave Roussy (IGR) reported a 16-year series that included 169
patients with locally recurrent, unresectable head and neck cancer (including
non-squamous histology) (7). These patients were assigned to three groups. The
first group consisted of 27 patients receiving treatment from 1980 to 1996 with
radiotherapy alone at a total dose of 65 Gy in 2-Gy fractions as a continuous
course. The second group consisted of 106 patients who received treatment
with a split-course re-irradiation and a concomitant chemotherapy regimen of
5-fluorouracil (5-FU) at 800 mg/m2 and hydroxyurea at 1.5 g per day administered daily in a week on–week off fashion. The third group consisted of 36
patients receiving hyperfractionated radiation (1.5 Gy twice a day) with a concomitant chemotherapy regimen of mitomycin, 5-FU, and cisplatin, also
administered in a week on–week off fashion. The median cumulative dose after
the second course of radiation was 120 Gy (6,7). Results of this study showed
that it was feasible to safely administer a second course of radiation with concomitant chemotherapy. Grade 3 and 4 mucositis was the most common early
toxicity, occurring in 14%–32% of treated patients. Late toxicities, occurring 6
months post-therapy, included cervical fibrosis, trismus, and soft tissue necrosis.
Five patients also died from carotid hemorrhage (7). Despite the significant toxicities observed, the study showed complete response rates in the range of 25%
to 41%. The highest rates were seen with the FHX (5-FU, hydroxyurea, daily
radiation) regimen. This was statistically higher than the response rates of 10%
seen with palliative chemotherapy. Median survival was 10–11 months for all
three groups, with 13 patients achieving long-term DFS (6,7).
The University of Chicago treated 115 patients on seven different protocols
over 15 years and recently reported a retrospective review of the experience.
These studies differed from the IGR study in two key aspects: (a) the strict
selection of patients with squamous cell histology and (b) the use of salvage
surgery for complete resection or optimal debulking before re-irradiation in 49
patients (6,8). All patients were treated with variants of the FHX regimen,
including varying doses of hydroxyurea and 5-FU; the use of daily versus
twice-daily radiation; as well as the addition of cisplatin, paclitaxel, irinotecan,
or gemcitabine to the FHX regimen at varying doses (8). Nineteen patients
died of treatment-related toxicity. Six patients had carotid hemorrhage, and
only one of these survived. Thirteen patients also developed osteoradionecrosis
requiring surgical repair (8). The median cumulative radiation dose was 131
Gy with 3-year OS, progression-free survival, locoregional control, and freedom from distant metastases rates of 22%, 33%, 51%, and 61%, respectively,
27
106
36
81
115
105
240 (to be
accrued)
De Crevoisier et al.
(7)
Horwitz et al.
Wong et al. (6)
(ongoing)
STD fx RT
H, 5-FU/STD fx RT
MMC, 5-FU, CDDP/ HYP fx RT
H, 5-FU/HYP fx RT
STD fx RT, HYP fx RT with
various chemotherapy
regimens
CDDP, paclitaxel/HYP fx RT
CDDP, paclitaxel/HYP fx RT
CT alone
CDDP, 5-FU
CDDP, paclitaxel
CDDP, docetaxel
Treatment
65.4
60 (planned)
65
60
60
60
64.8
Median RT
Dose (Gy)
NA
NA
NA
24 (2 y)
10 (2 y)
NA
51 (3 y)
Locoregional
Control (%)
25.9 (2 y)
NA
16.9 (2 y)
22 (3 y)
25 (2 y)
Overall
Survival (%)
CDDP, cisplatin; CT, chemotherapy; 5-FU, 5-fluorouracil; H; hydroxyurea; HYP fx RT, hyperfractionated radiation; MMC, mitomycin ; NA, not
available; RT, radiotherapy; STD fx RT, standard fractionated radiation.
Spencer et al.
Salama et al. (8)
No. of
Patients
Phase II–III Clinical Trials in Re-Irradiation for Squamous Cell Carcinoma of the Head and Neck
Study
(References)
Table 1.
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65
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66
Management of Recurrent Disease
which were statistically significant when compared to palliative chemotherapy
alone (6,8). Multivariate analysis identified surgical resection, re-irradiation
dose, and use of triple-agent chemotherapy (i.e., cisplatin, paclitaxel, or irinotecan with FHX) as independent prognostic indicators for response and survival (6,8).
Common toxicities seen with re-irradiation include xerostomia, mucositis,
tissue fibrosis, trismus, osteoradionecrosis, poor healing in soft tissues and
bones, dysphagia, and hypothyroidism. Less common severe life-threatening
complications include vessel rupture (e.g., carotid artery blow-out) (5,6,8).
These two series were followed by three cooperative group trials conducted by the Radiation Therapy Oncology Group (RTOG). Two of these
trials, RTOG 96-10 and RTOG 96-11, have been completed and are summarized in Table 1 (6). A third ongoing phase III trial (RTOG 0421) is
being conducted to compare re-irradiation and concomitant chemotherapy
to chemotherapy alone in patients with locally recurrent or second primary SCCHN who are inoperable with a prior history of radiation (6).
Although the role of radiation (with or without concomitant chemotherapy) in the setting of recurrent SCCHN still remains to be defined, its
role in the setting of palliative care is definitive (9). Patient selection
includes those with a relatively good performance status who experience
significant impairment in their quality of life due to cancer-related causes
(e.g., severe pain and limited mobility due to osseous and spinal metastases). These patients should be referred to a radiation oncologist for consultation regarding palliative radiation (9).
Systemic Therapy for Recurrent
Head and Neck Cancer
Palliative treatment with systemic therapy includes conventional chemotherapy and novel targeted therapy. Response rates with these therapies
are variable, with several phase II–III clinical trials showing overall
response rates to combination chemotherapy in the order of 20%–40%
and single-agent therapy, including non-cytotoxics, in the order of 5%–
15% (10,11).
Although these response rates are clinically significant, it also important to remember that systemic therapy has not been adequately demonstrated to improve OS, and its role in therapy continues to be a palliative
one with the goal of controlling symptoms and improving quality of life
(10,11). This distinction is important to recognize in the selection of patients
for treatment, with consideration given to treatment toxicity and tolerability (10,11).
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67
Evolution of Systemic Chemotherapy
Combination chemotherapy has demonstrated the highest response rates
in systemic therapy for recurrent and metastatic SCCHN, and is currently
the standard of care. Several phase II–III studies comparing combination
chemotherapy versus single-agent therapy have shown statistically significant improvement in tumor response with combination chemotherapy
over single-agent therapy (10,12). Single-agent therapy is currently recommended in cases in which prior combination chemotherapy has failed and
toxicity is of concern (10,13).
Although combination chemotherapy has been shown to have higher
response rates than single-agent therapy, the incidence of high-grade toxicity is
significantly higher. One exception to this has been the combination regimen
of cisplatin and 5-FU. The effective response rates and favorable toxicity profile have led to this combination regimen becoming the most widely recommended as first-line treatment for recurrent or metastatic SCCHN (10,13).
Other agents currently used in the treatment of SCCHN include the platinum agents (cisplatin and carboplatin), the taxanes (paclitaxel and docetaxel),
5-FU, capecitabine, gemcitabine, pemetrexed, as well as bleomycin and
methotrexate (MTX), which were both the most widely used cytotoxic agents
before the advent of the platinum agents (10,13).
Common Chemotherapy Agents Used for Recurrent
Head and Neck Cancer
Platinum Agents
The platinum agents are among the most widely used agents in the treatment
of SCCHN (10,13). These agents act through covalent binding to cell DNA.
Cisplatin has been the most widely used and most favored for systemic therapy in recurrent SCCHN, in large part due to its statistically higher and rapid
response rates when compared to other agents. Response rates for cisplatin in
single-agent therapy and combination chemotherapy are 10%–15% and
25%–40%, respectively, depending on prior therapy. Its derivative compound,
carboplatin, has been tested in phase II–III trials and found to have acceptable,
though arguably lower, response rates. Adverse effects of platinum agents
include nephrotoxicity, neurotoxicity, nausea, and vomiting (which can be
quite severe), as well hypersensitivity reactions (10,13,14).
Taxanes
The taxanes include paclitaxel and docetaxel, which have both found use in
single-agent therapy and as part of combination chemotherapy (10,13,15).
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68
Management of Recurrent Disease
These agents act through inhibition of microtubule assembly in rapidly
dividing cells. Single-agent responses range between 20% and 40% in
uncontrolled trials (10,15). Both agents are administered on either weekly or
every 21-day schedules, with paclitaxel administered as a 3-hour infusion
and docetaxel as a 1-hour infusion (10,15). Premedication is given with paclitaxel to prevent possible hypersensitivity reaction and with docetaxel to
also prevent edema. Common toxicities include neutropenia, alopecia,
fatigue, gastrointestinal symptoms, and peripheral neuropathy (15).
Methotrexate
MTX was approved by the U.S. Food and Drug Administration (FDA) for
cancer treatment in 1953 (10,14). Before the advent of platinum agents, this
drug was one of the more widely used cytotoxic agents in the treatment of
SCCHN (10,13,14). MTX is a cell cycle–specific analog that is active in the Sphase of the cell cycle and inhibits the activity of dihydrofolate reductase (13).
Single-agent response rates seen in phase II–III studies vary considerably,
depending on prior therapy, but typically range between 5% and 10%, with
higher response observed in patients with no prior treatment (10,13).
Other commonly used agents, such as bleomycin and 5-FU, have singleagent response rates of 5%–10% and 15%, respectively (10).
Clinical Trials Using Combination Chemotherapy
in Recurrent Head and Neck Cancer
Several clinical trials using combination chemotherapy have shown improvement in response rates (10), especially with platinum-containing regimens.
However, no regimen has been shown to be better in improving survival
over another (10,14).
Cisplatin and 5-Fluorouracil
The cisplatin and 5-FU combination regimen has become a reference regimen for doublet therapy in part due to its reasonable response rates and
favorable toxicity profile when compared to other regimens (10,12–14).
Since the regimen emerged in the early 1990s, several clinical trials have
been conducted comparing this regimen with other combination regimens
and single-agent therapies (10,13). The summation of the trials has been
overall response rates for recurrent disease in the range of 30% to 40%
and median OS of 6–8 months (10,13,14).
Two noteworthy trials were published in 1992, one by Jacobs et al. (16)
and another by Forastiere et al. (12). The study by Jacobs et al. involved
249 patients who were randomized to three clinical treatment arms (cis-
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Management of Recurrent Disease
69
platin and 5-FU, cisplatin alone, and 5-FU alone). Results from this study
showed the combination cisplatin and 5-FU regimen was statistically superior in overall response rates (32%) compared to single-agent cisplatin
(17%) or 5-FU alone (13%) (10,16). The second study by Forastiere et al.
compared cisplatin and 5-FU and carboplatin and 5-FU to single-agent
MTX. Results from this randomized control trial of 227 patients also validated the superiority of cisplatin and 5-FU, with response rates to cisplatin
and 5-FU, carboplatin and 5-FU, and MTX being 32%, 21%, and 10%,
respectively. Neither of the two studies demonstrated improvement in survival between the different regimens, though there appeared to be an association between survival and patient performance status (10,12,16).
Taxanes and 5-Fluorouracil
After the introduction of platinum-based combination therapy, studies
were also conducted using the taxanes paclitaxel and docetaxel. To date,
no major studies have demonstrated superior response rates to the combination of cisplatin and 5-FU. One multicenter phase II study of docetaxel
and 5-FU in 63 patients with recurrent and metastatic SCCHN showed an
overall response rate of approximately 20%, with higher response rates
observed in the cohort arm with a history of prior therapy (10,17,18).
Combination Therapy with Platinum Agents and Taxanes
Several promising phase II and phase III trials investigating taxanes in
combination with platinum agents have also been conducted. Gibson et al.
