Prostate Cancer

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Prostate Cancer
William G. Nelson, H. Ballentine Carter, Theodore L. DeWeese, and Mario A. Eisenberger

S U M M ARY

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prostate cancer treated with external beam radiation therapy. • A progressive rise in the serum PSA after treatment indicates prostate cancer recurrence. • Depending on the approach used, side effects associated with treatment of localized prostate cancer can include erectile dysfunction, irritative voiding symptoms or difficulties with urinary control, and rectal irritation. • Radiation therapy can be used to treat local prostate cancer recurrences following radical prostatectomy.

Incidence
• Prostate cancer is the most commonly diagnosed life-threatening cancer in men (218,890 cases and 27,050 deaths in 2007). • Small prostate cancers are present in 29% of men between age 30 and 40 and 64% of men between age 60 and 70. • The lifetime risk of a prostate cancer diagnosis is 1 in 6, and the risk of dying from prostate cancer is 1 in 35. • Age, family history, diet and lifestyle, and ethnicity are risk factors for prostate cancer development.

• Defects in the functions of NKX3.1, PTEN, and CDKN1B are common in prostate cancer cells.

Prevention
• The type 2 5α-reductase inhibitor finasteride reduced the overall number of prostate cancers, but may have increased the number or the detection of high-grade cancers, in a randomized clinical trial. • The antioxidants selenium and vitamin E are under scrutiny in a large randomized clinical trial for prevention of prostate cancer.

Molecular Pathogenesis
• Germline mutations in RNASEL and MSR1, encoding proteins that function in host responses to infection, appear responsible for some cases of hereditary prostate cancer. • An inflammatory lesion, proliferative inflammatory atrophy (PIA), may be an early precursor to prostate cancer. • Somatic inactivation of GSTP1, encoding a carcinogen-detoxification enzyme, may initiate prostatic carcinogenesis by increasing the vulnerability of prostate cells to damage mediated by oxidant and electrophilic carcinogens. • Gene fusions, involving TMPRSS2 and ETS family transcription factor genes, may contribute to the androgen dependence of prostate cancers.

Screening and Diagnosis
• Prostate cancer screening using serum prostate-specific antigen (PSA) and digital rectal examination detects prostate cancers early, when the disease is clinically localized to the prostate gland. • Transrectal ultrasound (TRUS)-guided core needle biopsies are used to diagnose prostate cancer. • Stage, histological grade (Gleason score), and serum PSA levels are prognostic factors.

Treatment of Advanced Disease
• Androgen suppression, most often accomplished via the use of luteinizing hormone-releasing hormone (LHRH) agonists, with or without anti-androgens, is the most commonly used treatment. • Side effects can include loss of libido, hot flashes, gynecomastia, loss of lean muscle mass and bone density, and the development of metabolic syndrome. • Docetaxel chemotherapy improves the survival of men with progressive androgen-independent prostate cancer. • Bisphosphonates antagonize loss of bone density accompanying androgen deprivation, and reduce skeletal complications associated with metastatic prostate cancer progression. • Other agents, including various immunotherapies, are under development in clinical trials.

Treatment of Localized Disease
• Treatment options include watchful waiting, anatomic radical retropubic prostatectomy, external beam radiation therapy, and brachytherapy. • Adjuvant androgen suppression can improve survival for some men with

INTRODUCTION
In 2007, an estimated 218,890 prostate cancer diagnoses will be made in the United States, accompanied by an estimated 27,050 prostate cancer deaths.1 Since about 1994 to 1996, with widespread use of serum prostate-specific antigen (PSA) testing and digital rectal examination for prostate cancer screening, and with increased treatment of clinically localized prostate cancer with surgery or radiation therapy, age-adjusted prostate cancer death rates have fallen steadily. Although this trend might indicate a beneficial impact of prostate

cancer screening and/or early prostate cancer treatment on prostate cancer mortality, mass screening of the general population for prostate cancer remains controversial.2,3 One challenge for prostate cancer screening is the prevalence of the disease in the U.S.: autopsy series have revealed small prostate cancers in as many as 29% of men between age 30 and 40 and 64% of men between age 60 and 70.4 Obviously, not all of these men are at risk for symptomatic or lifethreatening prostate cancer progression. In fact, many such men, if diagnosed with prostate cancer, may be at greater risk for treatmentassociated morbidity.

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Currently, for U.S. men, the lifetime risk of a diagnosis of prostate cancer is about 1 in 6, while the lifetime risk of death from prostate cancer is on the order of 1 in 35.1 Over the past two decades, treatment approaches for men with prostate cancer have changed dramatically, with improvement in established prostate cancer treatments and the introduction of new prostate cancer treatment approaches. Now, men diagnosed with prostate cancer often face a bewildering array of treatment choices. Physicians must weigh the risks of prostate cancer progression against the potential for side effects from treatment, in the context of other health risks and life choices, to use the current collection of treatments for the greatest benefit. This chapter provides an overview of prostate cancer etiology, biology, screening, detection, diagnosis, prevention, and treatment.

PROSTATE ANATOMY AND FUNCTION
The prostate is a male sex accessory gland that surrounds the urethra and contributes secretions to the ejaculate (Fig. 88-1). Located in the pelvis, the prostate sits adjacent to the bladder and rectum, is surrounded incompletely by a thin capsule composed of collagen, elastin, and smooth muscle, and at the apex of the gland, forms part of the urethral sphincter apparatus.5 Nerves to the corpora cavernosa of the penis, needed for penile erection, travel through fascia along the posterolateral surface of the prostate. These nerves can be recognized as a neurovascular bundle by urologists and preserved during radical prostatectomy to minimize sexual dysfunction postoperatively.6,7 The prostate parenchyma has been divided into three zones that can be seen by transrectal ultrasonography, and recognized readily by surgical pathologists examining radical prostatectomy specimens: a central zone, surrounding the ejaculatory ducts and accounting for some 25% of the prostate; a transition zone, near the prostatic urethra with 10% of prostate tissue normally; and a peripheral zone, with the bulk of prostate tissue encompassing posterolateral region of the prostate (Fig. 88-2).8,9 In addition to prostate cancer, the prostate also frequently manifests benign enlargement (benign prostatic hyperplasia [BPH]) and chronic or recurrent inflammation (prostatitis). Like prostate cancer, each of these conditions can elevate the serum prostate-specific antigen (PSA), confounding the use of serum PSA testing for prostate cancer screening. When present, BPH usually is located near the

prostatic urethra (in the transition zone), while prostate cancer, as well as the prostate cancer precursor lesion prostatic intraepithelial neoplasia (PIN), usually arises in the periphery (the peripheral zone). Prostatic inflammation, although often prominent in the peripheral zone, can be seen throughout the prostate. Although prostate cancer, BPH, and prostatitis all commonly afflict U.S. men, and can be simultaneously present in a single prostate gland, mechanistic associations of the three diseases have been difficult to demonstrate. The prostate requires androgenic hormones and an intact androgen receptor for normal growth and development. In the prostate, the major circulating androgenic hormone, testosterone, produced by Leydig cells in the testes upon stimulation by luteinizing hormone (LH), is converted by 5α-reductase (nicotinamide-adenine dinucleotide phosphate-dependent ∆(4)-3-ketosteroid 5α-oxidoreductase) to 5α-dihydrotestosterone (DHT).10 DHT, a more potent androgen than testosterone, binds to intracellular androgen receptors, alters androgen receptor conformation to promote dissociation from chaperone proteins, triggers androgen receptor dimerization and transport into the cell nucleus, and activates the expression of selected target genes.11,12 Stereotypically, androgen receptor target genes are characterized by the presence of androgen response element (ARE) DNA sequences within the transcriptional regulatory region, permitting direct binding and trans-activation by the androgen receptor.13 For genes like PSA, which are activated by the androgen receptor selectively in prostate cells, and not in cells of other tissues, the transcriptional regulatory region also contains additional DNA sequences (prostate-specific enhancer [PSE]) conferring prostate-specific expression.14 The normal prostate epithelium is composed of (1) basal epithelial cells, characterized by the expression of cytokeratins K5 and K14, and p63; (2) columnar secretory epithelial cells, which express the androgen receptor, PSA, cytokeratins K8 and K18, prostate-specific membrane antigen (PSMA), and prostate-specific acid phosphatase (PAP); and (3) rare neuroendocrine cells, which secrete chromogranin A, neuron-specific enolase, and synaptophysin (Fig. 88-3).15,16 The basal epithelial cell compartment likely contains pleuripotent prostatic stem cells, capable of self-renewal proliferation and of differentiation. In contrast, columnary secretory cells, specialized to produce secretions for the ejaculate, are terminally differentiated, particularly under the influence of androgenic hormones. The

Dorsal v. complex

Sy
Striated urethral sphincter

m

ph

.

Seminal vesicle Vas deferens

Bladder Prostate Ureter

Urethral lumen

Figure 88-1 • The anatomy of the prostate: rectum, bladder, dorsal vein complex, striated urethral sphincter, pelvic plexus, and neurovascular bundle.

Left neurovascular bundle

Rectum

Pelvic plexus

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Transition zone

Figure 88-2 • Zones of the prostate. The peripheral zone, accounting for 70% of the prostate gland, is the site of origin of ≥70% of prostate cancers; the central zone, approximately 25% of the prostate gland, gives rise to only 1% to 5% of prostate cancers; and the transition zone, ∼5% to 10% of the prostate gland, gives rise to 20% of prostate cancers and is the site of origin of benign prostatic hyperplasia (BPH). (From Green DR, Shabsign R, Scardino PT: Urological ultrasonography. In: Walsh PC, Rettic AB, Stamey CA, Vaughan ED Jr [eds]: Campbells’s Textbook of Urology, 6th ed. Philadelphia, WB Saunders, 1992.)
Peripheral zone

Central zone

Anterior fibromuscular stroma

prostate epithelium is supported, in turn, by a stroma containing fibroblasts, smooth muscle cells, nerves, and blood vessels. Stromal cells, which also express the androgen receptor, secrete polypeptide growth factors, such as keratinocyte growth factor (KGF), that contribute to the regulation of epithelial homeostasis via a paracrine signaling mechanism.17,18 Abnormal stromal–epithelial interactions, with disordered regulation of epithelial cell proliferation and differentiation, may contribute to the pathogenesis of both prostate cancer and BPH.19 Prostate cancer cells and PIN cells arise from the prostatic epithelium. Even though transformed, such cells typically retain many of the phenotypic attributes characteristic of differentiated columnar secretory cells, including the expression of androgen receptor, PSA,

PSMA, and PAP. Prostate cancers reminiscent of basal epithelial cells are exceptionally rare; prostate cancers with features of neuroendocrine cells are somewhat more common.20 However, unlike normal columnar epithelial cells, neoplastic prostate epithelial cells are capable of proliferation. This feature has led to the concept that the target cell for neoplastic transformation in the prostate may be an “intermediate” cell, in transit from a basal epithelial stem cell to a differentiated columnar secretory epithelial cell, with properties of both stem cells and differentiated cells.15,16 Another feature of neoplastic prostate epithelial cells, as compared to normal basal or columnar secretory cells, is that the neoplastic cells appear to use androgen receptor signaling not only for differentiation, but also for proliferation, as most prostate cancer cells tend, at least initially, to display

Glandular Secretory lumen cell Epithelial Golgi Secretory compartment granule Microvilli aparatus

Epithelial compartment Desmosome

Figure 88-3 • The prostate epithelium.

Smooth Nerve muscle cell terminals

Basal Fibroblast Capillary Basement cell membrane

Neuroendocrine cell

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some dependence on androgens for maintenance of growth and survival.21 Somatic fusions between an androgen-regulated gene, TMPRSS2, at chromosome 21q22, and genes encoding members of the ETS family of transcription factors, commonly found in prostate cancers, may provide a mechanistic explanation by which androgen signaling can promote prostate cancer cell growth.22 Ultimately, in life-threatening prostate cancer, prostate cancer cells escape from the prostate gland, proliferate to lymph nodes, in bones, and in other organs, and become less and less dependent on androgenic hormones.

ETIOLOGY OF PROSTATE CANCER
Genetic Predisposition to Prostate Cancer
Familial clusters of prostate cancer have been recognized since at least 1956, when Morganti and colleagues23 reported that men with prostate cancer were more likely to have relatives with prostate cancer than men without a prostate cancer diagnosis. In a study conducted more than 3 decades later, when detailed family histories were collected from men with prostate cancer and their spouses, the men with prostate cancer were more likely to have a brother or father with prostate cancer.24 Furthermore, the presence of one, two, or three affected family members appeared to increase the risk of prostate cancer to first-degree relatives by two-, five-, and eleven-fold, respectively, while the risk to more distant relatives was only marginally increased.24 Similar findings have been reported in a number of additional studies. Twin studies, comparing the tendency for concordant prostate cancer development between monozygotic twins, sharing all of their genes, and dizygotic twins, sharing half of their genes, also have hinted at a significant contribution of hereditary to prostate cancer. In one study of 44,788 pairs of twins in Sweden, Denmark, and Finland,25 42% of the prostate cancer cases (with a 95% confidence interval of 29% to 50%) were attributed to heredity. In principle, familial clustering of prostate cancer cases could be a result of inherited susceptibility genes, shared exposure to carcinogenic stresses, or to some sort of detection or diagnosis bias (e.g., the brother of a man diagnosed with prostate cancer may be more likely to pursue screening for prostate cancer). To discriminate these possibilities, several complex segregation analyses have been undertaken testing the mode of prostate cancer inheritance in familial prostate cancer clusters. In one study, rare autosomal dominant prostate cancer genes were predicted to account for as many as 43% of prostate cancer cases before age 55 and some 9% of all prostate cancer cases.26 In another study, an additional X-linked gene also appeared to be responsible for inherited prostate cancer in certain families.27 Mendelian inheritance of prostate cancer risk has been further supported by a number of genome-wide screens of polymorphic DNA markers; when data from more than 1233 hereditary prostate cancer families have been combined, several regions of linkage have been identified.28 Genetic mapping studies have identified RNASEL and MSR1 as potential prostate cancer susceptibility genes.29,30 RNASEL, a candidate HPC1, encodes a latent endoribonuclease component of an interferon-inducible 2′,5′-oligoadenylate-dependent RNA decay pathway that functions to degrade viral and cellular RNA upon viral infection.31 The evidence that RNASEL mutations might predispose to hereditary prostate cancer development included the finding that four brothers with prostate cancer were found to carry RNASEL alleles with a base substitution 795G→T, predicted to result in the conversion of a glutamic acid codon to a termination codon at amino acid position 265 (aa256glu→X), and that four of six brothers with prostate cancer in another family were found to carry RNASEL alleles with a base substitution 3G→A, affecting the initiator methionine codon (aa1met→ile).29 In addition, in a case-control study, a common polymorphic variant RNASEL allele with a base substitution

1385G→A, encoding a less active enzyme (with an amino acid change aa462arg→glu), was correlated with increased prostate cancer risk (P = 0.011).32 In this study, the polymorphic RNASEL allele accounted for as many as 13% of all prostate cancer cases. Provocatively, a new retrovirus, XMRV, has been detected in prostate tissues from men with RNASEL defects.33,34 Whether this virus may lead, directly or indirectly, to prostate cancer in these men has not been determined. MSR1 encodes subunits of a trimeric class A macrophage scavenger receptor capable of binding bacterial lipopoylsaccharide and lipoteichoic acid, and oxidized high- and low-density serum lipoproteins (oxidized HDL and LDL).35 For MSR1, mutations not only have been linked to prostate cancer susceptibility in some prostate cancer families, but one mutant allele, encoding a receptor subunit polypeptide with an aa293arg→X expected to have “dominant negative” function, has been detected in ∼3% of non-hereditary prostate cancer (HPC) cases but only 0.4% of unaffected men (P < 0.05).30,36 The identification of RNASEL and MSR1 as candidate prostate cancer susceptibility genes has intensified interest in the possibility that infection and/or inflammation might contribute to the pathogenesis of human prostate cancer. In mice, targeted disruption of RnaseL leads to increased diminished interferon-α activity and increased susceptibility to viral infection,37 while targeted disruption of Msr-A leads to increased vulnerability to infection with Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, and herpes simplex virus type 1.35,38–40 Further genetic support for this etiologic mechanism has come from analyses of common variants of other genes encoding participants in host inflammatory responses, including TLR4, and other members of toll-like receptor signaling pathways, MIC-1, IL1-RN, and COX-2, also have been associated with prostate cancer risk.41–45 Androgenic hormones are necessary for prostate growth and development. Thus, it is not surprising that polymorphic variants of genes involved in androgen action, such as AR, CYP17, and SRD5A2, may affect prostate cancer risk. Polymorphic polyglutamine (CAG) repeats, varying in length from 11 to 31 amino acids,46 and polymorphic polyglycine (GGC) repeats, varying in length from 10 to 22 amino acids, have been described for AR. For the polyglutamine repeats, androgen receptors with shorter repeats may possess increased transcriptional trans-activation activity.47 African-Americans, who have higher prostate cancer risks than Asians, also have shorter androgen receptor polyglutamine repeats. Furthermore, genetic epidemiology analyses have correlated high prostate cancer risk with short androgen receptor polyglutamine repeats.48–51 Variations in androgen receptor polyglycine repeats also may affect prostate cancer risk.48,50–52 SRD5A2, encoding the type 2 5α-reductase, the enzyme that generates DHT from testosterone in the prostate, has several polymorphic variants.53,54 Some variant alleles encoding enzymes with increased activity have been associated with increased prostate cancer risk, and with poor prostate cancer prognosis.53,55 5α-reductase variants also may respond differently to inhibition by finasteride, used to treat BPH and under scrutiny as a prostate cancer prevention drug.56,57 CYP17, encoding cytochrome P450c17α, an enzyme that functions to synthesize sex steroids, also has polymorphic variants. One variant allele, with a T→C transition in the transcriptional regulatory region of the gene that creates an Sp1 transcription factor recognition site, has been subjected to both population and genetic linkage analyses for association with prostate cancer, with inconsistent results.58

Prostate Cancer Epidemiology
Accumulated epidemiologic evidence implicates the environment as the major contributor to the development of most prostate cancers. Prostate cancer incidence and mortality display wide geographic variation, with high rates of prostate cancer incidence and mortality in the United States and Western Europe, and low prostate cancer risks more characteristic of Asia.59 African-Americans in the United

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States have very high prostate cancer risks.60 The geographic variation in prostate cancer incidence and mortality can best be explained by lifestyle influences, as Asian immigrants to North America typically adopt higher prostate cancer risks.61–63 The key aspect of lifestyle in the United States most likely responsible for high prostate cancer incidence and mortality is the diet, generally rich in animal fats and meats and poor in fruits and vegetables. In the Health Professions Follow-up Study, a prospective cohort study involving 51,529 men, total fat intake, animal fat intake, and consumption of red meats were associated with increased risks of prostate cancer development.64 Red meat consumption was similarly correlated with prostate cancer risks in the Physicians’ Health Study65 and in a large cohort study in Hawaii.66 The cooking of red meats at high temperatures, or on charcoal grills, is known to lead to the formation of both heterocyclic aromatic amine and polycyclic aromatic hydrocarbon carcinogens.67,68 Ingestion of 2-amino-1methyl-6-phenylimidazopyridine (PhIP), one of the heterocyclic amine carcinogens that appear in “well-done” red meats, leads to prostate cancer in rats.69 Consumption of dairy products also appears to increase prostate cancer risks, an effect that may be more attributable to calcium intake than to dietary fat or protein.70 Consumption of vegetables and antioxidant micronutrients reduces prostate cancer risks. High intake of tomatoes, which contain lycopene, and of cruciferous vegetables, which contain sulforaphane, may protect against prostate cancer development.71,72 Lycopene likely prevents prostate cancer development by acting as an antioxidant. As part of a recent clinical trial, men were provided tomato sauce-based pasta dishes for three weeks before radical prostatectomy for prostate cancer.73 For these men, tomato consumption was associated with increased lycopene levels in the blood and in the prostate, with decreased oxidative genome damage in leukocytes and in prostate cells, and with a reduction in serum PSA.73 Sulforaphane, a compound that can prevent cancer in animals by triggering induction of carcinogen-detoxification enzymes, also can act as an antioxidant.74–76 In addition to lycopene and sulforaphane, other antioxidants, such as the micronutrients vitamin E and selenium, also may reduce prostate cancer risks.77–79 A clinical trial of supplementation with vitamin E and selenium to prevent prostate cancer (the SELECT Trial), involving a planned 32,400 men, has just been initiated.80 The consistent finding of a protective effect of various antioxidants against prostate cancer development suggests that oxidative stresses might contribute to prostatic carcinogenesis. Oxidants can be generated by metabolic processes, by a number of different exposures, and by inflammation.81,82 Androgens, necessary for normal prostate development and function, have been reported to increase oxidant production in prostate cancer cells.83,84

Prostate Inflammation, Proliferative Inflammatory Atrophy, and Prostate Cancer
Chronic or recurrent inflammation is known to play a causative role in the development of many human cancers, including cancers of the liver, esophagus, stomach, large intestine, and bladder. Inflammatory changes have been recognized in prostate tissues for many years, leading to speculation that inflammation might contribute in some way to prostate cancer development.85 However, over the past few years, evidence has accumulated in support of a more critical role for prostatic inflammation in the pathogenesis of prostate cancer. Inflammatory changes are present in almost all radical prostatectomy specimens from men with prostate cancer. Because inflammation in the prostate usually is not associated with symptoms, the prevalence of prostate inflammation is not known, and the association with prostate cancer has been difficult to test.86,87 A syndrome of irritative voiding symptoms and pelvic pain, perhaps attributable to inflammation near the prostatic urethra, is reported by about 9% or more of men between 40 and 79 years of age, with as many as 50% of such men suffering more than one episode by age 80 years.88 Most episodes of symptomatic prostatitis are not clearly attributable to specific infectious agents. Even so, sexually transmitted infections do appear to increase prostate cancer risks.89,90 Nonetheless, if prostate infection and inflammation lead to prostate cancer, the mechanism does not appear likely to involve direct transformation of prostate epithelial cells by microbial DNA. Instead, the production of microbicidal oxidants by inflammatory cells, such as superoxide, nitric oxide, and peroxynitrite, may promote prostate cancer development by triggering cell and genome damage.91,92 Increased production of oxidants by inflammatory cells in the prostate may be why decreased prostate cancer risk has been associated with intake of a variety of antioxidants or of nonsteroidal anti-inflammatory drugs, and why RNASEL and MSR1, the two prostate cancer susceptibility genes identified thus far, encode proteins that function in host responses to infections. Despite these provocative hints, the contribution of prostate inflammation to prostatic carcinogenesis has been difficult to assess. However, in 1999, De Marzo and associates93 provided the most compelling linkage of prostate inflammation to prostate cancer by proposing that a prostate lesion might be a precursor to PIN and to prostate cancer (Fig. 88-4). Areas of the prostate containing epithelial cells that do not fully differentiate into columnar secretory cells have long been recognized as focal atrophy lesions by prostate pathologists.85,94 The term proliferative inflammatory atrophy (PIA) has been used to describe those focal atrophy lesions that contain proliferating epithelial cells, are associated with chronic inflammation, and often

Normal prostate Columnar cells

Proliferative inflammatory atrophy

Prostatic intraepithelial neoplasia

Prostate cancer

Figure 88-4 • Proliferative inflammatory atrophy (PIA) as a precursor to prostatic intraepithelial neoplasia (PIN) and prostate cancer. (Adapted from Nelson WG, DeMarzo AM, Isaacs WB: Prostate cancer. N Engl J Med 2003;349:366–381.)

Basal cells

Inflammatory cells

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Part III: Specific Malignancies Box 88-1.

PROSTATE INFLAMMATION AND PROSTATE CANCER

Several lines of evidence have stimulated a renewed interest in the notion that prostate infection and/or inflammation may contribute to the development of prostate cancer. First, two of the inherited susceptibility genes so far identified for prostate cancer, RNASEL and MSR1, encode proteins that function in host responses to infection. Second, a new candidate prostate cancer precursor lesion, proliferative inflammatory atrophy (PIA), appears to arise as a consequence of prostate inflammation. Third, prostate cancer cells typically acquire defects in genes, like GSTP1, that encode enzymes that defend against cell and genome damage inflicted by oxidants, such as those elaborated by inflammatory cells. Finally, epidemiology and early clinical trial data suggest that consumption of a variety of different antioxidants, including selenium, vitamin E, and lycopene, may protect against prostate cancer development.

noxious stimulus, may be precursors to PIN and/or prostate cancer.97 However, whether prostatic inflammation is initiated in response to a prostatic infection or to some other provocation has not been ascertained. Finally, whether prostate cancer risks can be reduced by therapeutically attenuating prostate inflammation must be tested in clinical trials.

