Epidemiology of Prostate Cancer

Accumulated epidemiological 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 risk more characteristic of Asia.⁴³ African Americans in the United States have very high prostate cancer risk.⁴⁴ The geographic variation in prostate cancer incidence and mortality can best be explained by lifestyle influences, because Asian immigrants to North America typically adopt a higher prostate cancer risk.^47–47

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.⁴⁸ Red meat consumption was similarly correlated with prostate cancer risks in the Physicians Health Study⁴⁹ and in a large cohort study in Hawaii.⁵⁰ 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.^51,52 Ingestion of 2-amino-1-methyl-6-phenylimidazopyridine (PhIP), one of the heterocyclic amine carcinogens that appear in “well-done” red meats, leads to prostate cancer in rats.⁵³ Consumption of dairy products also appears to increase prostate cancer risk, an effect that may be more attributable to calcium intake than to dietary fat or protein.⁵⁴ In contrast, adequate consumption of vegetables and antioxidant micronutrients is accompanied by reduced prostate cancer risk. Consumption of tomatoes, which contain lycopene, and of cruciferous vegetables, which contain sulforaphane, may protect against prostate cancer development.^55,56 Antioxidant micronutrients, such as vitamin E and selenium, may reduce prostate cancer risk only when correcting dietary deficiencies: a large trial (SELECT) of supplementation with vitamin E and selenium to prevent prostate cancer failed to show a benefit.⁵⁷

Prostate Inflammation 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.⁵⁸ 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 is not usually associated with symptoms, the prevalence of prostate inflammation is not known, and the association with prostate cancer has been difficult to test.^59,60 A syndrome of irritative voiding symptoms and pelvic pain, perhaps attributable to inflammation near the prostatic urethra, is reported by some 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.⁶¹ Most episodes of symptomatic prostatitis are not clearly attributable to specific infectious agents. Even so, sexually transmitted infections do appear to increase prostate cancer risk.^62,63 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.^64,65 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 antiinflammatory drugs, and why RNASEL and MSR1, two of the 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 et al. provided the most compelling linkage of prostate inflammation to prostate cancer by proposing that a prostate lesion, termed proliferative inflammatory atrophy (PIA), might be a precursor to PIN and to prostate cancer (Figure 84-4).⁶⁶ 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.^58,67 The term PIA has been used to describe those focal atrophy lesions that contain proliferating epithelial cells, are associated with chronic inflammation, and are often located adjacent to PIN lesions and/or prostate cancers.⁶⁸ The epithelial cells in PIA lesions typically express high levels of stress-response polypeptides such as GSTP1, GSTA1, and cyclooxygenase 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.⁶⁹

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. 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. Provocative new data hint that PIA lesions appear to be more common in the prostate peripheral zone in men from high-risk prostate cancer regions than in men from low-risk prostate cancer regions. To better test the association of prostate inflammation and prostate cancer, perhaps new biomarkers of prostate inflammation, assayable in blood, urine, or prostate fluid, can be developed for use in epidemiology studies. In addition, polymorphic genes encoding regulators of immune responses will likely need to be systematically evaluated for prostate cancer risk associations. Ultimately, if the hypothesis is correct, prostate cancer risks may be reduced by therapeutically attenuating prostate inflammation.

Changes in Gene Expression in Prostate Cancers

Alterations in gene expression in prostate cancers have been catalogued using cDNA microarray technologies.131–142 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 androgen-independent progression. Hepsin, located at 19q11-13.2, encodes a transmembrane serine protease, expressed at high levels in many normal tissues.¹⁴³ 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.¹⁴⁴ 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.^145,146 Germline AMACR mutations lead to adult-onset neuropathy.¹⁴⁷ Immunohistochemistry studies, which have revealed that AMACR is occasionally 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.^146,148 The polycomb protein enhancer of zeste homolog 2 (EZH2), a transcriptional regulatory protein, is elevated in metastatic androgen-independent prostate cancer.¹⁴⁹ 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.¹⁴⁹

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.¹⁵⁰ Growth dysregulation accompanying the development of most human cancers tends to lead to cell proliferation in the absence of telomerase, and to shortened chromosome telomeres.¹⁵¹ Critically shortened telomere sequences may promote genome instability by increasing illegitimate DNA recombination.^152,153 Mice carrying disrupted genes needed for a functioning telomerase show increased numbers of cancers, especially when crossed to mice with defective p53 genes.¹⁵⁴ In the prostate, short telomere repeat sequences appear characteristic of cells both in PIN lesions and in prostate cancer.^157–157 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.¹⁵⁵

Digital Rectal Examination

In men with early-stage prostate cancers, physical findings, if present, are usually limited to an abnormal DRE, used for both screening 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 benign prostatic hyperplasia (BPH), and by prostatic stones. DRE has only fair reproducibility in the hands of experienced examiners.¹⁵⁸ When used alone for detection of prostate cancer, DRE misses from 23% to 45% of the cancers that are subsequently detected by prostate biopsies done for serum PSA elevations or for transrectal ultrasound (TRUS) abnormalities.^161–161 In addition, prostate cancers detected by DRE are at an advanced pathological stage in more than 50% of men.^162,163

The positive predictive value of DRE (the fraction of men who have prostate cancer if the DRE is abnormal) ranged from 4% to 11% in men with PSA levels from 0.0 to 2.9 ng/mL, and from 33% to 83% in men with PSA levels of 3.0 to 9.9 ng/mL or more.¹⁶⁴ When DRE and PSA are used in prostate cancer screening, detection rates are higher with PSA than with DRE and highest with both tests together.¹⁶⁵ Furthermore, a DRE abnormality tends to be associated with the presence of high-grade cancer.¹⁶⁶ Thus DRE and PSA are generally considered to be complementary tests and a prostate biopsy is usually recommended for men with an abnormality on DRE that is suspicious for prostate cancer regardless of the PSA level.

Serum PSA

PSA is a member of the human kallikrein gene family of serine proteases encoded by KLK3 located on chromosome 19.¹⁶⁷ A component 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 are generally higher in African Americans. Cross-sectional population data suggest that the serum PSA increases 4% per milliliter of prostate volume, and that 30% and 5% of the variance in PSA can be accounted for by prostate volume and age, respectively.¹⁶⁸

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).¹⁶⁹ 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 inhibitors, like finasteride and dutasteride, lower PSA levels by 50% after 12 months of treatment.¹⁷⁰ 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.

Serum PSA and Prostate Cancer Detection

The serum PSA value, along with the findings at DRE, correlate directly with the risk of prostate cancer at biopsy (Table 84-1). Furthermore, the PSA level at a young age anticipates the future risk of being diagnosed with prostate cancer decades later (Figure 84-9). Gann et al. first showed that the risk of a prostate cancer diagnosis, including the diagnosis of life-threatening disease, 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.^173–173 These observations may allow a more targeted approach to prostate cancer screening using a baseline PSA value to direct screening intensity.^174,175

In the early years of PSA testing, most clinicians used PSA as a dichotomous test (i.e., the PSA was “elevated” or not) with elevations triggering a prostate biopsy. However, data from the placebo arm of the Prostate Cancer Prevention Trial (PCPT¹⁷⁶), which accrued men with a serum PSA value <3.0 ng/mL, has suggested that there is no PSA cut-off level with both high sensitivity and high specificity for prostate cancer, and that virtually no level is low enough to exclude the presence of prostate cancer. Instead, serum PSA tests may be more appropriately thought of as measures of a continuum of prostate cancer risk, with the risk of cancer (and of high-grade cancer) rising directly with the PSA level, an observation first made by Gann et al. using a cohort population study design.¹⁷¹ In recent years, more emphasis has been placed on integrating several variables associated with the risk of prostate cancer (e.g., age, family history, race, DRE findings, prior biopsy results) to construct risk calculators for estimating the need for a prostate biopsy.^177,178 The future will likely see further integration of genome and other molecular biomarker tools in prostate cancer screening algorithms.