(19) compared cisplatin/paclitaxel to cisplatin/5-FU in a phase III trial that
enrolled 218 patients. The overall response rates (26% and 27% in the
paclitaxel and 5-FU arms, respectively) and median OS (8.1 months and
8.7 months in the paclitaxel and 5-FU arms, respectively) were nearly
identical. Other phase II trials using platinum and taxane combinations
have demonstrated overall and complete response rates of 41%–70% and
27%–52%, respectively (10,19,20).
Triple-Agent Regimens
Treatment with triple-agent regimens has yielded higher response rates,
both overall and complete, but with increasing toxicity (10,21). Three
common regimens have included (a) cisplatin with paclitaxel and 5-FU;
(b) docetaxel, cisplatin, and 5-FU; and (c) paclitaxel, ifosfamide, and cisplatin. Overall response and complete response rates for these regimens
are comparable, 40%–60% and 12%–50% respectively, with the highest
responses and toxicities seen with cisplatin, paclitaxel, and 5-FU; median
survival for patients treated with these regimens ranges between 9 months
and 14 months (10,21).
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Management of Recurrent Disease
Despite the improvements seen in response rates, results from phase III
trials of triple-agent regimens also show increased toxicity, particularly
grade 3–4 myelosuppression. As such, when considering patients for treatment with triple-agent regimens, the observation of increased toxicity
needs to be balanced against modest gains seen in survival (10,21).
Novel Targeted Therapy
Despite an increase in the number of available cytotoxic agents and their new
uses in combination, median survival for these remains relatively unchanged
when compared to single-agent therapy and appears to have reached a plateau. Toxicity, therefore, becomes a major consideration in therapy that is palliative rather than curative. This issue, along with new understanding of
tumorigenesis, has led to the development of novel targeted therapy (10,22).
Epidermal Growth Factor Receptor
As early as the mid-1960s, the epidermal growth factor receptor (EGFR)
and its ligands were identified as playing a critical role in tumor cell proliferation as well as response to therapy. Most recently, in the 1990s it was
observed that 80%–100% of SCCHN had an abnormal level of EGFR
expression (10,22,23). This generated interest in therapy through the inhibition of EGFR expression via antibodies (e.g., cetuximab) and small molecule inhibitors (e.g., gefitinib and erlotinib) (10,11,22–25).
Cetuximab was approved for use in colorectal cancer in 2004 and in 2006
as single-agent therapy for patients with platinum refractory, recurrent, or
metastatic SCCHN. Several phase II clinical trials have been conducted to study
the efficacy of cetuximab in recurrent SCCHN. A European study enrolled 103
patients with recurrent or metastatic SCCHN and progression of disease after
treatment with platinum-based chemotherapy. Subjects were administered
cetuximab at an initial dose of 400 mg/m2 followed by a weekly dose of 250
mg/m2 until disease progression. After disease progression, these patients were
then offered the option of salvage therapy with cetuximab and the addition of
the platinum agent that they previously had been treated with (10,11,22–25).
Interim data from this study were first presented in 2004 by Trigo et al. (24)
and later by Vermoken et al. (25) in 2005, who demonstrated that cetuximab
monotherapy was well tolerated, with a response rate of 13%, disease control
rate of 46%, and a median survival of 5.9 months, results that were comparable to those seen with first-line therapy and that represented a 2.5-month
increase in median survival compared to platinum-refractory historical controls
(10,22–25). Moreover, two phase II studies that each enrolled patients after failure of a platinum-containing doublet regimen to continue platinum in combination with cetuximab revealed an 11% response rate (25–27). In addition, a
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Management of Recurrent Disease
71
phase III trial comparing cisplatin with or without cetuximab in first-line recurrent or metastatic SCCHN observed a significant improvement in the secondary end point of response rate in the experimental arm (26% vs. 10%;
P = .03) (28). The data, thus, suggest that cetuximab is an active agent in recurrent/metastatic SCCHN. Table 2 highlights some of the recent trials involving
cetuximab in the treatment of recurrent or metastatic SCCHN.
Tyrosine kinase inhibitors directed against the EGFR also appear to be
active single agents, with both gefitinib and erlotinib demonstrating objective
responses (11% and 4%, respectively) (11). A phase II study of gefitinib dosing at 250 mg in recurrent or metastatic SCCHN was recently conducted at
the University of Chicago, and results demonstrated gefitinib to be well tolerated at 250 mg, with modest benefit and without significant deterioration in
overall quality of life (29).
Randomized trials testing the role of gefitinib in SCCHN are under way.
Almost every trial administering an EGFR inhibitor in SCCHN has also noted
an association between development of skin toxicity related to the agents and
improved outcome. Whether this association reflects a true biologic phenomenon and the possible mechanisms underlying it remain to be elucidated (11).
Abidoye et al. (30) recently completed a phase II study of lapatinib, a dual
inhibitor of EGFR and erbB2 tyrosine kinases, in patients with recurrent or
metastatic SCCHN. Preliminary data from this study did not indicate a statistically significant survival benefit when compared to best supportive care;
however, further studies are ongoing (11,30).
Other Agents
Other agents under investigation in trials for recurrent or metastatic SCCHN
include sorafenib, an inhibitor of Raf kinase and the vascular endothelial
growth factor (VEGF) receptor, which recently gained FDA approval in the
treatment of renal cell carcinoma. Two phase II trials of sorafenib as singleagent therapy in recurrent or metastatic SCCHN have demonstrated a response
rate of approximately 5% (31,32). Bevacizumab, an anti-VEGF monoclonal
antibody, has been combined with erlotinib in recurrent/metastatic SCCHN,
with a 14% response rate reported, suggesting the possibility of enhancement
of EGFR-inhibitor activity. In addition, a phase I study of gefitinib with celecoxib, a cyclooxygenase-2 inhibitor, demonstrated tolerability of the combination and a promising response rate of 22% (33).
Conclusion
Even though the majority of patients with SCCHN present with local disease
and there have been vast improvements in therapy of locally advanced disease,
the majority of patients will eventually experience recurrent or metastatic
manifestations. The treatment of recurrent or metastatic disease can involve
72
76
117
103
Herbst et al.
(27)
Burtness et
al. (28)
Vermoken et
al. (25)
200 mg/m2 loading;
125 mg/m2 weekly;
cisplatin, 100 mg/
m2 q4wk
400 mg/m2 loading;
250 mg/m2 weekly
1 prior platinumcontaining
regimen
1 prior platinumcontaining
doublet
1 prior platinumcontaining
doublet
No prior chemotherapy
400 mg/m2 loading;
250 mg/m2 weekly
400 mg/m2 loading;
250 mg/m2 weekly
Prior
Therapy a
Cetuximab Dose/
Schedule
bResponse
therapy represents patient eligibility restrictions in these trials.
rate of cisplatin plus cetuximab.
96
Baselga et al.
(26)
aPrior
No. of
Patients
Study
(References)
13
26b
10
10
Response
Rate (%)
2.3
4.2
2.8
2.2
Progression-Free
Survival (mo)
5.9
9.2
6.1
5.2
Overall
Survival (mo)
Table 2. Clinical Trials of Cetuximab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
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Management of Recurrent Disease
73
Locally recurrent or distal recurrence/metastatic disease
Locally recurrent
Distal recurrence
Metastatic disease
Is patient surgically resectable or operable?
YES
Consider
salvage surgery
with or without
adjuvant
radiation
NO
Consider treatment with
radiation alone (if no
prior) or with re-irradiation
with concurrent
chemotherapy
OR
Consider clinical trial
or systemic therapy
with chemotherapy
OR
EGFR inhibitor
Progression of disease
Consider clinical trial OR therapy with
single-agent chemotherapy OR EGFR inhibitor
Further progression of disease
Consider clinical trial OR single-agent chemotherapy
Discuss goal of care, consider hospice if progression continues
Figure 1. Treatment approach to patients with recurrent or metastatic
squamous cell carcinoma of the head and neck. EGFR, epidermal growth factor inhibitor.
surgery or re-irradiation if the disease is confined to locoregional recurrence,
whereas systemic therapy is used with palliative intent in most patients. Cytotoxic doublet therapy is active but has reached an efficacy plateau. Novel targeted agents are being intensely studied as monotherapy and in combination
with conventional chemotherapeutic agents in recurrent or metastatic SCCHN
in an effort to improve outcome, with inhibitors of EGFR already approved by
regulatory authorities. Figure 1 displays a recommended treatment approach
to the patient with recurrent or metastatic SCCHN.
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line platinum based therapies. Proc Am Soc Clin Oncol 2005;23(16S):5505.
Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination
with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin
Oncol 2005;23:5568–5577.
Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent
and refractory squamous cell carcinoma of the head and neck. J Clin Oncol
2005;23:5578–5587.
Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern
Cooperative Oncology Group study. J Clin Oncol 2005;23(34):8646–8654.
Kane MA, Cohen EE, List M, et al. Phase II study of 250-mg gefitinib in
advanced squamous cell carcinoma of the head and neck (SCCHN). Proc Am
Soc Clin Oncol 2004;22(14S):5586.
Abidoye OO, Cohen EE, Wong SJ, et al. A phase II study of lapatinib
(GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the
head and neck (SCCHN). Proc Am Soc Clin Oncol 2006;24(18S):5568.
Williamson SK, Moon J, Huang CH, et al. A phase II trial of BAY 43-9006 in
patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): a Southwest Oncology Group (SWOG) trial. Proc Am Soc
Clin Oncol 2006;24(18S Part I):5550.
Siu LL, Winquist M, Agulnik SF, et al. A phase II study of BAY 43-9006 in
patients with recurrent and/or metastatic head and neck cancer squamous cell
carcinoma (HNSCC) and nasopharyngeal cancer (NPC). Proc Am Soc Clin
Oncol 2005;23(16S):5566.
Wirth LJ, Haddad RI, Lindeman NI, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck.
J Clin Oncol 2005;23:6976–6981.
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❖
Integration of Chemotherapy
into Organ Preservation
Strategies for Squamous Cell
Head and Neck Cancer
David J. Adelstein, MD
Treatment Goals
The appropriate identification of a treatment goal is critical in the management of any malignancy. Cure, when possible, is clearly the end point of greatest importance. However, for patients with cancers of the head and neck,
achievement of that cure often comes with a significant cost. Surgical resection, the historical standard of care, can result in the loss or compromise of
crucial anatomic structures involved in important human functions, including
speech, swallowing, and non-stomal breathing. As such, the concept of organ
preservation has emerged as another important end point in head and neck
cancer management.
It is important, however, that organ preservation be distinguished from
organ function conservation. Although it may seem obvious that preservation
of the organ is a necessary prelude to preservation of its function, this is an
oversimplification. Current reconstruction and rehabilitation techniques often
allow for successful preservation and/or restoration of organ function even
after surgical resection. Conversely, nonoperative management, such as radiation with or without chemotherapy, may obviate primary site resection yet still
result in significant functional disability. Furthermore, aggressive attempts to
preserve one organ function may significantly and adversely affect another, as
CME
77
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Integration of Chemotherapy into Organ Preservation
in the patient who retains his or her larynx at the expense of significant interference in swallowing. Attempts to preserve an organ that is destroyed by the
initial tumor extent are, as such, ill advised.
In patients with advanced laryngeal and hypopharyngeal cancers, the
organ at risk is the larynx. Although partial laryngeal surgery is possible in
many patients, larger primary site tumors often mandate a total laryngectomy
for optimal oncologic care. Stomal breathing and loss of normal vocalization
result. For patients with oropharyngeal cancer, the definition of the organ at
risk is less clear. Little functional impairment is expected after resection of an
early tonsil or tongue lesion. Surgery for larger tumors, however, particularly
of the base of tongue or pharyngeal wall, may require significantly morbid
procedures, including total glossectomy and/or laryngectomy, and may produce marked interference with normal speech and swallowing. Efforts to minimize the resultant functional impairments are critical.
It is also critical that we, as oncologists, remember our patients’ charge.