MOLECULAR PATHOGENESIS OF PROSTATE CANCER
Somatic Genome Alterations in Prostate Cancer Cells
Prostate cancer cells typically contain a plethora of somatic genome alterations, including gene mutations, gene deletions, gene amplifications, chromosomal rearrangements, and changes in DNA methylation (Fig. 88-5). In the United States, prostate cancer diagnoses typically are made in men 60 to 70 years of age, while small prostate cancers have been detected at autopsy in nearly 30% of men between 30 and 40 years of age.4 Thus, the somatic genome changes present in prostate cancers often have accumulated over many decades. The acquisition of somatic genome changes in the prostate may be influenced by lifestyle as well: although small prostate cancers have been detected at autopsy in men from geographic regions with low prostate cancer mortality, these small prostate cancers usually are present only in much older men.98–100 In the United States, prostates removed at radical prostatectomy for prostate cancer usually contain more than one prostate cancer lesion. Several techniques, including karyotyping, fluorescence in situ hybridization (FISH), comparative genome hybridization, and loss of heterozygosity analyses, have been used to catalog somatic genome changes in prostate cancers. Often, these analyses reveal different chromosomal abnormalities in different cancer cases, in different cancer lesions in the same cancer case, and in different areas within the same cancer lesion (Fig. 88-6). Chromosomal abnormalities, including gains and losses, tend to be distributed throughout the genome.101 The propensity to develop such a heterogeneous collection of somatic genome lesions over so many years, and in a manner so sensitive to environment and lifestyle, suggests strongly that prostate cancers likely arise as a consequence of either chronic or recurrent exposure to genome-damaging stresses, defective protection against genome damage, or some combination of both processes. The resultant genomic instability may be the

are located adjacent to PIN lesions and/or prostate cancers.95 The epithelial cells in PIA lesions typically express high levels of stressresponse polypeptides such as GSTP1, GSTA1, and cyclo-oxygenase 2 (COX-2). Loss of GSTP1 expression in rare PIA lesions, attributable to de novo GSTP1 CpG island hypermethylation, may be what leads to the development of PIN and prostate cancer.96 The hypothesis that inflammation might promote prostate cancer development offers new challenges to prostate cancer epidemiology, to the search for prostate cancer susceptibility genes, and to the molecular pathogenesis of prostate cancer (Box 88-1). Although prostatic inflammation is common in regions of the world with high prostate cancer risks, whether regions of the world with low prostate cancer risks have less prostatic inflammation has not been determined. New strategies for assessing the presence and extent of PIA and of prostate inflammation may be needed. Perhaps new biomarkers of prostate inflammation, assayable in blood, urine, or prostate fluid, can be developed for use in epidemiology studies. In addition, it probably will be necessary to evaluate polymorphic genes encoding regulators of immune responses systematically for prostate cancer risk associations. As for prostate cancer pathogenesis, PIA lesions, appearing to arise in response to prostatic inflammation or some other

Normal prostate epithelium

Germline mutations RNASEL, MSR1 Chromosome 8q gain Chromosome 8p loss TMPRSS2-ETS family Prostatic Gene fusions intraepithelial Loss of sequences neoplasia 10q, 13q, 16q
Localized prostate cancer

Proliferative inflammatory atrophy

GSTP1 CpG island hypermethylation Decrease in p27

Figure 88-5 • The molecular pathogenesis of prostate cancer.

Decrease in NKX3.1

Gains of sequences at 7p, 7q, Xq
Metastatic prostate cancer Androgen independent cancer

Decrease in PTEN hAR gene mutation/ amplification

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Transition zone

Peripheral zone

A
2 cm

B

Carcinoma High-grade prostatic intraepithelial neoplasia Atrophy

reason some prostate cancers progress to become life-threatening. Although most prostate cancers initially respond well to therapeutic reductions in circulating androgens, the cancers ultimately become androgen-independent, a process likely resulting from selection of pre-existing variant androgen-independent cancer cell clones, spontaneously generated via the acquisition of critical somatic genome changes.102,103 One newly described somatic genome alteration drives the production of fusion transcripts between an androgen-regulated gene, TMPRSS2, at chromosome 21q22, and members of the ETS family of transcription factors (Fig. 88-7).22 Fusion partners for TMPRSS2 include ERG (also at chromosome 21q22), ETV1 (at chromosome 7p21), and ETV4 (at chromosome 17q21).22,104,105 The occurrence of these fusion transcripts provides a plausible mechanism for the dependence of prostate cancer cells on androgenic hormones for growth and survival, as the expression of ETS family transcription factors can be stimulated by androgen action. TMPRSS2-ERG fusions have been detected in about 60% of prostate cancers and in more than 20% of PIN lesions.106 ERG is highly expressed by many prostate cancers, although whether ERG expression or the presence of ERG fusion transcripts has an impact on the prognosis of prostate cancer has not been determined.106–109 Hypermethylation of CpG island sequences encompassing the regulatory region of GSTP1, encoding the π-class glutathione Stransferase (GST) is the most common somatic genome change yet reported for prostate cancer.110,111 GSTs catalyze the detoxification of carcinogens, and of other reactive chemical species, via conjugation with the intracellular scavenger glutathione. In mice, targeted disruption of π-class GST genes leads to increased skin tumors after treatment with the carcinogen 7,12 dimethylbenz anthracene (DMBA).113 Similarly, human prostate cancer cells devoid of GSTP1 appear especially vulnerable to genome damage mediated by exposure to N-OH-PhIP, the charred meat carcinogen that causes prostate cancer when fed to rats, and by exposure to oxidant stresses.114 In the normal prostate epithelium, GSTP1 is present in basal cells, but in lower amounts than in columnar secretory cells, although the enzyme can be induced in columnar epithelial cells subjected to genome-damaging stresses. In contrast, the enzyme is almost never

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TMPRSS2 3194 142 365
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ETV1 268 322
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ERG443 225
3 4 11

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Figure 88-6 • Multiple foci of prostate cancer, and of prostate cancer precursor lesions, in the peripheral zone of the prostate. (From Nelson WG, DeMarzo AM, Isaacs WB, et al: Prostate cancer. N Engl J Med 2003;349:366– 381, with permission.)

TMPRSS2:ERGa

1

4

MET28-LN

71 226 AG C GC G GC A G G A A G C C T T A T

Figure 88-7 • Fusion of transcripts from the androgen-regulated TMPRSS2 gene and ETS family genes ETV1 and ERG in prostate cancers. (Adapted from Tomlins SA, Rhodes DR, Perner S, et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644–648).

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present in prostate cancer cells. For more than 90% of prostate cancer cases, this absence of GSTP1 expression in prostate cancer cells can be attributed to hypermethylation of GSTP1 CpG island sequences, a somatic genome change that prevents GSTP1 transcription. Absence of GSTP1 expression and GSTP1 CpG island hypermethylation also may be characteristic of cells comprising PIN lesions, thought to be precursors to prostate cancer.115 The mechanism by which hypermethylated GSTP1 CpG island alleles arise during prostatic carcinogenesis remains to be elucidated. Nonetheless, prostate cells carrying inactivated GSTP1 genes appear to enjoy some sort of selective growth advantage early during the development of prostate cancer. NKX3.1 encodes a prostate-specific homeobox gene essential for normal prostate development that may be a target for somatic loss on chromosome 8p21.116 NKX3.1 has been shown to bind DNA and to repress PSA expression via interactions with ETS transcription factors.117,118 Mice carrying one or two disrupted Nkx3.1 alleles manifest prostatic epithelial hyperplasia and dysplasia.119,120 In men, loss of 8p21 DNA sequences occurs early during prostatic carcinogenesis, with 63% of PIN lesions and more than 90% of prostate cancers showing loss of heterozygosity at polymorphic 8p21 marker sequences in one report.121 However, although mapping studies have indicated that NKX3.1 lies within a common region of deletion, encompassing two megabases at 8p21, molecular pathology analyses have not yet established NKX3.1 as a somatic target for inactivation during prostatic carcinogenesis because somatic NKX3.1 mutations have not been identified. Nonetheless, loss of NKX3.1 expression does appear to accompany prostate cancer progression. PTEN, a tumor suppressor gene encoding a phosphatase active against both proteins and lipid substrates, appears to be a common target for somatic alteration during prostate cancer progression.122–129 PTEN is an inhibitor of the phosphatidylinositol 3′-kinase/protein kinase B (PI3K/Akt) signaling pathway needed for cell cycle progression and cell survival. Although PTEN is expressed by normal prostate epithelial cells, and by cells present in PIN lesions, the expression of PTEN is often diminished in prostate cancers, with many prostate cancers containing collections of neoplastic cells with no PTEN.130 PTEN defects have been found in a wide variety of cancers and cancer cell lines.124 For prostate cancer, a number of somatic PTEN alterations have been reported, including homozygous deletions, loss of heterozygosity, mutations, and probable CpG island hypermethylation. However, despite common losses of 10q sequences near PTEN in prostate cancers, somatic mutations at the remaining PTEN alleles are not as frequent. In a study of prostate cancer metastases recovered at autopsy, somatic PTEN alterations were even more common than in primary prostate cancers, and a significant heterogeneity in PTEN defects in different metastatic deposits from the same patient was also evident.129 Haploinsufficiency for PTEN may contribute to the phenotype of transformed cells in the prostate. Pten+/− mice display prostatic hyperplasia and dysplasia, and crosses of Pten+/− mice with Nkx3.1+/− mice have revealed that Pten+/−kx3.1+/− mice and Pten+/− kx3.1−/− mice develop lesions reminiscent of human PIN.131–133 Defective regulation of p27, a cyclin-dependent kinase inhibitor encoded by CDKN1B, also may accompany prostatic carcinogenesis.134,135 In PIN cells and prostate cancer cells, p27 levels almost always are diminished, although the mechanism(s) for the reduction in p27 levels appear complex: somatic loss of DNA CDKN1B sequences at 12p12–13 has been reported for only 23% of localized prostate cancers, 30% of prostate cancer lymph node metastases, and 47% of distant prostate cancer metastases.136 In place of CDKN1B gene alterations, p27 polypeptide levels may be lowered indirectly by inadequate PTEN repression of the PI3K/Akt signaling pathway.137–139 In this way, low p27 levels may be as much a result of loss of PTEN function as of CDKN1B alterations. The critical contribution of PTEN to epithelial growth regulation in the prostate is evident in mice, where disruption of Cdkn1b alleles leads to prostatic hyperplasia, and Pten+/−dkn1b−/− mice develop prostate cancer by 3 months of age.134,140

Metastatic prostate cancer almost always is treated with androgen deprivation, anti-androgens, or a combination of androgen deprivation and anti-androgens.141,142 However, despite such treatment, androgen-independent prostate cancer cells eventually emerge and progress to threaten life. Curiously, in these cells, androgen receptor expression and androgen receptor signaling remain intact despite the absence of androgens.21,143 Somatic alterations of AR have been reported for many prostate cancers, especially for androgenindependent prostate cancers. AR amplification, accompanied by high-level expression of androgen receptors, may promote the growth of androgen-independent prostate cancer cells by increasing the sensitivity of the cells to low androgen levels.144 AR mutations encoding androgen receptors with altered ligand specificity also have been detected; for some of the mutant androgen receptors, even antiandrogens can act as agonist ligands.145–147 When 44 mutant androgen receptors from prostate cancers were evaluated for transcriptional regulatory capabilities, 16% of the receptors had lost transcriptional activation activity, 45% of the receptors had gained some transcriptional regulatory ability, 32% of the receptors maintained some partial transcriptional modulatory activity, and the remaining 7% behaved like wild-type receptors.148 In addition to somatic AR gene changes, androgen-independent prostate cancer cells with wild-type androgen receptors may activate androgen receptor signaling even in the absence of androgens, via post-translational modifications of the androgen receptor and/or androgen receptor co-activators in response to other growth factor signaling pathways.21,149–152

Changes in Gene Expression in Prostate Cancers
Alterations in gene expression in prostate cancers have been catalogued using cDNA microarray technologies.153–164 Among the many genes exhibiting over- or underexpression in prostate cancers, the products of at least two genes appear consistently increased, and the product of a third gene appears to become elevated during androgenindependent progression. Hepsin, located at 19q11–13.2, encodes a transmembrane serine protease, expressed at high levels in many normal tissues.165 Hepsin may contribute to prostate cancer progression: forced overexpression of hepsin in mouse prostates leads to disorganization of the epithelial basement membrane and increased metastasis.166 α-Methylacyl-CoA racemase (AMACR), a mitochondrial and peroxisomal enzyme that acts on pristanoyl-CoA and C27-bile acyl-CoA substrates to catalyze the conversion of R- to S-stereoisomers in order to permit metabolism by β-oxidation, has been reported to be overexpressed in almost all prostate cancers.167,168 Germline AMACR mutations lead to adult-onset neuropathy.169 Immunohistochemistry studies, which have revealed that AMACR occasionally is present in normal prostate cells, increased in PIN cells, and further elevated in prostate cancer cells, have prompted the use of antibodies against AMACR as tools for prostate cancer diagnosis by surgical pathologists.168,170 The polycomb protein enhancer of zeste homolog 2 (EZH2), a transcriptional regulatory protein, is elevated in metastatic androgen-independent prostate cancer.171 The mechanism by which EZH2 contributes to prostate cancer progression has not been established. However, elevated EZH2 expression in primary prostate cancers portends a poor prognosis.171

Telomere Shortening During Prostatic Carcinogenesis
Telomeres, containing repeat DNA sequences at the termini of chromosomes, protect against loss of chromosome sequences during genome replication. DNA ends tend to shorten each generation as a consequence of bidirectional DNA synthesis (the “end-replication” problem); the telomere repeat sequences serve as templates for the enzyme telomerase, which can extend the chromosome termini and maintain chromosome integrity through cell division.172 Growth dysregulation accompanying the development of most human cancers

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tends to lead to cell proliferation in the absence of telomerase, and to shortened chromosome telomeres.173 Critically shortened telomere sequences may promote genome instability by increasing illegitimate DNA recombination.174,175 Mice carrying disrupted genes needed for a functioning telomerase show increased numbers of cancers, especially when crossed to mice with defective p53 genes.176 In the prostate, short telomere repeat sequences appear characteristic of cells in both PIN lesions and prostate cancer.177–179 At some point, most cancer cells activate the expression of telomerase, providing some maintenance of chromosome termini. Telomerase expression has been detected in prostate cancers, but not at high levels in normal prostate tissues or in BPH.177

PREVENTION OF PROSTATE CANCER
The high lifetime risks of prostate cancer development, the morbidities associated with treatment of established prostate cancer, and the inability to eradicate life-threatening metastatic prostate cancer offer compelling reasons for prostate cancer prevention. In addition, epidemiology data, indicating a dominant role for lifestyle factors in prostate cancer development, suggest that prostate cancer risk modification may be feasible, if only through lifestyle modification. Also, because prostatic carcinogenesis takes many decades, there may be a broad window of opportunity to make lifestyle changes in an effort to retard prostate cancer development. Clearly, although the specific lifestyle factors fostering prostate cancer development have not been conclusively identified, it is likely that consumption of a diet rich in fruits, vegetables, and antioxidant micronutrients, and poor in saturated fats and “well-done” red meats, may significantly reduce risks of prostate cancer development, and of the development of other diseases characteristic of life in the developed world. Nonetheless, as the etiology of prostate cancer is better understood, new opportunities for prostate cancer prevention will arise. For example, if prostate inflammation contributes to prostate cancer development, anti-inflammatory drugs might be considered candidate prostate cancer prevention drugs. For drugs to be developed and tested for prostate cancer prevention, randomized clinical trials, capable of assessing both drug safety and drug efficacy, will be required.180 Ideally, such trials can be targeted at men with a high risk for prostate cancer development, analogous to women thought to be at high risk for breast cancer development identified by the Gail model.181 Thus far, two classes of agents, 5α-reductase inhibitors and antioxidant micronutrients, have been subjected to large randomized clinical trials.

normal digital rectal examination were randomized to treatment with finasteride (5 mg/day) or to placebo.57 While on-study, men with a PSA elevation or an abnormal rectal examination were subjected to prostate biopsy; in addition, at the end of the treatment period, a prostate biopsy was planned for all of the men in the trial. The Data and Safety Monitoring Committee for PCPT closed the study 15 months before the anticipated completion, with some 9060 men evaluable for the presence of prostate cancer.57 Prostate cancer was detected in 18.4% of the men treated with finasteride versus 24.4% of men receiving placebo (P < 0.001).57 Of concern, however, highgrade prostate cancers appeared more commonly associated with finasteride treatment than with placebo (6.4% versus 5.1%).57 This may mean that finasteride prevents or treats low-grade cancers better than high-grade cancers. Also, some 37% of men treated with finasteride, versus 29% of men receiving placebo (P < 0.001), discontinued treatment, usually citing side effects of reduced ejaculate volume, erectile dysfunction, loss of libido, and gynecomastia.57 These mixed results—a reduction in overall prostate cancer prevalence, but an increase in high-grade prostate cancers—associated with finasteride treatment make recommendations for healthy men who want to reduce their prostate cancer risks very difficult. A large clinical trial testing the effects of dutasteride, an inhibitor of both type 1 and type 2 5α-reductases used to treat BPH, on prostate cancer development is ongoing.189

Selenium and Vitamin E Cancer Prevention Trial
Epidemiologic studies have provided compelling evidence that intake of selenium and of vitamin E might diminish prostate cancer risks.190–196 In addition, two clinical trials have provided further evidence for protection against prostate cancer through consumption of these antioxidant micronutrients.77–79,112,197 In one of the studies, men and women (N = 1312) with a history of nonmelanoma skin cancer received 200 µg selenized brewer’s yeast or a placebo daily to ascertain whether selenium consumption might decrease the risk of a second skin cancer.78 Although selenium supplementation failed to prevent new skin cancers, a reduced risk of prostate cancer was noted for men receiving selenium supplements, particularly men with low baseline selenium levels.77,78,197 In the other study, α-tocopherol, β-carotene, the combination of α-tocopherol and β-carotene, or placebo was administered to male smokers (N = 29,133) in Finland for lung cancer prevention.112 Again, although neither of the supplements appeared to prevent lung cancer, a reduced risk of prostate cancer was evident for men receiving α-tocopherol.79,112 A prospective, randomized, placebo-controlled clinical trial of selenium and vitamin E, the Selenium and Vitamin E Cancer Prevention Trial (SELECT; N > 32,400) was initiated in 2001 to test the ability of the antioxidant micronutrients to prevent prostate cancer.198 Selenium (200 µg selenomethionine), α-tocopherol (400 mg), the combination of selenium and α-tocopherol, or neither, will be given to men randomized to four different treatment groups, using a 2 × 2 factorial design, for 7 to 12 years.198 The trial subjects will be men, age 55 years or older (50 years or older for African Americans), with an unremarkable digital rectal examination and a serum PSA of 4 ng/mL or less.198 Until the SELECT results are available, it will be difficult to make definitive recommendations about micronutrient supplementation to prevent prostate cancer. Nonetheless, the limited data available from epidemiology studies and early clinical trials suggest that men with low blood levels of the micronutrients tend to be at the highest risk for prostate cancer development, and that micronutrient supplementation might be most effective at preventing prostate cancer if given to such men.191,192,196,197 For this reason, perhaps a supplementation strategy designed to correct antioxidant micronutrient deficiencies might ultimately prove generally safe and effective. The risks and benefits of high doses of antioxidant micronutrients, or other supplements, are not known.

Prostate Cancer Prevention Trial
In the Prostate Cancer Prevention Trial (PCPT), the propensity for the type 2 5α-reductase inhibitor finasteride to reduce the prevalence of prostate cancer in healthy men age 55 years and older when given for 7 years was tested.57 Finasteride, which has been marketed both for BPH and for alopecia, was known to have few worrisome side effects and to lower the serum PSA in some men with prostate cancer.182,183 Also, 5α-reductase inhibitors had shown promising activity in preventing prostate cancer development and/or prostate cancer progression in animal models.184–186 However, the effects of finasteride on prostate cancer development in various clinical trials have not been as encouraging. In one randomized placebo-controlled trial, in which finasteride was used to treat BPH (N = 3040), 4.7% of men treated with finasteride and 5.1% of men treated with placebo ultimately were diagnosed with prostate cancer (P = 0.7).187 In another randomized trial (N = 52), 30% of men with an elevated serum PSA but no cancer on an initial prostate biopsy who were given finasteride for 12 months had cancer on a subsequent prostate biopsy versus 4% of men who did not receive finasteride.188 In this small trial, finasteride also had little beneficial activity in men with PIN.188 For PCPT, 18,882 men with a PSA of 3.0 ng/mL or less and a

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PROSTATE CANCER SCREENING, DIAGNOSIS, AND STAGING
Clinical Evaluation
The staging system for prostate cancer includes the results of histopathology analysis and of imaging studies in the stage assignment (Table 88-1). Prostate cancer rarely causes symptoms early in the course of the disease, because most of the adenocarcinomas arise in the periphery of the gland (the peripheral zone) distant from the urethra. The presence of symptoms attributable to prostate cancer suggests locally advanced or metastatic disease. With progressive growth of prostate cancer into the urethra, or into the bladder neck, lower urinary symptoms of obstruction (e.g., urinary hesitancy, decreased force of urine stream, intermittency) and irritation (e.g., urinary frequency, nocturia, urgency, urge incontinence) can occur. Local progression of prostate cancer and obstruction of the ejaculatory ducts can result in hematospermia and a decrease in the ejaculate volume. Extension of prostate cancer outside the prostate capsule can damage the branches of the pelvic plexus (neurovascular bundle) responsible for innervation of the corpora cavernosa and cause erectile dysfunction. Metastatic cancer involving the axial or appendicular skeleton can lead to bone pain, or, via replacement of the bone marrow, can cause pancytopenia. Lower extremity edema can result from cancerous involvement of the pelvic lymph nodes and compression of the iliac veins. Less common consequences of metastatic disease include malignant retroperitoneal fibrosis from dissemination of cancer cells along the periureteral lymphatics, paraneoplastic syndromes from ectopic hormone production by small cell variants of adenocarcinoma, and disseminated intravascular coagulation (DIC). Although men with prostate cancer can present with voiding symptoms suggesting locally advanced cancer, or with signs and symptoms suggesting metastatic cancer, currently more than 90% of men diagnosed with prostate cancer are initially detected as a result of digital rectal examination (DRE) abnormalities or of serum PSA elevations.

Table 88-1 TNM and AUA Staging Systems for Prostate Cancer
TNM STAGING SYSTEM PRIMARY TUMOR (T)
TX Primary tumor cannot be assessed. T0 No evidence of primary tumor T1 Clinically inapparent tumor neither palpable nor visible by imaging T1a Tumor incidental histologic findings in ≤5% of tissue resected T1b Tumor incidental histologic finding in >5% of tissue resected T1c Tumor identified by needle biopsy (e.g., because of elevated PSA) T2 Tumor is confined within prostate.* T2a Tumor involves one half of a lobe or less T2b Tumor involves more than one half of lobe, but not both lobes T2c Tumor involves both lobes† T3 Tumor extends through the prostate capsule. T3a Unilateral extracapsular extension T3b Bilateral extracapsular extension T3c Tumor invades seminal vesicle(s) T4 Tumor is fixed or invades adjacent structures other than seminal vesicles. T4a Tumor invades bladder neck, external sphincter, or rectum. T4b Tumor invades levator muscles or is fixed to pelvic wall, or both.

NODE (N)
NX Regional lymph nodes cannot be assessed. N0 No regional node metastasis N1 N2 N3 Metastasis in single lymph node, ≤2 cm Metastasis in a single node, >2 cm but ≤5 cm Metastasis in a node >5 cm

METASTASIS (M)
MX Presence of metastasis cannot be assessed. M0 No distant metastasis M1 Distant metastasis M1a Nonregional lymph node(s) M1b Metastasis in bone(s) M1c Metastasis in other site(s)

Digital Rectal Examination
In men with early-stage prostate cancers, physical findings, if present, usually are limited to an abnormal DRE, used for both diagnosis and staging. Palpable areas of induration, or asymmetric firmness of the gland, suggest the presence of prostate cancer, but these findings can also be caused by prostate inflammation (especially granulomatous prostatitis), by BPH, and by prostatic stones. DRE has only fair reproducibility in the hands of experienced examiners.199 When used alone for detection of prostate cancer, DRE misses 23% to 45% of the cancers that are subsequently detected by prostate biopsies done for serum PSA elevations or for transrectal ultrasound (TRUS) abnormalities.200–202 In addition, prostate cancers detected by DRE are at an advanced pathological stage in more than 50% of men.203,204 The positive predictive value of DRE (the fraction of men who have prostate cancer if the DRE is abnormal) depends on age, race, and PSA level.205,206 African-American race, older age, and higher PSA levels are associated with a higher positive predictive value for DRE.206 The positive predictive value of a suspicious DRE was 5%, 14%, and 29% in white men, and 8%, 37%, and 50% in black men with PSA levels of 0 to 1.0, 1.1 to 2.5, and 2.6 to 4.0 ng/mL, respectively (Table 88-2). The positive predictive value of a suspicious DRE ranged from 33% to 83% in men with PSA levels of 3.0 to 9.9 ng/mL or more.200–202,207–211 A prostate biopsy usually is recommended for men with an abnormality on DRE that is suspicious for prostate cancer, regardless of the PSA level.

AUA STAGING SYSTEM STAGE A: CLINICALLY UNSUSPECTED DISEASE
A1 A2 B1 B2 C1 C2 Focal carcinoma, well differentiated Diffuse carcinoma, usually poorly differentiated Small, discrete nodule of one lobe of gland Large or multiple nodules or areas of involvement Tumor outside prostate capsule, estimated weight ≤70 g, seminal vesicles uninvolved Tumor outside prostate capsule, estimated weight >70 g, seminal vesicles involved

STAGE B: TUMOR CONFINED TO PROSTATE GLAND

STAGE C: TUMOR LOCALIZED TO PERIPROSTATIC AREA

STAGE D: METASTATIC PROSTATE CANCER
D1 Pelvic lymph node metastases or ureteral obstruction causing hydronephrosis, or both D2 Bone, soft tissue, organ, or distant lymph node metastases
AUA, American Urological Association; PSA, prostate-specific antigen; TNM, tumornode-metastasis. *Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2, not as T3. † Tumor found in one or both lobes by needle biopsy but not palpable or visible by imaging is classified as T1c.