PSA “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.¹⁷⁹ Because benign prostate enlargement is a growth of the transition zone tissue, and because serum PSA levels are largely a reflection of transition zone volume in men with benign prostate enlargement, 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 distinction between those with prostate cancer and those with benign prostate enlargement.^180–183 PSA density is also directly associated with the presence of high-grade cancer on prostate biopsy, and is therefore useful for identifying those men less likely to have high-grade cancer most appropriate for active surveillance.¹⁸⁴

PSA “Velocity”

Carter et al., using frozen serum samples from an aging study cohort, demonstrated that a PSA “velocity” (PSAV; the rate of change of serum PSA in ng/mL per year upon repeated testing) of 0.75 ng/mL per year or greater had a specificity of 90% for distinguishing men with prostate cancer in the setting of benign prostatic enlargement, and a specificity of 100% for distinguishing men with prostate cancer in the absence of benign prostatic enlargement when PSA levels were in the range of 4.0 to 10.0 ng/mL (Figure 84-9).¹⁸⁵

The PSAV tends to be higher in men with high-grade and high-stage prostate cancer as compared to men with lower grade and stage disease.186,187 Furthermore, men with a PSAV above 2.0 ng/mL per year in the year before a diagnosis of prostate cancer appear to be at an increased risk of prostate cancer death after surgical intervention when compared with men with a PSA velocity of 2.0 ng/mL per year or less.¹⁸⁸ For PSAV 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 has been associated with a prostate cancer–specific survival 25 years later of 92%, compared with 54% with a PSAV greater than 0.35 ng/mL per year.¹⁸⁹ There is also a direct relationship between the number of times the PSAV exceeds a given threshold (e.g., 0.4 ng/mL per year), a concept known as “risk count,” and the risk of high-grade cancer.^190,191 Thus a continuously increasing serum PSA should raise the suspicion of high-grade prostate cancer if there is no other explanation for the rise.

Molecular Forms of PSA

PSA in the bloodstream circulates in both bound and unbound forms. Most of the detectable PSA in the serum (65% to 90%) is bound to α₁-antichymotrypsin (“complexed” PSA or cPSA, whereas the rest (10% to 35%) remains unbound (“free” PSA or fPSA).¹⁶⁷ The serum PSA tests in common use for prostate cancer detection and monitoring effectively measure the sum of fPSA and cPSA, providing a determination of the “total” serum PSA (tPSA). Assays that can distinguish fPSA and cPSA have been developed and approved by the U.S. FDA specifically for use in the early detection of prostate cancer. In general, men with prostate cancer have a greater fraction of serum tPSA bound to α₁-antichymotrypsin (cPSA), and a commensurately lower fraction of tPSA that is unbound (fPSA), 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 %fPSA appears most useful in distinguishing men with and without prostate cancer in the setting of tPSA levels between 2 and 10 ng/mL.¹⁹² An fPSA of 25% and a PSA density of 0.078 were shown to have comparable specificity for prostate cancer diagnosis at biopsy (at a sensitivity of 95%), but %fPSA does not require a TRUS for determination.¹⁹³ Most urologists use %fPSA determinations for 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. New assays for cPSA exhibit comparable specificity and sensitivity for prostate cancer diagnosis as %fPSA, with the potential advantage of using one assay for cPSA versus two assays to determine the %fPSA (measuring both tPSA and the %fPSA).

Benign PSA (BPSA), a degraded isoform of fPSA, is preferentially found in nodular tissue involved in benign prostatic enlargement and has been shown to be elevated among men with benign prostatic hyperplasia.¹⁹⁴ A second isoform, proPSA, is an inactive precursor of PSA that contains differing leader sequences of amino acids. When compared to men without prostate cancer, the tissues and serum of prostate cancer patients have an increased proportion of proPSA that is fPSA, a difference that has been used to improve the discrimination of men with and without prostate cancer.¹⁹⁵ A Beckman Coulter “Prostate Health Index” (PHI) uses proPSA, fPSA, and tPSA in a formula (proPSA/fPSA) × (tPSA)^1/2 that was shown to improve prostate cancer detection over total and %fPSA.¹⁹⁶ Additionally, there is some evidence that proPSA is associated with a more aggressive prostate cancer phenotype.¹⁹⁷

Urine Biomarkers of Prostate Cancer

PCA-3, a noncoding prostate-specific RNA, was found to be overexpressed in prostate cancer tissue compared with benign tissue.198,199 Urine assays for PCA3 have been developed that appear to improve the specificity of prostate cancer detection in response to an abnormal serum PSA,²⁰⁰ When compared with %fPSA, a PCA3 score (the ratio of PCA3 RNA to PSA mRNA × 1000) has been shown to be a superior predictor of prostate cancer on a repeat biopsy when an initial biopsy was negative.²⁰¹ Although PCA3 may have a higher specificity when used for prostate cancer detection, urine testing for PCA3 exhibits a lower sensitivity when compared with serum PSA testing.

A number of other urinary molecular biomarkers have been evaluated for prostate cancer detection, including hypermethylated GSTP1 genes, AMACR proteins, and TMPRSS2-ERG fusion mRNA transcripts. In a multicenter evaluation of urinary DNA methylation markers, including GSTP1, the negative predictive value of the urine test for prostate cancer diagnosis was 87% for men with a PSA of 4.1 to 10.0 ng/mL.²⁰² Although such DNA methylation urine tests might spare men unnecessary repeat biopsies, the addition of TMPRSS2-ERG mRNA urine testing (expected to be present in half of men with prostate cancer) to PCA3 RNA urine testing may provide a positive predictive value as high as 95%, steering men who harbor prostate cancer despite a previous negative biopsy toward a definitive diagnosis.^199,203 The discovery and development of new molecular biomarkers is progressing very quickly; in the future, such biomarkers (or biomarker panels) will need to be incorporated into algorithms along with standard measures of risk (e.g., age, family history, race) to selectively identify men who should undergo further evaluation for the presence of prostate cancer.²⁰⁴

TRUS-Guided Prostate Biopsy

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.²⁰⁵ 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-guage 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. Injection of a local anesthetic around the periphery of the prostate is used by most urologists 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. More recently, a rise in fluoroquinolone-resistant E. coli strains have been implicated in higher rates of hospitalization for postbiopsy sepsis,²⁰⁶ leading to more liberal use of targeted antibiotic prophylaxis, based on rectal swab cultures done prior to a biopsy.²⁰⁷

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. Magnetic resonance imaging (MRI) may have a role in improving the specificity of prostate cancer detection and in identification of sites within the prostate for directing prostate biopsies.²⁰⁸ At this point, it is not clear whether this use of MRI will improve health outcomes or reduce (vs. increase) the costs of care.