List et al. (1) reported the results of a study examining the relative value
assigned by patients to specific outcomes after treatment of head and neck
cancer. The most important patient-defined treatment goal was cure, with survival prolongation in second place. Symptomatic and functional concerns,
such as freedom from pain, ability to swallow, and retention of a natural
voice, proved less important. Maximizing a patient’s chance for cure, even at
the cost of functional impairment, remains the top priority. Although individual patients may choose to sacrifice curative potential or survival benefit for
functional preservation, this is not the rule, and these issues require careful
exploration when treatment options are reviewed.
Thus, although organ preservation and, more specifically, organ function
conservation are desirable treatment goals, they are secondary end points. The
survival equivalence of a nonoperative organ-preserving intervention and conventional surgical treatment must be established before such an organ-preservation strategy can be considered acceptable. Furthermore, better assessments
of long-term organ function and measurements of overall patient satisfaction
must be designed and implemented. In the absence of these tools, however, the
potential for organ preservation often provides the best measure of organ
function conservation.
Organ-Preservation Strategies
Radiation Therapy and Surgery
Radiation therapy is the original organ-preserving treatment strategy in
squamous cell head and neck cancer, and these malignancies are generally
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Integration of Chemotherapy into Organ Preservation
79
considered to be very radiosensitive. However, organ function–preserving
surgical procedures are now welldefined for many head and neck primary
sites and may be equally, if not more, successful in achieving primary site
control and preserving primary site function (2). Thus, small primary site
tumors (T1–T2) may be approached with either single-modality radiation
therapy or surgery with, in many cases, relatively similar results. In the
absence of definitive studies comparing these two treatment approaches,
the choice is often based on institutional expertise and patient preference.
Treatment of the primary site must also be considered separately from
treatment of the neck. Organ preservation and organ function conservation reflect an approach to the primary site tumor. The presence of clinical
neck node involvement or the possibility of spread to neck nodes must also
be considered in all patients. A neck dissection can be accomplished irrespective of the approach taken for the primary site and is often indicated
even when definitive radiation therapy is chosen as the primary management. Although there can be functional deficits resulting from a neck dissection, these rarely interfere with speech or swallowing.
For patients with larger (T3–T4) primary site tumors, the relative success
of surgical resection and postoperative radiotherapy, compared to definitive
radiation therapy alone (with subsequent surgical salvage if necessary), is
unknown. It is in this group of patients that the addition of systemic chemotherapy to definitive locoregional management has had the greatest impact.
Integration of Systemic Chemotherapy
Systemic chemotherapy, as a single-treatment modality, can produce significant tumor shrinkage in previously untreated patients with squamous cell
head and neck cancer. Response rates of 70%–90% (complete in 30%–
50%) have been reported and led to considerable enthusiasm about the
potential impact of this treatment modality (3). It was disappointing when
the phase III studies that tested chemotherapy given either before definitive
management or as an adjuvant after locoregional treatment were unable to
demonstrate a reproducible survival benefit (3–5). When chemotherapy
and radiation were given concurrently, however, whether as the definitive
nonoperative treatment or in the postoperative adjuvant setting, a clear
improvement in overall survival was demonstrated. As such, concurrent
radiation and systemic chemotherapy became an integral part of the standard care for many patients with locoregionally advanced squamous cell
head and neck cancer (3,4).
Whether systemic chemotherapy can also improve the possibility of organ
preservation can be evaluated in several ways. Optimally, a phase III trial
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80
Integration of Chemotherapy into Organ Preservation
should be performed comparing a nonsurgical, chemotherapy-based, organpreserving approach with a primary operative intervention. The objective of
such a study would be to demonstrate an improvement in organ preservation
(and by inference, organ function conservation) without a reduction in survival. Alternatively, and less definitively, comparative clinical trials of definitive
nonoperative approaches (e.g., radiotherapy versus concurrent chemoradiotherapy) can report the likelihood of local disease control—a reasonable measure of organ preservation in the absence of planned surgical resection.
Although the likelihood of organ preservation in surviving patients has often
been cited as an end point of interest, it reflects a measure of limited importance if significant numbers of patients do not survive. A more meaningful end
point is the likelihood of survival with an intact organ.
The potential for chemotherapy to favorably impact the likelihood of
organ preservation in patients with squamous cell head and neck cancer was
first reported by Jacobs et al. in 1987 (6). Twelve head and neck cancer
patients who had experienced a pathologic complete response at the primary
site after induction chemotherapy with 5-fluorouracil and cisplatin were
treated with definitive radiation therapy alone, rather than the originally
planned laryngectomy, glossectomy, or composite resection. When this experience was reported, 8 of the 12 patients so treated were free of disease, with a
survival rate equivalent to patients who had undergone definitive surgery.
Other investigators repeated this experience, often focusing on larynx cancer
(7–10). Avoidance of a laryngectomy was thought to be a sufficiently compelling reason to justify an organ-preservation strategy, particularly as salvage
laryngectomy, even after failure of definitive radiation, was a well-established
and successful procedure.
This phase II experience led to the design and performance of the large
Department of Veterans Affairs (VA) Laryngeal Cancer Study Group larynx
preservation trial, first reported in 1991 (11). Three-hundred thirty-two
patients with advanced larynx cancer were randomized to receive either induction chemotherapy with cisplatin and 5-fluorouracil followed by radiation
therapy in responders or to a laryngectomy followed by radiation. Chemotherapy nonresponders underwent laryngectomy and postoperative radiation.
Patients on the nonsurgical arm with residual or recurrent disease after definitive radiation were also offered salvage laryngectomy.
The response to induction 5-fluorouracil and cisplatin was equivalent to the
best of the induction chemotherapy regimens previously reported, with an
overall response rate of 85% and a complete response rate of 31%. Similar to
other induction trials being completed at this time, no survival benefit was
identified for those patients who received the induction chemotherapy. However, there was also no loss of survival potential on this treatment arm. Furthermore, for the chemotherapy-treated patients, larynx preservation was possible
in approximately 2/3 of the survivors, and survival with an intact larynx at 3
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Integration of Chemotherapy into Organ Preservation
81
years was 31%. The results of this study supported the contention that chemotherapy might substitute for surgical resection in responsive patients, perhaps
by enhancing the benefit achieved from the radiation therapy. Alternatively, it
was suggested that a response to induction chemotherapy might have only
served to identify those patients likely to experience a good response after
definitive radiation therapy. Chemotherapy (and therefore radiotherapy) nonresponders were thus identified early and better served by an immediate surgical resection. Regardless, the absence of a clear survival difference between
these two treatment arms justified a nonoperative, organ-preserving approach
for patients with advanced resectable larynx cancer and legitimized the concept
of organ preservation as an appropriate end point in the management of this
disease.
The potential for organ preservation has been supplemented by long-term
functional assessments that have been reported from this study (12,13). Most
patients undergoing laryngectomy were able to re-establish some kind of vocal
communication, whether by esophageal speech, a tracheoesophageal puncture,
or an artificial larynx. Objective evaluation, however, demonstrated significantly better speech intelligibility in patients randomized to the nonoperative
treatment. Swallowing assessments, as reported by the patient, were equivalent
between the two treatment arms, but overall quality of life was better in the
larynx-preservation arm.
A similar study was reported by the European Organisation for Research
and Treatment of Cancer (EORTC) in patients with primary hypopharyngeal tumors using a nearly identical study design (14). Survival again proved
statistically equivalent between the two treatment arms, and the 3-year survival with a functional larynx was 28% in the patients treated with chemotherapy. A third, smaller trial, reported in 1998 by the French Groupe
d’Etudes des Tumeurs de la Tête et du Cou also used the same study design
in previously untreated patients with T3 disease, all presenting with a fixed
vocal cord (15). This study was terminated prematurely because of patient
refusal to be randomized to the surgical arm. Despite this early closure, survival and disease-free survival proved significantly worse in the group given
induction chemotherapy, a result discordant with the other two, larger studies (Table 1). A metaanalysis of updated individual patient data from these
three randomized trials noted a nonsignificant trend suggesting a survival benefit in those patients randomized to laryngectomy despite the clear improvement in organ preservation on the chemotherapy arm (Table 2) (16).
A closer look at this study design, however, leads one to conclude that the
impact of the chemotherapy is not clear. Indeed, the survival equivalence
between the two treatment arms seen in the VA and EORTC trials may only
reflect the equivalence of a primary surgical and a primary radiotherapeutic
approach in patients with advanced laryngeal and hypopharyngeal cancers.
This observation led to the development and performance of a second-
82
F, 5-fluorouracil; P, cisplatin.
Department of Veterans
Affairs Laryngeal Cancer Study Group (11)
European Organisation
for Research and Treatment of Cancer (14)
Groupe d’Etudes des
Tumeurs de la Tête et
du Cou (15)
Group
(Reference)
Larynx
Hypopharynx
Larynx
1996
1998
Primary Site
1991
Year
68
202
332
No. of
Patients
PF
PF
PF
Chemotherapy
Advantage:
surgery
No difference
No difference
Survival
Table 1. Randomized Organ Preservation Trials of Induction Chemotherapy and Radiation
versus Surgical Resection and Radiation
—
28% (3 y)
31% (3 y)
Alive/Organ
Preserved
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Integration of Chemotherapy into Organ Preservation
83
Table 2. Metaanalysis: Larynx Preservation Trials of
Neoadjuvant Chemotherapy
Overall
survival
Diseasefree
survival
Response Rate
(95% Confidence
Interval)
Chemotherapy
(%)
No Chemotherapy
(%)
1.19 (0.97–1.46)
39
45;
P = .1
1.18 (0.97–1.44)
34
40;
P = .1
Note: Survivors with functional larynx at 5 years = 58%.
Information compiled from Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy
added to locoregional treatment for head and neck squamous-cell carcinoma: three
meta-analyses of updated individual data. Lancet 2000;355:949–955.
generation Head and Neck Intergroup larynx preservation trial (Radiation
Therapy Oncology Group 91-11) (17,18). In this trial, the successful experimental arm from the VA laryngeal cancer study (induction chemotherapy followed
by radiation in responders) was compared to radiation therapy alone and to a
third arm of radiation therapy with concurrent single-agent, high-dose cisplatin
in patients with resectable stage III and IV larynx cancer. A laryngectomy arm
was not included in this study, and laryngectomy was reserved for persistent or
relapsed disease or for nonresponders to induction chemotherapy. A neck dissection was planned for all patients with N2 or N3 disease at the time of diagnosis. The results of this study demonstrated no significant difference in larynx
preservation or in locoregional control when the induction chemotherapy arm
was compared to the radiation therapy–alone arm. The concurrent radiation
and single-agent cisplatin treatment arm, however, proved superior for both end
points. It should be noted, however, that in the most recent update of this study,
reported at the 2006 meeting of the American Society of Clinical Oncology, the
combined end point of laryngectomy-free survival was equivalent for the induction and the concurrent arms and was superior to radiation therapy alone (18).
Survival remained the same between all three treatment arms, an observation
attributed at least in part to the success of salvage laryngectomy.
A similar observation was made in a smaller trial reported from the Cleveland Clinic (19). This study randomized non–site-specific patients with resectable stage III and IV head and neck cancer to either definitive radiation
therapy or definitive radiation and concurrent chemotherapy. The concurrent
chemoradiotherapy regimen consisted of radiation, cisplatin, and 5-fluorouracil. Provisions for salvage surgery were incorporated into the study for
patients with no clinical response after 50–55 Gy of radiation, with persistent
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84
Integration of Chemotherapy into Organ Preservation
disease after the completion of a full course of radiation, or with a subsequent
locoregional recurrence. Recurrence-free interval, local control without surgical resection, and overall survival with primary site preservation proved statistically superior in the concurrent chemoradiotherapy arm. An unplanned
subset analysis demonstrated an improvement in overall survival with primary
site preservation for both the patients with laryngeal cancer and hypopharyngeal cancer when treated with concurrent chemoradiotherapy. When required,
salvage surgery proved successful in between 63% and 73% of patients, and,
as a result, there was no difference in overall survival between the two treatment arms.