Serum Prostate-Specific Antigen
PSA is a member of the human kallikrein gene family of serine proteases encoded by genes located on chromosome 19.212 A component

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Table 88-2 Positive Predictive Value of DRE and PSA in a Multicenter Screening Trial
DRE
Abnormal Any

PSA
Any PSA >4 4–10 >10

PPV (%)
21.4 31.5 26.1 52.9 24.4 10.0 40.8 69.1

Normal Abnormal

PSA >4 PSA <4 4–10 >10

DRE, digital rectal examination; PPV, positive predictive value; PSA, prostatespecific antigen. Data from Catalona WJ, Richie JP, Ahmann FR, et al: Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283.

of the ejaculate, PSA is produced by columnar secretory cells in the prostate. PSA expression is regulated by androgens, becoming detectable in serum at puberty accompanying increases in luteinizing hormone and testosterone. In the absence of prostate cancer, serum PSA levels increase with age and prostate volume and usually are higher in African-American men. Cross-sectional population data suggest that the serum PSA increases 4% per mL of prostate volume, and that 30% and 5% of the variance in PSA can be accounted for by prostate volume and age, respectively.213 Serum PSA elevations likely occur as a result of disruption of the normal prostate architecture, permitting PSA to diffuse into the prostate parenchyma and gain access to the circulation. This can occur in the setting of both benign and malignant prostate diseases (prostatitis, BPH, and prostate cancer) and as a result of prostate manipulation (prostate massage and prostate biopsy).214 Although the presence of some type of prostate disease is the most important determinant driving elevation of the serum PSA, an increased serum PSA is not specific for prostate cancer. Furthermore, not all men with prostate disease have elevated serum PSA levels. Treatments targeting the prostate gland (for BPH or for prostate cancer) can lower serum PSA by decreasing the number of prostatic epithelial cells capable of producing PSA, and by decreasing the amount of PSA produced by each cell. Modulation of sex steroid hormone levels for treatment of BPH or prostate cancer, radiation therapy for prostate cancer, and surgical ablation of prostate tissue for BPH or prostate cancer can all lead to decreases in serum PSA. 5α-reductase inhibitor such as finasteride and dutasteride lower PSA levels by 50% after 12 months of treatment.215 Thus, for men treated with these agents for 12 months or more, the serum PSA level should be doubled to estimate the “true” PSA value. Interpretation of serum PSA values should always take into account the presence of prostate disease, previous diagnostic procedures, and prostate-targeted treatments. Numerous studies have documented the validity of serum PSA testing as a strategy for assessing the risk that prostate cancer is present. Routine use of serum PSA testing increases the detection of prostate cancer over that of DRE, improves the predictive value of the DRE for cancer, and leads to detection of prostate cancers at an early stage. The lead time (time by which a cancer diagnosis is advanced) with PSA screening has been estimated to be, on average, ∼10 years.216,217 As a result of the lead time associated with PSA screening, most men today are diagnosed with early-stage disease that is considered appropriate for curative intervention with radiation or surgery. The extent to which PSA screening has contributed to the decline in prostate cancer mortality that began in the early 1990s,

and whether early detection of prostate cancer does more harm than good, are being debated.218 The serum PSA value is correlated directly with prostate cancer risk.201 Gann and coworkers first showed that the risk of a cancer diagnosis increases incrementally and directly with PSA over the decade after a baseline measurement, even at low PSA levels (below 4.0 ng/mL), a finding that has now been confirmed by many others, including recent data from the PCPT.219,220 These observations emphasize that the serum PSA should be used not as a dichotomous test, but rather as a test that represents a continuum of prostate cancer risk. The probability that prostate cancer is present varies according to PSA and DRE results (see Table 88-2). The most effective method for early detection of prostate cancer is the combined use of DRE and serum PSA testing. When DRE and the serum PSA are used as screening tests for prostate cancer, detection rates are higher with serum PSA determinations than with DRE alone, and highest with a combination of both tests. Because DRE and serum PSA determinations are not always simultaneously abnormal in the presence of prostate cancer, the tests are complementary when used for prostate cancer detection. Experts disagree on the use of DRE for screening when PSA levels are very low, because in that setting, the DRE has a relatively poor positive predictive value. The widespread use of PSA for early detection of prostate cancer has stimulated efforts to improve the sensitivity (i.e., the percentage of men correctly identified as having prostate cancer among those with the disease) and specificity (i.e., the percentage of men correctly identified as free of prostate cancer among those without the disease) of the test. Altering the serum PSA threshold value used to trigger prostate biopsy, adjusting the PSA level for the prostate volume (the PSA “density”),221–228 monitoring the rate of change in serum PSA values over time (the PSA “velocity”),229–231 and the selective assay of various molecular forms of PSA in the serum232,233 have all been evaluated as methods of distinguishing prostate cancer from BPH and other prostate diseases.

Prostate-Specific Antigen Threshold for Prostate Biopsy
The choice of a serum PSA threshold value or “cut-point,” above which further evaluation to rule out prostate cancer (by prostate biopsy) should be recommended historically has been a controversial issue. However, it is now widely recognized that there is virtually no serum PSA value below which prostate cancer, even an aggressiveappearing prostate cancer, can be excluded as a diagnosis.234 Thus, there has been a greater emphasis on using serum PSA testing as part of a risk assessment algorithm that might include age, race, PSA velocity, etc.235,236 Physicians should discuss the likelihood of a prostate cancer diagnosis, given the serum PSA level and these other factors, with those men who have chosen to undergo serum PSA testing before recommending further evaluation.

Prostate-Specific Antigen “Density”
The major source of serum PSA in men without prostate cancer is the transition zone (TZ) epithelium, not the epithelium of the peripheral zone.237 Since BPH represents an enlargement of the transition zone, and since serum PSA levels are largely a reflection of transition zone volume in men with BPH, adjusting the serum PSA for either prostate volume (PSA density) or more specifically, the transition zone volume (PSA-TZ), has been shown to improve the detection of prostate cancer (Table 88-3). Volume adjustment of the serum PSA value is used most often to determine the need for a repeat biopsy in men with a prior negative biopsy, a clinical setting in which a missed cancer is suspected because of a persistently elevated serum PSA.238

Prostate-Specific Antigen “Velocity”
Carter and colleagues,229 using frozen serum samples from an aging study cohort, demonstrated that PSA “velocity” (PSAV; the rate of

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Table 88-3 Age-Specific Reference Ranges for Serum PSA and PSA Density
Age Range (yr)
40–49 50–59 60–69 70–79

Molecular Forms of Prostate-Specific Antigen
PSA in the bloodstream circulates in both bound and unbound forms. Most of the detectable PSA in the serum (65%–90%) is bound to α1-anti-chymotrypsin, while the rest (10%–35%) remains unbound or “free.”212 The assays primarily used for prostate cancer detection and monitoring detect both “free” and “complexed” PSA, providing a determination of the “total” serum PSA. Newer assays that can distinguish “free” and “complexed” serum PSA have more recently been developed and approved by the U.S. Food and Drug Administration (FDA) for use in the early detection of prostate cancer. In general, men with prostate cancer have a greater fraction of serum “total” PSA that is bound to α1-anti-chymotrypsin, and a commensurately lower fraction of “total” PSA that is “free,” than men without prostate cancer. This difference is thought to be due to the differential expression of PSA isoforms by cells in the transition zone (the zone of origin for BPH) tissue as compared with peripheral zone (the zone where most prostate cancers arise) tissue. The percentage of “free” serum PSA appears most useful in distinguishing between men with and without prostate cancer in the setting of “total” serum PSA levels between 2 and 10 ng/mL (Table 88-4). Most urologists use “free” serum PSA determinations to help make decisions about the need for a repeat biopsy in a man with a persistently elevated serum PSA and previous negative prostate biopsies, where the possibility of a missed prostate cancer may be a concern. Measurement of “complexed” serum PSA, using a single assay, has been promoted by some investigators as a better method for assessing prostate cancer risk, in place of the two assays (“total” serum PSA and “free” serum PSA) needed for determination of percent “free” serum PSA.

Serum PSA (ng/mL)
0.0–2.5 0.0–3.5 0.0–4.5 0.0–6.5

PSA Density (ng/mL)
0.0–0.10 0.0–0.12 0.0–0.14 0.0–0.16

PSA, prostate-specific antigen. Data from Osterling J, Jacobsen S, Klee G, et al: Free, complexed, and total serum prostate specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios using newly developed immunofluorometric assays (IFMA). J Urol 1995;154:1090, with permission.

change of serum PSA in ng/mL per year on repeated testing) was higher among men destined to be diagnosed with prostate cancer, even at a time when serum PSA levels could not distinguish between men with and without the disease (Fig. 88-8). For men with serum PSA levels between 4.0 and 10.0 ng/mL at 5 years before prostate cancer diagnosis, a PSAV of 0.75 ng/mL per year or greater had a specificity of 90% percent for distinguishing men with prostate cancer in the setting of BPH, and a specificity of 100% for distinguishing men with prostate cancer and no BPH. Not only has PSAV been shown to be higher among men with prostate cancer when compared to men without prostate cancer, but PSAV also has been found to be higher in men with high-grade and high-stage prostate cancer as compared with men with lower-grade and lower-stage disease.239,240 Furthermore, men with a PSAV above 2.0 ng/mL per year in the year before a diagnosis of prostate cancer were at an increased risk of prostate cancer death after surgical intervention when compared with men with a PSAV of 2.0 ng/mL per year or less.241 Even when PSAV was measured 10 to 15 years before prostate cancer diagnosis (when most men had PSA levels below 4.0 ng/mL), a PSAV less than 0.35 ng/mL per year was associated with a prostate cancer-specific survival 25 years later of 92% (with a 95% confidence interval of 84% to 96%), while a PSAV greater than 0.35 ng/mL per year was associated with a prostate cancer-specific survival of 54% (with a 95% confidence interval of 15% to 82%, P < 0.001). All of these data suggest that PSAV is a marker of lifethreatening prostate cancer and may be useful as part of the algorithm for determining the need for a prostate biopsy, rather than using absolute serum PSA levels alone.
20 18 16 14 12 10 8 6 4 2 0 20

Transrectal Ultrasound-Guided Prostate Biopsy
Transrectal ultrasound (TRUS) is not an accurate method for localizing early prostate cancer and is not recommended for use in prostate cancer screening. The primary role of TRUS in prostate cancer detection and diagnosis is to ensure accurate sampling of prostate tissue by prostate biopsies in men suspected of harboring cancer based on serum PSA levels and DRE.242 This is best accomplished by targeting peripheral zone lesions that appear hypoechoic by TRUS for biopsy, along with performing systematic sampling biopsies of areas without hypoechoic lesions in the prostate periphery. TRUS-guided prostate biopsies are performed routinely with an 18-gauge needle fired from a spring-loaded gun through a port mounted on the TRUS probe. Most commonly, in preparation for a biopsy procedure, men are administered a fluoroquinolone antibiotic and given a cleansing enema. Most urologists inject a local

PSA level (µg/L)

Controls BPH cases Local/regional Metastatic

Table 88-4 Probability of Cancer Based on PSA and Percent of FPSA Results
PSA (ng/mL)
0–2 2–4 4–10 >10

Probability of Cancer (%)
1 15 25 >50

FPSA (%)
0–10 10–15 15–20 20–25 >25

Probability of Cancer (%)
56 28 20 16 8

15

10 5 Years before diagnosis

0

Figure 88-8 • Longitudinal increases in serum prostate-specific antigen (PSA) levels in men with and without prostate cancer. BPH, benign prostatic hypertension. (From Fromter HB, Pearson JD, Metter EJ, et al: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215.)

FPSA, free prostate-specific antigen; PSA, prostate-specific antigen. Men with nonsuspicious digital rectal examination results, any age: % FPSA can stratify risk for men with PSA of 4–10 ng/mL. Data from Catalona WJ, Partin AW, Slawin KM, et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998;279:1542.

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anesthetic around the periphery of the prostate to reduce discomfort associated with prostate biopsy. Major complications, such as bleeding and/or infection requiring hospitalization, are rare, although hematuria and hematospermia are common sequelae of the procedure. The optimal biopsy technique, including the number and placement of biopsies for tissue procurement that will minimize the chance of missing a relevant cancer, remains controversial. Nonetheless, the best evidence available suggests that biopsies placed more laterally within the peripheral zone of the prostate may be important to exclude prostate cancer in men with elevated serum PSA values and a nonsuspicious DRE.

Screening for Prostate Cancer
There are legitimate concerns about population screening of asymptomatic men using PSA and DRE, despite the 30% decline in prostate cancer mortality between 1993 and 2003 (http://seer.cancer. gov/faststats/) that has been attributed in part to PSA testing.218 First, the lifetime risk (from age 0 to 90 years) of death from prostate cancer is 3%, and the lifetime risk of a diagnosis of prostate cancer is 17%. Thus, in the absence of markers that accurately identify those men who have life-threatening cancers, screening will result in the overdiagnosis (i.e., detection of a cancer through screening that would have otherwise remained clinically silent) and over-treatment of some men. In a recent observational study of men over age 65 years who were detected with low to intermediate risk prostate cancer in the PSA testing era, the findings suggested that 200 men would need to be treated over 12 years to prevent 1 prostate cancer death.243 Remarkably, even though competing causes of death reduce the benefits of screening and treatment among older men, rates of screening in the elderly are higher than the rates of screening among younger men.244 Second, screening for prostate cancer in asymptomatic men results in false-positive results prompting unnecessary prostate biopsies, and treatment of prostate cancer, by any means, can result in unwanted side effects—a poor tradeoff if the treatment results in no benefit in terms of years of life saved. Third, the costs of screening may not be justified if the societal harm of diagnosis and treatment are far greater than any health benefits obtained. All of these as yet incompletely addressed issues are considerations of any screening program and not unique to prostate cancer screening. The PLCO (Prostate, Lung, Colon, Ovary) Trial of the National Cancer Institute and the ERSPC (European Randomized Study of Screening for Prostate Cancer) are ongoing randomized trials designed to address whether or not prostate cancer screening reduces prostate cancer mortality. At this time, no organization endorses universal or mass screening for prostate cancer (Box 88-2). The U.S. Preventive

Services Task Force concluded that the evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA testing or DRE.245 This conclusion was based on good evidence that PSA testing can lead to the detection of prostate cancer at an early stage, but inconclusive evidence that early detection improves health outcomes. Specialty organizations such as the American Cancer Society (http://www.cancer.org/docroot/home/index.asp) and the American Urological Association recommend that prostate cancer screening with PSA and DRE be offered to all men over age 50 years and that the risks and benefits of screening be discussed with the patient. Although the value of PSA screening remains controversial, men who present for periodic health examinations should be made aware of the availability of the PSA test, so that they can make an informed decision about the need for routine screening. The general enthusiasm for screening in the United States suggests that most men will elect to be tested.246

Histopathology of Prostate Cancer
Microscopic analysis of prostate tissue by a surgical pathologist is needed for the diagnosis of prostate cancer, for determining prostate cancer stage after prostatectomy, and for histological grading, via the assignment of a Gleason score, to predict the behavior of prostate cancer (Table 88-5). Most prostate cancers are adenocarcinomas, although other types of cancers can appear. Most often, the diagnosis of prostate cancer is made using core needle biopsy specimens, which sample small amounts of prostate tissue. In many cases, needle biopsies contain only small numbers of prostate cancer cells among more plentiful noncancerous cells. Also, several prostate conditions, including acute, chronic, or granulomatous prostate inflammation, epithelial atrophy, and PIN, exhibit histological features that mimic some of those present in prostate cancers.247 Thus, prostate cancers can be difficult to recognize in needle biopsy specimens, and difficult to distinguish from other prostate abnormalities. Most experienced prostate pathologists use a combination of architectural, cytological, and ancillary findings to make a diagnosis of prostate cancer on needle biopsy.247–249 In addition, because normal prostate glands, but not glands present in prostate cancers, contain basal epithelial cells, immunohistochemical staining for basal epithelial cell markers, such as cytokeratins K5 and K14, can be used to help distinguish benign from malignant glands in prostate tissue samples. Also, immunohistochemical staining for AMACR, a prostate cancer biomarker discovered through cDNA microarray transcriptome profiling, can aid in prostate cancer diagnosis.168,170,250 Neither of these immunohistochemistry reagents perfectly distinguishes prostate cancer: the absence of basal epithelial cell markers is not always diagnostic of prostate cancer, and AMACR expression is absent in some prostate cancers and present in PIN.247 For all of these

Box 88-2.

POPULATION SCREENING FOR PROSTATE CANCER

Table 88-5 Cancer-Specific Mortality Rates*
AGE (YR) Gleason Score
2–4 5 6 7 8–10

There is no proof yet that prostate-specific antigen (PSA) screening in asymptomatic men prevents prostate cancer deaths. Nonetheless, the use of serum PSA testing, along with digital rectal examination (DRE), to screen men for prostate cancer has been proven to detect prostate cancer at earlier stages. As a result, prostate cancers discovered by screening are more likely to be treated with curative intent via surgery or radiation therapy. The major concern about prostate cancer screening is the potential for overdiagnosis of prostate cancers that would be unlikely to pose a threat for morbidity or mortality. For these reasons, screening approaches for prostate cancer are still evolving, with the optimal screening test (serum PSA vs. other molecular forms of PSA), the optimal screening population (younger vs. older men), and the optimal screening interval yet to be determined.

50–59
4% 6% 18% 70% 87%

60–64
5% 8% 23% 62% 81%

65–69
6% 10% 27% 53% 72%

70–74
7% 11% 30% 42% 60%

*Probability of dying of prostate cancer within 15 years of diagnosis in men with clinical stage prostate cancer treated conservatively. Data from Albertsen PC, Hanley JA, Gleason DF, et al: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively from clinically localized prostate cancer. JAMA 1998;280:975.

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reasons, second opinion interpretations of prostate biopsy findings, especially when foci of atypical glands suspicious for cancer are identified, are often helpful. High-grade PIN, a lesion characterized by the proliferation of malignant-appearing prostate epithelial cells within the confines of otherwise normal glandular structures, is identified in about 5% of men subjected to prostate biopsies.251,252 The evidence that highgrade PIN is a likely precursor to prostate cancer includes the findings that (1) high-grade PIN is more commonly present in prostates that also contain prostate cancer; (2) high-grade PIN and prostate cancer both tend to arise in the peripheral zone of the prostate and often are directly contiguous; and (3) high-grade PIN and prostate cancer express similar biomarkers and share many somatic genome abnormalities.253,254 The notion that high-grade PIN lesions might be prostate cancer precursors has stimulated interest in possibly treating men with high-grade PIN to prevent prostate cancer.254 Unfortunately, the natural history of individual high-grade PIN lesions is not known. Furthermore, high-grade PIN lesions, which can be recognized only by sampling prostate biopsies, are not easily monitored. These limitations have hindered the use of high-grade PIN as a response surrogate for cancer prevention drug development. Because high-grade PIN is not currently treated, the major significance of the finding of highgrade PIN, in the apparent absence of prostate cancer, by prostate biopsy is that prostate cancer may have been missed by the prostate sampling strategy used for the biopsy procedure. As serum PSA screening was first introduced, men with an elevated serum PSA and high-grade PIN by prostate biopsy seemed to have as high as a 50% chance of having prostate cancer when subjected to repeat prostate biopsies. With more widespread adoption of serum PSA screening strategies, for men with an elevated serum PSA, the chance that a second set of prostate biopsies will detect prostate cancer after an initial diagnosis of high-grade PIN on a first set of prostate biopsies has fallen to 23% to 35%, only slightly greater than the 20% chance that repeat prostate biopsies will detect prostate cancer even in the absence of an initial diagnosis of high-grade PIN.255–257 Of interest, unlike prostate cancer, prostate inflammation, or BPH, PIN lesions are not thought to perturb prostate architecture enough to elevate the serum PSA. Recently, increasing attention has been afforded the notion that PIA lesions might be precursors to PIN and/or prostate cancer. Like PIN, PIA lesions tend to arise in the peripheral zone of the prostate, where prostate cancers arise, and some PIA cells acquire somatic genome alterations reminiscent of prostate cancer cells.93,258 Currently, men with PIA lesions are not subjected to any kind of treatment, and the presence of PIA on an initial prostate biopsy is not thought to predict the detection of prostate cancer on repeat biopsy. The major significance of PIA in regard to the diagnosis of prostate cancer by prostate biopsy may be the propensity for such lesions occasionally to exhibit features that mimic prostate cancer.247 The most commonly used approach to histological grading of prostate cancer is Gleason scoring.259 The Gleason grade refers to architectural prostate cancer patterns, numbered 1 (well-differentiated) to 5 (poorly differentiated). Because prostate cancers often are heterogeneous, Gleason scoring (sometimes referred to as the “combined” Gleason grade) is accomplished by adding the Gleason grade of the most abundant pattern to the Gleason grade of the second most abundant pattern (e.g., a Gleason score of 4 + 3 = 7). The Gleason score, when applied by an expert pathologist, is one of the best tools available for predicting the outcomes of men treated with radical prostatectomy or with radiation therapy; prostate cancers with Gleason scores of 8 to 10 are much more likely to recur after primary treatment than prostate cancers with Gleason scores of 2 to 6.260,261 Furthermore, for prostate cancers with a Gleason score of 7, Gleason 4 + 3 = 7 appears more correlated with prostate cancer recurrence than Gleason 3 + 4 = 7. One challenge presented by Gleason grading is the variability in Gleason scores assigned to the same prostate cancers by different pathologists.262,263 To address this challenge, Internet educational tools have been developed by expert pathologists

to improve the fidelity of Gleason scoring by community pathologists.264 Of note, since Gleason scoring applies pattern grades to the architecture of cancer within the prostate, metastatic prostate cancers detected by biopsies of metastatic deposits are not assigned a Gleason score.

Evaluation of the Extent of Prostate Cancer
The extent of prostate cancer is correlated with tumor stage, Gleason score (the sum of two Gleason grades), and serum PSA level.265 Nomograms, incorporating clinical stage, estimated using DRE findings, the serum PSA level, and the Gleason score, have been shown to be capable of predicting both prostate cancer extent (when compared to the pathological stage evident at the time of prostate surgery) and the long-term outcome following primary tumor treatment.266–268 D’Amico and associates268 have suggested that men with prostate cancer can be stratified into low-risk (stages T1c to 2a, serum PSA <10 ng/mL, and Gleason score of ≤6), intermediate-risk (stage T2b, or serum PSA of 10–20 ng/mL, or Gleason score of 7), and high-risk (stage T2c, or serum PSA >20 ng/mL, or Gleason score of ≥8) groups, reporting that the fraction of men free of prostate cancer 10 years after radical prostatectomy is significantly different for the risk categories: 83% of men with low-risk prostate cancer, 46% of men with intermediate-risk prostate cancer, and 29% of men with highrisk prostate cancer. When undertaken before initiating prostate cancer treatment, risk stratification of men with prostate cancer aids in counseling such men about the expected outcome of aggressive local prostate cancer treatment, providing estimates of the chance that local treatments might be curative.

Radiographic Imaging
Although CT scanning is used routinely by radiation oncologists for prostate cancer treatment planning, no imaging technique available today has been proven to add additional useful information when used to evaluate the extent of prostate cancer in men with low and intermediate risk disease.269 TRUS and MRI give the most accurate definition of prostatic architecture and anatomy, but current imaging technologies do not provide very precise assessments of cancer extent within the prostate or the presence of microscopic foci of prostate cancer that have escaped the confines of the prostate gland. Radionuclide bone scans detect metastatic prostate cancer in less than 1% of men with a serum PSA value less than or equal to 20 ng/mL and are not recommended for the initial evaluation of men with low or intermediate risk prostate cancer.270 Positron emission tomography (PET) has not yet been found to be useful in the evaluation of men with prostate cancer and has no place in the prostate cancer staging.271 New imaging technologies, including three-dimensional color Doppler, contrast-enhanced color Doppler, magnetic resonance spectroscopy, and high resolution MRI with magnetic nanoparticles, have great potential for improving the assessment of local and distant prostate cancer extent.269,272 Cross-sectional imaging of the pelvis, by CT scan or MRI, for the purpose of detecting lymph node metastases, and radionuclide bone scans for the detection of bony metastases, should be reserved for men with high-risk prostate cancer. 111 In-capromab penditide, a radioimmunoconjugate featuring a monoclonal antibody to an intracellular domain of prostate-specific membrane antigen (PSMA; ProstaScint, Cytogen Corporation) has been approved by the FDA for use in the evaluation of men for treatment of clinically localized prostate cancer. There is some evidence that when 111In-capromab pendetide immunoscintigraphy is used in combination with other pretreatment prostate cancer staging tools, the predictive value for presence of lymph node metastases increases.273 However, this scan is not being used routinely today for assessment of prostate cancer extent, in large part because of frequent difficulties in scan interpretation, and because of the lack of scan sensitivity, even among men with fairly high-risk prostate cancer.