Screening for Prostate Cancer

Opportunistic PSA-based screening has been widespread in the United States since the early 1990s. It has been estimated that 45% to 70% of the 30% decline in prostate cancer mortality that occurred in the 1990s could be attributed to the stage migration and earlier treatment of prostate cancer associated with PSA testing.²⁰⁹ Ecological studies of prostate cancer mortality comparing countries with different rates of PSA uptake, suggest that the detection of more aggressive disease with PSA testing could explain mortality differences.²¹⁰

Two randomized trials of prostate cancer screening reported different results in 2009.211,212 In the Prostate, Lung, Colon, and Ovary (PLCO) trial, no difference in mortality was found between the screening and control groups, whereas in the European Randomized Study of Screening for Prostate Cancer (ERSPC), there was a 21% reduction in prostate cancer deaths in men randomized to screening at a median follow-up of 9 years. However, the absolute reduction in deaths for men screened was only 0.71 per 1000 men, with 48 men diagnosed with prostate cancer and treated to prevent one death, raising a concern about overdiagnosis and overtreatment even despite the mortality reduction. Updated reports from both trials have shown few changes with longer follow-up.^213,214 With these conflicting data, as might be expected, champions of prostate cancer screening dismiss the results of the PLCO trial because of high contamination rates in the control arm, high rates of prescreening in the population prior to initiation of the trial, and low rates of follow-up for positive screening tests. Nevertheless, the findings of the PLCO trial do hint that in the setting of ongoing widespread screening as is seen in the United States, further intensification of screening would not likely improve health outcomes.²¹⁵

The worry about overdiagnosis and overtreatment of prostate cancer in the United States has led many to reconsider the value of serum PSA testing for prostate cancer screening. A draft recommendation on prostate cancer screening from the U.S. Preventive Services Task Force (USPSTF) was released in the fall of 2011 recommending against prostate cancer screening for men of all ages, regardless of race or family history.²¹⁶ These USPSTF guidelines may prompt an increase in shared decision making between patients and physicians prior to pursuing prostate cancer screening,²¹⁷ a more nuanced and targeted approach to screening for those who desire to pursue it,¹⁷⁵ and an individualized approach to prostate cancer treatment that includes active surveillance if a diagnosis of prostate cancer is made rather than the rush to curative intervention for all.²¹⁸

Prostate Cancer Prevention

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, epidemiological 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 change lifestyle 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. As the etiology of prostate cancer is even better understood, new opportunities for prostate cancer prevention may also arise. For example, if prostate inflammation contributes to prostate cancer development, antiinflammatory drugs might be considered candidate prostate cancer prevention drugs.²¹⁹ 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.²²⁰ Ideally, such trials can be targeted at men with a high risk for prostate cancer development.

Thus far, two classes of agents, 5α-reductase inhibitors and antioxidant micronutrients, have been subjected to large randomized clinical trials; neither class of agents has shown a convincing prostate cancer prevention benefit. In the Prostate Cancer Prevention Trial (PCPT), the propensity for the 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.²²¹ For the trial, men (n = 18,882) with a PSA of 3.0 ng/mL or less and a normal DRE were randomized to treatment with finasteride (5 mg/d) or to placebo.²²¹ 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. Prostate cancer was detected in 18.4% of the men treated with finasteride versus 24.4% of men receiving placebo (P < 0.001).²²¹ However, high-grade prostate cancers appeared more commonly associated with finasteride treatment than with placebo (6.4% vs. 5.1%).²²¹ Similarly, in the REDUCE trial, men (n = 6729) with an elevated serum PSA (2.5 to 10.0 ng/mL) and a recent negative prostate biopsy were randomized to receive the 5α-reductase inhibitor dutasteride (0.5 mg/d) or placebo.²²² For this trial, men underwent prostate biopsies after 2 and 4 years of treatment. With a result reminiscent of PCPT, overall prostate cancer detection was reduced from 25.1% to 19.9% for men receiving dutasteride, but high-grade prostate cancer, which was similar in the first 2 years of the trial for men treated with dutasteride versus placebo, was increased in dutasteride-treated men in the last 2 years of the trial from <0.1% to 0.5%. The findings of PCPT and REDUCE may mean that 5α-reductase inhibitors prevent or treat low-grade cancers better than high-grade cancers. These mixed results, a reduction in overall prostate cancer prevalence but an increase in high-grade prostate cancers, make prescribing 5α-reductase inhibitors to healthy men for the purpose of preventing prostate cancer very problematic, an opinion shared by the FDA, which has not approved either drug for such an indication.²²³

Epidemiological studies have provided compelling evidence that intake of selenium and of vitamin E might diminish prostate cancer risks, especially in the setting of inadequate dietary consumption.224–230 As a result, a prospective, randomized, placebo-controlled clinical trial of selenium and vitamin E (SELECT; n = 35,533) was undertaken to test the ability of the antioxidant micronutrients to prevent prostate cancer.²³¹ Selenium (200 µg selenomethionine), α–tocopherol (400 mg), the combination of selenium and α–tocopherol, or neither, were given to men randomized to four different treatment groups using a 2 × 2 factorial design, for 7 to 12 years.²³¹ The men studied were age 55 years or older (50 years or older for African Americans) with an unremarkable DRE and a serum PSA of 4.0 ng/mL or less.²³¹ Unfortunately, the trial failed to show any reduction in prostate cancer and showed a slight increase in prostate cancer incidence among men taking α–tocopherol.^57,232 When this result is considered in the context of the findings from epidemiology studies and previous smaller clinical trials, the data tend to suggest that men with low blood levels of the antioxidant micronutrients, who tend to be at the highest risk for prostate cancer development, might be the only men with any chance for benefit from supplementation.^{225,226,230,233} For this reason, correction of antioxidant micronutrient deficiencies might ultimately prove more generally safe and effective than widespread supplementation (and its risk of oversupplementation), which may carry a threat of harm with little benefit.

Life-Threatening Prostate Cancer Progression

Prostate cancer progression has long been understood to involve metastases to bones, which are often painful, and to lymph nodes. The predilection of the disease for bones may reflect a hospitable microenvironment capable of providing growth factor support in a collaboratively malignant milieu (Figure 84-10).²⁴⁹ In turn, prostate cancer cells perturb bone homeostasis in such a way as to increase osteoblast activity, which can be readily discerned by bone scanning. This activity forms the basis for bone scan imaging, such as with ^99mTc-methylene diphosphonate (MDP) and ¹⁸F-sodium fluoride (NaF), in which osteoblastic activity can be visualized throughout the entire skeleton.²⁵⁰ Reportedly, NaF positron emission tomography/computed tomography (NaF PET/CT), in which osteoblastic activity is coregistered with bone radiography, offers the highest sensitivity and specificity for bone metastasis.²⁵¹

More recent autopsy studies have provided newer insights into the phenotype(s) of lethal prostate cancer. In addition to expected bone and lymph node metastases, men dying of prostate cancer tend to exhibit common metastases to liver (64%), the dura (43%), and elsewhere.²⁵² The most troubling feature of lethal prostate cancer may be its heterogeneity. In different metastases from the same case, the expression of androgen receptor, and its target PSA, appears markedly variable, present in the majority of cells in some lesions but mostly absent for others.²⁵³ This likely reflects ongoing genome and epigenome instability. Genomewide assessment of somatic genetic and epigenetic defects in lethal prostate cancers at autopsy show that although disseminated metastatic disease emerges from a single clone, new defects continue to appear in individual metastases.²⁵⁴ Of interest, DNA hypermethylation changes tend to be maintained in all metastatic lesions in most cases, at least as much as any of the genetic alterations, whereas DNA hypomethylation, leading to activation of repressed embryonic genes, continues to evolve variably lesion to lesion.²⁵⁵ Of course, the greatest worry about ongoing genomic, epigenomic, and phenotypic heterogeneity in metastatic prostate cancer is the likelihood that treatment resistance will almost certainly emerge, regardless of the agent used.