The results from these two studies in patients with resectable head and
neck cancer are, therefore, consistent (Table 3). The addition of concurrent
chemotherapy to definitive radiation therapy can improve the potential for
organ preservation. Appropriate integration of surgical salvage appears to
blur any overall survival differences between these two treatment approaches,
although a survival benefit has been observed from concurrent chemoradiotherapy (compared to radiotherapy alone) in unresectable patients (20) and in
the postoperative setting (21,22).
It should again be noted, however, that the results after concurrent chemoradiotherapy in these two trials were not compared to definitive surgery-based
approaches. The survival equivalence (or superiority) of concurrent chemoradiotherapy and conventional surgery has not been established. There has been
only one reported study that has compared these two treatment approaches.
This study, from Singapore, compared concurrent 5-fluorouracil, cisplatin,
and radiation therapy with surgery and postoperative radiation in 119 randomized patients (23). Although there was significant difficulty in patient
compliance with both treatment regimens, no overall survival difference was
identified between the two treatment arms. Organ preservation was possible
in 42% of the entire patient cohort treated with chemoradiotherapy and in
62% of those patients with larynx or hypopharyngeal primaries.
The data for oropharynx cancer is considerably less clear. Phase II trials of
both induction and concurrent chemoradiotherapy programs have been
reported, and the possibility of avoiding surgical resection has been described
(24,25). Phase III trials of concurrent chemotherapy and radiation therapy
have suggested both a survival benefit and an improvement in locoregional
control when concurrent chemoradiotherapy is compared to radiation therapy alone (26,27). Once again, however, in the absence of conclusive randomized data, the survival equivalence of primary surgery and these nonoperative
approaches has not been proven. Furthermore, equivalence in long-term
organ function conservation can also not be assumed, and assessments of both
objective measurements of speech and swallowing as well as subjective measures of overall quality of life are required.
End Pointa
Radiation (%)
Chemoradiation (%)
estimates.
N.S., not statistically significant.
aFive-year
Intergroup (Radiation Therapy Oncology Group 91-11) (18)
Laryngeal preserva66
84
tion
Laryngectomy-free
34
47
survival
Locoregional control 51
69
Overall survival
54
55
Cleveland Clinic (19)
Survival with organ
34
42
preservation
45
77
Local control without surgery
Overall survival
48
50
Study
(Reference)
Table 3. Phase III Trials of Concurrent Chemoradiotherapy for Organ Preservation
<.01
.011
<.01
N.S.
.004
<.001
N.S.
45
55
59
—
—
—
Probability
71
Induction (%)
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85
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Integration of Chemotherapy into Organ Preservation
Identification of Optimal Treatment
An important question arises from these nonoperative, organ-preserving
treatment strategies. Can patients likely to do well with nonoperative intervention be identified early in their treatment course? If so, such patients could
more confidently be given definitive nonoperative therapy with the goal of
organ preservation. Patients not deemed likely to benefit from this approach
could undergo initial surgical resection. There are currently several clinical disease features that can identify patients less likely to do well with radiation therapy and more appropriate for surgical resection. Certainly, those patients
presenting with a destroyed organ will not experience any benefit from an
attempt to preserve this organ. Similarly, patients with advanced larynx or
hypopharynx cancer with subglottic extension or tumor directly invading into
neck, thyroid, or cricoid cartilage do not do well with primary radiation therapy–based approaches. In addition, comorbid illness or limited social supports
may actually mandate surgical resection as the less morbid of treatment
approaches, given the considerable toxicity associated with chemotherapy and
radiation.
In recognition of the observation that a response to induction chemotherapy is predictive of a subsequent response to radiation therapy (28), it has
been suggested that chemotherapy responsiveness may be useful in prospectively identifying those likely to benefit from nonoperative approaches. Investigators in Michigan have reported their results from a trial in stage III and IV
larynx cancer using this approach (29). After an initial course of chemotherapy, nonresponders proceeded to immediate laryngectomy while those achieving a response were treated with definitive concurrent chemoradiotherapy.
Larynx preservation proved possible in 70% of the patients in this series, with
a 3-year projected overall survival of 85%.
A similar approach has been incorporated into the current Intergroup
phase III trial for resectable oropharynx cancer (Figure 1). Patients entered on
this trial are randomized between definitive concurrent chemoradiotherapy
alone and induction chemotherapy followed by concurrent chemoradiotherapy in responders. Patients not responding to induction chemotherapy
undergo early surgical salvage. This study will hopefully shed light on both the
potential improvement in survival to be gained from adding induction chemotherapy to concurrent treatment, as well as the possibility that a failure to
respond to chemotherapy can identify those patients who will benefit from
early surgical salvage. Critical in the evaluation of results from this study will
be a careful assessment of both late toxicities and quality of life.
It must be pointed out that the use of induction chemotherapy should still
be considered an experimental intervention. This is important when interpreting the recent reports of randomized trials comparing the well-tested cisplatin
and fluorouracil induction regimen with the three-drug combination of cis-
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Integration of Chemotherapy into Organ Preservation
87
Nonresponders: Surgery*
R
A
N
D
O
M
I
Z
E
Induction:
Docetaxel (T), 75 mg/m2
Cisplatin (P), 75 mg/m2
5 FU (F), 1,000 mg/m2/d × 4
– one course –
Concurrent:
RT: 70 Gy at 2 Gy/d
Cisplatin, 100 mg/m2
q21d × 3
Responders: TPF × 2 (3 total)
Concurrent:
RT: 70 Gy at 2 Gy/d
Cisplatin, 100 mg/m2
q21d × 3
Figure 1. Treatment schema for the current Intergroup phase III trial of concurrent chemoradiotherapy, with or without induction chemotherapy for
resectable squamous cell carcinoma of the oropharynx. *Unresectable patients
or those refusing surgery proceed to concurrent chemoradiotherapy. 5-FU,
5-fluorouracil; RT, radiation therapy.
platin, fluorouracil, and a taxane (3,30). Although the three-drug induction
regimens have consistently produced a superior response rate, the impact of
these induction regimens on the results achieved after optimal concurrent chemoradiotherapy is unknown and is the question being asked by several ongoing phase III trials such as the Intergroup study previously discussed (see
Figure 1). Indeed, Calais and colleagues (31) have recently reported their
results comparing induction cisplatin and fluorouracil with or without docetaxel followed by radiation therapy for larynx preservation. Although radiation therapy alone, as definitive management, must be considered a suboptimal
choice, both the response rate and the laryngeal preservation rate were superior in the docetaxel arm. These results are intriguing and certainly confirm
greater activity for this three-drug chemotherapy combination. Although such
an induction regimen may ultimately prove of benefit in conjunction with
optimal concurrent treatment, induction chemotherapy is currently only
appropriate within the context of a clinical trial.
Recent results from a large phase III trial comparing radiation therapy with
radiation therapy and cetuximab have been reported (32). An improvement in
both overall survival and locoregional control was found in those patients
treated with cetuximab, although this benefit appeared to be confined to
patients with oropharynx cancer treated with the concomitant boost radiotherapy schedule. No impact on distant metastases was seen from the addition
of cetuximab. Incorporation of this kind of targeted intervention into current
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88
Integration of Chemotherapy into Organ Preservation
chemotherapy and radiation therapy schedules is being intensively explored
with the hope that an improvement in both organ preservation and survival
will result.
Conclusion
An agenda for clinical investigation has emerged. Although it is unlikely that
any additional true organ-preservation trials with a surgery-based control
arm will be conducted in the future, investigation will continue to focus on
the optimal integration of chemotherapy, radiation therapy, and the newer
targeted agents. An improvement in survival remains the most important
treatment goal, but attention to not just organ preservation but to a careful
assessment of organ function and quality of life is mandatory. These answers
will only come through continued close cooperation between all professionals involved in the care of these patients and continued entry of these
patients onto well-designed and carefully conducted clinical trials.
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resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group trial. J Clin Oncol 2005;23:88–95.
Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated
radiotherapy limits the additional benefit of simultaneous chemotherapyresults of a multicentric randomized German trial in advanced head and neck
cancer. Int J Radiat Oncol Biol Phys 2001;50:1161–1171.
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27. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and
Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69–76.
28. Ensley JF, Jacobs JR, Weaver A, et al. Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously
untreated patients with advanced squamous cell cancers of the head and neck.
Cancer 1984;54:811–814.
29. Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects
patients with advanced laryngeal cancer for combined chemoradiation: a new
treatment paradigm. J Clin Oncol 2006;24:593–598.
30. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing
cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction
chemotherapy followed by chemoradiotherapy in locally advanced head and
neck cancer. J Clin Oncol 2005;23:8636–8645.
31. Calais G, Pointreau Y, Alfonsi M, et al. Randomized phase III trial comparing
induction chemotherapy using cisplatin (P) fluorouracil (F) with or without
docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000-01. 2006 Annual Meeting Proceedings Part
1. J Clin Oncol 2006;24(abstract):281s.
32. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for
squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:
567–578.
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❖
Intensity-Modulated
Radiation Therapy:
Promises and Practice
Gregory Russo, MD, and Mitchell Machtay, MD
Introduction of a New Treatment Approach
Intensity-modulated radiation therapy (IMRT) is a relatively new way of
delivering three-dimensional conformal radiation therapy (3D CRT). Ideally,
IMRT allows for delivery of high doses of highly conformal radiation therapy
to clinical target volumes while preserving critical normal structures. Since its
introduction into clinical use in the late 1990s, it has resulted in a flurry of
activity in research and clinical practice to identify the ideal clinical situations
to which it should be applied, how to safely and effectively implement a treatment program, and how to develop the necessary complementary technologies to take full advantage of its capabilities.
Since the 1990s, IMRT has become standard practice in the treatment of
selected types of head and neck cancers at many academic and private centers.
Recently, preliminary reports of the first prospective randomized trial of
IMRT versus traditional radiation therapy were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2005 that
showed the benefits in the preservation of salivary gland function (1).
As with any new technology, there is a learning curve associated with
IMRT that appears to be very large. As institutional experiences are reviewed,
the benefits of IMRT in the preservation of normal critical structures and
improvement of target coverage come at a cost of increased resources and, in
some cases, increased treatment-related toxicity. In this chapter, we provide an
CME 91
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overview of the differences between IMRT and traditional radiation therapy,
the potential benefits and stumbling blocks associated with this technology,
and the selection of patients for whom IMRT is an appropriate treatment.
Intensity-Modulated Radiation Therapy—
Definition and Historical Perspective
Before the introduction of IMRT into clinical practice, most head and neck
cancers were treated with a combination of large opposed lateral (right and left
laterally directed) radiation fields to encompass the primary tumor and
regional lymphatics in the upper and mid-neck, plus an anteriorly directed radiation field to encompass the lower neck and supraclavicular fossa (Figure 1).
Through the use of custom blocking, some critical structures peripherally or
centrally located can be partly or wholly shielded from radiation exposure to
decrease acute and/or long-term toxicity. Within the entire treatment field, the
dose of radiation measured in centigrays was homogeneous. This provided
good assurance that the target(s) was/were being irradiated appropriately, but
it also meant that large volumes of normal tissues were receiving very high
doses of radiation. For example, in the treatment of pharyngeal carcinomas
(especially nasopharynx cancer), the dose received by almost the entirety of
both parotid glands was equal to the dose received by the tumor. Consequently,
the rate of late grade ≥2 xerostomia in large prospective clinical trials was at
least 35%–50% with standard radiation therapy alone. The introduction the
radioprotectant drug amifostine has shown some improvement in rates of
xerostomia with radiation treatment (2,3). However, amifostine protection is
incomplete, and the drug is often poorly tolerated due to its side effects.
Figure 1. Three-field plan for radiation treatment of patient with locally
advanced larynx cancer status-post total laryngectomy—right and left lateral
portals to treat the primary tumor and regional lymphatics in the upper and
mid-cervical region (A and B) and anterior portal to treat lower cervical and
supraclavicular lymph nodes (C).