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Serum Biomarker Assays and “Molecular” Staging
Increases in serum PSA and in serum prostatic acid phosphatase (PAP)274 correlate directly with the extent (stage) of prostate cancer disease. As described earlier, the serum PSA is a useful tool for the preoperative assessment of prostate cancer extent, especially when considered along with other pretreatment parameters. Radioimmunoassays for PAP appear more sensitive, but less specific, than enzymatic assays, when used to detect serum PAP as a marker of advanced prostate cancer. Several studies have documented a correlation between the presence of advanced prostate cancer and elevations of serum PAP.275–277 Elevated serum PAP values, and serum PAP levels in the upper half of the normal range, portend a high likelihood (>80%) of extra-prostatic cancer.276,277 However, normal serum PAP levels are not very predictive of the absence of extra-prostatic disease. For men thought to have clinically localized prostate cancer based on the results of serum PSA, DRE, and Gleason score, serum PAP testing rarely adds additional information. The use of serum PAP testing for prostate cancer staging has declined substantially, giving way to the use of serum PSA testing. “Molecular” staging for prostate cancer refers to the detection of circulating prostate cancer cells and/or cell fragments, either indirectly, by identifying mRNA species, such as those encoding PSA or PSMA, characteristically expressed by epithelial cells from the prostate,278 or directly, by recovering prostate cancer cells using centrifugation/immunostaining methods.279,280 To detect prostate lineage mRNAs or prostate cancer DNAs, polymerase chain reaction (PCR) approaches, capable of astonishing sensitivity, typically are used. Reverse transcriptate-PCR (RT-PCR) for PSA mRNA in the blood has been reported to be more predictive of pathologic prostate cancer stage when compared to other pretreatment predictors such as serum PSA and Gleason score,281 and to be an independent predictor of disease-free survival after treatment.282 However, as many as one in four men with localized prostate cancer who underwent radical prostatectomy for cancer confined to the prostate had “positive” RTPCR assays for PSA mRNA in blood specimens in one study.281 These men would be denied aggressive treatment if the presence of circulating prostate cells indicated the presence of distant blood-borne prostate cancer metastases. In another study, 7% of men without prostate cancer exhibited “positive” RT-PCR assays for PSA mRNA in blood.283 The relation between circulating prostate cancer cells, regardless of how they are detected, and the development of metastatic prostate cancer is not well understood, but is likely that the formation of metastatic prostate cancer deposits in bone and at other sites may be a relatively inefficient process, and that dissemination of prostate cancer cells into the bloodstream may be necessary, but not sufficient, for metastasis.278,284 Until the predictive value of a “positive” RT-PCR assay for PSA mRNA in the blood has been established for a cohort of men with long-term follow-up after treatment for clinically localized prostate cancer, the assay will remain a investigational test.

Box 88-3.

TREATMENT OF MEN WITH CLINICALLY LOCALIZED PROSTATE CANCER

Men with localized prostate cancer have several treatment options, including watchful waiting, radical prostatectomy, interstitial brachytherapy, and external beam radiation therapy. Age, life expectancy, and medical history, as well as prostate cancer prognostic factors, such as stage, Gleason score, and serum prostate-specific antigen (PSA), typically are used to guide treatment recommendations. For example, men with a life expectancy of less than 5 years and lowrisk prostate cancer (defined as stage T1 or T2, a Gleason score of 2–6, and a serum PSA value of 10 ng/mL or less) often are counseled to consider watchful waiting or radiation therapy, while men with a life expectancy of more than 20 years and low-risk prostate cancer might be offered radical prostatectomy or radiation therapy. Men with a life expectancy of more than 5 years and intermediate-risk prostate cancer (stage T2b to T2c, Gleason score of 7, or serum PSA of 10–20 ng/mL) usually are referred for radical prostatectomy or radiation therapy. Men with a life expectancy of more than 5 years and high-risk cancer (stage T3a to T3b, Gleason score 8–10, or serum PSA higher than 20 ng/mL) tend to be candidates for radiation therapy, administered along with adjuvant androgen deprivation therapy.

groups for prostate cancer recurrence after treatment, providing some guidance as to likely treatment efficacy. Age, comorbidity, and life expectancy also should be considered in treatment selection (Table 88-6). Some prostate cancers exhibit a very indolent natural history, progressing slowly to threaten symptoms or survival. Many older men likely die with such cancers rather than because of them. The increased use of serum PSA for prostate cancer screening and early detection, particularly if applied to older men, may tend to overdiagnose such cancers. In contrast, young, healthy men with more aggressive prostate cancers may benefit from early prostate cancer detection and definitive treatment. Since the mid-1980s, both surgery and radiation therapy for prostate cancer have improved dramatically, providing effective local control of cancer in the prostate while reducing the threat of side effects. At this point, the optimal treatment approach for men with localized prostate cancer who are appropriate candidates for surgery and radiation therapy has not been fully resolved. Comparisons between the treatment approaches remain difficult because there have been no randomized clinical trials testing differences in treatment

Table 88-6 Life Expectancy of Men (All Races) in the United States of America, by Age
LIFE EXPECTANCY (YR) Age (yr)
50 55 60 65 70 75 80 85

TREATMENT OF LOCALIZED PROSTATE CANCER
Selection of Treatment Approach
Men thought to have localized prostate cancer face a number of treatment choices, including watchful waiting, radical prostatectomy, interstitial brachytherapy, and external beam radiation therapy (Box 88-3). Not all of these treatment approaches are appropriate for every man with prostate cancer. The different treatment approaches tend to be associated with different potential side effects. Also, men diagnosed with prostate cancer may have other medical conditions that can increase the chance or severity of such side effects. Prognostic factors, including prostate cancer stage, Gleason score, and serum PSA, are used to stratify men into low-, intermediate-, and high-risk

1989
26.4 22.3 18.5 15.1 12.1 9.4 7.1 5.3

2000
27.9 23.8 19.9 16.3 13.0 10.1 7.6 5.6

Data from Arias E: United States life tables, 2000. Natl Vital Statistics Rep 2002;51:1–42.

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outcomes. Furthermore, historical data offer only limited assistance in choosing between surgery and radiation therapy because each approach has improved in the time since most men were treated in case series with long-term follow-up data, and because most men treated in the past with radiation therapy tended to be older, have more substantial comorbidities, and have more aggressive (i.e., higher stage and grade) prostate cancers. The 2007 National Comprehensive Cancer Network (http:// www.nccn.org) guidelines for the management of clinically localized prostate cancer reflect the need for consideration of both life expectancy and the risk for prostate cancer recurrence in making treatment recommendations. In these guidelines, men with a life expectancy of less than 5 years and low-risk prostate cancer (defined as stage T1 or T2, a Gleason score of 2 to 6, and a serum PSA value of 10 ng/mL or less) are recommended for watchful waiting or for radiation therapy, while men with a life expectancy of more than 10 years and low-risk prostate cancer would be recommended for radical prostatectomy or for radiation therapy. Men with a life expectancy of more than 5 years and intermediate-risk prostate cancer (stage T2b to T2c, Gleason score of 7, or serum PSA of 10 to 20 ng/ mL) also are recommended for radical prostatectomy or radiation therapy. Men with a life expectancy of more than 5 years and highrisk cancer (stage T3a to T3b, Gleason score 8 to 10, or serum PSA greater than 20 ng/mL) are recommended for radiation therapy and some sort of adjuvant androgen deprivation therapy, or, in certain specific cases, for radical prostatectomy. No adjuvant chemotherapy has yet been shown to benefit men with clinically localized prostate cancer.

Watchful Waiting (Conservative or Expectant Management)
Even when detected before widespread use of serum PSA for prostate cancer screening, the natural history of localized prostate cancer treated conservatively was characterized by slow progression of the disease, with few deaths within 10 years but a substantial risk of death at 15 years, especially for men with Gleason combined scores of 6 or greater.285,286 Thus, most men with life expectancies beyond 10 years are thought to be candidates for curative therapy. No long-term studies of conservatively managed patients with prostate cancers detected by serum PSA screening are available. However, several observations suggest that conservative management may be a very reasonable option for selected men with prostate cancers diagnosed after serum PSA screening. First, the lead-time for prostate cancer diagnosis using serum PSA screening has been estimated to be 6 to 12 years.216,287 Second, among men with palpable (stage T2) disease that was not detected using serum PSA screening, 8 years of followup were required to demonstrate an absolute difference of 7% in prostate cancer-specific survival in a randomized trial of surgery versus conservative management that showed an advantage for surgical treatment.288 Thus, only a small minority of men with palpable prostate cancer benefit from surgery at 8 years. For men diagnosed with nonpalpable prostate cancer via serum PSA screening, with a lead-time of 6 to 12 years, it seems unlikely that most men age 70 years and older will derive much benefit from aggressive treatment. Such men should be offered watchful waiting as an alternative to surgery or radiation therapy. In addition, some younger men who are thought to have small-volume prostate cancer also may not benefit from aggressive treatment. With the adoption of serum PSA screening, an estimated 20% to 30% of men detected to have nonpalpable prostate cancer (stage T1c) appear to have small-volume cancers (0.5 mL or less) that are not poorly differentiated.204,289 Given the long natural history of prostate cancer, and the high rates of prostate cancer overdiagnosis (i.e., detection of cancer that would not have been detected without PSA testing) with serum PSA screening, especially for older men, watchful waiting should be considered in selected men with nonpalpable,

serum PSA-detected, non-poorly differentiated (Gleason score of 6 or less) prostate cancers. Most watchful waiting approaches have involved periodic general follow-up with initiation of palliative treatment as needed for symptomatic prostate cancer progression or for the appearance of cancer metastases. However, the ability to use serum PSA as a biomarker for prostate cancer activity has led to newer approaches where older men who are thought to harbor small-volume prostate cancers are followed more closely, with initiation of aggressive treatment with curative intent if and when it becomes appropriate. The challenges for these approaches are to identify men with small-volume disease who may be candidates for such an approach, and to identify which triggers can be used to change the management strategy from conservative to curative. Epstein and coworkers204 have presented criteria for identifying men with small-volume cancers. In their analyses, if the serum PSA “density” was less than 0.15 and there were no adverse pathologic findings detected by prostate needle biopsy (Gleason score 6 or less, less than 3 biopsy cores containing prostate cancer, and no more than 50% involvement of any biopsy core with prostate cancer), at the time of radical prostatectomy, 79% of such men had tumors of 0.5 mL or less that were organ-confined and were not high grade.204 In contrast, if the PSA density was 0.15 or greater, or if any adverse needle biopsy findings were present (Gleason score 7 or higher, more than 2 biopsy cores containing prostate cancer, or more than 50% involvement of any biopsy core with prostate cancer), 83% of men had prostate cancers that were larger than 0.5 mL, cancers that were not confined to the prostate, or cancers that were high grade at radical prostatectomy. The predictive value of these criteria subsequently was confirmed in a prospective study.290 When the criteria were used to identify a cohort of men (median age 67 years) with small-volume prostate cancer for a watchful waiting program, featuring serial serum PSA determinations and DREs as well as yearly surveillance prostate biopsies, some 30% of the men followed for more than 1 year were found to have adverse findings on surveillance biopsies that prompted a recommendation for curative treatment.290 Nevertheless, 90% of the men found to have adverse prostate biopsy findings in this cohort still were thought to have curable prostate cancer when treatment was recommended.290 The absence of prostate cancer on subsequent surveillance biopsies was strongly correlated with an absence of adverse pathology findings on future surveillance biopsies, but serum PSA determinations (including “free” PSA and PSA “velocity”) were not helpful in predicting the future appearance of adverse pathology.290 Thus, watchful waiting, conducted with curative intent, may be a reasonable approach for selected men above age 65 years with a high likelihood of harboring small-volume prostate cancer based on serum PSA and prostate biopsy criteria.

Radical Prostatectomy
Radical prostatectomy is used to treat men with clinically localized prostate cancer who have a life expectancy of at least 5 years. Although there are not specific or universally accepted age limits for radical prostatectomy, the life expectancy of men above 70 to 75 years of age is low enough that few men in this age range undergo radical prostatectomy.291 Clearly, men with uncontrolled or acute medical conditions are not candidates for surgery. Previous pelvic surgery or radiation therapy, which can lead to increased complications, are relative contraindications to radical prostatectomy. Preoperative assessment of men for radical prostatectomy typically includes a history and physical examination, hematology studies, serum electrolyte studies (with a serum creatinine determination), a urinalysis, coagulation studies, and an electrocardiogram. Surgery for prostate cancer is usually delayed for 6–8 weeks after prostate needle biopsy to permit resolution of hematomata caused by the biopsy procedure. In anticipation of surgery, men avoid aspirin, nonsteroidal antiinflammatory agents, or high doses of vitamin E that might promote

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excess bleeding. Some men bank blood for possible transfusion if necessary. Anesthesia for radical prostate surgery has been provided using general, spinal, and epidural approaches; however most surgeons today prefer regional anesthesia, which has been reported to be associated with less blood loss and a lower risk for pulmonary emboli.292,293 The most common radical prostatectomy performed today uses a retropubic approach that has been perfected to better remove all cancer in the prostate and to better preserve anatomic structures essential for erectile function and urinary control.6,7,294 Other surgical procedures for removal of the prostate gland include radical perineal prostatectomy and laparoscopic approaches to radical prostatectomy.295–297 The radical retropubic prostatectomy proceeds via performance of a staging pelvic lymphadenectomy, division of puboprostatic ligaments, identification, ligation, and division of the dorsal vein complex to control blood loss, division of the urethra, identification and preservation of the neurovascular bundles needed for penile erection (unless wide excision of a neurovascular bundle is necessary for cancer control), division of the bladder neck and resection of the seminal vesicles, and construction of a urethrovesical anastomosis to best provide urinary continence.298 The most common intraoperative complication is hemorrhage, although blood loss greater than 1000 mL is uncommon for most procedures.298 Much less frequently, the obturator nerve can be injured during the pelvic lymphadenectomy, a ureter can be injured near the bladder, or the rectum can be injured during the dissection of the apex of the prostate gland. In the immediate postoperative period, complications include deep venous thrombosis and pulmonary emboli.299 The operative mortality (death within 30 days) for radical prostatectomy is around 0.2%.298

structures (the neurovascular bundles) visible at the time of radical prostatectomy. This revelation led Walsh and colleagues7 to propose a modification of the radical prostatectomy procedure to preserve the neurovascular bundles in an effort to maintain erectile function postoperatively. Wide adoption of this modification has led to improvements in sexual potency rates following radical prostatectomy. As many as 91% of young men (<50 years of age) with good preoperative erectile function and low-stage prostate cancers who undergo an anatomic radical prostatectomy with preservation of both neurovascular bundles can expect recovery of potency after surgery.310 Improvement in sexual function following surgery tends to occur gradually over at least 24 months or more.303,311 Poor recovery of erectile function after surgery is correlated with increasing age (75% of men 50–60 years of age, 58% of men 60–70 years of age, and 25% of men 70 years of age or older were potent after radical prostatectomy in one series), poor potency before surgery, advanced prostate cancer stage (with capsular penetration or seminal vesicle invasion), and excision of neurovascular bundles.310,312 Population studies have confirmed these predictors of erectile dysfunction after radical prostatectomy, with as many as 60% of men reporting impotence following surgery and some 42% reporting that poor sexual function was a significant problem.301 In the best case series, 86% of men were able to have erections sufficient for sexual intercourse by 18 months.303 Interposition grafts, from the sural nerve, have been used in attempts to repair nerves severed when wide excision of neurovascular bundles was required during radical prostatectomy, but the effectiveness of this procedure has been questioned.313,314 Many men use seldenafil citrate (Viagra, Pfizer, Inc.) to improve sexual function following radical prostatectomy.315

Urinary Continence after Radical Prostatectomy
Urinary incontinence rates after radical prostatectomy vary greatly in different reports, with incontinence rates as high as 31% for men in the general population who underwent radical prostatectomy and as low as 10% or less for men who underwent radical prostatectomy at centers of excellence.300–303 Some of the variation in reported incontinence rates may be attributable to differences in definitions of incontinence (stress incontinence versus more severe difficulties with urinary control), differences in the time after surgery when urinary continence was assessed (urinary control can continue to improve for as long as a year following surgery), and differences in whether incontinence was reported by treating surgeons in case series or by patients in survey questionnaires. However, surgical technique likely has significant consequences for urinary control following radical prostatectomy. Both the striated urinary sphincter musculature and smooth muscle surrounding the urethra can be injured during surgery.298 Postoperative strictures at the site of the vesicourethral anastomosis also can affect control of urination.304 Such strictures can be dilated, if necessary, to improve urination. Avoidance of such injuries, accompanied by modifications of the urethrovesical anastomosis, has led to improved urinary control rates by expert surgeons.305,306 In the best case series, as many as 95% of men are completely dry 2 years after radical prostatectomy, and as many as 98% of men report no significant urinary problems.303,307 Men with persistent or severe urinary incontinence after radical prostatectomy can be treated with periurethral collagen injections or with placement of an artificial urinary sphincter.308,309

Control of Prostate Cancer by Radical Prostatectomy
Radical prostatectomy is an effective means of treating localized prostate cancer. In a randomized trial (N = 695 men) comparing radical prostatectomy with watchful waiting, the odds ratio for death due to prostate cancer for men treated with surgery was 0.50 (with a 95% confidence interval of 0.27 to 0.91, P = 0.02)288 (Fig. 88-9). Following surgery, serum PSA levels should fall to undetectable levels. A persistently detectable serum PSA after radical prostatectomy most often reflects the presence of disseminated cancer, occasionally indicating an incomplete resection of prostate tissues. After the serum PSA has declined to an undetectable level following radical prostatectomy, subsequent detection of PSA in the serum always indicates prostate cancer recurrence, preceding clinically significant prostate cancer progression by as many as 6 years or more.316 Most modern case series examining outcomes of men with prostate cancer treated by radical prostatectomy feature the serum PSA as a surrogate biomarker for recurrence of prostate cancer. In such series, some 80% of men remain free of prostate cancer recurrence by 5 years following surgery.317–321 In multivariate statistical analyses, the risk of serum PSA recurrence after radical prostatectomy has been correlated with clinical stage, Gleason score in prostate biopsies, and serum PSA values, determined preoperatively, and with pathological stage and Gleason score in the resected prostate specimen, determined postoperatively.266,267

Radiation Therapy
Radiation therapy has been used in the management of prostate cancer for nearly a century. Following Roentgen’s discovery of the x-ray in 1895,322 and the isolation of radium by Pierre and Marie Curie in 1898,323 several pioneering physicians began treating prostate disorders, including prostate cancer, with radiation. In 1910, Paschkis and Tittinger inserted radium into the prostatic urethra with a cystoscope in what may be the first use of radiation for prostate cancer. Not long after, Hugh Hampton Young from Johns Hopkins

Erectile Function after Radical Prostatectomy
Before 1982, most men subjected to radical prostatectomy were rendered impotent by the procedure. At that time, Walsh and Donker6 meticulously assessed the anatomy of the nerves traversing the lateral surface of the prostate en route to the corpora cavernosa of the penis, discerning the close proximity of the nerves to vascular

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0.40 0.35 Cumulative hazard rate 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 1 2 3 4 Years
281 275
Radical prostatectomy Watchful waiting

5

6

7

8

A

No. at Risk Radical prostatectomy Watchful waiting

347 348

343 346

339 337

308 302

233 231

185 185

134 121

89 82

0.40 0.35 Cumulative hazard rate 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 1 2 3 4 Years
263 262
Radical prostatectomy Watchful waiting

Figure 88-9 • Results of a randomized clinical trial of radical prostatectomy versus watchful waiting. A, Cumulative hazard rates of prostate cancer death. B, Cumulative hazard rates of prostate cancer metastasis. (Data from Holmberg L, Bill-Axelson A, Helgesen F, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–789, with permission.)

5

6

7

8

B

No. at Risk Radical prostatectomy Watchful waiting

347 348

340 341

331 329

294 291

220 216

172 167

126 106

82 69

reported the relatively large experience of treating prostate cancer patients with urethral and rectal radium “applicators.”324 These and other early studies revealed that even when radiation was applied in this crude manner, it could improve symptoms and kill prostate cancer. However, treatment was technically difficult for the physician and uncomfortable for the patient. In 1928, the first report on the use of externally delivered low-energy kilovoltage radiation for prostate cancer was offered by Barringer.325 The associated dosimetry was not well worked out and, thus, men were treated until their skin turned red. These types of low-energy radiation machines were used until cobalt machines became available and provided the first opportunity to treat tumors more deeply seated in the body. The first reported series of prostate cancer patients treated with 60Co0 therapy was by George and associates in 1965 and featured men with unresectable disease.326 It was also during this time (beginning in the late 1950s) that the megavoltage linear accelerator was being developed at Stanford University.327 The pioneering work of Bagshaw, Kaplan, Del Regato, and others, ushered in the modern era of radiation therapy for prostate cancer.328,329

Now men with prostate cancer have several different radiotherapeutic options, each of which can be employed with very high precision and with great effectiveness. The integration of computer-based technology for the design of three-dimensional conformal treatment plans, and use of high-energy accelerators with sophisticated dynamic shielding, allows men with prostate cancer to be treated with high doses of radiation while at the same time sparing surrounding normal tissues. In addition, the development of permanently implantable radioactive sources, along with the use of real-time imaging and treatment planning, also has provided the opportunity for sophisticated prostate brachytherapy techniques resulting in safe and efficacious treatment of men with prostate cancer. Traditionally, men with prostate cancer referred for radiation therapy tended to be older, to be in poorer health, and to have higherrisk, more advanced tumors than those patients treated surgically. Consequently, results using less sophisticated radiation therapy techniques were less than optimal, raising concerns that radiation therapy might not be as effective as radical prostatectomy. However, with long-term results obtained across a broad range of patients, it is now

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clear that radiation therapy for prostate cancer provides excellent disease-free survival, comparable to radical prostatectomy for men at similar risk of prostate cancer recurrence. The following section provides a brief description of how men are evaluated and risk-stratified for radiation therapy, followed by a description of treatment techniques, and a review of treatment outcomes for men with low-, intermediate-, and high-risk prostate cancer. The use of radiation therapy to treat local prostate cancer recurrences after radical prostatectomy is also reviewed.

mL and 6% for patients with levels above15 ng/mL. The routine monitoring of serum PSA to detect cancer recurrence following primary treatment spurred interest in escalating radiation doses to improve cancer control.

Toxicity of Conventional External Beam Radiation Therapy
Dose escalation with conventional external beam radiation therapy has been limited by the toxicity of treatment (Table 88-7). Most men experience dysuria and/or diarrhea during the course of prostate cancer therapy, but these symptoms generally resolve weeks after completion of treatment. Long-term sequelae of conventional external beam radiation therapy (i.e., delivered without the use of conformal techniques) were reviewed in an analysis of 1020 patients treated in RTOG trials 75–06 and 77–06.339 The incidence of late grade 3 or 4 urinary complications, such as hematuria, cystitis, bladder contracture, or urethral stricture, was 7.7%, with surgical intervention needed for 0.5%. Grade 3 or 4 rectal complications, such as bleeding, ulceration, proctitis, rectal/anal stricture, or chronic diarrhea, were seen in 3.3%, with surgery for bowel obstruction or perforation needed in 0.6%. Notably, the risk of complications was significantly higher when doses greater than 70 Gy were administered by these nonconformal techniques. Data on the incidence of erectile dysfunction after external beam radiation therapy have been widely variable. Sexual function has many facets that are difficult to evaluate or quantify. A commonly used qualitative definition of sexual potency is the ability to achieve spontaneous erections sufficient for intercourse. While potency rates after radical prostatectomy have increased with use of nerve-sparing techniques, the mechanism of radiation-related erectile dysfunction appears unrelated to the neurovascular bundles. Zelefsky and colleagues340 specifically addressed this topic by performing duplex ultrasound studies before and after prostaglandin injection to stimulate erections in men with radiation-related erectile dysfunction. A diminished peak penile blood flow rate (<25 mL/min) was evident in 63% of such men, with abnormal distensibility of the corpora cavernosa in 32%. Thus, the primary mechanism of radiation therapyassociated impotence may be vascular damage rather than nerve damage. Fisch and associates341 demonstrated a correlation between incidence of erectile dysfunction post-radiation therapy and radiation dose to the vascular penile bulb. Men receiving more than 70 Gy to more than 70% of the bulb of the penis are at greatest risk of experiencing radiation therapy-associated erectile dysfunction. A steady decline in potency rates over time is characteristic for men treated with external beam radiation therapy. In a large series (N = 434) of men treated with radiation therapy at Stanford University, 86% of the men remained potent at 15 months after treatment, but

Conventional External Beam Radiation Therapy for Localized Prostate Cancer
For over three decades, external beam radiation therapy and radical prostatectomy have been widely used for the definitive management of clinically localized prostate cancer. Although there have been no large randomized trials in North America or Europe that have directly compared the two treatment modalities, retrospective comparisons are plentiful, but limited by the tendency of older men with higher prostate cancer to have been treated with suboptimal radiation doses and techniques. In general, the conventional techniques used standard radiation fields, based on bony pelvic landmarks, to define the region of clinical interest for a dose range of 65 to 70 Gy delivered to the prostate. Commonly, a four-field pelvic box with custom Cerrobend (Cerro Metal Products Company, Bellefonte, PA) blocking was used to treat the prostate, seminal vesicles, and proximal lymphatic drainage. These fields were treated to a dose of 45 to 50 Gy in 1.8- to 2.0-Gy fractions. The prostate, and sometimes the seminal vesicles plus a safety margin, were then boosted to 65 to 70 Gy. Cerrobend blocking was used to shield, if possible, the posterior wall of the rectum, anal canal, and any small bowel. In spite of its limitations, this version of external beam radiation therapy was fairly effective: although overall survival numbers generally were higher for men treated with radical prostatectomy (often younger and healthier men), cause-specific survival rates were not significantly different.330 In an analysis of pathologically staged men with stage A2-B prostate cancer treated as part of Radiation Therapy Oncology Group (RTOG) Trial 77–06, 5- and 10-year survival rates, 87% and 63%, respectively, were comparable to age-matched controls without prostate cancer.331 The prostate cancer-specific survival was 86%, which was similar the to outcomes of some surgical series.332,333 With the ready availability of serum PSA testing, current outcome comparisons focus on PSA as a marker of prostate cancer recurrence following primary treatment (“PSA relapse”-free survival). A rising serum PSA after radiation therapy for prostate cancer is correlated with the appearance of progressive or metastatic prostate cancer on further follow-up.334 Furthermore, the rate of serum PSA rise may help distinguish between a local or distant treatment failure. Men with slow rates of serum PSA increases are more likely to have local prostate cancer recurrences, whereas men with a rapid serum PSA rise appear more likely to have distant prostate cancer metastates.335 In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) issued a consensus statement establishing the definition of recurrence of prostate cancer following radiation therapy as three consecutive rises in serum PSA levels (“biochemical” treatment failure) with determination made at least 3 months apart.336 Before these criteria were formulated, treatment outcomes in different studies and case series were difficult to compare because of the lack of uniformity in defining treatment failure. Pretreatment serum PSA levels are particularly predictive of radiation treatment outcome. In a case series of men (N = 461) with stage T1-T2 prostate cancer treated at M.D. Anderson Cancer Center, 5-year PSA relapse-free survival rates for men with pretreatment PSA levels of less than 4 ng/mL, 4 to 10 ng/mL, 10 to 20 ng/mL, and more than 20 ng/mL were 91%, 69%, 62%, and 38%, respectively.337 In another study, Zietman and coworkers338 reported 4-year PSA relapse-free survival of 65% for pretreatment PSA level below 15 ng/

Table 88-7 Radiation Therapy Oncology Group Criteria for Late Morbidity after Radiation Therapy
Grade
1 2 3

Criteria
Minor symptoms requiring no treatment Symptoms responding to simple outpatient management, lifestyle not affected Distressing symptoms altering patient’s lifestyle Hospitalization for diagnosis or minor surgical intervention (such as urethral dilatation) may be required.