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.²⁶² 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.²⁶³ 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.²⁶⁴ 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.^262,265,266 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.

¹¹¹In-capromab pendetide, a radioimmunoconjugate featuring a monoclonal antibody to an intracellular domain of prostate-specific membrane antigen was approved by the FDA for use in the evaluation of men with clinically localized prostate cancer but is rarely used today for assessment of prostate cancer extent, even for men with high-risk prostate cancer, in large part because of low scan sensitivity and frequent difficulties in scan interpretation. There may be a role for ¹¹¹In-capromab pendetide imaging with single photon emission computed tomography used in coregistration with computed tomography (SPECT/CT) for prognostic staging.²⁶⁷ New nuclear medicine agents capable of detecting PSMA appear promising in early development.²⁵⁰ Perhaps, one of these tools may overcome the inadequacies of ¹¹¹In-capromab.

Serum Biomarker Assays and “Molecular” Classification for Prognosis

The serum PSA level at the time of a prostate cancer diagnosis is correlated with both intermediate and long-term outcomes including tumor volume, stage, grade, and freedom from relapse after treatment.²⁶⁸ However, the serum PSA cannot be used alone to predict disease extent for an individual patient. Instead, PSA values are more typically used as part of multivariable models for predicting the extent of disease and the probability that a cancer will behave in an aggressive manner.^269,270 The NCCN recommends the use of the D’Amico classification scheme using serum PSA, clinical stage, and biopsy Gleason score to stratify men into low-, intermediate-, and high-risk groups for selecting management strategies and for counseling patients about prognosis.²⁷¹ Other PSA forms used in the detection and diagnosis of prostate cancer, such as %fPSA, proPSA, and so forth, are not part of commonly employed risk stratification and prognosis tools.

“Molecular” classification of tumor cells for prognosis refers to the detection of circulating prostate cancer cells and/or cell fragments, either indirectly, by identifying mRNA species, like those encoding PSA or PSMA, characteristically expressed by epithelial cells from the prostate,²⁷² or directly, by recovering “circulating” prostate cancer cells by a variety of isolation methods.^275–275 To detect prostate lineage mRNAs or prostate cancer DNAs, polymerase chain reaction (PCR) approaches, capable of astonishing sensitivity, are typically used. Circulating tumor cells (CTCs) appear early in the course of prostate cancer, though simple enumeration of the cells does not provide clear prognostic information for those with localized cancers.^276,277 Further, the presence of CTCs at diagnosis does not accurately predict the development of metastatic disease posttreatment.

Observational Strategies

Watchful waiting was a common strategy in the pre-PSA era when most cancers were detected at an incurable stage and the morbidity of primary treatments was high. The primary intent of watchful waiting was to avoid treatment until symptoms emerged and non-curative palliative treatment might be necessary.²⁷⁹ In contrast, active surveillance, a more modern approach, involves the selective delayed curative treatment of men found to have disease progression while being carefully monitored. Active surveillance implies a much more diligent monitoring regimen than watchful waiting.

The Scandinavian Prostate Cancer Group Study 4 (SPCG-4), a trial conducted before the PSA screening had been adopted, randomized men (n = 695) with localized prostate cancer to surgery or watchful waiting (Figure 84-12).²⁸⁰ Although these men would not have been considered optimal candidates for active surveillance by current criteria, as most of the men had palpable disease by DRE, surgery was accompanied by a 40% reduction in prostate cancer deaths for men with 15 men needing treatment to prevent a single prostate cancer death. Of note, the benefits of surgery were restricted to men under the age of 65 years. The Prostate cancer Intervention Versus Observation Trial (PIVOT), a study conducted in the setting of common PSA screening, randomized men (n = 731) with a mean age of 67 years to surgery or watchful waiting.²⁸¹ The distribution of prostate cancer cases among the study subjects included 43% low-risk, 36% intermediate-risk, and 20% high-risk disease. These data, which have been presented but not yet published, suggest that through 12 years of follow-up there has been no difference in cancer-specific survival attributable to treatment. Thus older men with low-risk, screen-detected, prostate cancers may not derive great benefits from radical prostatectomy.

Active surveillance seeks to individualize prostate cancer care primarily among men thought to harbor low-grade prostate cancers who would otherwise be fit for curative treatment. The intent is to intervene early with curative therapy if the disease should progress,²⁷⁹ while sparing men with more indolent prostate cancer the side effects of aggressive primary therapy.^282,283 This management approach, which relies on diligent monitoring for signs of disease progression, has been called a variety of names, including “expectant management with curative intent” and others, but active surveillance is the terminology most often used today.^270,278,284

The rationale for active surveillance has been derived from medical evidence reflecting a variety of reported studies, including competing risk analyses, surgical series, nonrandomized cohort studies, and randomized trials. Taken together, the findings indicate that using a time horizon of 10 to 15 years, less than 3% of men diagnosed with well-differentiated tumors (Gleason score 6 or below) classified as low-risk (based on a serum PSA <10.0 ng/mL and tumor stage of T2a or less) will die of prostate cancer whether treated or not.281,285–288 Such data clearly call into question the need for treating men with low-risk disease and a life expectancy of less than 10 to 15 years. Unfortunately, curative intervention for favorable-risk prostate cancer appears to be undertaken as commonly as curative intervention for higher-risk disease.^291–291 This is of concern because at least half of newly diagnosed men with prostate cancer have favorable risk disease, and 80% to 90% of these men undergo some form of treatment even when the age at diagnosis is above 75 years. Overtreatment of nonthreatening prostate cancer probably reflects the combination of a fear of harm from cancer, of litigation if aggressive treatment is not recommended, and of misaligned incentives that favor treatment in spite of evidence that nonintervention may be the most rational option.

Despite these biases driving overtreatment of favorable-risk prostate cancer, there has been a growing interest in active surveillance approaches as evidenced by the number of academic centers reporting outcomes from single-arm cohort studies.184,218,270,278,284 As of yet, there is no standard approach to selection of men for active surveillance, nor are there established guidelines for monitoring regimens, or for criteria to be used as triggers for curative intervention, for men managed by active surveillance. The “ideal” candidate may be a man with favorable-risk prostate cancer (very low-risk to low-risk), a life expectancy less than 15 years, and a personal desire to avoid the side effects of prostate cancer treatments. Typical monitoring strategies tend to involve DRE and serum PSA determinations at 3- to 6-month intervals, with repeated prostate biopsies at intervals of 1 to 4 years. The most common intervention triggers are a rising serum PSA and an increase in Gleason score of cancer seen on repeat biopsy, a finding that may result from undersampling by the initial biopsy or from “dedifferentiation” of a low-grade cancer. When managed in this way, approximately 25% to 50% of men will undergo curative intervention within 5 to 10 years of surveillance. Of the men proceeding to curative treatment, 25% will do so because of personal preference and without any trigger, 30% to 40% will do so because of a higher Gleason score, and 30% to 40% will do so because of an inexorably rising serum PSA.^270,284 In one active surveillance series for men with prostate cancer (30% intermediate-risk disease and 70% with favorable-risk disease), the 10-year prostate cancer actuarial survival was 97%.²⁹² An ongoing trial, the Prostate Testing for Cancer and Treatment (ProtecT) trial, which started in the United Kingdom in 2001, has randomized men with prostate cancer, ages 50 to 69 years to conformal radiotherapy, radical prostatectomy, or active surveillance.²⁹³ Results from this trial may further inform the difficult decision that men with localized prostate cancer face in choosing between active surveillance and curative intervention.