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Figure 2. A–F: Radiation treatment portals for six-field intensity-modulated
radiation therapy plan to treat a patient with locally advanced oropharynx cancer.
Within each portal, the varying degrees of red color indicate increasing (white =
low dose, red = high dose) intensity of radiation delivered at that location.
In contrast to conventional 3D CRT, IMRT allows the delivery of high
doses of radiation to the same targets and differentially decreased doses of
radiation to critical normal structures even when they are relatively close to
one another. This is accomplished by delivering radiation from multiple angles
and with multiple beam segments of variable intensity (Figure 2) (hence the
use of the term intensity-modulated); the summation of these beams results in
a highly variable, heterogeneous dose distribution within the patient. This
becomes obvious when reviewing the set of slices from the radiation therapy
treatment planning computed tomography (CT) scan (Figures 3–5). It is
important to note that the radiation being delivered is physically the same as
with conventional radiation therapy; it is simply delivered in a different way.
Most modern linear accelerators can be used for either conventional radiation
therapy or IMRT.
The user (radiation oncologist) dictates the complexity of any IMRT plan
with regard to number of beams and beam segments, size of beam segments,
and a set of dose constraints for targets and normal tissues. Increasing the
number of allowed beams and beam segments, decreasing the size of beam
segments, and demanding more highly conformal dose constraints can produce a plan with better conformality and steeper dose gradients. This is done
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Figure 3. Axial (A and B) and coronal (C and D) images from intensitymodulated radiation therapy treatment plan. Red color indicates high-dose
regions, and blue indicates low-dose regions. White marks indicate location
of the parotid glands. The left parotid gland is receiving a lower radiation
dose in an attempt to spare parotid function, whereas a higher dose is being
given to the gross tumor volume and clinical target volume.
at the expense of a longer treatment planning time (potentially delaying the
patient from starting radiation therapy), longer actual patient treatment time
(potentially 20–40 minutes per day), and increased exposure of the patient to
moderate levels of background radiation (4). There has been much focus on
developing treatment-planning algorithms that reach an acceptable balance
between quality of treatment plan and increased treatment time. However,
there are currently no universally accepted standards of care for IMRT planning and delivery; the closest such series of guidelines are those set forth in
several actively accruing Radiation Therapy Oncology Group (RTOG) clinical
trials (e.g., RTOG 0522).
There are essentially two ways of planning IMRT: forward planning and
inverse planning. In both situations, the treating radiation oncologist defines
targets and normal structures. Dose constraints are then assigned for each
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Figure 4. Axial (A and B) and coronal (C and D) images from intensity-modulated radiation therapy treatment plan showing coverage of the parapharyngeal tissues and posterior cervical lymph nodes while delivering a differentially
lower dose of radiation to the spinal cord and posterior neck tissues.
individual structure. For forward-planned IMRT (FP-IMRT), the gantry
angles and beam segments are defined by the radiation oncologist; a series of
manual iterations to optimize the intensity of each segment is then performed
until a satisfactory plan is achieved (5). In contrast, for inverse-planned IMRT
(IP-IMRT), the gantry angles are defined by the treatment team, but the treatment planning software determines the exact number and shape of segments
as well as the dose intensity to be delivered through each segment within predefined constraints. This process is done automatically, based on a preprogrammed series of treatment planning algorithms plus the dose constraints
prescribed by the radiation oncologist.
Treatment times tend to be shorter with FP-IMRT, although treatment
planning time can be substantial due to the need for manual “trial by
error” technique. Plan quality is probably comparable between the two
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Intensity-Modulated Radiation Therapy
Figure 5. Axial (A), coronal (B), and sagittal (C) images of intensity-modulated
radiation therapy treatment plan for a patient with diffuse squamous cell carcinoma of the paranasal sinuses. High-dose region ends abruptly with sharp dose
gradient to spare the optic chiasm, indicated by the white arrow (A and C); dose
is bent around the eyes to deliver high-dose radiation to the sinuses (C).
types of IMRT planning, although IP-IMRT potentially offers improved
ability to achieve extremely sharp radiation dose gradients adjacent to or
wrapping around critical structures (e.g., spinal cord).
Volume Definition for Intensity-Modulated
Radiation Therapy Treatment Planning
One of the most critical steps in formulating an effective IMRT treatment plan
for patients with head and neck cancer is the accurate definition of the target
volumes and normal tissue structure volumes. These volumes include (a) the
gross tumor volume (GTV), representing a region(s) with proven cancer;
(b) the clinical target volume(s) (CTVs), one or more identifiable regions at
risk for microscopic spread of disease; (c) the critical normal structures,
referred to as organs at risk (OAR); and (d) planning volumes, which represent the other types of volume plus a “safety margin” to account for various
uncertainties such as changes in target volume size and shape over time. Errors
in target and/or OAR delineation cannot be easily rectified through the course
of the patient’s treatment and can have a large impact on the actual administered doses to the tumor and OAR. These errors can potentially affect the
probability of tumor control and/or normal tissue complications.
Gross Tumor Volume
The GTV is defined by using information from physical examinations, anatomic imaging, invasive staging (e.g., panendoscopy) and, more recently, func-
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tional imaging. The radiation treatment planning CT scan provides the critical
information for the IMRT treatment plan, including the geometry of the
patient with respect to the incident radiation beams, the relative positions of
targets and critical structures, and the relative density of tissues within the
region of interest. CT scans have also proved to be superior to other imaging
modalities in evaluating for bony invasion that can be present, particularly
with tumors of the nasopharynx and oral cavity (6). Through the use of image
fusion software, magnetic resonance imaging (MRI) and positron emission
tomography (PET) scans can be fused to the treatment planning CT scan and
used as adjuncts to CT image information.
Several groups have shown that MRI can provide critical information
with regard to invasion of soft tissues, particularly in the parapharyngeal
spaces and retropharyngeal lymph nodes (7). In addition, PET has been
investigated for radiation treatment planning and has been shown to
increase or decrease the size of the GTV by up to 49% in selected patients
(8). Other groups have shown that PET fusion has proved instrumental in
defining the extent of the primary tumor and regional nodal metastases in
patients thought to have N0 cancer by other means of evaluation (9,10).
Organs at Risk
OARs include those structures that can be irreparably damaged by exposure to high doses of radiation and cause permanent morbidity or mortality. In the region of the head and neck, OARs can include the spinal cord,
brain stem, optic apparatus (chiasm, optic nerves, retina, cornea, lens),
parotid glands, organs of speech and swallowing, temporal lobes, and the
cerebellum. These structures should be defined anatomically using information from the treatment planning CT scan.
Clinical Target Volume(s)
The definition of the CTV(s) for patients receiving IMRT for head and
neck cancer has proved to be a difficult task. There are two important
components of the CTV as it applies to IMRT planning: (a) areas at risk
for direct invasion by tumor and (b) lymph nodes at risk for micrometastases. The former is defined with knowledge of the pathologic features of the
tumor, its location, and the natural history of the disease entity being
treated. The latter has required a fair amount of adaptation from previous
techniques and is based on knowledge of the natural history of the disease
entity, including studies dating back more than 30 years (11).
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Figure 6. Axial computed tomography images (A–C) of a patient with
locally advanced larynx cancer status post-laryngectomy and bilateral neck
dissections. Clinical target volume 58 (CTV58) and planning target volume 58
(PTV58) in right side of neck indicated by inner and outer lines, respectively.
CTV66, CTV60, and PTV60 in left side of neck. CTV66 is boost to the operative
bed innermost green contour, CTV63 inner purple is the region of removed
cervical lymph nodes containing metastatic cancer, and PTV63 is the outermost purple contour. Note the distortion of the anatomic planes.
Whereas bony landmarks previously served to separate different lymph
nodal levels at risk, an exact anatomic delineation is now necessary. Several
groups have published atlases of cross-sectional anatomy to define the different nodal stations in the head and neck (12–15). A consensus conference
was convened for the purpose of developing an atlas of neck lymph nodes
and is available on the RTOG’s web site (www.rtog.org) (16). Once defined,
different doses of radiation therapy can be assigned to different nodal levels
based on knowledge of patterns of metastatic spread.
The task of CTV definition can be further complicated in patients who have
had either the primary tumor or regional lymphatics removed before radiation
therapy. Surgical manipulation distorts the boundaries of natural tissue planes
and introduces more uncertainty into the process of target definition (Figure 6).
Planning Volumes
For several reasons, before starting IMRT planning, it is necessary to add a
“safety margin” around the GTV, CTV, and at least the most critical OARs.
The volume defined by a target volume plus this safety margin is called a planning target volume (PTV). The volume defined by a critical OAR plus this
safety margin is called a planning at-risk volume (PRV). The reason for adding
these safety margins and thus creating PTV/PRVs is to account for various
uncertainties (errors) in treatment planning and delivery. These potential
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errors may include uncertainties in volume definitions (as discussed in the section “Volume Definition for Intensity-Modulated Radiation Therapy Treatment Planning”), changes in volume size/shape during a course of radiation
therapy or even during an individual radiation treatment (organ motion and/
or deformation), and systematic and/or random setup errors that may occur
on a day-to-day basis.
Determining the size of the safety margin (CTV-to-PTV margin) is complex, controversial, and may require a great deal of individualization. Factors that influence the size of this margin include reproducibility of setup
and availability of adequate patient immobilization. Several groups have
done dosimetric analyses to simulate random setup errors, evaluate their
influence on target coverage, and identify the appropriate CTV-to-PTV
margin to minimize target under-dosing (17–20).
Ultimately, the size of the PTV margin should be customized to each individual clinic and be based on an analysis of daily setup reproducibility. Most
clinics have adopted a CTV-to-PTV margin size of between 3 mm and 8 mm. A
large margin will result in extensive overlap between the target volume(s) and
one or more OARs; this situation can result in the IMRT computer planning
system “failing” to achieve a satisfactory treatment plan. Similarly, the use of a
PRV margin has been shown to decrease the likelihood of delivering unacceptably high doses of radiation to critical normal structures, but can cause further
overlap with adjacent PTVs. Overlapping structures ultimately complicates the
treatment planning process and the ability to interpret treatment plans. In contrast, a small margin affords the potential for an improved computer-generated
IMRT plan but, theoretically, a greater risk of tumor recurrence/progression if
there are clinically relevant errors/uncertainties in treatment planning.
To combat these issues, proper patient immobilization and positioning
verification that eliminates setup variability can help to minimize possible
errors while allowing a modest-sized PTV margin. Consequently, the doses
to surrounding normal structures and resultant probabilities for long-term
morbidity can be reduced (21). To accomplish this, some centers have implemented daily positioning verification protocols with two-dimensional orthogonal portal imaging or three-dimensional imaging with accelerator-mounted
cone beam CT scanners. This is referred to as daily image-guided IMRT (IGIMRT) and is quickly gaining popularity.