4 5

Major surgical intervention (such as laparotomy, colostomy, cystectomy) or prolonged hospitalization Fatal complication

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only 50% were potent 6 years later, and only 30% maintained erectile function for the remainder of their lives.342 Sildenafil administration resulted in improvement of erectile function in 74% of men with radiation therapy-associated erectile dysfunction in a study at Memorial Sloan-Kettering Cancer Center.343 Men who do not respond to sildenafil may respond to intracavernosal prostaglandin injections. Second malignancy after definitive radiation therapy for prostate cancer is uncommon. Using data from the Surveillance, Epidemiology, and End Results (SEER) program cancer registry, Brenner and coworkers344 compared second malignancy risks for men (N = 51,584) who received radiation therapy for prostate cancer from 1973 to 1993 versus the risks for men (N = 70,539) who underwent radical surgery during the same time period, finding a small but significant increase in second malignancy attributable to radiation treatment. The most common radiation-induced tumors were carcinomas of the bladder and rectum, and sarcoma. The absolute risk of second malignancy for men who were treated with radiation therapy was 1 in 290. For survivors more than 10 years after treatment, the risk increased to 1 in 70.

Three-Dimensional Conformal Radiation Therapy
The advent of CT-based simulation and treatment planning and the innovation of multileaf collimators in modern linear accelerators have allowed for increased precision and accuracy in radiation therapy. Three-dimensional reconstructions of acquired CT images are generated, and target volumes (e.g., prostate and seminal vesicles) are delineated. Critical structures (e.g., bladder and rectum) to be avoided also are contoured. Computerized treatment planning software allows the iterative process of designing beam arrangements that will deliver a prescribed dose to the regions of interest and minimize dose to a given volume of a critical organ. Target volumes and normal organs are visualized in three dimensions (permitting the so-called “beam’seye view,” a portrayal of the target area as if looking straight down the path of the radiation beam). Computerized multileaf collimators shape each individual beam to conform to the shape of the target in the beam’s-eye view. The treatment planning system generates a dose-volume histogram for a selected treatment plan, a graphic description of the relationship between dose administered and volume of an organ that is receiving a given dose (Fig. 88-10), which allows

an objective assessment of the anticipated performance of a proposed radiation treatment plan. Since these technologies became clinically available in the 1990s, they have been used in dose escalation studies in prostate cancer. The profound effect of radiation dose escalation on treatment outcomes for prostate cancer has been demonstrated through work from several institutions.345–348 Men with intermediate-risk prostate cancer (serum PSA values of 10–20 ng/mL) may benefit most from dose-escalation. However, in a large cohort of men (N = 1100) treated with three-dimensional conformal radiation therapy (3DCRT) at Memorial Sloan-Kettering Cancer Center, a significant benefit of dose escalation was evident regardless of the pretreatment PSA.347 Initially, men with prostate cancer were treated with conventional radiation dose levels of 64.8 to 70.2 Gy using 3D-CRT techniques, and then the radiation dose was increased to as high as 86.4 Gy. At a median follow-up of 60 months, PSA relapse-free survivals for men with low-risk prostate cancer treated to radiation doses of 64.8 to 70.2 Gy versus 81 Gy, were 77% and 98%, respectively.347 Men with intermediate- and high-risk prostate cancers also showed significant improvement. Will improved treatment outcomes from 3D-CRT, evidenced by reduced numbers of men with prostate cancer relapses detected as a rising serum PSA, result in improvements in disease-free survival, freedom-from-distant metastasis, or overall survival? A randomized dose escalation trial detected a substantial improvement in prostate cancer control rates for men with prostate cancer, especially men with a pretreatment PSA higher than 10 ng/mL (Fig. 88-11).345,349 This study involved the stratification of men (N = 305) with stage T1-T3 prostate cancer to undergo treatment to a total dose of either 70 Gy using conventional radiotherapeutic techniques, or to 78 Gy utilizing a six-field 3D-CRT boost after the delivery of an initial 46 Gy. Results revealed a freedom-from-PSA relapse of 64% and 70% at 6 years for the 70 Gy and 78 Gy groups, respectively (P = 0.03). Men who had a pretreatment PSA higher than 10 ng/mL were found to have the most significant benefit from radiation dose escalation, with freedom-from-PSA relapse rates of 62% for the 78 Gy arm and 43% for the 70 Gy arm (P = 0.01), a benefit not seen for men with a pretreatment PSA below 10 ng/mL. Overall survival was not significantly different between the two radiation doses, but a trend toward an improved freedom-from-distant metastasis was evident in men treated on the 78-Gy arm, 98% versus 88% at 6 years (P = 0.056).

Dose volume histogram 1.0 0.9 0.8 Normal volume 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1000 2000 3000 4000 5000 Dose (cGy) 6000 7000 8000

A

B

Figure 88-10 • Intensity-modulated radiation therapy (IMRT). A, A representative axial CT slice from a man with low-risk prostate cancer treated by using a seven-field IMRT plan. The isodose distribution is displayed. Dark inner line, prescription isodose curve. B, The IMRT treatment plan shown as a dose/volume histogram: the curves from left to right represent bladder, rectum, and prostate.

Prostate Cancer • CHAPTER 88
PSA ≤ 10 ng/mL
78 Gy 70 Gy

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1.0 0.9 Fraction free of failure 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 20
P=0.46

of previous transurethral resection of the prostate (TURP). Grade 3 hematuria appears in as many as 0.5% of men, with grade 2 hematuria in 13% of men treated to a dose of 75.6 Gy or higher and 4% of men treated to lower total doses. Urinary incontinence is rare following treatment with 3D-CRT (<0.2% with 2% in the setting of a prior TURP).352

Intensity-Modulated Radiation Therapy
Intensity-modulated radiation therapy (IMRT) equipment and treatment planning software have become increasingly available, with the technology attracting interest from both academic and community cancer centers for the treatment of a variety of malignancies. The largest experience with IMRT to date has been in the treatment of prostate cancer. Via inverse planning, IMRT allows identification of the region to be treated along with surrounding critical normal organs so that radiation dose and volume goals can be prescribed for each target and structure. The treatment planning software then derives an optimized dose distribution by modifying the number, orientation, and intensity of the beams across the designated volume. This is in contrast to 3D-CRT, where beam arrangement and field shapes must be designed manually to accomplish radiation dose-volume goals, a task that typically requires multiple time-consuming iterations. In a case series (N = 772) of men with clinically localized prostate cancer treated with IMRT at Memorial Sloan-Kettering Cancer Center, a reduction in late rectal toxicity was seen in comparison to 3D-CRT.353 Most of the men (698 of the 772) were treated to a total dose of 81 Gy while the remainder received 86.4 Gy. With a median follow-up of 24 months, actuarial rate of grade 2 or higher rectal bleeding at 3 years was 4%, and only 0.5% of men experienced any grade 3 rectal toxicity (no grade 4 rectal toxicity was seen). However, despite the increased conformality of incident radiation and the decreased bladder volumes receiving high radiation doses, there was no improvement in late urinary toxicity with IMRT versus 3D-CRT, with 15% of men suffering late grade 2 urinary toxicity. Because this may be the result of high-dose radiation to the urethra, decreasing urethral doses for men with prostate cancer limited to the peripheral zone of the prostate may be a means of reducing late urinary toxicity with IMRT, but better diagnostic imaging is necessary to identify men with such cancers. One concern with IMRT techniques, in general, is the potential for inadequate treatment at the margins of radiation fields with increasingly conformal radiation dose delivery. However, preliminary treatment outcome data obtained thus far with IMRT appear similar to those with 3D-CRT, with 3-year actuarial PSA relapse-free survival rates, using American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria, for men with low-, intermediate-, and high-risk prostate cancer of 92%, 86%, and 81%, respectively.353 It should be noted that planning target volume (PTV) definitions for IMRT often are the same as those used with 3D-CRT. If tighter PTV definitions are to be used, better prostate immobilization and localization techniques are likely needed. This strategy currently is being investigated in several centers with the use of electronic portal imaging (EPI), a real-time treatment set-up verification system, and of B-mode acquisition and targeting (BAT), an ultrasound-based real-time localization system.354

A

40 60 80 Months after radiotherapy PSA>10 ng/mL

100

1.0 0.9 Fraction free of failure 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 20
P=0.012
78 Gy 70 Gy

B

40 60 80 Months after radiotherapy

100

Figure 88-11 • Kaplan-Meier actuarial probability of relapse-free survival after radiation therapy for prostate cancer, stratified by radiation dose (78 Gy vs. 70 Gy). A, Men with favorable-prognosis prostate cancer (serum prostatespecific antigen [PSA] ≤10 ng/mL). B, Men with poorer-prognosis prostate cancer (serum PSA, 10 ng/mL). (From Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097– 1105.)

Toxicity of Three-Dimensional Conformal Radiation Therapy
While the use of 3D-CRT was intended to minimize the effects of high-dose radiation on normal tissues, increased late toxicities have been noted with escalating radiation doses used in 3D-CRT.348,350 In the Fox Chase case series, the 5-year incidence of grade 3 or 4 rectal toxicity at a dose of 75 to 76 Gy was 8%. However, after the anterior rectal wall was shielded to keep the dose to this region under 72 Gy, grade 3 or 4 rectal toxicity was evident in only 2% of patients. From the M.D. Anderson Cancer Center dose escalation case series, men who received more than 70 Gy to 30% or more of the defined rectal volume had a significantly higher risk of rectal toxicity.351 Zelefsky and colleagues350 reported a 1.2% actuarial risk of grade 3 or higher rectal toxicity by 5 years with 3D-CRT. Grade 2 rectal bleeding was seen in 17% of men who received 75.6 Gy or more as compared to 6% for men receiving 64.8 to 70.2 Gy. Furthermore, even if the rectum was completely shielded in each field above a dose of 72 Gy, grade 2 rectal bleeding was seen in 15% of men. As for urinary toxicity with 3D-CRT, urethral strictures have been observed in 1.5% of treated men, with a 4% incidence of stricture in men with a history

Brachytherapy
Prostate brachytherapy refers to the implantation of radioactive sources into the prostate under transrectal ultrasound (TRUS) guidance. In principle, brachytherapy offers an attractive means for radiation dose escalation and conformality in the treatment of clinically localized prostate cancer. Modern prostate brachytherapy techniques that use ultrasound or CT-based targeting, a perineal template for precise seed implantation, and computerized treatment planning

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A

B
Figure 88-12 • Interstitial brachytherapy for prostate cancer. A, Radiograph obtained after implantation of radioactive seeds. B, CT image showing radioactive seed location within prostate. (From Speight JL, Roach M III: Imaging and radiotherapy of the prostate. Radiol Clin North Am 2000;38:159–177.)

have gained in popularity over the past 15 years (Fig. 88-12). For the patient with prostate cancer, this option may be most convenient, allowing a rapid return to normal lifestyle and activity. A typical brachytherapy procedure is performed in 2 hours, often under spinal anesthesia, and does not require an overnight hospital stay. Before the procedure, an ultrasound or CT-based volume study is performed and a preplan is formulated, specifying three-dimensional seed distribution to deliver a prescribed dose to the prostate and a periprostatic margin. Typically, peripherally biased seed distributions provide a relatively lower dose to the urethra. In the operating room, using spinal or general anesthesia and with Foley catheter in place, the patient is placed in the dorsal lithotomy position, a TRUS of the prostate volume is registered to approximate the prostate volume obtained from a preprocedure study (some centers use real-time intraoperative treatment planning systems to make adjustments to optimize the dose distribution because the prostate volume may be slightly different from that of the preplan), hollow needles are guided

into the prostate through the perineum using a template, and radioactive sources are deposited in the prostate according to the plan as the needles are withdrawn (through use of the Mick applicator or with seeds strewn on ribbons with equal spacing). Post-treatment CT scans are then routinely done to evaluate the quality of the implant procedure.355 Thus far, every use of permanent brachytherapy for prostate cancer reported has been a retrospective analysis of a case series from a single institution. Comparisons among these series, or to results from external beam radiation therapy or radical prostatectomy, are fraught with difficulty due to the lack of uniformity in reporting of patient selection and treatment outcome criteria. Additionally, implantation techniques, isotopes, dosimetry, and operator experience vary widely from one prostate cancer brachytherapy series to the next. Many practitioners have recommended brachytherapy for men with low-risk prostate cancer, but have added supplementary external beam radiation therapy to brachytherapy for men with prostate cancer at higher risk for extraprostatic extension. Combinations of brachytherapy and external beam radiation therapy also have been advocated for use in all men with clinically localized prostate cancer.356 In 1999, the American Brachytherapy Society recommended that brachytherapy using radioactive iodine or palladium might be appropriate for men with prostate cancer of clinical stage T1-T2a, with a serum PSA of 10 ng/mL or less, and a Gleason score 6 or less, and that supplemental external beam radiation therapy should be added for men with higher risk disease.357 This recommendation was based in part on inferior outcomes reported for men with high-risk prostate cancer treated with brachytherapy.358 It is possible that favorable outcomes may be achieved even in some men with prostate cancer and some high-risk features through the use of generous periprostatic treatment margins at the time of implant and/or the use of supplemental external beam therapy.359–361 In the absence of a prospective randomized trial, the routine use of prostate brachytherapy in the treatment of clinically localized prostate cancer has been based on retrospective studies with varying follow-up time. Recently, treatment outcomes for more than 2500 men with prostate cancer, treated at 11 different institutions with permanent interstitial brachytherapy, were reported.362 The median follow-up for this group of men with stage T1 or T2 prostate cancer was 63 months, and all were treated with either 125I or 103Pd without use of hormonal therapy. Men with low-, intermediate-, and highrisk prostate cancer had 8-year actuarial PSA relapse-free survivals of 82%, 70%, and 48%, respectively, using ASTRO criteria. As in previous studies, the dosimetric quality of the implant was critical to outcome: for men in whom 90% of the prostate (D90) received 130 Gy or more, the 8-year PSA relapse-free survival was 93%, while for men in whom the prostate D90 was less than 130 Gy, the 8-year PSA relapse-free survival was 76%. Three other series have reported long-term results with brachytherapy.363–365 Ragde and associates365 reported 12-year treatment results from a group of men (N = 229) with T1-T3 prostate cancer who underwent 125I or 103Pd implantation. Men with low-risk prostate cancer (N = 147) in this case series were treated with brachytherapy alone, whereas men with high-risk prostate cancer (N = 82) received external beam radiation therapy followed by implant. The PSA relapse-free survival was 66% for men with low-risk prostate cancer and 79% for men with high-risk prostate cancer. In light of subsequent superior results in men with lowrisk prostate cancer treated with brachytherapy alone, a possible explanation for the poor performance of brachytherapy alone in this case series is that there has been significant refinement of technique and treatment planning since many of these men were treated. In another case series, men with low-risk prostate cancer treated in 1986–1987 exhibited a significantly worse progression-free survival than men treated in 1988–1990.364 The addition of supplemental external beam radiation therapy to brachytherapy remains somewhat controversial. Davis and coworkers examined the radial distance of extra-prostatic extension of prostate

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cancer and found it to be almost always 5 mm or less, which would be within a typical brachytherapy dose distribution.366 Thus, generous periprostatic margins in brachytherapy planning may obviate the need for supplemental external beam radiation therapy. Proponents of combination therapy point to the advantage of higher biologic doses and the ability to smooth out cold spots inherent with brachytherapy, the so-called “spackle effect.” Sylvester and colleagues367 recently reported a retrospective review of 232 men with clinically localized prostate cancer treated with either 125I or 103Pd brachytherapy and external beam radiation therapy administered before placement of the implant. At a median follow-up of 9.4 years, the biochemical relapse-free survival for the entire study group was 74%, with biochemical relapse-free survival for low-risk prostate cancer of 85.8%, for intermediate-risk disease of 80.3%, and for the high-risk group of 67.8%. These results compare favorably with all other surgical and/or radiation series with respect to long-term durable prostate cancer control. The RTOG is studying a similar combination therapy approach using brachytherapy and external beam radiation therapy; the results of this study will help to determine the incremental benefit of supplemental external beam radiation therapy in each risk group, as the addition of this therapy nearly doubles the cost of treatment.368 Relative contraindications to the use of prostate brachytherapy are large prostate size, preimplant obstructive urinary symptoms, history of prior TURP, and the presence of perineural prostate cancer invasion on prostate biopsy. Large prostate size has been perceived to be associated with a higher risk of urinary morbidity postimplant and with unsuitability for implant due to pubic arch interference. Men with a prostate volume of greater than 50 mL have been either counseled against brachytherapy or placed on androgen deprivation therapy in an attempt to reduce gland size. Nonetheless, the implantation of large prostates with radioactive seeds has been described with acceptable morbidity.369,370 In one case series, postimplant dosimetry quality was found to be independent of prostate size or use of androgen deprivation therapy.370 The use of the extended dorsal lithotomy position and steering of needles around the pubic arch increases the fraction of men that can be implanted with radioactive seeds by experienced radiation oncologists.371 The correlation of preimplantation obstructive urinary symptoms and postimplantation urinary obstruction is not yet resolved. Terk and associates372 reported that a high International Prostate Symptom Score (I-PSS), a measure of obstructive urinary symptoms, predicted postimplant urinary retention. With the use of α-blockers before and after implant procedures, others have noted no association between preimplant I-PSS and urinary obstruction.373 A prospective study examining preimplant urinary flow rate and postvoid residual, in addition to I-PSS, showed no association of obstructive urinary symptoms with postimplant urinary retention or long-term urinary function.374 TURP is thought to be a relative contraindication to prostate brachytherapy, because it has been associated with unacceptably high rates of urinary incontinence. This may be attributable to seed loading approaches that result in a high central dose to the TURP defect. However, by using a peripheral source loading approach to limit dose to the TURP defect to 110% of the prescription dose, the incidence of urinary incontinence may be reduced.375 Finally, because prostate cancers exhibiting perineural invasion have been shown to be associated with inferior outcome in radical prostatectomy series, this adverse prognostic finding will likely also be associated with inferior outcome from brachytherapy.376 Curiously, in one case series no difference in brachytherapy treatment outcome attributable to the presence of perineural invasion was evident.377 A phenomenon peculiar to prostate brachytherapy that deserves mention is the so-called “PSA spike.” With a time of onset between 12 and 30 months postimplantation, approximately one third of men with prostate cancer treated with brachytherapy will experience a transient increase in serum PSA.378 This spike may be due to radiation-associated prostatitis that compromises prostate architecture,

Table 88-8 Physical Differences Between 125 I and 103Pd Radioactive Seeds
125

I

103

Pd

Year introduced Photon energy (keV) Half-life (days) Initial dose rate (for monotherapy) RBE
RBE, relative biologic effectiveness.

1965 28 59.4 7 cGy/hr 1.4

1986 21 17 18–20 cGy/hr 1.9

permitting more PSA to appear in the serum. Such PSA spikes portend no worse long-term outcome. Another controversy for prostate brachytherapy concerns the choice of isotope and use of androgen deprivation therapy. The most common sources in use today are 125I and 103Pd (Table 88-8). Thus far, there have been no compelling data to support the superiority of one isotope or the other. It has been hypothesized that the higher initial dose rate of 103Pd might be advantageous for the treatment of cancers with a relatively low α/β ratio (more radioresistant) such as prostate cancer; however, retrospective data for prostate cancer have been inconclusive.379 A prospective randomized trial directly comparing 125I to 103Pd for prostate cancer brachytherapy is ongoing. Most of the experience with prostate brachytherapy has been with permanent low dose-rate (LDR) implants. Several centers have collected experience with temporary high dose-rate (HDR) implants for prostate cancer brachytherapy.380–382 Although this treatment approach is not widely used, the available results appear comparable to those of permanent brachytherapy for clinically localized prostate cancer. HDR approaches have a theoretical advantage over LDR brachytherapy for the treatment of cancers with a low α/β ratio that approximates that of normal tissue. That is, a higher biologically equivalent radiation dose (BED) with HDR implants could be delivered with similar rates of morbidity as compared to LDR implants. Therefore, HDR implants would seem to be ideal for prostate cancer. Further study is needed to validate this theory. Androgen deprivation therapy has been used with prostate cancer brachytherapy both to reduce the size of the prostate gland and to improve outcomes. Most prostate glands exhibit some decrease in volume after 3 months of androgen deprivation therapy, with an average 30% to 40% reduction and little further volume decreases.383 About 10% of prostate glands will show no volume reduction at all in response to androgen deprivation. Decreasing the size of the prostate may reduce pubic arch interference in selected men. Blank and coworkers384 reported that men treated with androgen deprivation therapy tended to have smaller prostates that required fewer seed implants. However, at this point there are no data to suggest that smaller prostate volumes correlate with reduced acute or late morbidity from brachytherapy. Furthermore, although prospective randomized trials have demonstrated improved survival in those men with locally advanced prostate cancer treated with external beam radiation therapy and androgen deprivation therapy, it is not clear that these results can be extrapolated to men treated with brachytherapy. A retrospective matched-pair analysis of men (N = 60) with prostate cancer treated at Memorial Sloan-Kettering Cancer Center showed no benefit for the addition of androgen deprivation therapy to brachytherapy for men with low-, intermediate-, or high-risk prostate cancers.385

Toxicity of Brachytherapy
The short- and long-term sequelae of brachytherapy for prostate cancer differ from those of external beam radiation therapy and

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radical prostatectomy. Kleinberg and colleagues386 described the morbidity outcomes of the early Memorial Sloan-Kettering Cancer Center experience with permanent transperineal brachytherapy, reporting that the most common side effects were nocturia and dysuria (80% and 48%, respectively, 2 months after implantation). By 12 months following implantation, these figures had declined (to 45% and 20%, respectively). Urinary retention is seen in 3% to 14% of men and usually lasts 1 week or less. The most bothersome late complications of prostate cancer brachytherapy are urethral stricture and urinary incontinence. Ragde and associates387 reported a 5.1% incidence of urinary incontinence in men treated with prostate cancer brachytherapy and followed for 7 years; each of the men with incontinence had a history of TURP. Urethral stricture developed in 14.4% of the men. Others also have seen an increased incidence of urinary incontinence in the setting of a history of TURP.388 In a cohort study of Medicare beneficiaries (N = 2124) who were treated with brachytherapy, urinary incontinence was noted in 6.6%, and bladder outlet obstruction requiring intervention was found in 8.3%.389 In a more recent report from the RTOG multi-institution prospective trial (RTOG 98–05) of definitive brachytherapy alone, 23% of the men experienced urinary toxicity of a grade greater than 2.390 Rectal morbidity after brachytherapy includes change in bowel habits, rectal bleeding or ulceration, and fistula. Kleinberg and coworkers386 reported that 25% of men treated with prostate cancer brachytherapy had a change in bowel habits within 2 months of implant. By 12 months postimplant, no patient had grade 2 or higher rectal symptoms. The 3-year actuarial incidence of rectal bleeding was 31% and the incidence of ulceration was 16%. With more operator experience, rates of rectal complications subsequently fell: an update of the Memorial Sloan-Kettering Cancer Center experience revealed only a 9% incidence of rectal bleeding.391 Among Medicare beneficiaries, rectal injury not requiring colostomy was reported in 5.1% of men treated with prostate cancer brachytherapy, while colostomy was required in 0.3%.389 Radiation proctitis was reported in 2.2%, fistula in 1.8%, and ulceration in 1.1%.389 Generally, late rectal complications have their onset within 3 years of implant. Conservative measures usually generally result in spontaneous resolution of bleeding. In the recent RTOG trial of brachytherapy for prostate cancer (RTOG 98–05), 5% of men suffered grade 2 bowel toxicity, and no man experienced long-term grade 3 or 4 bowel toxicity.390 As the popularity of prostate brachytherapy for clinically localized prostate cancer grew in the 1990s, a commonly cited advantage of the treatment modality was a lower incidence of treatment-associated erectile dysfunction compared with external beam radiation therapy or radical prostatectomy. Undoubtedly, this selling point tipped the scales in favor of brachytherapy for many men faced with selecting a treatment for early-stage prostate cancer. For instance, Stock and colleagues392 reported a 2 year potency rate of 94% after implant, while Wallner and associates393 reported a 3-year potency rate of 86%. Studies with longer follow-up, however, have shown a continued decrease in sexual potency over time. With more long-term follow-up in other case series, only 57% of men retained potency at 5 years.391 Even Stock and coworkers394 subsequently reported a 6year potency rate of 59% in their case series. Notably, their study found that 70% of men with normal erectile function before implant retained potency at 6 years, whereas men with “erectile function sufficient for intercourse” but suboptimal erections had only a 34% 6year potency rate. Using postimplant dosimetry studies, Merrick and colleagues395 demonstrated that dose to the penile bulb correlated with postimplant erectile dysfunction. In most men who retained potency, the dose delivered to 50% of the penile bulb was less than 50 Gy. This knowledge potentially may result in improved morbidity outcomes with technical attention to this dose threshold. Erectile dysfunction is not the sole complication of prostate brachytherapy

with the potential to affect sexual quality of life, however; there have been reports of hematospermia in 28%, orgasmalgia in 15%, and alteration in the intensity of orgasm in 38% of patients.396 These side effects tend to be transient in most men. Recently, health-related quality-of-life instruments have become available to evaluate morbidity outcomes for prostate cancer treatments. A prospective study of health-related quality-of-life outcomes in men treated with brachytherapy, external beam radiation therapy, or radical prostatectomy was recently reported.397 Men treated with external beam radiation therapy did not show significant changes in health-related quality of life following completion of treatment, whereas men treated with brachytherapy and radical prostatectomy had significant decreases in health-related quality of life within the first month following treatment. By 12 months after treatment, health-related quality of life had returned to baseline in each of the three treatment groups.