Radical Prostatectomy

Radical prostatectomy is most often recommended for treatment of men with clinically localized prostate cancer who have a life expectancy of at least 10 years or more (Table 84-3). Although there are not specific or universally accepted age limits for radical prostatectomy, increasing age is associated with a lower likelihood of receiving surgical treatment for prostate cancer. For example, among men with low-risk or intermediate-risk disease, 3 in 4 at ages 56 to 65 years, 2 in 5 at ages 66 to 75, and 1 to 2 in 10 at age >75 years undergo surgical intervention for prostate cancer.²⁹⁴

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. Many surgeons recommend a delay of 6 to 8 weeks after prostate needle biopsy to permit resolution of hematomata/inflammation caused by the biopsy procedure. In anticipation of surgery, men avoid aspirin, nonsteroidal antiinflammatory agents, or high doses of vitamin E that might promote excess bleeding.

Radical prostatectomy was not commonly recommended for localized prostate cancer prior to the 1980s because of blood loss, and associated complications of incontinence and erectile dysfunction. But by 1990, surgery was the most commonly chosen option for management of prostate cancer.²⁹⁵ The increasing rates of radical prostatectomy relative to other management options was in large part due to the description of an anatomic approach to radical retropubic prostatectomy (RRP) that dramatically decreased operative morbidity, to the widespread use of PSA testing that led to an earlier diagnosis of disease, and to the ease of detection of prostate cancer with TRUS-directed prostate biopsies.⁶

Radical prostatectomy can be performed under regional or general anesthesia using a perineal, retropubic, or laparoscopic approach. Radical perineal prostatectomy is not a commonly performed procedure today; rather, the most common approach to removal of the prostate for treatment of prostate cancer is robot-assisted laparoscopic radical prostatectomy (RALRP). With RALP, the robotic system (a console connected to robotic arms) translates the movement of the surgeon’s fingers into movement of robotic arms attached to the laparoscopic instruments used to perform the surgery. Claims of advantages of RALP over other approaches have been widely touted by surgeons, hospitals, and the device manufacturer, resulting in increased usage of surgery overall, especially in older men.²⁹⁶ However, there is no evidence for improved disease-free or functional outcomes with RALP compared to RRP.^299–299 Instead, both disease-free and quality-of-life outcomes after radical prostatectomy depend more on the experience of the surgeon than on the surgical approach used.³⁰⁰ With any surgical approach, prior pelvic surgery or radiation therapy tends to be associated with an increased risk of surgical complications.

Regardless of the surgical technique used, in most cases (especially in the setting of intermediate-risk or high-risk disease), the radical prostatectomy proceeds via a staging pelvic lymphadenectomy, focusing on the pelvic lymph nodes surrounding the external iliac vein and obturator fossa. The remaining steps of the operation include ligation of the dorsal vein complex anterior to the prostate to control blood loss, division of the urethra, identification and preservation of the neurovascular bundles containing branches of the pelvic nerves innervating the corpora cavernosa necessary for penile erection (unless wide excision of a neurovascular bundle is necessary for cancer control), division of the bladder neck, resection of the seminal vesicles, and construction of a urethrovesical anastomosis.

Hemorrhage and injury to surrounding structures (blood vessels, obturator nerve, ureter, and rectum) are the most common intraoperative complications of radical prostatectomy. In the immediate postoperative period, complications can include deep venous thrombosis and pulmonary emboli, urine anastomotic leak, and postoperative bleeding. The operative mortality rate (death within 30 to 60 days) after radical prostatectomy is from 0.4% to 1.6%, depending on age and comorbidity.³⁰¹ Following surgery, most men spend 1 to 2 nights in the hospital and have an indwelling urinary catheter for 1 to 2 weeks to allow healing of the vesicourethral anastomosis. After catheter removal, the most common long-term complications of surgery are urinary incontinence as a result of intrinsic sphincter deficiency, and erectile dysfunction from injury to the cavernous nerves innervating the corporal bodies of the penis, both of which negatively impact quality of life.

Urinary Function after Radical Prostatectomy

Urinary incontinence rates after radical prostatectomy vary greatly in different reports: from 5% to as high as 50%, with as many as 5% to 10% of men undergoing another procedure for incontinence after radical prostatectomy.²⁹⁷ Some of the variation in reported incontinence rates may be attributable to differences in definitions of incontinence (stress incontinence vs. more severe difficulties with urinary control), in the time after surgery when urinary continence was assessed (urinary control can improve over as long as a year following surgery), in whether incontinence was reported by treating surgeons in case series or by patients in survey questionnaires, and in the age of the patients undergoing surgery (older age is associated with higher incontinence rates). 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.^302,303 Using validated questionnaires to assess urinary incontinence and bother, Sanda et al.³⁰⁴ found urinary incontinence (any pad use) two years after treatment in 20% of men postsurgery, with a moderate-to-severe urinary problem in 7% (Table 84-4). Most men after radical prostatectomy have some degree of stress incontinence for a period of time that usually resolves within the first postoperative year, after which incontinence is not likely to improve further.

Surgical technique 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.³⁰⁵ Postoperative strictures at the site of the vesicourethral anastomosis can also affect return of urinary control.³⁰⁶ Avoidance of strictures (scars) by performance of a careful, tension-free, vesicourethral anastomosis has led to improved urinary control rates by expert surgeons.^307,308 Men with persistent or severe urinary incontinence after radical prostatectomy can be treated with periurethral injections of bulking agents (silicone) that increase resistance at the bladder outlet, a pelvic sling placed through the perineum that repositions the urethra, and an artificial urinary sphincter—a three-piece device made up of a compressing urethral cuff, a fluid-filled reservoir placed in the abdomen that transmits pressure to the urethral cuff, and an activating pump placed in the scrotum that transfers fluid from the cuff to the reservoir allowing the cuff to open and the bladder to empty.

Erectile Function after Radical Prostatectomy

In 1982, Walsh and Donker described the anatomy of the nerves traversing the lateral surface of the prostate en route to the corpora cavernosa of the penis, discerning the proximity of the nerves to vascular structures (the neurovascular bundles) visible at the time of radical prostatectomy.⁵ This revelation led Walsh et al. to propose a modification of the radical prostatectomy procedure to preserve the neurovascular bundles in an effort to maintain erectile function postoperatively.⁶ Wide adoption of this modification led to improvements in erectile function following radical prostatectomy, and this approach is routinely used today when preservation of these nerves will not compromise removal of all cancer.