Intensity-Modulated Radiation Therapy
Treatment Planning and Evaluation
Once the targets and OARs are defined, specific dose constraints must be
applied to each structure. Typically a goal, maximum, and minimum dose as
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Table 1. Typical Intensity-Modulated Radiation Therapy Dose Constraints
Used for Organs at Risk in the Head and Neck Region
Organ
Maximum Dose
Whole Organ Dose
Spinal cord
Brain stem
Optic nerves
Optic chiasm
Parotid/submandibular glands
Temporal lobes
Mandible/temporomandibular joint
Oral cavity/lips
1% of PTV not to exceed 50 Gy
1% of PTV not to exceed 60 Gy
1% of PTV not to exceed 60 Gy
1% of PTV not to exceed 60 Gy
At least 50% of organ <30 Gy
45 Gy
54 Gy
54 Gy
54 Gy
Mean dose, 26 Gy
<1% PTV to receive >65 Gy
1 cc of PTV not to exceed 75 Gy
60 Gy
70 Gy
As low as possible (typically
20–30 Gy)
1% not to exceed 65 Gy
—
—
Tongue
Larynx/pharynx
55 Gy
Mean dose, 45 Gy
PTV, planning target volume.
well as the volumetric percentage of each structure allowed to receive dose
above and below the goal are defined; this process attempts to dictate the
degree of allowable heterogeneity to minimize hot and cold areas within the
treatment field. For standard fractionated radiation therapy, the typical dose
for gross disease is 66–72 Gy; for resected disease with a positive surgical margin or for lymph nodes with extracapsular extension, the goal is 63–66 Gy; for
completely resected disease with negative surgical margins, the goal is approximately 60 Gy; and for electively irradiated nodal regions for microscopic disease, the goal is 50–55 Gy. The classic values used for normal tissue toxicity
limits were defined by Emami et al. in 1991 (22) and have been adapted for the
purposes of IMRT (Table 1). After completing the process of defining targets,
OARs, and dose specifications, the radiation oncologist works closely with a
team of radiation physicists and dosimetrists to achieve an optimized computer-generated IMRT plan. This process can require a variable amount of
time—from several hours to several weeks. Once treatment planning is completed, the actual doses to each target and critical normal structure needs to be
compared to the predefined constraints. There are few instances where every
single dose constraint can be met with perfection, and the radiation oncologist
and physics/dosimetry team strive to optimize the plan as best as possible.
A detailed discussion of the processes involved in IMRT planning is
beyond the scope of this chapter, and the reader is referred to a consensus
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report from the American Society of Therapeutic Radiology/Oncology and the
American Association of Physicists in Medicine (23). In general, during the
process of IMRT planning and evaluation of plans, compromises are made,
and this is part of both the art and science of medicine. The highest priorities
are given to achieving adequate coverage of the GTV and strict avoidance of
exceeding maximum tolerated dose limits on the spinal cord and optic apparatus. A somewhat lower level of prioritization is assigned to the CTVs, and
the lowest (albeit still significant) priority is given to normal structures that are
important but not life sustaining (e.g., the parotid glands).
The reliability of any IMRT plan to accomplish its preset goals of delivering highly conformal radiation to target tissues and the sparing of OARs is
dependent on maintaining setup reproducibility, both internally in and externally. External patient setup reproducibility can be accomplished with standard treatment aids and image guidance (for details, see section “Planning
Volumes”). Internal reproducibility can be affected by rapidly responding
tumors and/or patient weight loss, resulting in changes in the patient’s external
contour or relative positions of targets and OARs within the patient. Because
of certain physical properties of ionizing radiation, these changes can alter the
final location of high- and low-dose regions of radiation within the patient,
potentially undertreating portions of the target(s) and delivering higher than
intended doses to critical structures. Mid-treatment repeat CT scanning and
replanning in select patients has shown significant deviations in the intended
doses to the target and critical structures, suggesting that this may need to be
considered routine for similar patients (24).
Intensity-Modulated Radiation Therapy
in Clinical Use—Potential Advantages
The leading rationale for head/neck IMRT has been to achieve excellent radiation therapy coverage of all relevant target volumes while minimizing radiation therapy dose to the parotid glands. In addition, IMRT has proved useful
in other areas that previously presented significant challenges in radiation
treatment planning. These included elimination of uncertainty at match lines,
coverage of deep and midline structures, sparing of optic nerves/chiasm in
treating tumors of the nasal cavity and paranasal sinuses, and sparing of other
structures, such as those responsible for swallowing, to decrease long-term
morbidity related to dysphagia and aspiration.
Since 2000, there have been a number of clinical, retrospective series reporting outcomes with IMRT-based radiation therapy for head and neck cancer.
Although these studies compare current patients to retrospective or concurrent
nonrandomized patient groups and, hence, lack the power and rigor of phase
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Intensity-Modulated Radiation Therapy
III randomized trials, the studies do strongly suggest that locoregional control
is not compromised by IMRT, at least when given at an experienced academic
center that treats a substantial number of head and neck cancer patients with
IMRT (25–28). It is hypothesized that IMRT might actually improve locoregional control over standard radiation therapy because IMRT can yield a
higher mean target volume dose (even if the prescription dose at the edge of the
target volume is numerically the same as that with standard x-ray therapy).
In contrast, there has been a well-documented locoregional control
advantage to altered (hyper- and/or accelerated) fractionation radiation therapy (29,30), at least for stage III–IV nonoperative head and neck cancer.
Altered fractionation radiation therapy has become less commonly used in
the era of concurrent chemoradiation therapy but is still highly relevant. The
use of altered fractionation with IMRT is the subject of ongoing investigation. The currently accruing major RTOG trial (RTOG 0522) allows investigators to use altered fractionation IMRT (6 fractions per week) together
with systemic therapy.
Several investigators are exploring the use of a new type of altered fractionation based on IMRT; specifically, accelerated hypofractionation. Accelerated
hypofractionation refers to the use of one fraction per day at a larger than
normal daily dose (2.2–3.0 Gy), significantly increasing the biologic intensity
of the radiation therapy course. With standard radiation therapy, accelerated
hypofractionation is feasible but requires an attenuation of the cumulative
radiation therapy dose and/or the deletion of concurrent chemotherapy. It is
hypothesized that IMRT can overcome these obstacles by strictly limiting the
volume of tissue irradiated to an ultra-high-dose intensity. This technique has
been labeled the “SMART” (simultaneous modulated accelerated radiotherapy) technique as piloted at Baylor University (31). Phase I–II studies of this
approach appear to show acceptable toxicity for IMRT-based accelerated
hypofractionation alone (32,33), but rigorous data combining this technique
with concurrent chemotherapy are scant (34). As of this writing, patients
receiving IMRT with concurrent chemotherapy are generally prescribed conventional daily dose/fractionation schedules.
Parotid Sparing
One of the most significant long-term toxicities in patients treated with radiation therapy for head and neck cancer is xerostomia caused by excessive doses
delivered to the major salivary glands (see Figure 6). Rates of grade 2 or
higher xerostomia following head and neck irradiation range up to 68% in
large randomized studies (30). Maintenance of good salivary flow is essential
for good oral health (35); grade 2 xerostomia indicates moderately severe dry-
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ness with significant functional impact. The potential for IMRT to spare the
parotid glands and decrease late xerostomia has been extensively investigated.
Initial work by investigators at the University of Michigan identified the
threshold dose of radiation to the parotid gland—approximately 26 Gy—
above which permanently decreased salivary flow resulted. In patients treated
with IMRT with limited doses to a single parotid gland (36), improvement in
quality of life with regard to eating, communication, pain, and emotion was
noted (25,37). Subsequently, other studies have been published, illustrating the
ability of IMRT to decrease treatment-related xerostomia when treating head
and neck cancer, particularly nasopharyngeal and oropharyngeal tumors.
There has been one randomized trial comparing IMRT to standard radiation therapy, specifically in early stage nasopharyngeal carcinoma (NPC). This
study has only been reported in abstract form (ASCO 2005), and long-term
results are pending. However, preliminary results showed that patients randomized to IMRT had significantly less xerostomia 1 year after treatment,
with dramatically better parotid function and whole saliva flow compared
with standard radiation therapy. However, quality of life as assessed by questionnaires was not significantly different between the two arms.
In addition to parotid gland sparing, there have been attempts to limit dose
to the submandibular glands. Significant decreases in salivary flow were noted
among patients who did not have submandibular gland sparing versus those
who did. Patients with submandibular gland sparing IMRT reported less
xerostomia and decreased need for saliva substitutes (38).
Of course, salivary gland sparing should not be attempted if there is a
high risk of cancer recurrence in the nodal region directly adjacent to the
parotid gland. In general, parotid sparing is attempted for the contralateral
parotid gland in patients with well-lateralized cancers with clinically or
pathologically cancer-free contralateral neck lymph nodes. Patterns of failure studies in patients receiving parotid-sparing IMRT have shown that the
preponderance of locoregional failures are not in the region adjacent to the
spared parotid gland and are, instead, within the regions that were confirmed to have received high doses of radiation. The failures seem to be more
likely in patients who have clinicopathologic features of their tumors that
are predictive of failure, such as positive surgical margins, extracapsular
extension, multiple positive nodes, and postoperative patients, possibly indicating hypoxic regions portending relative radioresistance (39,40).
Match Line Dosimetry
IMRT also offers other benefits in addition to parotid gland sparing when
treating cancers of the head and neck. As noted in the section “Definition
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and Historical Perspective,” the traditional means of treating the entire
neck, from skull base to supraclavicular fossa, was with lateral fields treating the upper neck matched to a lower neck field (see Figure 1). In patients
with extensive neck nodal disease and/or low-lying primary tumors (larynx/pharynx), where the match line would have to be through very highrisk regions, this can cause an area of underdosing (or overdosing) due to
uncertainty at the match line (41). IMRT allows for the treatment of the
entire neck in one uninterrupted field (see Figures 3C, 3D, 4C, and 4D).
This eliminates the uncertainty at the match line (42) and reduces the possibility of neck failures in selected patients. Treatment of the entire neck in
a single field does increase treatment time and may not be appropriate for
patients with limited neck disease that does not cross the match line. In
such cases, treatment of the primary tumor/surgical bed and the upper
neck lymphatics can be treated with IMRT and a matching anterior lowneck field. Because IMRT treatment plans do not produce sharp dose gradients at the field edge similar to a half-beam blocked static field, there is
also uncertainty inherent in this process. Strategies have been formulated
to eliminate the uncertainty of matching IMRT fields with static fields
(43,44).
Coverage of Nasopharynx/Parapharyngeal Tissues
For cancers of the nasopharynx in which coverage of the parapharyngeal
spaces and retropharyngeal lymph nodes is crucial in achieving local control, IMRT has proved superior to traditional techniques of matching
photon and electron fields where significant cold regions can exist at the
match line (see Figure 4) (45). A study at Princess Margaret Hospital
showed that conventional planning/treatment of NPC resulted in poor
dose coverage of the tumor volume and a relatively high rate of local
recurrence (46). Several modern series of IMRT-based treatment for NPC
suggest that local control rates in excess of 90% are achievable (47).
This compares favorably to the U.S. Intergroup standard experience with
conventional chemoradiotherapy that showed approximately 75% local
control (Table 2) (48).
Several groups have reviewed their experience treating nasopharyngeal
cancer with IMRT. Outcomes indicate excellent locoregional control rates
and survivals at least equivalent to traditional radiation therapy techniques
with decreased rates of toxicity (see Table 2). A recently completed RTOG
phase II (RT 02–25) trial of IMRT for nasopharyngeal cancer will be the
first multi-institutional data showing the utility of IMRT in the treatment of
nasopharyngeal cancer.
I–IV
I–IV
63
67
97
92
91
100 (T1/T2)
83 (T3/T4)
95.7
Local
Control (%)
98
98
93
Regional
Control (%)
66
79
94.2
78
Metastasis-Free
Survival (%)
88
90
92.1
83
Overall
Survival (%)
MSKCC, Memorial Sloan Kettering Cancer Center, New York, NY; PWH, Prince of Wales Hospital, Hong Kong, China; QMH, Queen Mary Hospital, Hong Kong, China; UCSF, University of California, San Francisco, CA.
aKwong DL, Sham JS, Leung LH, Cheng AC, Ng WM, Kwong PW, Lui WM, Yau CC, Wu PM, Wei W, Au G. Preliminary results of radiation dose
escalation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):374–381.
bWolden SL, Chen WC, Pfister DG, Kraus DH, Berry SL, Zelefsky MJ. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer:
Update of the memorial sloan-kettering experience. Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):57–62.
cKam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: The Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60(5):1440–1450.
dLee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53(1):12–22.