Proton Beam Radiation Therapy
Although proton beam radiation therapy is available only at a few centers worldwide, there has been interest in its use for prostate cancer. The unique physical properties of protons make them ideal for the treatment of disease in close proximity to critical structures. Specifically, protons deposit the majority of their energy at the very end of their linear tracks, a phenomenon termed the Bragg peak. The dose falls off very rapidly at depths beyond the Bragg peak, a feature that is particularly useful in the treatment of prostate cancer, to minimize rectal and bladder dose. Investigators from Loma Linda University reported their experience treating men (N = 1255) with T1-T3 prostate cancer.398 Men were treated with protons alone to 74 cobalt Gray equivalents (CGE) or with photons to 45 Gy followed by proton boost to 75 CGE. The median follow-up was 62 months, and the 8-year actuarial biochemical disease-free survival rate was 73%. In a recent prospective, randomized trial of 70.2 GyE versus 79.2 GyE (combination of photons plus protons) for men (N = 393) with stage T1b-T2b prostate cancer and a serum PSA below 15 ng/ mL, at a median follow-up of 5.5 years, 61.4% of the men treated with 70.2 GyE versus 80.4% of men treated with 79.2 GyE were free of biochemical treatment failure, supporting the concept that higher doses of radiation result in a statistically significant reduction in the risk of recurrence of localized prostate cancer.399

Adjuvant Endocrine Therapy and Radiation Therapy for Low-Risk Localized Prostate Cancer
Androgen deprivation therapy has been found to improve survival in randomized trials of men with high-risk prostate cancer treated with external beam radiation therapy (Fig. 88-13).400–402 The role of androgen deprivation therapy in men with low-risk prostate cancer is unknown. D’Amico and associates reported results of a large retrospective study (N = 1586) of men treated with 3D-CRT plus or minus androgen deprivation therapy for low-risk, intermediate-risk, and high-risk prostate cancer.403 In this study, the median radiation dose was 70.2 Gy and androgen deprivation therapy was used for 276 of the men for two months before radiation therapy, during treatment, and for two months after treatment was completed. With a median follow-up of 51 months, the 5-year PSA relapse-free survival for men with low-risk prostate cancer was 92% with the addition of androgen deprivation therapy versus 84% without (P = 0.09). Men with intermediate- and high-risk prostate cancer also faired significantly better when given androgen deprivation therapy. RTOG Trial 94–08, which completed accrual in 2001, has been designed to ascertain whether men with stage T1b-T2 prostate cancer and a serum PSA of 20 ng/mL or less benefit from the addition of “complete androgen blockade” given for four months before and concomitantly with external beam radiation therapy.

Prostate Cancer • CHAPTER 88
100 90 Overall survival (%) 80 70 60 50 40 30 20 10 0 0
O 81 50 N 206 207
Log-rank test P<0.0001, hazard ratio 0.51 (95% Cl 0.36–0.73)

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Radiotherapy alone Combined treatment

Biochemically defined disease-free survival (%)

Figure 88-13 • Kaplan-Meier estimates of survival for men with prostate cancer from a prospective randomized clinical trial comparing a combination of androgen-deprivation therapy (goserelin acetate for a total of 3 years with cyproterone acetate for 1 month) and radiation therapy versus radiation therapy alone. A, Overall survival. B, Relapse-free. O, number of deaths; N, number of subjects. (From Bolla M, Collette L, Blank L et al: Long-term result with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer [an EORTC study]: a phase II randomized trial. Lancet 2002;360:103– 106.)

1

2 3 4 5 6 Time since randomization (yrs)
177 183 No. of patients at risk 146 106 70 166 142 93 46 71

7

8

A

199 197

30 43

16 24

100 90 80 70 60 50 40 30 20 10 0 0
O 36 56 N 66 170
Log-rank test P<0.0001, hazard ratio 0.42 (95% Cl 0.28–0.64)

Radiotherapy alone Combined treatment

1

2 3 4 5 6 Time since randomization (yrs)
59 157 No. of patients at risk 50 29 17 138 116 76 9 50

7

8

B

64 169

4 26

3 13

Adjuvant Endocrine Therapy and Radiation Therapy for Intermediate- and High-Risk Localized Prostate Cancer
Men with intermediate-risk prostate cancer (clinical stage T2b, Gleason score of 7, or PSA of 10–20 ng/mL) fall at the break-point of defined prognostic subgroups in many case series reporting treatment outcomes, making treatment recommendations difficult. Although dedicated phase III trials evaluating the role and technique of radiation therapy with this group of men have not been performed, intermediate-risk men often are included in studies of radiation treatment for both men with low-risk prostate cancer and those with more advanced disease. Radiotherapeutic options for men with intermediate-risk prostate cancer include external beam radiation therapy, prostate brachytherapy, or a combination of both modalities. The need for adjuvant androgen deprivation therapy in this subset of men is debatable, but a potential benefit can be inferred from phase III clinical trials and single institution case series. One recent trial of a limited course of androgen deprivation combined with radiation (N = 206) for clinically localized prostate cancer (Gleason score > 7 or a serum PSA > 10 ng/mL or evidence of extraprostatic disease) randomized men to receive radiation therapy to a dose of 70 Gy alone

or 70 Gy radiation plus 6 months of androgen deprivation therapy. At a median follow-up of 4.52 years, men treated with the combination of radiation plus androgen deprivation had a significantly higher overall survival than men treated with radiation alone (actuarial 5 year survival = 88% vs. 78% respectively).404 High-risk prostate cancer (clinical stage T2c-T4, Gleason score of 8–10, or serum PSA > 20 ng/mL) usually is treated with androgen deprivation therapy in conjunction with radiation therapy. The optimal duration and sequencing of androgen deprivation therapy, however, remains to be determined. Brachytherapy, usually in conjunction with both androgen deprivation therapy and external beam radiation therapy, also has been used to treat men with high-risk prostate cancer.

Adjuvant Endocrine Therapy and Radiation Therapy for Locally Advanced Prostate Cancer
Combined modality treatment using androgen deprivation therapy in conjunction with external beam radiation therapy takes advantage of separate and noncompeting modes of cell death such that cells that can survive the insult of one modality cannot survive the other or the additive/synergistic properties of the two.405 Androgen deprivation

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therapy has been used along with radiation therapy for many years in an attempt to modify the outcome of men with stage C (T3) prostate cancer.406 Historically, the rationale for this treatment approach was that these men had an inferior outcome compared with men with earlier-stage prostate cancer treated with radiation therapy. In addition, the tumors often were quite bulky, and it was thought that a course of cytoreductive therapy might provide a more favorable geometry for external irradiation. However, the use of androgen deprivation therapy in combination with radiation was not universally accepted throughout the 1970s and 1980s. Radiation therapy techniques were improving, and the results from early case series exploring the benefit of androgen deprivation therapy before and/or during radiation therapy often were negative.407,408 In the early 1980s, two case series reported encouraging results with the use of androgen deprivation therapy and external beam radiation therapy to treat men with locally advanced prostate cancer.409,410 Pilepich and coworkers411 also found that men with histologically unfavorable prostate cancers who had been treated with androgen deprivation therapy and external beam radiation therapy as part of RTOG trial 75–06 exhibited similar disease-free survival and overall survival rates to those of men with more favorable prostate cancers who did not receive androgen deprivation therapy along with radiation therapy. More recently, phase III clinical trials have established the local control and survival benefits of androgen deprivation therapy given along with external beam radiation therapy for locally advanced prostate cancer. The advantage of androgen deprivation therapy before irradiation, as opposed to starting androgen deprivation therapy and external beam radiation therapy together, has never been established by a direct comparison. RTOG 86–10 was a randomized phase III clinical trial of external beam radiation therapy alone (standard treatment arm) versus neoadjuvant and concomitant total androgen suppression and external beam radiation therapy (experimental treatment arm).412 Eligible men had bulky (>25 cm2), locally advanced prostate cancer (stage T2b-T4, N0-N1, M0). Men randomized to receive total androgen suppression were treated with goserelin acetate, 3.6 mg, every 28 days and flutamide, 250 mg, three times daily for 2 months before the start of, and during, radiation therapy. Standard radiation techniques were utilized, with 45 Gy delivered to the pelvis followed by a 20- to 25-Gy boost to the prostate. Extended fields were used to treat the lymph nodes when they were involved. A total of 471 men were enrolled and randomized to one of the two treatment arms. Analysis of the trial results revealed that men treated with total androgen suppression and radiation had a significant improvement in local control at 5 years compared with those men treated with radiation only (P < 0.001). A recent update of this trial, with a median follow-up over 6 years, continues to report a statistically significant difference in the 5-year probability of local treatment failure (22% vs. 35%, P = 0.004) as well as an increase in both disease-free survival (33% vs. 21%, P = 0.004) and cause-specific mortality (23% vs. 31%, P = 0.05), when considering the entire group, in favor of combined treatment. In subset analyses, there also was an improvement in overall survival for those men with Gleason score 2 to 6 prostate cancer (70% vs. 52%, P = 0.015), in favor of combined treatment. This improvement in overall survival was not seen when evaluating all men in the study. There are several possible explanations. It is possible that there may not be an overall survival benefit for men when total androgen suppression is added in this fashion and/or in this patient population as a whole. However, it is important to note that this study was limited in that it did not routinely obtain serum PSA levels from all men before entry, a parameter now recognized to be an extremely important prognostic factor and indicator of disease extension. Therefore, it is likely that there were a large number of men with elevated serum PSA levels in the range commonly associated with a high risk for micrometastatic prostate cancer. The study also included men with node-positive disease, also recognized to be a poor risk factor, for which the value of any treatment modality to

overall survival can be debated. Nonetheless, this was an important study, performed in rigorous fashion, and revealing important and measurable benefits attributable to the addition of androgen deprivation therapy to external beam radiation therapy for these men with prostate cancer. The RTOG 85–31 trial also targeted men with locoregionally advanced prostate cancer, including men who had undergone radical prostatectomy and were identified at pathologic examination as being at high risk.402,413 The aim of this phase III trial was to evaluate the role of long-term adjuvant androgen suppression in men with highrisk prostate cancer. Men enrolled on the trial who underwent definitive radiation were those with clinical stage T3 (>25 cm2), or T1-T2 disease and radiographic or histologic lymph node involvement. Men were eligible after prostatectomy if prostate cancer with capsular penetration and positive surgical margins or with seminal vesicle involvement was found. A total of 945 evaluable men were enrolled and followed for a median of 4.5 years. Conventional radiation therapy techniques were used to deliver a total dose of 44 to 46 Gy to the whole pelvis with a 20- to 25-Gy boost to the prostate or postoperative prostatic fossa, for a total dose of 65 to 70 Gy. Androgen deprivation therapy was accomplished using goserelin acetate, 3.6 mg, monthly, beginning the last week of radiation therapy. Actuarial projections at 5 years revealed 84% of men receiving adjuvant androgen deprivation versus the 71% of men on the observation arm who remained without evidence of local recurrence (P < 0.0001). The corresponding figures for freedom-from-distant metastases and disease-free survival were 83% versus 70% (P < 0.001) and 60% and 44% (P < 0.0001). The 5-year survival rate for the entire population was 75% on the adjuvant androgen deprivation arm versus 71% on the observation arm (P = 0.52). However, in men with prostate cancers with a Gleason score of 8 to 10, a statistically significant difference in actuarial 5-year survival of 66% versus 55% favoring the adjuvant androgen deprivation arm was evident (P = 0.03). The most recent update of this trial with a median follow-up of 5.6 years confirmed the statistically significant improvement in both absolute and cause-specific survival for adjuvant androgen deprivation given with external beam radiation therapy.413 Bolla and colleagues400,401 published results of the European Organization for Research and Treatment of Cancer (EORTC) 22863 trial. This phase III trial enrolled 415 men with stage T3-T4 prostate cancer of any grade or stage T1-T2 World Health Organization (WHO) grade 3 prostate cancer with no evidence of nodal or metastatic disease. Men were randomized to receive external beam radiation therapy alone (control arm) or androgen deprivation therapy plus external beam radiation therapy (experimental arm). Androgen deprivation consisted of oral cyproterone acetate, 50 mg, three times daily for 4 weeks before radiation and goserelin acetate, 3.6 mg, started on the first day of radiation and continued every month for 3 years. Radiation therapy was delivered as 50 Gy to prostate and regional lymph nodes, followed by a 20-Gy boost to the prostate, for a total prostate dose of 70 Gy. A total of 401 men were studied, with a median follow-up of 45 months. Overall survival at 5 years was 79% in the androgen deprivation therapy plus external beam radiation therapy arm and 62% in the external beam radiation therapy alone arm (P = 0.001). The local recurrence-free survival was 97% for men treated with androgen deprivation therapy plus external beam radiation therapy versus 77% for men treated with external beam radiation therapy alone (P < 0.001). The relapse-free survival was reported to be 85% for combined treatment and 48% for radiation alone (P < 0.001). The most recent update of this trial, at a median follow-up of 66 months, confirmed the durability of these initial results with 5-year overall survival of 78% versus 62%, favoring the androgen deprivation therapy plus external beam radiation therapy arm (P = 0.0002).401 Five year relapse-free survival also continued to favor the combination treatment (74% versus 40%). The RTOG 92–02 Trial, which completed accrual in 2000, is a phase III prospective randomized trial of androgen deprivation

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therapy plus external beam radiation therapy for men with locally advanced prostate cancer.414 This study compared the efficacy of short-term androgen deprivation, as was administered in RTOG 86–10, with that of long-term androgen deprivation, similar to that used in the EORTC 22863 trial. A total of 1554 men with locally advanced prostate cancer stage T2c-T4 with serum PSA below 150 ng/mL were enrolled in the trial and followed for a median of 4.8 years. All men received 4 months of goserelin acetate and flutamide, 2 months before and during radiation therapy. Men were then randomized to receive either no further therapy (short-term androgen deprivation) or to be treated with goserelin acetate for an additional 24 months (long-term androgen deprivation). The radiation dose was 65 to 70 Gy to the prostate and 44 to 50 Gy to the pelvic nodes. At 5 years, the long-term androgen deprivation group showed significant improvement in disease-free survival of 54% versus 34% (P = 0.0001), in clinical local progression of 6.2% versus 13% (P = 0.0001), and in freedom-from-distant metastasis of 11% versus 17% (P = 0.001). Five-year overall survival was not significantly different between the two treatment arms (78% versus 79%). Subset analyses were performed for direct comparison of this trial to both the EORTC 22863 study and RTOG 85–31. The first subset included men with highrisk prostate cancer defined by clinical stage T3-T4 or stage T2 with a Gleason score of 8 to 10 for comparison to the results reported by Bolla and associates.400,401 There was no overall survival difference (77% versus 80%) at 5 years but a significant advantage in diseasefree survival for long-term androgen deprivation of 90% versus 86% (P = 0.03). A second subset included all men with Gleason score 8 to 10 prostate cancer for comparison with results from RTOG 85– 31.415 Five-year overall survival (80% versus 69%, P = 0.02) and disease-free survival (90% versus 78%, P = 0.007) were significantly better with long-term androgen deprivation. The results of RTOG 92–02 have helped to establish the superiority of more protracted courses of androgen deprivation therapy for men with high-risk or locally advanced disease. The optimal sequencing of androgen deprivation therapy and radiation, however, has come into question. Currently it is not known whether the effects of androgen deprivation therapy on prostate cancer control were merely additive to the tumoricidal effects of radiation or were synergistic, providing an enhancement of tumor killing. Of interest in this regard, RTOG 94–13 Trial compared whole-pelvic radiation to prostateonly radiation and neoadjuvant and concomitant androgen deprivation therapy, given 2 months prior and 2 months during radiation therapy, to adjuvant androgen deprivation therapy, given after completion of radiation treatment for 4 months.416 A total of 1295 men with prostate cancer and an estimated risk of lymph node involvement of more than 15% (based on the equation “+ lymph node = (2/3) serum PSA + (Gleason score − 6) × 10)” were randomized to one of the four treatment arms. There was no difference in outcome for neoadjuvant versus adjuvant androgen deprivation therapy; however, this may be confounded by a lead-time bias because the follow-up time for men on the neoadjuvant arm is 2 months longer than on the adjuvant arm. When comparing all four treatment arms, there was a progression-free survival advantage for whole-pelvis radiation therapy plus neoadjuvant and concomitant androgen deprivation therapy arm versus the other three arms (61% versus 45%, 49% and 47% respectively; P = 0.005). So far, the follow-up (median 59.5 months) is too short to adequately detect a difference in overall survival.

rationale for prophylactic irradiation of pelvic lymph nodes is based on well-established surgical data that predict a rate of lymph node positivity, ranging from 5% to 50% for men with prostate cancer and one or more high-risk features.417 Since the advent of 3D-CRT and its progressive refinement into more accurate dose delivery techniques, the debate of whether or not to treat pelvic nodes has intensified. Because a potentially higher risk of complications may be associated with whole-pelvis irradiation, it would be considered desirable not to treat such a large radiation portal if it were not beneficial. The RTOG 77–06 Trial found no advantage to pelvic radiation for men with T1/T2 prostate cancer.418 However, this study included men estimated to be at low risk for lymph node involvement, including some proven to be pathologically lymph node-negative. RTOG 76–05, which randomized T3/T4 men to pelvis-only versus pelvic and para-aortic radiation therapy, also failed to detect an advantage for the extended radiation treatment field.419 Of note, this trial often has been misinterpreted as suggesting that there is no role for radiation of pelvic nodes in men with prostate cancer, although it really only examined the efficacy of para-aortic radiation. More recently, results of the phase III randomized RTOG 94–13 trial have provided further insight into the use of larger radiation fields,416 as described previously. In brief, the study featured a 2 × 2 factorial design comparing whole-pelvic radiation to prostate-only radiation (and neoadjuvant and concomitant androgen deprivation therapy to adjuvant androgen deprivation therapy). Whole-pelvis radiation therapy consisted of a conventional four-field technique with a minimum field size of 16 × 16 cm treated to a maximum dose of 50.4 Gy. An additional 19.8 Gy was then delivered to the prostate using a conedown boost technique. Prostate-only radiation therapy was limited to the prostate and seminal vesicles, with a maximum field size of 11 × 11 cm, to a total dose of 70.2 Gy. Four-year progression-free survival (PFS) was 56% for whole pelvic radiation therapy compared with 46% for prostate-only radiation therapy (P = 0.014), with no difference in overall survival. There also was no significant difference in acute or late gastrointestinal or genitourinary toxicities between the two treatment approaches.

Postprostatectomy Adjuvant Radiation Therapy
Pathologic features that portend a higher risk of local recurrence are common after radical prostatectomy. A positive surgical margin is associated with a risk of approximately 50% of prostate cancer recurrence.338,420–423 Other features associated with recurrence are extracapsular extension, seminal vesicle invasion, and Gleason score of 7 or greater. Several retrospective series have demonstrated improved PSA relapse-free survival with the addition of adjuvant radiation therapy following radical prostatectomy for men with these risk factors.424–426 In one study of men (N = 149) with pathologic stage T3N0 prostate cancer and an undetectable postoperative serum PSA, adjuvant radiation therapy was given to a median dose of 64.8 Gy to some men (N = 52), while the remainder (N = 97) underwent no further treatment.424 In a matched-pair analysis, the 5-year freedomfrom-PSA relapse rate was 89% in the adjuvant radiation therapy group versus 55% for treatment with surgery alone (P < 0.01). Three prospective randomized trials have been completed that tested the benefits of adjuvant radiation therapy versus observation following radical prostatectomy in men with prostate cancer and poor pathologic features. The EORTC has published clinical trial results revealing an improvement in biochemical relapse-free survival and locoregional progression-free survival for the men with pT3 tumors or pT2/T3 prostate cancer and positive surgical margins treated with adjuvant radiation therapy.401 In a second study targeting the same patient population conducted by the Southwest Oncology Group (SWOG), men with prostate cancer who received adjuvant radiation not only enjoyed better biochemical and local control, but also appeared likely to have better metastasis-free survival and overall survival, although these improvements were not yet statistically

Risk of Pelvic Lymph Node Involvement and Determination of Radiation Field Size
Considerable effort has been directed toward defining the optimal radiation treatment volumes for men with prostate cancer. Men with high-risk prostate cancer are of particular interest in this regard because there is no universally accepted standard of care for this group of men with a defined risk of pelvic lymph node involvement. The

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significant even at a median follow-up of 10 years.427 Nonetheless, men treated with adjuvant radiation therapy were less likely to need hormonal therapy at 5 years (10% vs. 21%, P < 0.001). Avoidance of androgen deprivation therapy is likely of significant clinical benefit, reducing or delaying significant morbidity, including hot flashes, diminished bone density, sexual dysfunction, cognitive dysfunction, and overall reduced quality of life. Finally, a third randomized trial comparing adjuvant radiation and observation after prostatectomy, which enrolled only men with pT3 disease regardless of surgical margin status, was reported by the German Cancer Study Group.428 As with the other two studies, men treated with adjuvant radiation experienced a superior biochemical relapse-free survival with median follow up of only 3.3 years. Thus, overall, data available today provide a convincing case for adjuvant radiation treatment after prostatectomy. However, it is clear that not all men benefit from such treatment. A more precise way to stratify men for adjuvant radiation therapy is needed: one such group may be men with positive surgical margins after radical prostatectomy.

Salvage Radiation Therapy after Radical Prostatectomy
Salvage radiation therapy refers to the use of radiation therapy postprostatectomy in the setting of recognized prostate cancer recurrence. As many as 27% to 53% of men who undergo radical prostatectomy for prostate cancer will have a detectable PSA within 10 years of surgery.316 Subsequently, approximately 25% of men who undergo radical prostatectomy will be treated with salvage radiation therapy for recurrent prostate cancer.429 In the setting of persistent or rising serum PSA following radical prostatectomy, it is important to rule out distant metastatic prostate cancer with bone scan, chest radiography, and CT scan of the abdomen and pelvis, prior to the initiation of salvage radiation therapy. Partin and coworkers430 correlated the rate of serum PSA rise with likelihood of local versus distant relapse after surgery. A serum PSA rise of 0.75 ng/mL/yr was associated with local recurrence. In 1999, an ASTRO consensus panel concluded that treatment of men with local prostate cancer recurrence after radical prostatectomy and a preradiation therapy serum PSA below 1.5 ng/ mL was more likely to be successful.431 In addition, doses above 64 Gy were recommended in the salvage setting. Several studies have demonstrated a Gleason score greater than 7 to be associated with a low likelihood of successful salvage after prostate cancer recurrence postprostatectomy.432,433 Cadeddu and colleagues433 reported no men free of PSA relapse treated with salvage radiation therapy after prostatectomy for prostate cancers with Gleason scores of 8 or above. Similarly, Song and associates432 found only 2 of 14 men with Gleason score of 8 or above to be prostate cancer-free at the time of analysis. These results indicate that men with recurrent prostate cancer and a Gleason score of 8 or greater are unlikely to benefit from salvage radiation therapy due to the likelihood of microscopic systemic prostate cancer metastases. However, the largest multi-institution retrospective series to date (N = 501 men) has provided a clearer view of the likelihood of benefit for various subgroups of men with local prostate cancer recurrence after prostatectomy.434 In this study, predictors of a poor response to salvage radiation included Gleason score of 8 to 10, preradiation PSA level higher than 2 ng/mL, PSA doubling time after prostatectomy of 10 months or less, negative surgical margins, and seminal vesicle invasion. Nonetheless, a significant fraction of men with one or more of these negative prognostic features still experienced a durable response to salvage radiation, particularly if the radiation was given prior to a PSA level of 2 ng/mL. Even for the group of men with the worst combination of prognostic features, a Gleason score of 8 to 10 and a preradiation PSA of 2 ng/mL or higher, salvage radiation produced a progression-free survival of 12% at 4 years. While these results hint at marked benefit to salvage radiation therapy after prostatectomy, the study itself was retrospective and may have been confounded by selection bias. Prospective studies are needed to deter-

mine definitively whether patients with one or more poor prognostic features derive benefit from salvage radiation. However, given the available data and considering the limited morbidity of this treatment, especially with IMRT, it is reasonable to consider salvage radiation for postprostatectomy patients with PSA recurrence regardless of prognostic factors. The role of androgen deprivation therapy concomitant with radiation therapy given as an adjuvant to surgery as salvage for prostate cancer recurrence following surgery has not been established. In the RTOG 85–31 Trial, a subgroup of men with pathologic T3N0 prostate cancer who underwent radical prostatectomy received adjuvant radiation therapy to a dose of 60 to 65 Gy and then were randomized to immediate androgen deprivation or androgen deprivation initiated at the time of PSA relapse.435 At 5 years, 65% of men treated with immediate androgen deprivation versus 42% of men treated with delayed androgen deprivation were free of PSA relapse. There are no prospective trials examining the addition of androgen deprivation therapy to salvage radiation therapy for local prostate cancer recurrence after prostatectomy. Taylor and coworkers436 reported a benefit to the addition of androgen deprivation therapy to salvage radiation therapy in a retrospective case series. In this series, adjuvant androgen deprivation therapy was given to men who received salvage radiation therapy for a median duration of 24 months. At 5 years, 81% of men receiving androgen deprivation therapy (versus 54% not treated with androgen deprivation) were free of PSA relapse. In contrast, Song and colleagues432 reported identical median disease-free survivals of 26 months for men treated with or without concurrent androgen deprivation therapy along with salvage radiation therapy for prostate cancer recurrence. The 1999 ASTRO Consensus Panel concluded that there was insufficient evidence to support routine use of androgen deprivation therapy with postprostatectomy radiation therapy.431

Toxicity of Postprostatectomy Radiation Therapy
In general, men receiving radiation therapy postprostatectomy experience little in the way of additional morbidity. The incidence of urinary incontinence does not seem to be increased, and erectile function does not seem to be worsened in men treated with adjuvant radiation therapy after prostectomy.437,438 Bastasch and associates439 reported that 100% of men who were potent after nerve-sparing radical prostatectomy remained potent after adjuvant IMRT. Despite these promising reports, side effects remain possible. Katz and coworkers440 noted that 19% of men experienced grade 2 or 3 genitourinary toxicity (hematuria or urethral stricture), and 12% of men experienced grade 2 bowel toxicity (with no grade 3 or higher toxicity noted), following salvage radiation with 3D conformal techniques.