As is the case with urinary continence after radical prostatectomy, reports of return of erectile function vary greatly from 31% to 86% with study differences likely due to definitions of potency used, the methods for assessing return of sexual function, the cohort studied, and timing of assessment after surgery.³⁰⁹ Return of erections after surgery inversely correlates with age, and is directly associated with the quality of preoperative erections, the frequency of sexual activity preoperatively, and the quality and extent of nerve preservation. In a study using validated questionnaires to assess sexual function, sexual dysfunction was found to remain a big problem one year after treatment in 26% of men who underwent radical prostatectomy, with distress related to sexual dysfunction described by 44% of sex partners postoperatively.³⁰⁴ Most of the improvement in erections occurs within the first 2 years after surgery.³¹⁰

Common approaches to managing erectile dysfunction after surgery include PDE-5 inhibitors, vacuum erection devices, vasoactive agents placed intraurethrally or injected directly, and placement of a penile prosthesis. Current thinking is that injury to the nerves (even when preserved at surgery) supplying corporal tissues results in injury to the corporal tissues that may be ameliorated by increased penile blood flow. Thus most sexual medicine experts encourage men to aggressively pursue attempts to achieve erections as soon as possible after surgery. If spontaneous erections do not occur with stimulation and PDE-5 inhibitors, men are encouraged to pursue other options described above, the greatest success achieved being with penile injection therapy.³¹¹

Control of Prostate Cancer by Radical Prostatectomy

Because PSA is a prostate-specific biomarker, successful removal of all prostate tissue after radical prostatectomy should result in an undetectable serum PSA. A detectable PSA after surgery, and/or a rising PSA, is an indication of residual prostate cancer that is referred to as a biochemical recurrence. Most series define a biochemical recurrence after surgery as a serum PSA that is above 0.2 ng/mL or rising. Biochemical recurrence rates vary directly with the risk assignment before surgery (low-risk, intermediate-risk, high-risk; see Table 84-3), age, the extent and grade of the cancer found on final pathological assessment. In modern surgical series, for men with localized prostate cancer, biochemical recurrence-free survival at 5, 10, and 15 years is reported at 84%, 74%, and 66%, respectively.³¹²

Biochemical recurrence is not a surrogate for cancer-specific mortality because most men with a biochemical recurrence as the only evidence of residual disease do not die of prostate cancer. A study of the natural history of biochemical recurrence in a cohort of men (n = 450) who underwent surgery for presumed localized prostate cancer, had rising serum PSA, and received no treatment until the development of overt metastases, at a median follow-up of 8 years, revealed that only 30% of the men had developed metastatic disease.³¹³ For these men, the median time from surgery to biochemical recurrence was 3 years and the median metastasis-free survival was 10 years. The Gleason score and PSA doubling time were independent predictors of metastasis-free survival, with no evidence of metastases in 94% of men with prostate cancer and a Gleason score of 6 or less versus 19% of those with Gleason scores of 8 to 10, and no evidence of metastases in 72% of men with recurrent prostate cancer and a PSA doubling time of >15 months versus 7% of those with a PSA doubling time of 3 to 9 at 10 years, respectively.

Cancer-specific survival after radical prostatectomy was recently evaluated in a multiinstitutional study of men (n = 11,521) with prostate cancer diagnosed in the PSA era, revealing a cumulative incidence of prostate cancer deaths at 15 years of only 7%.²⁸⁷ Predictors of prognosis include the Gleason grade and the presence of seminal vesicle invasion, with prostate cancer mortality rates of 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11%, and 26% to 37% for Gleason scores of 6 or less, 3+4, 4+3, and 8 to 10, respectively, and 0.8% to 1.5%, 2.9% to 10%, 15% to 27%, and 22% to 30% for organ-confined cancer, cancer with extraprostatic extension, cancer with seminal vesicle invasion, and cancer accompanied by lymph node metastasis, respectively.²⁸⁷ Because these results were from a single-arm study without a comparison group, it is not possible to know to what extent the favorable surgical results for screen-detected cancers were a result of surgical intervention for a lethal phenotype versus the intrinsic indolent biological behavior of many such cancers. Hopefully, results from PIVOT, comparing surgery with watchful waiting, and from ProtecT, comparing conformal radiotherapy, prostatectomy, and active surveillance will provide more definitive answers to this question.

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 1895,³¹⁴ and the isolation of radium by Pierre and Marie Curie in 1898,³¹⁵ 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 use of radiation for prostate cancer. Not long after, Hugh Hampton Young from Johns Hopkins reported the relatively large experience of treating prostate cancer patients with urethral and rectal radium “applicators.”³¹⁶ 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 proffered by Barringer.³¹⁷ 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 more deeply seated tumors in the body. The first reported series of prostate cancer patients treated with ⁶⁰Co therapy was by George et al. in 1965 and featured men with unresectable disease.³¹⁸ During this time (beginning in the late 1950s), the megavoltage linear accelerator was being developed at Stanford University.³¹⁹ Using this new technology, the pioneering work of Bagshaw, Kaplan, Del Regato, and others, ushered in the modern era of radiation therapy for prostate cancer by offering the possibility of cure with radiation therapy in this disease.^320,321

Now men with prostate cancer have several different radiotherapy 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, has also 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 have tended to be older, to be in poorer health, and to have with higher risk, more advanced tumors than those patients treated surgically. As such, 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 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. In this section, a brief description of how men are evaluated and risk-stratified for radiation therapy will be provided, 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 will also be reviewed.

External Beam Radiotherapy for Localized Prostate Cancer using 3D-Conformal and Intensity-Modulated Approaches

For more than four decades, external beam radiotherapy has been widely used for the definitive management of clinically localized prostate cancer. More recently, technical advances have permitted the safe delivery of 80 Gy to the prostate, while minimizing radiation exposure of nearby normal tissues. Historically, a four-field pelvic box with shielding of the posterior wall of the rectum and anal canal was used to treat the prostate, seminal vesicles, and proximal lymphatic drainage to a dose of 45 to 50 Gy in 1.8- to 2.0-Gy fractions, with a boost to the prostate to 65 to 70 Gy. Even at these doses, external beam radiation therapy was fairly effective: although overall survival numbers were generally higher for men treated with radical prostatectomy (often younger and healthier men), cause-specific survival rates were not significantly different.³²² Although the four-field box radiation therapy technique is of historic significance only, it is worth noting that side effects (rectal bleeding, dysuria, bowel dysfunction, etc.) associated with this technique were higher than those seen with contemporary technologies and delivery.

To improve on these outcomes, new technical innovations, such as CT-based simulation/treatment planning, the introduction of multileaf collimators in modern linear accelerators, and advances in treatment planning software have allowed for increased precision and accuracy in prostate cancer radiotherapy. For three-dimensional conformal radiation therapy (3D-CRT), three-dimensional reconstructions of pelvic CT images are generated to create more accurate target volumes (e.g., prostate and seminal vesicles) for treatments, enabling better identification of critical structures (e.g., bladder and rectum) to be avoided. An iterative process is then used to design beam arrangements that will deliver a prescribed dose to the regions of interest and minimize dose to a given volume of an adjacent organ. In this way, the incident radiation volume “conforms” to target volume. The treatment target volumes and normal organs can then be visualized in three dimensions, creating a “beam’s-eye view,” a portrayal of the target area as if looking straight down the path of the radiation beam. During treatment delivery, computerized multileaf collimators then shape each individual beam to conform to the shape of the target in the beam’s-eye view. Intensity-modulated radiation therapy (IMRT) builds on the advantages of 3D-CRT by using treatment planning software capable of even further optimizing dose distribution for prostate cancer treatment, by modifying not just the orientation and shape of the incident beams but also the intensity across the designated treatment volume (Figure 84-13).