31
29
25
III–IV b
50
QMH, Hong
Kongb
PWH, Hong
Kong c
UCSFd
Median
Follow-Up (mo)
35
74
MSKCCa
Stage
I–IV
Patient
Number
Source
Table 2. Reported Results for Treatment of Nasopharyngeal Cancer with Intensity-Modulated Radiation Therapy
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Intensity-Modulated Radiation Therapy
Laryngopharyngeal Sparing
IMRT can also be used to decrease the radiation dose to the pharyngeal
constrictor muscles and the glottic/supraglottic larynx. These structures
are centrally located and often receive large doses of radiation when treating lymph nodes in the neck. When large volumes of these structures
receive radiation doses in excess of 50 Gy (V50) there is a substantial risk
of developing long-term dysphagia and/or aspiration. Contouring the
laryngopharynx, defining it as an OAR, and setting dose constraints to
limit the V50 may theoretically decrease the risk of developing dysphagia
and/or aspiration (49).
Sparing of Optic Structures
IMRT is also used to treat cancers of the nasal cavity and paranasal sinuses
(see Figure 5). Traditional radiation treatment fields resulted in large doses to
the optic apparatus, which puts patients at risk for the development of radiation-induced optic neuritis, a catastrophic side effect of radiation therapy that
can cause complete blindness. Dosimetric analyses have shown good coverage of the CTV with less dose delivered to the optic structures with IMRT
compared to 3D CRT (50), and IMRT to be especially useful when the upper
cervical lymph nodes are included in the treatment volume (51). In one study
of 39 patients treated with postoperative IMRT for T2–T4b ethmoid sinus
cancer, 2-year overall survival and local control rates were 68% and 73%,
respectively; these are comparable to historic controls with decreased rates of
vision impairment and no radiation-induced blindness (52).
Coverage of Midline Structures
IMRT can also produce superior dose profiles and coverage of target volumes
that cross the midline and wrap around central structures such as the spinal
cord. One such organ is the thyroid gland. In the past, treatment of substantial
volumes of the thyroid gland to doses ≥45 Gy was limited by the spinal cord
tolerance. The ability of IMRT treatment plans to wrap dose around central
structures in a horseshoe pattern has made treatment of the much larger volumes of the thyroid with substantially higher doses of external beam radiation
therapy possible (53,54). This has correlated to good clinical outcomes in the
published experience of the Memorial Sloan-Kettering Cancer Center, treating
20 patients with nonanaplastic thyroid carcinoma, showing 85% locoregional
control rates and no increase in toxicity (55).
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Intensity-Modulated Radiation Therapy
107
Re-Irradiation of Head and Neck Cancer
IMRT has also made re-irradiation of head and neck cancers more feasible,
particularly for patients with local or regionally recurrent nasopharynx cancer.
A Chinese group reported on their initial experience re-irradiating 49 patients
with recurrent nasopharynx cancer. They showed that the treatment was feasible with acceptable toxicity and encouraging response rates and local control
(56). Others have evaluated IMRT for re-irradiation in other subsites of the
head and neck and have shown encouraging response rates, with 50% of
patients showing partial or complete response with acceptable toxicity (57).
Potential Disadvantages of Intensity-Modulated
Radiation Therapy
Risk of Marginal Miss
As the reader can probably discern from the section on IMRT volume definition and treatment planning, IMRT is a technically demanding exercise. There
is little room for error at every stage in this planning process. Theoretically, the
use of small margins around target volumes and irradiation plans with sharp
dose gradients between these target volumes and normal structures could
result in a higher rate of local recurrence. There have been reports of recurrences in areas adjacent to a “spared” parotid gland after IMRT.
Risk of Secondary Malignancy
The increased complexity of IMRT treatment plans requires an increased
amount of time to deliver any single fraction of radiation therapy. Increased
treatment time can create problems with patients being unable to tolerate lying
still in the treatment position for extended periods of time; this may be overcome with the use of sedatives, nursing, and psychosocial support. However,
another theoretical concern is that increased radiation therapy beam-on time
and the use of numerous beam angles and segments exposes patients’ total
body to a low-dose of radiation. This amount of irradiation is difficult to measure and well below the threshold for causing typical radiation therapy-induced
organ damage but may be relevant for radiation carcinogenesis. In vivo measurements show that together these factors result in an increase in total body
radiation dose of from 242 mSv for conventional treatment to 1,969 mSv for
IMRT (58). It has been estimated that the risk for development of secondary
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Intensity-Modulated Radiation Therapy
malignancies could be two- to eightfold higher with IMRT than that for
patients treated with conventional radiation therapy (58,59). In the case of
head and neck cancer in which 6 MeV photons are predominantly used, the
relative risk of fatal second malignancy is 3.0–3.7 (60,61).
To date, there have not been any clinical reports to support or refute
this concern, but because IMRT is an exceptionally new technology and
because clinical studies of radiation carcinogenesis require many years and
large numbers of evaluable patients, these data may not be available until
the mid-2010s. Clinicians should be cognizant of this potential risk when
treating patients in their 50s and 60s and balance this against the potential
risks of conventional radiation therapy that contribute to late morbidity
and mortality: radionecrosis, aspiration, and dental complications.
Increased and/or “New” Toxicity(ies)
Due to the high degree of dose heterogeneity in IMRT plans, there is the
potential for unplanned “hot spots” receiving over 120% of the prescribed
dose. With an ideally optimized IMRT plan, these hot spots are within the
GTV; however, they may also occur in normal tissues. This can cause
increased acute and chronic side effects such as severe mucositis, osteoradionecrosis, trismus, and/or tissue necrosis. Strategies to control hot spot
formation have been used in the planning process and have proved effective, but it is important to note the location and possible consequences of
these hot regions when evaluating treatment plans.
Another drawback of IMRT is the potential to have an increased radiation
dose to the skin, resulting in increased rates of grade 3 and 4 radiation dermatitis, necessitating treatment breaks and resulting in poor compliance with
treatment. Multiple factors have been implicated in this process, including the
bolus effect from immobilization devices (i.e., Aquaplast mask), contouring of
CTV and PTV near to the skin surface, and the use of multiple tangential radiation beams. Strategies to reduce skin toxicity have been suggested, including
use of virtual bolus during treatment planning to allow for adequate build-up
so that the optimizer does not favor tangential beams, assigning dose limits to
the skin as an OAR, or editing PTV contours to be at least 5 mm inside the
skin when it is not a part of the CTV (62,63).
Cost/Resources
To treat a patient with IMRT, there is a significant increase in the necessary
resources, and, hence, the monetary cost of the treatment. The hardware and
software for IMRT planning and delivery are considerably more expensive
Posner.bk Page 109 Friday, October 20, 2006 11:41 AM
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109
than that for conventional radiation therapy. There is an increase in physician,
dosimetrist, therapist, and physicist time over conventional radiation therapy.
Increased beam on-time translates to a need for more regular maintenance of
linear accelerators and a busier treatment schedule, which can create a need
for increased clinic hours and the subsequent costs of overhead and staffing.
Conclusion
IMRT has come far since its introduction in the clinic. There exists an
expanding wealth of knowledge regarding the potential benefits and pitfalls
of this new technology. It is significantly more labor intensive from planning
to delivery, requiring many more resources. IMRT is likely not appropriate
for all patients. It remains uncertain as to which patients will benefit most
clearly from IMRT. The most likely beneficiaries from IMRT are patients
who would otherwise receive extremely high doses to their parotid glands
and/or unacceptably high irradiation dose to the optic apparatus. This suggests that IMRT may be more useful in cancers of the nasopharynx, oropharynx, and paranasal sinuses than for cancers located in the lower neck.
However, from a technical standpoint, IMRT might decrease some of the
dosimetric problems associated with comprehensive head and neck irradiation for a multitude of types of head and neck cancer, ranging from cancers
of the tongue to the larynx/hypopharynx and cancer to the thyroid.
Taken together, the reports in the peer-reviewed literature convey a tone of
cautious optimism. Longer follow-up and extensive quality control reviews are
necessary to determine if the risk of second malignancies is clinically relevant,
and to determine if “marginal misses” are occurring near structures that have
been intentionally underdosed via IMRT. Larger, multicenter studies of IMRT
are currently lacking; at this time it is unclear if the promising results with
IMRT achieved at several centers of excellence can be duplicated in the general
radiation oncology community. Efforts at standardization and quality assurance across multiple centers have lagged behind the enthusiasm about the use of
IMRT in the community. New technologies in head and neck radiation therapy,
such as IG-IMRT, are constantly evolving, and this or any review on IMRT will
likely be very different in 1, 2, or 5 years. Each investigator using IMRT must
pay close attention to new developments and determine if, when, and how to
adapt his or her treatment algorithms based on the current state of the art.
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❖
Index
Note: Page numbers followed by f refer to figures;
page numbers followed by t refer to tables.