SYSTEMIC TREATMENT OF METASTATIC CANCER
Natural History of Metastatic Prostate Cancer
Over the past decade, widespread and routine clinical use of serum PSA testing has changed not only screening and diagnosis of prostate cancer, but virtually all aspects of prostate cancer management.441,442 Current estimates of prostate cancer incidence by stage illustrate a major prostate cancer stage migration with a categorical shift toward less advanced cancer at the time of diagnosis. Similarly, outcome data from large cohorts and from contemporary large-scale prospective randomized clinical trials reveal that time-to-progression and survival from prostate cancer have changed substantially over the past decade. Previously collected outcome data must be scrutinized and considered in the context of more contemporary findings before making treatment recommendations or designing new clinical trials. For example, for men with newly diagnosed metastatic prostate cancer who have not received androgen suppression therapy (stage D2

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disease; sometimes referred to as “hormone-naïve”), randomized prospective trials conducted before the serum PSA testing era consistently have shown a median time-to-progression ranging from 12 to 18 months, and a median survival ranging from 24 to 30 months. Men with limited metastatic prostate cancer (appendicular skeleton and/or nonvisceral soft tissue metastases) tended to have a median survival of 52 months, whereas men with extensive bony metastases and/or visceral disease had a median survival of 24 months. Also, the distribution of men with prostate cancer according to extent of disease in the earlier studies typically included as many as 80% with extensive metastatic disease, while more contemporary studies often have less than 50% of men in this category. In a case series, the median metastasis-free survival of men with recurrent prostate cancer after radical prostatectomy at the Johns Hopkins Hospital who underwent routine yearly follow-ups, with serial serum PSA determinations and bone scans, from the time of biochemical relapse following surgery, was more than 6 years.316 One explanation for the relatively long survival of these men may be that the overwhelming majority who developed distant metastasis had limited metastatic disease, most likely due to an increased lead-time in diagnosis of metastatic prostate cancer resulting from intensive follow-up featuring serum PSA assays. This lead-time effect also is apparent in men who suffer prostate cancer progression following initial androgen deprivation therapy. The survival of men with androgen-independent (sometimes called hormone-refractory) prostate cancer in chemotherapy trials conducted over a decade ago ranged between 6 and 12 months, whereas in more contemporary studies, median survival has ranged between 15 and 20 months. Furthermore, a large and increasing proportion of men with metastatic prostate cancer who progress after initial androgen deprivation therapy are first identified because of rising serum PSA values without other evidence of prostate cancer progression. Not unexpectedly, survival for men with serum PSA increases as the only manifestation of prostate cancer progression is significantly longer than for men with evidence of radiologic and/or clinical progression (i.e., new findings on physical examination and/or cancer-related symptoms) in addition to rising serum PSA levels (Table 88-9).

Endocrine Approaches to Prostate Cancer Treatment
The dependence of prostate cancer cells on androgens for growth and differentiation has been well recognized for at least five decades443 (Fig. 88-14). Testosterone, produced by Leydig cells in the testes upon stimulation by LH, is converted to DHT by the action of 5αreductase.10 DHT, a more potent androgen than testosterone, binds to intracellular androgen receptors to activate the expression of target genes.11,12 Androgen deprivation therapy for prostate cancer involves maneuvers that reduce circulating testosterone to levels around or below levels present in castrated men (<50 ng/mL). Forced reduction of testosterone levels by castration, or via gonadal suppression, triggers a wave of apoptosis in both normal and neoplastic prostate cells, with little or no acute effect on nonandrogen target tissues, providing one of the most effective systemic palliative treatments known for solid organ cancers. Unfortunately, despite the magnitude of the initial beneficial treatment response, prostate cancer inexorably evolves to androgen-independence.21 As of yet, no therapeutic maneuver has been shown to prevent this sequence of progression.

Strategies for Androgen Deprivation
Currently, the general consensus is that a reduction in testosterone produced by the testes represents the best standard approach to androgen deprivation therapy for prostate cancer (Box 88-4). This can be accomplished by surgical removal of the testis (bilateral orchiectomy), by inhibition of the synthesis and release of pituitary gonadotropins by gonadotropin-hormone-releasing hormone analogues (GnRH or LHRH analogues and LHRH antagonists), or by the administration of pharmacologic doses of estrogens. Bilateral orchiectomy results in a rapid decline of testosterone to 5% to 10% of normal values and remains the treatment of choice for severely symptomatic patients. Although the suppression of testosterone production associated with LHRH analogues is comparable to bilateral orchiectomy, the nadir of serum testosterone levels is not reached until after 3 to 4 weeks of treatment. The LHRH analogues, highly potent LHRH agonists, initially stimulate LH release by the pituitary, but on chronic administration subsequently suppress LH and testosterone production.444,445 Thus, LHRH analog treatment also is associated with an initial rise in LH and in serum testosterone in virtually all patients. This brief elevation of testosterone levels has been reported to be associated with a flare of the prostate cancer, manifested by an increase in pain in symptomatic patients, or by more worrisome consequences of prostate cancer progression, including epidural cord compression and urinary obstruction.446 Longeracting depot preparations of LHRH analogues (administered monthly, every 3 or 4 months, or yearly) are available for clinical use. Clinical trials comparing bilateral orchiectomy to a variety of LHRH analogues have revealed comparable short- and long-term efficacy in patients with metastatic prostate cancer. Because of convenience, and the ability to avoid surgery, LHRH analogues have become the most widely used method for reducing serum testosterone. New LHRH antagonists have been introduced to achieve a reduction in serum testosterone without the brief flare associated with initial stimulation of pituitary gonadotropin secretion and testicular androgen production associated with LHRH analogues. These agents appear to be generally as effective as LHRH analogues, achieving a faster suppression of gonadal androgen production to the castrate range with comparable long-term sustained reductions of serum testosterone and no evidence of flare reactions.447 The efficacy of LHRH antagonists as treatments for prostate cancer, in comparison to bilateral orchiectomy or to LHRH analogues, has not been fully evaluated. Nonetheless, because LHRH agonists can lower the serum testosterone rapidly, like bilateral orchiectomy, these agents may well offer an attractive alternative to the LHRH analogs for the treatment of men with symptomatic prostate cancer for whom a flare reaction might threaten significant morbidity.

Table 88-9 Prognostic Factors for Men with Androgen-Independent Prostate Cancer Treated with Chemotherapy
Prognostic Factor
Performance status Baseline hemoglobin Liver metastases (metastasis to other visceral sites)

Significance
Definite: seen in virtually all studies Possible: seen in some studies (associations detected using multivariate analysis of uncontrolled clinical trials; not shown to be correlated with survival in randomized trials)

Baseline serum acid phosphatase, alkaline phosphatase, lactate dehydrogenase Time from initiation of androgendeprivation therapy to initiation of chemotherapy Response to chemotherapy (reduction in measurable cancer deposits and/or ≥50% decline in serum PSA for ≥4 wk) Baseline serum PSA Extent of disease (on bone scan) Continuation of androgendeprivation therapy
PSA, prostate-specific antigen.

Equivocal: more data needed

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Hypothalamus - PR
Leuprolide acetate Goserelin acetate GnRH agonists and antagonists

-

+

AR ER

GnRH

Pituitary

Progestational antiandrogens type I Cyproterone acetate - Megestrol acetate Pure antiandrogens Flutamide Bicalutamide Nilutamide

Prolactin

LH

LH-R
Cholesterol conversion inhibitors Cholesterol

Testosterone

G H nR

ER AR

-R

Estrogens Cholesterol

ACTH Cholesterol conversion inhibitors Glucocorticoids Ketoconazole Aminoglutethamide

Adrenal androgens

Adrenal glands Adrenal androgens AR

AR Testosterone T

DHT

Testis T Peripheral organs
5α-reductase inhibitors

Gene expression DHT Prostate

Figure 88-14 • Sites of action of different treatments that affect androgen action. ACTH, adrenocorticotropic hormone; AR, androgen receptor; DHT, 5α-dihydrotestosterone; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PR, progesterone receptor; T, testosterone.

The administration of pharmacologic doses of synthetic estrogens represented the earliest strategy for drug treatment of prostate cancer.448 Initial studies using diethylstilbestrol (DES) revealed a dose-dependent suppression of serum testosterone to the castrate range. When used for prostate cancer progression, DES provided clinical benefits comparable to those achieved with bilateral orchiec-

Box 88-4.

SYSTEMIC TREATMENT OF MEN WITH METASTATIC PROSTATE CANCER

Androgen deprivation therapy, usually accomplished via the administration of luteinizing hormone-releasing hormone (LHRH) agonists, remains the standard treatment approach for men with symptomatic metastatic prostate cancer. In certain cases, antiandrogens are used to prevent the flare reaction associated with initiating LHRH agonist treatment. With the widespread use of serum prostate-specific antigen (PSA) testing as a monitoring tool for prostate cancer relapse after surgery or radiation therapy, a major new challenge has confronted physicians who treat prostate cancer: many men with recurrent prostate cancer have no symptoms attributable to the disease and no evident metastatic cancer deposits that can be detected by radiographic imaging. Which of these men should be considered for treatment, and when should treatment be initiated? Although these issues have not been fully resolved, available data indicate that the time between surgery or radiation therapy and PSA relapse, the Gleason score at the time of primary treatment, and the PSA doubling time are predictive of the risk and timing of overt metastatic prostate cancer. Men at high risk for progressive metastatic prostate cancer are likely the best candidates for systemic treatment.

tomy. In a clinical trial conducted by the Veterans Administration Cooperative Urological Research Group (VACURG Study 1), men with prostate cancer treated with DES had a prostate cancer-specific survival comparable to men treated by bilateral orchiectomy.448,449 However, men in this study treated with DES (at a dose of 5 mg daily) suffered a high incidence of cardiovascular deaths.450 A subsequent clinical trial (VACURG Study 2) evaluated different daily doses of DES (0.2 mg, 1.0 mg, and 5.0 mg) versus placebo.448,449 Results suggested that the 1.0 mg daily DES dose was as effective as the 5.0 mg daily dose in terms of prostate cancer deaths, but was associated with a lower incidence of fatal cardiovascular complications. Subsequent analyses of men treated with DES at a daily dose of 1 mg revealed that testosterone often was not adequately suppressed, especially in younger patients with initially normal gonadal function.448,449,451 All of these findings led to the recommendation that DES, at a 3-mg daily dose (known to result in effective long-term suppression of testosterone comparable to bilateral orchiectomy), constituted an effective prostate cancer treatment despite the fact that the safety and efficacy of this DES dose, relative to lower or higher doses, remain untested in prospective randomized clinical trials. With the ready availability of LHRH analogues, synthetic estrogens are not currently used for prostate cancer treatment. Accumulated data from prospective randomized clinical trials in men with metastatic prostate cancer have revealed comparable efficacy of the various forms of androgen deprivation therapy, regardless of the outcome measure used, including rates of subjective and/or objective improvement, time-to-cancer-progression, or survival. However, in 1984, after leuprolide acetate, the first commercially available LHRH analog in the United States, was shown to be comparable to DES in treatment efficacy but associated with fewer serious complications, particularly congestive heart failure and thromboembolic events, DES was virtually abandoned in favor of LHRH analogues for the initial treatment of metastatic prostate cancer. Goserelin acetate, another commercially available LHRH analogue,

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also has been found to be comparable to bilateral orchiectomy in men with metastatic prostate cancer.

Anti-Androgens and 5a-Reductase Inhibitors
Anti-androgens compete with androgenic hormones for binding to the androgen receptor, blocking transcriptional activation of androgen target genes.21 Anti-androgens have been used as adjuncts to androgen deprivation therapy (so-called “complete” or “maximal” androgen blockage) and as single agents, in an attempt to preserve sexual function. However, anti-androgen monotherapy is not without side effects: approximately 50% of men treated with bicalutamide at a 150-mg daily dose develop gynecomastia, and although libido often can be maintained, fewer men remain potent.452 Bicalutamide monotherapy has been reported to provide similar survival outcomes to bilateral orchiectomy in men with nonmetastatic advanced prostate cancer (stage T3 and T4).452 Nonetheless, anti-androgens used alone appear inferior to androgen deprivation therapy in prospective randomized clinical trials in men with metastatic prostate cancer.452 The efficacy of anti-androgens used earlier in the natural history of prostate cancer (as adjuvant therapy for men with high-risk prostate cancer treated with radical prostatectomy or as treatment for men with a rising serum PSA after failure of cancer control with primary therapy) remains to be established. Flutamide, bicalutamide, and nilutamide are the nonsteroidal anti-androgens available currently in the United States. Although DHT is a more potent androgen than testosterone, 5α-reductase inhibitors have not been found to be particularly effective in the treatment of metastatic prostate cancer when used alone.183 A combination of the type 2 5α-reductase inhibitor finasteride and the nonsteroidal anti-androgen flutamide has been explored in clinical trials; the results obtained thus far do not suggest any striking advantage for combination treatment.453 Dutasteride, an inhibitor of both type 1 and type 2 5α-reductases, has not been fully tested against prostate cancer.

“Complete” Androgen Blockade
A substantial amount of basic research has been devoted to enhancing the understanding of critical mechanisms involved in the hormonal control of prostate cancer growth, and the emergence of androgenindependent prostate cancer.21 Prostate cancers contain populations of cancer cells that are heterogeneous with regard to androgen dependency and sensitivity. In the 1980s, Labrie and colleagues454,455 hypothesized that prostate cancer cells could adapt to the low levels of androgens present after androgen deprivation therapy, some produced by the adrenals, and support prostate cancer growth. To neutralize the effects of adrenal androgens, a combination of bilateral orchiectomy (or LHRH analogues) and a nonsteroidal anti-androgen was promoted as “complete” androgen blockade. The initial reports of the efficacy of this treatment combination prompted the conduct of a unprecedented number of clinical trials to assess the possible advantages of “complete” androgen blockade for men with metastatic prostate cancer: 7987 men with metastatic prostate cancer were entered onto 27 prospective randomized clinical trials comparing the efficacy of bilateral orchiectomy (or LHRH analogues) alone (monotherapy) to almost every possible combination of bilateral orchiectomy (or LHRH analogues) and anti-androgens.456 A comprehensive review of all studies reported thus far has revealed that 24 of the 27 studies reported no significant differences in survival, while only 3 demonstrated modest, statistically significant, improvements in favor of “complete” androgen blockade.456 Even for the occasional trial showing an apparent benefit for “complete” androgen blockade, there was a lack of consistency when considered in the context of other trials. For example, flutamide resulted in a survival advantage in one trial in combination with an LHRH analogue, whereas nilutamide did not; and nilutamide resulted in a survival advantage in one trial

in combination with bilateral orchiectomy, whereas flutamide did not. For each of the trials hinting at a benefit for “complete” androgen blockade, at least one, and as many as five, similarly designed trials found no evidence for the benefit. Taken together, the large collection of clinical trial data testing the efficacy of “complete” androgen blockade suggest that any potential benefit of “complete” androgen blockage is likely minimal and of negligible clinical significance. The first published large-scale prospectively randomized clinical trial of “complete” androgen blockade was the National Cancer Institute (NCI)-sponsored trial INT-0036.142 Men (N = 603) with stage D2 prostate cancer were randomly assigned to receive daily subcutaneous injections (1 mg/day) of leuprolide acetate and the nonsteroidal anti-androgen flutamide versus leuprolide acetate and placebo. The median overall survival with “complete” androgen blockade was 36 months, while the median survival with monotherapy was 28 months (P = 0.035). While the NCI INT-0036 trial clearly showed a benefit to the treatment combination, several explanations other than the “complete” androgen blockage hypothesis have been proffered to account for the trial results. One argument was that the difference in favor of combination treatment could have been an attenuation of the LHRH analogue flare reaction by the anti-androgen.457 In support of this contention, men randomized to receive combination treatment exhibited a trend toward more favorable pain control, improvement in performance status, and reduction in PAP, as compared to men treated with monotherapy, that was evident during the first 12 weeks of treatment.142 However, this notion is not supported by the results of another study that discerned no difference in survival between men randomized to receive leuprolide acetate with 2 weeks of flutamide treatment versus leuprolide acetate alone.458 A second argument for the superiority of combination treatment in the NCI INT-0036 trial was that noncompliance with the daily leuprolide acetate injection regimen might result in inadequate gonadal suppression, providing the opportunity for an advantage for the combination of daily leuprolide and flutamide. Because routine evaluations of serum testosterone were not included on the study, this argument could not be effectively excluded. To address these issues, a confirmatory trial, using bilateral orchiectomy rather than leuprolide acetate for androgen deprivation, was conducted (the NCI INT-0105 trial). Bilateral orchiectomy represents the optimal method of reducing testosterone for testing the “complete” androgen blockade hypothesis because it is not associated with a flare reaction and/or compliance difficulties. The NCI INT-0105 clinical trial prospectively randomized men (N = 1387) with stage D2 prostate cancer to treatment with bilateral orchiectomy with flutamide versus bilateral orchiectomy with a placebo141 (Fig. 88-15). The trial was designed to have sufficient power to detect a 25% or better advantage in survival attributable to combination treatment. However, at a median follow-up time of ∼50 months, and with 70% deaths occurring by the date of final analysis, the trial failed to detect a survival advantage to “complete” androgen blockade, finding a median survival of 33 months for men treated with combination therapy versus 30 months for men treated with orchiectomy alone (hazard ratio = 0.91 for combination treatment, with a 90% confidence interval of 0.81–1.01, P = 0.14). Although a slightly greater fraction of men in the bilateral orchiectomy ± flutamide trial (20%) than in the leuprolide ± flutamide trial (13%) had minimal metastatic prostate cancer, men in the two trials otherwise had very similar characteristics with regard to age and other demographic features.141,142 The EORTC conducted a clinical trial (N = 327) comparing goserelin acetate plus flutamide to bilateral orchiectomy in men most of whom had stage D2 prostate cancer.459–462 Although an initial analysis of trial results, at a median follow-up time of 30 months, had disclosed no significant survival differences, a later analysis showed a 7-month improvement in median survival (P = 0.04) in favor of combination treatment. The Danish Prostatic Cancer Group

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100 80 60 40 20 0 0 24 48 72 Months of follow-up
178 152 32 32

Flutamide Placebo

Overall survival (%)

96

No. of Patients at Risk Flutamide 697 Placebo 685

424 408

0 0

A
100 80 60 40 20 0 0 24 48 72 Months of follow-up 96
Flutamide, extensive disease Placebo, extensive disease Flutamide, minimal disease Placebo, minimal disease

100
Progression-free survival (%)

Overall survival (%)

80 60 40 20 0 0 24

Flutamide, extensive disease Placebo, extensive disease Flutamide, minimal disease Placebo, minimal disease

48 72 Months of follow-up

96

No. of Patients at Risk Flutamide, ext. disease 556 Placebo, ext. disease 539 Flutamide, min. disease 141 Placebo, min. disease 146

310 295 115 114

120 101 58 51

20 16 13 16

0 0 0 0

No. of Patients at Risk Flutamide, ext. disease 556 Placebo, ext. disease 539 Flutamide, min. disease 141 Placebo, min. disease 146

213 196 97 92

86 74 48 46

16 12 11 13

0 0 0 0

B

C

Figure 88-15 • Results of a randomized clinical trial of orchiectomy plus flutamide versus orchiectomy plus placebo for men with metastatic prostate cancer. A, Overall survival. B, Overall survival, stratified by extent of disease. C, Progression-free survival stratified by extent of disease. (Data from Eisenberger MA, Blumenstein BA, Crawford ED, et al: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339:10036–10042.)