Complications of 3D-CRT and IMRT

Although the use of 3D-CRT was intended to minimize the effects of high-dose radiation on normal tissues, increased late complications, such as rectal and urinary toxicity, have been noted with escalating radiation doses used in 3D-CRT.323,324 Rectal toxicity encompasses urgency, frequency, pain, fecal incontinence, or bleeding. In a Fox Chase Cancer Center case series, the 5-year incidence of grade 3 or 4 rectal toxicity at a dose of 75 to 76 Gy was 8%, which upon better shielding of the anterior rectal wall, could be reduced to 2%. IMRT seems to be accompanied by less rectal complications. In one case series, men with clinically localized prostate cancer treated with IMRT to a total dose >81 Gy at Memorial Sloan-Kettering Cancer Center exhibited a reduction in late rectal toxicity when compared with 3D-CRT.³²⁵ With a median follow-up of 24 months, grade 2 or higher rectal bleeding was seen in 4% of men receiving IMRT, with grade 3 rectal toxicity in only 0.5% (and no grade 4 rectal toxicity) at 3 years. Urinary toxicity, including urethral strictures, tends to be similar for both 3D-CRT and IMRT, with as many as 15% of men suffering late grade 2 urinary complications. 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, but better diagnostic imaging will be necessary to identify men with such cancers. Overall, for external beam radiation therapy, 9% to 11% of men treated can expect to have some level of rectal or urinary distress 1 year after treatment (Table 84-4).³⁰⁴

Data on the incidence of erectile dysfunction after external beam radiotherapy has 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. Although 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 et al. specifically addressed this topic by performing duplex ultrasound studies before and after prostaglandin injection to stimulate erections in men with radiation-related erectile dysfunction.³²⁶ 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 therapy-associated impotence may be vascular damage rather than nerve damage. Fisch et al. demonstrated a correlation between incidence of erectile dysfunction postradiotherapy and radiation dose to the vascular penile bulb.³²⁷ Men receiving >70 Gy to >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 only 50% were potent 6 years later, and only 30% maintained erectile function for the remainder of their lives.³²⁸ 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.³²⁹ Men who do not respond to sildenafil may respond to intracavernosal prostaglandin injections.

Cancer Control by External Beam Radiation Therapy

With the ready availability of serum PSA testing, outcome comparisons between primary prostate cancer treatments tend to focus on PSA as a marker of prostate cancer recurrence (“PSA relapse”–free survival). Of course, if successful in controlling cancer, surgical removal of the prostate eliminates PSA production by both nonneoplastic and neoplastic cells, whereas radiation therapy may not abolish PSA production by residual prostate epithelial cells even as cancer cells are killed. Nonetheless, a rising serum PSA after radiotherapy for prostate cancer is correlated with the appearance of progressive or metastatic prostate cancer upon further follow-up.³³⁰ Furthermore, the rate of serum PSA rise may help distinguish between local versus 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.³³¹ In 2006, the American Society for Therapeutic Radiology and Oncology (ASTRO) issued a consensus statement establishing the definition of recurrence following radiation therapy as a serum PSA level that is 2.0 ng/mL over the nadir value.³³² This definition is an update to the 1997 ASTRO criteria for biochemical recurrence (three consecutive rises of the serum PSA determined at least 3 months apart³³³) and is now preferred for evaluating and comparing radiation treatment strategies. 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.

External beam radiation therapy using 3D-CRT and IMRT approaches achieves effective prostate cancer control.324,334–336 In a large cohort of men (n = 1100) treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center, the 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.³³⁶ Men with intermediate-risk and high-risk prostate cancers also showed significant improvement. In a randomized trial of radiation dose escalation, higher-dose treatment was associated with improvement in prostate cancer control rates for men with prostate cancer, especially men with a pretreatment PSA >10 ng/mL (Figure 84-14).^334,337 In this study, men (n = 305) with stage T1–T3 prostate cancer received either radiation therapy to a total dose of 70 Gy using conventional radiotherapeutic techniques, or to 78 Gy using a 3D-CRT approach. 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 with a pretreatment serum PSA >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). 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).

Brachytherapy

Prostate brachytherapy involves the implantation of radioactive sources into the prostate using image guidance (Figure 84-15). In principle, brachytherapy offers an attractive means for radiation dose escalation and conformality in the treatment of clinically localized prostate cancer. However, the most attractive feature for many men with prostate cancer is that 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. The most common sources in use today are ¹²⁵I (Iodine) and ¹⁰³Pd (Palladium) (Table 84-5). Thus far, there have been no compelling data to support the superiority of one isotope or the other. Theoretically, the higher initial dose rate emitted by ¹⁰³Pd might be advantageous for the treatment of cancers, like prostate cancer, with a relatively low αβ ratio (more radioresistant); however, retrospective data for prostate cancer have been inconclusive.³³⁸ To date, no long-term prospectively randomized data exist directly comparing ¹²⁵I with ¹⁰³Pd. Most 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.^341–341 Although this treatment approach is not widely used, the available results appear comparable with permanent brachytherapy for clinically localized prostate cancer.

Brachytherapy may exhibit its greatest benefits in the treatment of men with low-risk, clinically localized, prostate cancer, though in the absence of a prospective randomized trial, this recommendation has been based on retrospective studies with varying follow-up time. One of the largest of these studies reported outcomes for more than 2500 men with prostate cancer treated at 11 different institutions with permanent interstitial brachytherapy.³⁴² 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-risk, intermediate-risk, and high-risk prostate cancer had 8-year actuarial PSA relapse-free survivals of 82%, 70%, and 48%, respectively, using ASTRO criteria. The dosimetric quality of the implant was critical to outcome: for men in which 90% of the prostate (D₉₀) received ≥130 Gy, the 8-year PSA relapse-free survival was 93%, whereas for men in which the prostate D₉₀ was <130 Gy, the 8-year PSA relapse-free survival was 76%. There were few, if any, differences attributable to the use of ¹²⁵I versus ¹⁰³Pd implants.

The addition of supplemental external beam radiotherapy to brachytherapy remains somewhat controversial. Davis et al. examined the radial distance of extraprostatic extension of prostate cancer and found it to be almost always 5 mm or less, which would be within a typical brachytherapy dose distribution.³⁴³ Thus generous periprostatic margins in brachytherapy planning should obviate the need for supplemental external beam radiotherapy. Proponents of combinations of brachytherapy and external beam radiation therapy emphasize both the advantage of higher delivered doses and the ability to smooth out cold spots inherent with brachytherapy, the so-called spackle effect. Sylvester et al. have 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 the implant.³⁴⁴ 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.

Relative contraindications to the use of prostate brachytherapy are large prostate size, pre-implant 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 because of 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 (ADT) in an attempt to reduce gland size. Nonetheless, the implantation of large prostates with radioactive seeds has been described with acceptable morbidity.345,346 In one case series, postimplant dosimetry quality was found to be independent of prostate size or use of ADT.³⁴⁶ The correlation of preimplantation obstructive urinary symptoms and postimplantation urinary obstruction has not been fully resolved. Terk et al. reported that a high International Prostate Symptom Score (I-PSS), a measure of obstructive urinary symptoms, predicted postimplant urinary retention.³⁴⁷ With the use of α–blockers before and after implant procedures, others have noted no association between preimplant I-PSS and urinary obstruction.³⁴⁸ 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.³⁴⁹ TURP is thought to be a relative contraindication to prostate brachytherapy as it has been associated with unacceptably high rates of urinary incontinence. This could possibly be attributable to seed placement 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.³⁵⁰

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.³⁵¹ This spike may be due to radiation-associated prostatitis that compromises prostate architecture, permitting more PSA to appear in the serum. Notably, such PSA spikes portend no worse long-term outcome.