Accelerated hypofractionation,
defined, 102
American Association of Physicists
in Medicine, 101
American Joint Committee on
Cancer (AJCC) stage
III or IV disease, 13–
14
AJCC stage III or IV laryngeal
disease, 13–14
AJCC stage IV laryngeal cancer,
13–14
AJCC staging system, 14
American Society of Addiction
Medicine web site, 53
American Society of Clinical
Oncology (ASCO),
91
American Society of Therapeutic
Radiology/Oncology,
101
ASCO, 91
Aspiration, swallowing abnormalities and, 47–48
Baylor University, 102
Bevacizumab, for recurrent
SCCHN, 71
Cancer(s)
head and neck. See specific
types, sites, and Head
and neck cancer
laryngeal, AJCC stage IV,
13–14
Carboplatin, for head and neck
cancer, 10
Carboplatin/5-FU, for head and
neck cancer, 4t
Cetuximab
for head and neck cancer, 9
for recurrent SCCHN, 70–71,
72t
Chemoradiation
assessment after, 54, 56t–57t, 57
assessment during, 54, 55t–56t,
57
concurrent, 3–8, 4t–5t
docetaxel-based cisplatin/5-FU
chemotherapy vs.,
phase III trials comparing, 33–37, 35f–37f
115
Posner.bk Page 116 Friday, October 20, 2006 11:41 AM
116
Index
for head and neck cancer, 1–22
concurrent chemoradiation,
3–8, 4t–5t
history of, 1–2
induction chemotherapy followed by chemoradiation, 8–9
neoadjuvant or “induction” chemoradiation, 2–3
patient selection for, 12–14
regimens, 9–12, 11t
selection factors for, 14–17
therapeutic approaches, 12–
13
unanswered questions
related to, 2
“induction,” 2–3
in locally advanced SCCHN,
28–32, 29t, 30t
as new standard of care,
32
taxanes with, 29–32, 30t
vs. induction chemotherapy,
28–29, 29t
neoadjuvant, 2–3
radiation alone trials vs., for
SCCHN, 4t–5t
symptom management and,
41–60
history of, 41–42
measuring effects of, 42–43
symptom control issues, 43–
54, 46t, 49t, 52t–53t
Chemoradiotherapy. See Chemoradiation
Chemotherapy
combination, for recurrent
SCCHN, clinical trials
using, 68–70
induction. See Induction chemotherapy
in organ preservation for
SCCHN, 77–90. See
also Squamous cell
carcinoma of head
and neck (SCCHN),
organ preservation
strategies for
systemic
evolution of, 67
in organ preservation for
SCCHN, 79–84, 82t,
83t, 85t
Cisplatin, for head and neck cancer, 3–10, 4t–5t
Cisplatin/5-FU
in locally advanced SCCHN,
25–27, 27t
for recurrent SCCHN, clinical
trials using, 68–69
Clinical target volumes (CTVs), in
IMRT treatment plan,
97–98, 98f
Combined modality therapy, for
locally advanced
SCCHN, 25–37, 27t,
29t, 30t, 35f–37f. See
also specific modality,
e.g., Induction chemotherapy
Common Terminology Criteria for
Adverse Events, 49,
49t
Common Toxicity Criteria, 42–43
Concurrent chemoradiation, 3–8,
4t–5t
Cost(s), IMRT-related, 108–109
CTVs, in IMRT treatment plan,
97–98, 98f
Daily image–guided IMRT (IGIMRT), 99
Dana-Farber Cancer Institute, 33
Posner.bk Page 117 Friday, October 20, 2006 11:41 AM
Index
Department of Veterans Affairs
(VA) Laryngeal Cancer Study Group larynx preservation trial,
1, 3, 28, 80
Docetaxel, for head and neck cancer, 10
Docetaxel-based cisplatin/5-FU,
chemoradiation vs.,
phase III trials comparing, 33–37, 35f–37f
Docetaxel/cisplatin/5-FU, vs. cisplatin/5-FU, for head
and neck cancer, 11t
Dosimetry, match line, IMRT in,
103–104
Eastern Cooperative Oncology
Group, 34
EGFR, for recurrent SCCHN, 70–
71
EORTC, 28, 31
EORTC 22931 trial, 6, 7, 15–16
Epidermal growth factor receptor
(EGFR), for recurrent
SCCHN, 70–71
European Organisation for
Research and Treatment of Cancer
(EORTC), 28, 31
22931 trial of, 6, 7
European Organisation for
Research and Treatment of Cancer
(EORTC) systems, 42
FDA, 50, 68
5-Fluorouracil (5-FU), for head
and neck cancer, 10
5-Fluorouracil (5-FU)/carboplatin, for head and neck
cancer, 4t
117
5-Fluorouracil (5-FU)/cisplatin
for head and neck cancer, 10
for recurrent SCCHN, clinical
trials using, 68–69
5-Fluorouracil (5-FU)/hydroxyurea, for head and
neck cancer, 10
5-Fluorouracil (5-FU)/platinum, in
locally advanced
SCCHN, 25–27, 27t
5-Fluorouracil (5-FU)/taxanes, for
recurrent SCCHN,
clinical trials using, 69
Food and Drug Administration
(FDA), 50, 68
Forward-planned IMRT, 95–96
Functional Assessment of Cancer
Therapy, 42
Gefitinib, for recurrent SCCHN,
71
GETTEC, 27, 28, 81
GORTEC 2000–01 trial, 30t, 32
Gross tumor volume (GTV)
defined, 96–97
in IMRT treatment plan, 96–97
Groupement d’Etudes des
Tumeurs d la Tête et
du Cou (GETTEC),
27, 28, 81
Head and neck cancer. See also
specific types
chemoradiation for, 1–22. See
also Chemoradiation,
for head and neck
cancer
prevalence of, 1
recurrent, management of, 61–
75. See also Recurrent
disease, management
of
Posner.bk Page 118 Friday, October 20, 2006 11:41 AM
118
Index
re-irradiation of, IMRT in, 107
squamous cell carcinoma. See
Squamous cell carcinoma of head and
neck (SCCHN)
Hypofractionation, accelerated,
defined, 102
IG-IMRT, 99
“Induction” chemoradiation, 2–3
Induction chemotherapy
chemoradiation after, 8–9
in locally advanced SCCHN,
25–28, 27t
metaanalysis of results, 25
platinum/5-FU chemotherapy, 25–27, 27t
in resectable patients, 28
vs. chemoradiation, 28–29,
29t
Institut Gustave Roussy, 64
Intensity-modulated radiation
therapy (IMRT), 91–
114
advantages of, 101–102
in coverage of midline structures, 106
in coverage of nasopharynx/
parapharyngeal tissues, 104, 105t
defined, 92
disadvantages of, 107–109
cost/resources, 108–109
increased toxicity, 108
new toxicity, 108
risk of marginal miss, 107
risk of secondary malignancy, 107–108
forward-planned, 95–96
historical perspective of, 92–
96, 92f–96f
introduction of, 91–92
inverse-planned, 95–96
in laryngopharyngeal sparing,
106
in match line dosimetry, 103–
104
in parotid sparing, 102–103
planning of, 94–95
in re-irradiation of head and
neck cancer, 107
in sparing of optic structures,
106
Intensity-modulated radiation
therapy (IMRT) treatment plan
evaluation of, 99–101, 100t
volume definition for, 96–99,
98f. See also Volume
definition, for IMRT
treatment plan
Intergroup 0099 nasopharynx
cancer trial, 3
Inverse-planned IMRT, 95–96
Lapatinib, for recurrent SCCHN,
71
Laryngeal cancer, AJCC stage IV,
13–14
Laryngopharyngeal sparing, IMRT
in, 106
Locoregional therapies
for recurrent head and neck
cancer, 62–66, 65t
salvage surgery, 62–63
for recurrent SCCHN, radiation therapy, 63–66,
65t
Malignancy, secondary, IMRT
and, 107–108
Marginal miss, IMRT and,
107
MASCC, 45
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Index
Match line dosimetry, IMRT in,
103–104
Methotrexate, for recurrent
SCCHN, 68
Midline structures, coverage of,
IMRT in, 106
Minnie Pearl Cancer Research
Network Trial, 34
Mucositis, in head and neck cancer patients undergoing
chemoradiation, 43–
44
Mucositis Committee, of MASCC,
45
Mucositis-related symptoms, in
head and neck cancer
patients undergoing
chemoradiation, 44–
45
Multinational Association of Supportive Care in Cancer (MASCC),
Mucositis Committee
of, 45
Nasopharynx/parapharyngeal tissues, coverage of,
IMRT in, 104, 105t
Neck, cancer of. See Head and
neck cancer
Neoadjuvant chemoradiation, 2–3
Nutritional management, in head
and neck cancer
patients undergoing
chemoradiation, 45–
48
OARs, in IMRT treatment plan,
97
Optic structures, sparing of, IMRT
in, 106
119
Oral care, in head and neck cancer
patients undergoing
chemoradiation, 50–
51
Organ preservation, in SCCHN,
strategies for, chemotherapy integration in,
77–90. See also Squamous cell carcinoma
of head and neck
(SCCHN), organ preservation strategies for
Organs at risk (OARs), in IMRT
treatment plan, 97
Paclitaxel, for head and neck cancer, 10
Parotid sparing, IMRT in, 102–
103
Planning at-risk volume (PRV), for
IMRT treatment plan,
98
Planning target volume (PTV), for
IMRT treatment plan,
98–99
Planning volumes, in IMRT treatment plan, 98–99
Platinum agents
for head and neck cancer, 10
for recurrent SCCHN, 67
Platinum agents/taxanes, for recurrent SCCHN, clinical
trials using, 69
Platinum/5-FU, in locally
advanced SCCHN,
25–27, 27t
PRV, for IMRT treatment plan, 98
Psychological issues, in head and
neck cancer patients
undergoing chemoradiation, 51–54, 52t–
53t
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120
Index
PTV, for IMRT treatment plan,
98–99
Quality of life (QOL), symptom
control vs., 42–43
Radiation therapy (RT)
chemotherapy during, 3–8, 4t–
5t
chemotherapy with. See
Chemoradiation
intensity-modulated, 91–114.
See also Intensitymodulated radiation
therapy (IMRT)
for locally recurrent SCCHN,
63–66, 65t
for patients treated with salvage surgery for
SCCHN, 63
surgical resection with, in
organ preservation for
SCCHN, 78–79
Radiation Therapy Oncology
Group (RTOG), 3, 9,
66, 94. See also specific RTOG trials
Radiation Therapy Oncology
Group (RTOG) Salivary Gland Morbidity Scale, 49t
Reactive oxygen species (ROS),
43
Recurrent disease, management of,
61–75
approaches to, 61–62, 73f
locoregional therapies in, 62–
66, 65t
systemic therapy in, 66–71,
72t, 73f
chemotherapeutic agents,
67–68
combination chemotherapy,
clinical trials using,
68–70
EGFR, 70–71
evolution of, 67
methotrexate, 68
novel targeted therapy, 70–
71, 72t
platinum agents, 67
taxanes, 67–68
triple-agent regimens, 69–70
Re-irradiation
of head and neck cancer, IMRT
in, 107
for patients with recurrent head
and neck cancer, 63–
66, 65t
Resource(s), IMRT-related, 108–
109
ROS, 43
RTOG, 3, 9, 66, 94
RTOG 85-01 trial, 7
RTOG 90-03 trial, 7, 8
RTOG 91-11 trial, 3, 6
RTOG 95-01 trial, 6–7, 15
RTOG 99-14 trial, 7–8
RTOG H-0129 trial, 18
Salvage surgery, for recurrent
SCCHN, 62–63
radiation therapy with, 63
Sequential therapy, in locally
advanced SCCHN,
32–37, 35f–37f
compared with other therapies,
33–37, 35f–37f
docetaxel-based cisplatin/5-FU
chemotherapy and
chemoradiation, phase
III trials comparing,
33–37, 35f–37f
for unresectable disease, 32–33
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Index
“SMART” technique, 102
Sorafenib, for recurrent SCCHN,
71
Southwest Oncology Group Oropharynx trial, 34, 37,
37f
Squamous cell carcinoma of head
and neck (SCCHN)
chemoradiation vs. radiation
alone trials for, 4t–5t
locally advanced
defined, 23
treatment of, 23–40
chemoradiation in, 28–
32, 29t, 30t
combined modality
therapy in, 25–37,
27t, 29t, 30t, 35f–
37f
history of, 24
induction chemotherapy
in, 25–28. See also
Induction
chemotherapy, in
locally advanced
SCCHN
options in, 23–24
sequential therapy in,
32–37, 35f–37f
management of
approach to, 73f
goals in, 77–78
options in, 77–78
organ preservation strategies
for
best treatment options, early
identification of, 86–
88, 87f
chemotherapy integration
in, 77–90
radiation therapy and surgery, 78–79
121
systemic chemotherapy, 79–
84, 82t, 83t, 85t
recurrent
management of, 61–75. See
also Recurrent disease, management of
systemic therapy in, 66–71,
72t, 73f
re-irradiation for patients
with, 63–66, 65t
Supportive Care in Cancer, 45
Surgical resection, radiation therapy with, in organ
preservation for
SCCHN, 78–79
Swallowing abnormalities, aspiration due to, 47–48
Symptom control, quality of life
vs., 42–43
Symptom control issues, in head
and neck cancer
patients undergoing
chemoradiation, 43–
54, 46t, 49t, 52t–53t
mucositis, 43–44
mucositis-related symptoms,
44–45
nutritional management, 45–
48
oral care, 50–51
pretreatment evaluation, 52t–
53t
psychological issues, 51–54,
52t–53t
unintentional weight loss, 45–
48, 46t
xerostomia, 48–50, 49t
Systemic chemotherapy
evolution of, 6–7
in organ preservation for
SCCHN, 79–84, 82t,
83t, 85t
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122
Index
Systemic therapy, for recurrent
SCCHN, 66–71, 72t,
73f. See also Recurrent disease, management of, systemic
therapy in
TAX 323 trial, 30t, 31, 32
TAX 324 trial, 30t, 31, 34, 37
Taxane(s)
chemoradiation and, in locally
advanced SCCHN,
29–32, 30t
for recurrent SCCHN, 67–68
Taxane(s)/5-FU, for recurrent
SCCHN, clinical trials
using, 69
Taxane(s)/platinum agents, for
recurrent SCCHN,
clinical trials using,
69
Toxicity(ies), increased or “new,”
IMRT and, 108
Tyrosine kinase inhibitors, for
recurrent SCCHN,
71
University of Chicago, 34, 35f,
64
University of Michigan, 34, 103
University of Pennsylvania, 33
University of Texas M.D. Anderson Cancer Center,
14, 17
U.S. Food and Drug Administration (FDA), 50, 68
“VA Larynx Preservation Trial,”
1, 3
Vanderbilt University, 45
Vanderbilt University Medical
Center, 34
Volume definition, for IMRT
treatment plan, 96–
99, 98f
CTVs, 97–98, 98f
GTV, 96–97
OARs, 97
planning volumes, 98–99
Weight loss, unintentional, in head
and neck cancer
patients undergoing
chemoradiation, 45–
48, 46t
Xerostomia
adverse events associated with,
48–49, 49t
in head and neck cancer patients
undergoing chemoradiation, 48–50, 49t
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