(DAPROCA) conducted a virtually identical study, with the same treatment arms and approximately the same number of patients.463 This trial, which was completed at about the same time as the EORTC trial, revealed a longer overall survival with bilateral orchiectomy, although the difference was not statistically significant.463 The reason for the discordant results is not clear: both studies recruited similar patient populations. A combined analysis of both studies, undertaken to enhance statistical power, failed to detect significant differences between “complete” androgen blockade and bilateral orchiectomy.464 Several studies have examined the use of cyproterone acetate, a steroid anti-androgen, in combination with androgen deprivation therapy, and none reported significant survival benefits attributable to combination treatment.465–469 In fact, in a meta-analysis, there

appeared to be a trend toward decreased survival for men treated with cyproterone acetate as part of a “complete” androgen blockade regimen.470 The use of cyproterone acetate for “complete” androgen blockade is not recommended. In 1995, the Prostate Cancer Trialists’ Collaborative Group (PCTCG) reported the results of a meta-analysis from 22 randomized trials comparing “complete” androgen blockade to androgen deprivation alone for a total of 5710 men with prostate cancer471 (Fig. 88-16). To accomplish an intention-to-treat analysis, complete data for each man treated were requested from the investigators for each trial. Hazard ratios were calculated separately for every trial, based on the raw data, and then combined for all of the trials using log-rank statistics. This analysis revealed a 2.1% difference in survival in favor of “complete” androgen blockade (a 6.4% reduction in annual risk

Prostate Cancer • CHAPTER 88
100
Androgen suppression only Androgen suppression and antiandrogen

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80 Proportion alive (%) 8000 prostate cancer patients in 27 trials of antiandrogen (nilutamide, flutamide, or cyproterone acetate)

60

40 25.4% 20 23.6%
Absolute difference 1.8% (SE 1.8)

Treatment better by 0.7% (SE 1.1) logrank 2p>0.1

6.2% 5.5% 10

gens in the progression of metastatic prostate cancer is not established. On the other hand, new insights into the diverse molecular mechanisms associated with prostate cancer progression in the face of androgen deprivation therapy, with myriad alterations in androgen receptor function, activation of cell proliferation, loss of apoptosis, increase in tumor angiogenesis, modulation of tumor invasion and metastasis by the extracellular matrix, and maintenance of immune tolerance, have suggested that there is likely considerable heterogeneity in the androgen-independent prostate cancer phenotype.21 With all of these mechanisms possibly contributing to androgenindependent prostate cancer progression, it is not entirely surprising that the “complete” androgen blockade treatment approach proposed by Labrie and coworkers was not associated with a clinically significant survival benefit.454

0 0 5 Time since randomization (yrs)

Optimal Timing for Initiation of Androgen Deprivation Therapy
Although there is a general belief that immediate initiation of androgen deprivation therapy for men with metastatic prostate cancer may improve quality of life, there is no compelling evidence of a reduction in survival resulting from deferring treatment until symptomatic progression has occurred. Effects of the timing of androgen deprivation therapy on the survival of men with metastatic prostate cancer has become a more critical issue recently since an increasing number of men are recognized very early to have recurrent or metastatic prostate cancer because of increases in the serum PSA. The VACURG Study 1, testing the benefits of androgen deprivation therapy achieved by administration of DES, even though conducted decades ago, provides valuable insights into the effect of timing of androgen deprivation therapy on survival from metastatic prostate cancer. In the trial, men with advanced prostate cancer were randomized to initial treatment with bilateral orchiectomy plus a 5-mg daily dose of DES, bilateral orchiectomy plus a placebo, 5 mg DES per day alone, or placebo alone, with results indicating no significant differences in survival among the different treatment groups.448,449 However, men on the placebo arm who subsequently were crossed over to another treatment arm at the time of progression had a comparable survival to men initially treated on one of the other treatment arms, suggesting that immediate initiation of androgen deprivation therapy was without marked benefit. The Medical Research Council also evaluated immediate versus deferred androgen deprivation therapy for advanced prostate cancer.475 In their study, men with prostate cancer (N = 934 men; 434 men with and 500 men without prostate cancer metastasis) were randomized to either early androgen deprivation or to androgen deprivation initiated for symptomatic prostate cancer progression. Follow-up procedures were not strictly defined in the trial, relying on the discretion of the treating physicians, and 5% of the men who died of prostate cancer never received androgen deprivation therapy, while 10% or the men were not treated until they suffered a pathologic bone fracture or spinal cord compression. Using death from prostate cancer as a study endpoint for the men who had metastatic prostate cancer, no significant difference was detected between the early (65% prostate cancer deaths) versus late (69% prostate cancer deaths) treatment groups. In an initial report of trial results, the group of men with nonmetastatic prostate cancer appeared to have fewer deaths (32%) when treated with early androgen deprivation therapy than when treatment was delayed (49%). However, of the men in this group who died in the delayed treatment arm, 54% never received endocrine therapy. In a more recent report, reflecting greater followup time, no statistically significant differences were evident for men with prostate cancer treated with early versus delayed androgen deprivation therapy. The Eastern Cooperative Oncology Group carried out a randomized prospective trial of immediate androgen deprivation therapy versus observation in men (N = 98) who underwent radical

Figure 88-16 • A meta-analysis of survival from metastatic prostate cancer with maximal androgen blockade versus androgen deprivation alone. (From Prostate Cancer Trialists Cooperative Group: Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trial. Lancet 2000;355:1491–1498.)

of death) that was not statistically significant. The results were independent of the androgen deprivation strategy used or the anti-androgen selected for the combination. The Agency for Health Care Policy and Research (AHCPR; results published on the Web (http://www. ahcpr.gov/clinic/index.html#evidence; AHCPR report No.99-E012) also conducted a meta-analysis based on all published “complete” androgen blockade clinical trials. This meta-analysis found no difference in 2-year survival rates (hazard ratio = 0.970 with a 95% confidence interval of 0.866–1.087). Only 10 of the 27 trials reported 5-year survival data, in addition to the 2-year survival figures, and the combined results of these ten trials suggested a minimal 5-year survival difference in favor of “complete” androgen blockade of uncertain clinical significance (hazard ratio = 0.871 with a 95% confidence interval of 0.805–0.9887). Androgen deprivation therapy and anti-androgens are associated with a number of side effects, whether given alone or in combination, including hot flashes, loss of libido, loss of bone and muscle mass, fatigue, anemia, gynecomastia, and other symptoms. When the impact of such side effects were prospectively evaluated and compared to the beneficial impact of treatment, using a quality-of-life questionnaire, men treated as part of the NCI INT-0105 trial reported an improvement in quality of life attributable to treatment.472 However, the improvement was more pronounced for men treated with bilateral orchiectomy than for men treated with “complete” androgen blockade, with men receiving “complete” androgen blockade reporting a higher frequency of diarrhea and worsening emotional functioning.472 The quality-of-life benefit resulting from bilateral orchiectomy for treatment of metastatic prostate cancer appeared to be offset by the addition of anti-androgen treatment, primarily because of an increased incidence of side effects. A key feature of the “complete” androgen blockade hypothesis was that adrenal androgens might contribute to prostate cancer growth in the absence of gonadal androgens. In fact, Labrie and associates473,474 suggested that suppression of gonadal androgen production might be associated with an increased expression of enzymes, like 17β-hydroxysteroid dehydrogenase and 5α-reductase, in the prostate and elsewhere, capable of converting weak adrenal androgens (androstenedione and dehydroepiandrosterone) into testosterone and DHT, attributing as much as 30% to 50% of the intracellular pool of androgens to adrenal origin. At this point the role of adrenal andro-

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prostatectomy and were found to have lymph node metastases.476 After a median of 7.1 years of follow-up, a significant difference in survival, favoring immediate androgen deprivation therapy, was detected. This finding was surprising because a fairly large difference in survival was evident within a relatively short period of observation. In the trial, prostate cancer-specific survival in the observation group was 78% at 5 years. This is quite low compared to rates seen in men with prostate cancer and microscopic lymph node metastasis treated with radical prostatectomy alone. Furthermore, in a nonrandomized case series (N = 790) from the Mayo Clinic, representing the largest retrospective collection of data on men with lymph node-positive prostate cancer treated by radical prostatectomy, with almost three decades of follow-up, a survival advantage in favor of immediate androgen deprivation was seen only for men with prostate cancers that were diploid, and this survival advantage did not become apparent until 10 years after surgery.477 In that case series, men with aneuploid prostate cancers and lymph node metastases subjected to radical prostatectomy did not appear to benefit from immediate adjuvant androgen deprivation therapy. When men with diploid prostate cancers (N = 57) were treated similarly and followed for 10 years, there was also no improvement in survival attributable to adjuvant androgen deprivation therapy, but at 15 years of follow-up 14 men with diploid prostate cancers were alive, 12 who had received early androgen deprivation therapy and 2 who had not (83.2 ± 4.1% vs. 48.5 ± 13%). Thus, the finding of a benefit to early androgen deprivation therapy was based on the experience with 14 men of 790 men with lymph node-positive prostate cancer who underwent radical prostatectomy. Why are the ECOG study results, indicating a benefit for early androgen deprivation therapy, different from other data suggesting only a marginal benefit to immediate initiation of treatment? In an editorial that accompanied publication of the ECOG study findings, one concern raised was that this study never realized its projected accrual goal of 240 patients.478 This fact may be critically important, because the outcome of patients with prostate cancer nodal metastasis is extremely variable and difficult to predict. This problem could have been minimized if a sufficient number of men with prostate cancer were randomized to the different treatment arms. Unfortunately, the ECOG trial was relatively small and might have been affected by imbalances of factors that were not identified at the time the study began. In support of this concern, the fact that 50% of the men in the observation arm had progressed by 5 years, with 22% deaths, suggested that this control group most likely represented a collection of men with poor-risk and/or high-grade prostate cancers.476

other preclinical animal model studies have yielded conflicting results. When rats carrying a transplantable androgen-dependent prostate cancer were treated with immediate bilateral orchiectomy, with continuous high- or low-dose DES, or with intermittent high- or lowdose DES, rats treated with continuous androgen deprivation survived 38%to 50% longer than rats treated with intermittent androgen deprivation.480 These uncertainties from preclinical studies suggest the clinical use of intermittent deprivation therapy must be carefully evaluated in well-designed clinical trials before routine use in clinical practice. The efficacy and safety of intermittent versus continuous androgen deprivation is currently under scrutiny in clinical trials.

“Second-Line” Endocrine Treatment
During the past several years it has become evident that men suffering with prostate cancer progression after initial androgen deprivation therapy represent a heterogeneous group with varying degrees of residual sensitivity to hormonal manipulations. Kelly and colleagues described the “flutamide-withdrawal” syndrome, later found also to be associated with other anti-androgens, characterized by an improvement seen in 20% to 25% of men on discontinuation of antiandrogen treatment.481–483 This phenomenon occurred both for men who initially were treated with “complete” androgen blockade and for men who had received anti-androgens at some other time. The clinical observation of an “anti-androgen withdrawal” syndrome prompted a renewed interest in the biology of the androgen receptor in prostate cancer cells. A variety of AR alterations have been described in prostate cancers progressing after initial hormone manipulations, and AR mutations, encoding androgen receptors with altered ligand specificity, also have been detected for which anti-androgens can act as agonists.145,146,148 Among the agents reported to cause beneficial treatment responses (a drop in the serum PSA or other response) after adequate androgen deprivation treatment are bicalutamide (20%–24%), megestrol acetate (8%–13%), DES (26%–66%), ketoconazole with hydrocortisone (27%–63%), and glucocorticoids alone (18%–22%).484 PCSPES, a multi-component herbal mixture with estrogenic properties, was reported to produce treatment responses in men with androgenindependent prostate cancer.485 However, many PC-SPES lots were contaminated with prescription drugs, including DES, coumadin, and indomethacin, and as a result, PC-SPES is no longer available.486 Responses to second-line hormonal manipulations usually are brief, with median durations of benefit ranging from 3 to 4 months.

Clinical Approach to Men with AndrogenIndependent Prostate Cancer
Most men with androgen-independent prostate cancer demonstrate a rising PSA as the first manifestation of prostate cancer progression following androgen deprivation. In a prospective evaluation of men (N = 282) who had received first-line androgen deprivation therapy and suffered cancer progression, an increase in serum PSA levels occurred approximately 6 months before any other clinical (radiologic or bone scan) evidence of worsening cancer.487 However, for men initially treated with androgen deprivation based only on a rising serum PSA (and no clinical evidence of prostate cancer metastases), the time interval between subsequent serum PSA increases, indicating androgen-independent prostate cancer progression, and the appearance of clinically significant metastases is not known, although the serum PSA level at initial presentation, the rate of serum PSA rise, the Gleason score at the time of prostate biopsy or surgery, the clinical stage at presentation, and the response to androgen deprivation treatment are likely of prognostic significance.488 When the appearance of androgen-independent prostate cancer is suspected for men treated with androgen deprivation therapy, a determination of the serum testosterone (to ensure that androgen deprivation has been adequately accomplished), serum PSA, PAP, and alkaline

Intermittent Androgen Deprivation Therapy
Intermittent androgen deprivation therapy has the promise of reducing the impact of treatment-associated side effects while still maintaining some benefits from treatment. Additionally, findings from one group of animal model studies has suggested that intermittent reductions in testosterone levels, versus continuous androgen deprivation, might actually delay prostate cancer progression to androgenindependence.479 In these preclinical experiments, androgen-dependent cancer carried subcutaneously in mice was treated by bilateral orchiectomy once the tumors grew to 3 g. After the tumors had regressed 30%, they were transplanted into intact mice and then treated again by bilateral orchiectomy once the tumors had again grown to 3 g. This treatment cycle was continued until the cancer became androgen-independent. For comparison, mice carrying 3-g cancers were treated with a single cycle of androgen deprivation. Remarkably, androgen-independent cancer progression occurred 51 days after one-time bilateral orchiectomy versus 147 days for mice cycled through intermittent androgen deprivation. The mechanism for this difference, attributed to a superiority of intermittent androgen deprivation as cancer treatment, has not been fully elucidated. However,

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phosphatase, hematology and serum chemistry studies, radiographic imaging (including a bone scan), and a history and physical examination often are undertaken. For years it has been suggested that discontinuation of androgen deprivation in men who have not undergone bilateral orchiectomy may adversely affect prostate cancer progression and survival.436 The administration of exogenous testosterone and its derivatives is known to produce a significant prostate cancer flare with severe pain and neurologic, urologic, and coagulation complications in a small proportion of men.489–491 In a retrospective analysis of men (N = 205) with androgen-independent prostate cancer who were treated with chemotherapy, there appeared to be no difference with respect to prostate cancer progression and survival in men with prior bilateral orchiectomy as compared with men treated with gonadal androgen suppression that was discontinued at least 4 weeks before chemotherapy.492 Of course, many of the men treated with gonadal suppression likely never achieved normal serum androgen levels. Until the issue of whether discontinuation of gonadal suppression might compromise survival from androgen-independent prostate cancer has been resolved, maintenance of gonadal androgen suppression is recommended. Also, because stopping anti-androgen treatment at the time of prostate cancer progression can result in decreases in serum PSA levels, and in occasional symptomatic benefits or objective improvements in soft tissue and bone metastasis, men taking antiandrogens along with androgen deprivation therapy should be encouraged to discontinue these agents for at least 4 to 8 weeks before considering other treatment maneuvers.493

complications of metastatic prostate cancer, a single infusion of the drug prevented osteoporosis associated with a year of androgen deprivation therapy in a randomized controlled trial.505 Bisposphonate treatment has been associated with occasional but significant side effects, including renal dysfunction and osteonecrosis of the jaw.506

Bone-Targeted Radionuclides
The contribution of osteoblast action to the pathogenesis of prostate cancer bone metastases has stimulated interest in radioemitting calcium mimetics as treatments for progressive prostate cancer with skeletal involvement. 89Sr, given as 89SrCl, provides some pain palliation, without survival prolongation, for men with prostate cancer and symptomatic bone metastases.507 A β-emitter with a t1/2 of 50.5 days, 89 Sr accumulates in metastatic bone lesions. The most clinically significant toxicity of 89Sr is myelosuppression, with nadir blood counts 4 to 6 weeks after administration. This limits 89Sr therapy to men with adequate blood counts, precluding retreatment until after at least 6 months or so, and all but eliminating opportunities for other concurrent treatments. Nonetheless, in a provocative randomized clinical trial, men (N = 72) with androgen-independent prostate cancer and bone metastases who had responded to an induction chemotherapy regimen and received 89Sr in addition to doxorubicin enjoyed an improvement in survival when compared to men treated with doxorubicin alone.508 Newer bone-targeted radiopharmaceuticals, including 188Re-hydroxyethyldidene diphosphonate (188ReHEDP), which emits both β and γ particles and has a t1/2 of 16.9 hours, and 153Sm-ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), which emits both β and γ particles and has a t1/2 of 46.3 hours, may palliate painful bone metastases with less myelosuppression than 89SrCl.509,510

Bisphosphonates
Bone metastases, accompanied by destruction of bone architecture and accompanying pain, fracture, and spinal cord compression, arise commonly as part of prostate cancer progression. Furthermore, androgen deprivation therapy causes osteopenia/osteoporosis, with some 19.4% of men treated with androgen deprivation for at least 5 years reported to suffer pathologic bone fracture.494 Such skeletal complications, whether arising as a result of prostate cancer itself or of prostate cancer treatment, may accelerate life-threatening prostate cancer progression.495 Bisphosphonates promote bone ossification and have established benefits for the treatment of osteoporosis, hypercalcemia of malignancy, and cancer bone metastasis.496–499 For men with prostate cancer, almost any of the available bisphosphonates can treat osteoporosis associated with androgen deprivation. In one trial, men (N = 47) with prostate cancer and no bone metastases who required treatment with leuprolide were randomized to receive hormonal therapy alone or with pamidronate (60 mg every 12 weeks) and monitored for bone mineral density via dual-energy x-ray absorptiometry (DEXA) of the lumbar spine and proximal femur, and trabecular bone density via quantitative computed tomography of the lumbar spine.500 Results indicated that while androgen deprivation therapy decreased bone mineral density at all sites, the addition of pamidronate to hormone treatment prevented this complication. However, in the setting of established prostate cancer bone metastases, only zoledronic acid (4 mg every 3 weeks) has demonstrated benefit sufficient for regulatory agency approval. In a placebocontrolled trial for men with progressive prostate cancer and bone metastasis (N = 643), zoledronic acid therapy reduced skeletal complications by 22% (38% with zoledronic acid vs. 49% with placebo), with improvements in time-to-first skeletal complication and pain.501,502 The superiority of zoledronic acid over the other bisphosphonates for this indication may be a consequence of drug effects on both osteoblasts and osteoclasts.503 Preclinical models have hinted that bisphosphonate treatment of early-stage prostate cancer might reduce or delay the appearance of bone metastases, and clinical trials of bisphosphonates for the prevention of bone metastasis have been initiated.504 In addition to the efficacy of zoledronic acid in preventing skeletal

Treatment of Androgen-Independent Prostate Cancer
The tendency for prostate cancer to progress after androgen deprivation therapy poses the greatest threat of morbidity and mortality. For men with symptomatic metastatic prostate cancer despite adequate androgen deprivation therapy, randomized clinical trials have demonstrated that systemic treatment with mitoxantrone and corticosteroids tends to reduce bone pain and improve quality of life, but not to prolong survival.511–513 However, in 2004, two randomized clinical trials showed that docetaxel, alone or in combination with estramustine, improved the survival of men with metastatic androgenindependent prostate cancer in comparison to mitoxantrone and corticosteroids.514,515 As a consequence of these two clinical studies, the role of systemic chemotherapy in prostate cancer treatment is now well established, and vigorous clinical research is now ongoing to improve the outcomes achievable with taxane chemotherapy.516 In addition, new avenues of treatment, including prostate cancer immunotherapy, have progressed to advanced phases of clinical assessment (Box 88-5).

Docetaxel
Both paclitaxel, from the bark of the Pacific yew tree (Taxus brevifolia), and docetaxel, from the leaves of the European yew tree, disrupt microtubule function, required for chromosome segregation at mitosis in eukaryotic cells, and promote apoptosis.517,518 Nonetheless, the mechanism(s) by which these drugs act against prostate cancer cells is not clear. Prostate cancers tend to have very low growth fractions, as compared to many normal cells and most other cancers, yet prostate cancer cells remain sensitive to taxane drugs. One possibility is that microtubule function may be needed for other critical cell processes, such as for nuclear-cytoplasmic shuttling of critical regulatory proteins, essential for prostate cancer cell viability.519 Although both paclitaxel and docetaxel have shown promising activity against prostate cancer in early clinical trials, only docetaxel

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CHEMOTHERAPY FOR MEN WITH ANDROGEN-INDEPENDENT METASTATIC PROSTATE CANCER

Despite adequate androgen deprivation therapy, prostate cancer tends to progress to threaten morbidity and mortality. For men with metastatic androgen-independent prostate cancer, docetaxel chemotherapy, with or without estramustine, has been proven to prolong survival. Because the addition of estramustine to docetaxel produces an increase in cardiovascular side effects, without a clear benefit in prostate cancer survival, docetaxel, given every 3 weeks at a dose of 75 mg/m2, along with a corticosteroid, has become the standard systemic treatment for metastatic prostate cancer progressing after androgen deprivation therapy. New docetaxel combinations, with a variety of agents, are under active development in clinical trials.

has been subjected to large-scale trials testing effects on survival for metastatic androgen-independent prostate cancer. Docetaxel, given every 3 weeks (75 mg/m2) to men with prostate cancer in a small trial (N = 35), was associated with a 46% serum PSA response rate.520 In a series of clinical trials featuring weekly docetaxel (35–40 mg/m2), serum PSA response rates ranged from 41% to 64%.521–525 The addition of estramustine to docetaxel appeared also to produce significant benefits in early studies, both for serum PSA responses (45%–74%) and for measurable disease responses (11%–57%).526–530 One of the two large randomized trials featuring docetaxel (TAX327) assigned men with androgen-independent prostate cancer (N = 1006) to one of three treatment arms, directly comparing two different schedules of docetaxel (30 mg/m2 given weekly or 75 mg/m2 given every 3 weeks) and prednisone against mitoxantrone and prednisone514 (Fig. 88-17). In the trial, the median survival was 18.9 months for men treated with docetaxel (75 mg/m2 every 3 weeks) and prednisone, and only 16.5 months for men treated with mitoxantrone and prednisone, a difference that was statistically significant (P = 0.009). Weekly docetaxel treatment, with a median survival of 17.4 months, did not provide as compelling a benefit. Along with the survival improvement, docetaxel given every 3 weeks also resulted in a better serum PSA response rate (45% versus 32%) and better pain control (35% versus 22%) than mitoxantrone and prednisone

(P < 0.01). The other randomized trial (SWOG 99–16) targeted a similar group of men (N = 770) and compared treatment with docetaxel and estramustine to treatment with mitoxantrone and prednisone.515 Again, an improvement in median overall survival was evident for the docetaxel and estramustine regimen (17.5 months versus 15.6 months, P = 0.02). In both of the trials, docetaxel chemotherapy was associated with more side effects, including edema, gastrointestinal symptoms, neuropathy, and nail changes, than mitoxantrone treatment, and the combination of docetaxel and estramustine was also associated with a higher incidence of cardiovascular events. The additional complications, and uncertain benefit, accompanying the addition of estramustine to docetaxel has led to the establishment of docetaxel chemotherapy, given every 3 weeks, along with prednisone, as the standard-of-care for men with metastatic androgen-independent prostate cancer. To build on the success of docetaxel against metastatic androgen-independent prostate cancer, several docetaxel combinations—with calcitriol, bevacizumab, and a number of other agents—are being tested in phase 3 trials.516 In addition, docetaxel itself is being tested in the adjuvant therapy setting. In one phase 2 study, men (N = 77) at high risk for serum PSA recurrence following radical prostatectomy were treated with 6 cycles of docetaxel (35 mg/m2, days 1, 8, 15 every 28 days).531 With a median follow-up of more than 29 months, the median time-toPSA recurrence was 15.7 months.

Immunotherapy
The mechanistic basis for prostate cancer immunotherapy is that prostate cancer cells contain antigens that can be recognized by immune cells allowing for selective prostate cancer cell killing.532,533 T-cells respond to small peptides derived from intracellular proteins that are presented on specialized molecules at the surface of cancer cells. Prostate cancer cells can be recognized by virtue of containing new proteins, formed as a result of somatic gene mutations and translocations, or of expressing lineage proteins, representing prostate cell differentiation. Several such prostate lineage antigens, including PSA, prostate-specific acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), NKX3.1, and others, have become attractive targets for vaccine immunotherapy.534,535 Unfortunately, prostate cancer cells, and most other cancer cells, tend to evade destruction by immune cells by promoting antigen-specific tolerance, a state in which T cells that could kill cancer cells are inactive and respond poorly to stimuli, including vaccination.536 The major

100 Probability of overall survival (%) 90 80 70 60 50 40 30 20 10 0 0
No. at Risk Docetaxel every 3 wk Weekly docetaxel Mitoxantrone

Weekly docetaxel

Docetaxel every 3 wk

Mitoxantrone 3 6 9 12 15 18 Months 104 105 95 21 24 27 30 33

Figure 88-17 • Results of a randomized clinical trial of docetaxel, given at two different dosing schedules, and prednisone versus mitoxantrone and prednisone for men with androgen-independent metastatic prostate cancer. (Data from Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512.)

335 334 337

296 297 297

217 200 192

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vaccine strategies explored clinically have featured the delivery of prostate cancer antigens to antigen-presenting cells (APCs), such as dendritic cells (DCs) in the skin, which have the capability of stimulating specific T cells to attack prostate cancer cells. However, the clinical experience to date with prostate cancer vaccine immunotherapy has suggested that T-cell tolerance may constitute a significant barrier to treatment success: although measurable immune responses can be elicited by vaccination using a variety of vaccine strategies, these responses only occasionally are accompanied by disease responses.535 New immunotherapy approaches, featuring strategies to undermine T-cell tolerance, may increase the efficacy of vaccine approaches for prostate cancer.536,537 Two immunotherapy approaches have reached phase 3 clinical trials and merit attention. In one strategy, DC vaccines have been created using immature DC precursors recovered from blood mononuclear cells via leukapheresis and loaded with PA-2024, a recombinant protein consisting of PAP fused to GM-CSF.538,539 In phase 1 and 2 clinical trials of this immunotherapy approach, men with androgen-independent prostate cancer tolerated DC treatment well, exhibited immune responses to PA-2024 after vaccination, and showed a median survival of 29 weeks, with serum PSA responses in 3 men. Phase 3 trials of APC-8015, targeting men with asymptomatic metastatic androgen-independent prostate cancer, with a primary endpoint of objective time-to-progression, have been completed and submitted for regulatory agency approval. A second strategy has featured the use of vaccines created from prostate cancer cells, genetically modified to increase immunogenicity by secretion of GMCSF.540 The first clinical application of this strategy for prostate cancer involved genetic modification of autologous prostate cancer cells recovered at radical prostatectomy with GM-CSF cDNA.541 In a phase 1 trial (N = 8 men) of irradiated GM-CSF-secreting autologous prostate cancer cell vaccines, 7 of the vaccinated men exhibited delayed-type hypersensitivity (DTH) reactions against unnmodified autologous tumor cells and serum antibody responses to several proteins from prostate cancer cells. To overcome technical problems with generating sufficient numbers of vaccine cells from prostate cancer

cells recovered at the time of surgery, prostate cancer vaccine cells have been created by genetic modification of the prostate cancer cell lines LNCaP and PC-3 to permit high level secretion of GM-CSF.542 In phase 2 studies of this vaccine approach, men with androgenindependent metastatic prostate cancer have been treated with various doses and dose-schedules of GM-CSF-secreting LNCaP/PC-3 vaccines. After a median of 15 months of follow-up, the median survival had not been reached. Also, some 43% of the men had stable or improved bone scans. A phase 3 trial of this vaccine approach, randomized against treatment with docetaxel, for men with androgenindependent metastatic prostate cancer, has been started.

SUMMARY
Although mortality from prostate cancer has declined over the past few years, demographic trends, such as the general aging of the population, suggest that prostate cancer will remain one of the most common health threats for men in the developed world. Widespread implementation of prostate cancer screening using serum PSA has resulted in a changing character of prostate cancer at its initial presentation, with younger men being diagnosed at earlier stages than ever before. The use of serum PSA testing for disease activity monitoring has changed the character of prostate cancer throughout the rest of its natural history, with healthier men having less prostate cancer at later stages of the disease. These changes have put new demands on improving prostate cancer treatment, whether minimizing the morbidity of local prostate cancer treatment or increasing the efficacy of systemic prostate cancer treatment. In the very near future, large clinical studies of prostate cancer prevention, of the benefits of prostate cancer screening, of systemic adjuvant therapies given along with primary local prostate cancer treatment, of systemic chemotherapy for androgen-independent prostate cancer, and of a variety of new agents, will provide new insights of critical importance to prostate cancer care. Ultimately, new biomarkers, new imaging strategies, and new prevention and treatment approaches may hold the secret to eradicating prostate cancer morbidity and mortality.

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