Toxicity of Brachytherapy

The short- and long-term sequelae of brachytherapy for prostate cancer differ from those of external beam radiotherapy and radical prostatectomy. Kleinberg et al. 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).³⁵² By 12 months following implantation, these figures had declined (to 45% and 20%). 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 et al. 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.³⁵³ Urethral stricture appeared in 14.4% of the men. Others have also seen an increased incidence of urinary incontinence in the setting of a history of TURP.³⁵⁴ 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%.³⁵⁵ In all, as many as 16% of men treated with brachytherapy for prostate cancer can expect to suffer distressful urinary symptoms 2 years after treatment (Table 84-4).³⁰⁴ As is the case for external beam radiation therapy, rectal complications after brachytherapy tend to emerge within 3 years of implant placement, with rectal injury in 5% to 10% of men treated.^{356,355,357,304}

As 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 to external beam radiotherapy 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 et al. reported a 2-year potency rate of 94% after implant, whereas Wallner et al. reported a 3-year potency rate of 86%.358,359 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.³⁵⁶ Even Stock et al. subsequently reported a 6-year potency rate of 59% in their case series.³⁶⁰ 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% 6-year potency rate. Using postimplant dosimetry studies, Merrick et al. demonstrated that dose to the penile bulb correlated with postimplant erectile dysfunction. In the majority of men who retained potency, the dose delivered to 50% of the penile bulb was less than 50 Gy.³⁶¹ Potentially, this knowledge 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, with reports of hematospermia in 28%, orgasmalgia in 15%, and alteration in the intensity of orgasm in 38%.³⁶² These side effects tend to be transient in most men.

Proton Beam Radiotherapy

Though only available at a few centers worldwide, there has been an interest in proton beam therapy for prostate cancer. The unique physical properties of protons make them ideal for the treatment of disease in proximity to critical strictures. 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. This 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.³⁶³ 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 <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 results in a statistically significant reduction in the risk of recurrence of localized prostate cancer.³⁶⁴

Adjuvant Endocrine Therapy

ADT has been found to improve treatment outcomes in randomized trials of men with high-risk prostate cancer treated with external beam radiation therapy but not as convincingly for men treated with radical prostatectomy (Figure 84-16).^367–367 D’Amico et al. reported results of a large retrospective study (n = 1586) of men treated with 3D-CRT plus or minus ADT for low-risk, intermediate-risk, and high-risk prostate cancer.³⁶⁸ In this study, the median radiation dose was 70.2 Gy and ADT was used for 2 months before radiation therapy, during treatment, and for 2 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 ADT versus 84% without. Men with intermediate- and high-risk prostate cancer also fared significantly better when given ADT. Radiation Therapy Oncology Group (RTOG) Trial 94-08, which completed accrual in 2001 and was reported in 2012, was designed to ascertain whether men (n = 1917) 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 4 months before and concomitantly with external beam radiation therapy.³⁶⁹ Results of this trial revealed that the addition of androgen suppression to radiation significantly improved disease-specific and overall survival, reducing overall deaths from 8% to 4% at 10 years.

ADT has also 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 ADT, with an average 30% to 40% reduction, and little further volume decreases.³⁷⁰ 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 et al. reported that men treated with ADT tended to have smaller prostates that required fewer seed implants.³⁷¹ 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 radiotherapy and ADT, 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 ADT to brachytherapy for men with low-, intermediate-, or high-risk prostate cancers.³⁷²

Postprostatectomy Adjuvant Radiation Therapy

Pathological features that portend a higher risk of local recurrence are common after radical prostatectomy. A positive surgical margin is associated with an approximately 50% risk of prostate cancer recurrence.373–377 Other features associated with recurrence are extracapsular extension, seminal vesicle invasion, and Gleason score of 7 or greater. Several retrospective series have now demonstrated improved PSA relapse-free survival with the addition of adjuvant radiation therapy following radical prostatectomy in men with these risk factors.^380–380 In one study, men (n = 149) with pathological 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), whereas the remainder (n = 97) underwent no further treatment.³⁷⁸ In a matched-pair analysis, the 5-year freedom-from-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 pathological features. The European Organization for Research and Treatment of Cancer (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.³⁶⁶ 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; these improvements were not yet statistically significant even at a median follow-up of 10 years.³⁸¹ 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 ADT 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.³⁸² 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. What is needed for the future is a more precise way to stratify men for adjuvant radiation therapy: one such group may be men with positive surgical margins after radical prostatectomy.

Salvage Radiotherapy after Radical Prostatectomy

Salvage radiotherapy 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.³⁸³ Subsequently, approximately 25% of men who undergo radical prostatectomy will be treated with salvage radiation therapy for recurrent prostate cancer.³⁸⁴ 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 et al. correlated the rate of serum PSA rise with likelihood of local versus distant relapse after surgery.³⁸⁵ A serum PSA rise of 0.75 ng/mL/year 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 pre–radiation therapy serum PSA <1.5 ng/mL was more likely to be successful.³⁸⁶ 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.^387,388 Caddedu et al. reported no men free of PSA relapse treated with salvage radiation therapy after prostatectomy for prostate cancers with Gleason scores of 8 or above.³⁸⁸ Similarly, Song et al. found only 2 of 14 men with Gleason score of 8 or above to be prostate cancer free at the time of analysis.³⁸⁷ 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 because of the likelihood of microscopic systemic prostate cancer metastases.

However, the largest multiinstitutional 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.³⁸⁹ In this study, predictors of a poor response to salvage radiation included Gleason scores of 8 to 10, preradiation PSA level of greater 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, salvage radiation produced a progression-free survival of 12% at 4 years. In another large retrospective study, Trock et al. reported that men treated with salvage radiotherapy resulted in a 3-fold improvement in prostate cancer–specific survival compared with men who received no salvage treatment (HR = 0.32, 95% CI of 0.19 to 0.54; P < 0.001).³⁹⁰ Importantly, this benefit was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Although these findings hint at marked advantage to salvage radiation therapy after prostatectomy, the studies are retrospective and the results may be confounded by selection bias. Prospective studies are needed to definitively determine 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 ADT 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 pathological 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.³⁹¹ 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 ADT to salvage radiation therapy for local prostate cancer recurrence after prostatectomy. Taylor et al. reported a benefit to the addition of ADT to salvage radiation therapy in a retrospective case series.³⁹² In this series, adjuvant ADT was given to men who received salvage radiation therapy for a median duration of 24 months. At 5 years, 81% of men receiving ADT (vs. 54% not treated with androgen deprivation) were free of PSA relapse. In contrast, Song et al. reported identical median disease-free survivals of 26 months for men treated with or without concurrent ADT along with salvage radiation therapy for prostate cancer recurrence.³⁸⁷ The 1999 ASTRO Consensus Panel concluded that there was insufficient evidence to support routine use of ADT with postprostatectomy radiation therapy.³⁸⁶

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 prostatectomy.393,394 Bastasch et al. reported that 100% of men who were potent after nerve-sparing radical prostatectomy remained potent after adjuvant IMRT.³⁹⁵ Despite these promising reports, side effects remain possible. Katz et al. 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.³⁹⁶