Published: September 2013
Prostate cancer has evolved from a relatively common but infrequently discussed neoplasm to a major clinical entity with significant public health and economic ramifications. The widespread application of prostate-specific antigen (PSA) into clinical practice in the late 1980s has had a paradigm-shifting impact on the management of prostate cancer. Among the most visible consequences of PSA-based screening is the substantial increase in the percentage of patients who are believed to have clinically localized disease. This, in turn, has translated into a significant increase in the number of patients undergoing curative-intent surgery and radiotherapy. Additional prostate cancer subsets have been created, including patients with PSA-only evidence of disease following curative-intent therapy, termed biochemical failure, and patients with rising PSA levels following androgen-deprivation therapy, termed castrate progressive prostate cancer, biochemically defined.
It is estimated that in2013 approximately 238,590 men in the United States will be given a new diagnosis of prostate cancer. Although the vast majority present with early disease, more than 29,720 men are destined to die from advanced disease yearly. Prostate cancer is the most common malignancy in U.S. men (excluding nonmelanoma skin cancer), and it is the second most common cause of cancer death, after lung cancer, in American men.1 Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men.
There is, however, a significant disparity in incidence and mortality rates among world regions, with a very low incidence in China and Japan in contrast to the United States and parts of Western Europe. This wide variability in incidence is likely multifactorial, with varying effects of genetic predisposition, diet, environmental factors, and the increased frequency of prostate biopsies performed in asymptomatic men undergoing screening with PSA.
Prostate cancer is also a disease of the older adults, as has been demonstrated in various autopsy series showing 70% to 80% of men older than 80 years with some evidence of latent disease. It is this observation that has complicated the prostate cancer screening debate, with critics questioning the ability of screening to discriminate between clinically relevant disease and latent disease that is not destined to cause symptoms or affect survival.
The causes of prostate cancer remain poorly understood. The main predictors of prostate cancer risk are age, race or ethnicity, and family history. The incidence of prostate cancer in U.S. men increases significantly above age 50 years. African American men have a higher incidence of prostate cancer–related death than European American and Latin American men. Prostate cancer can be sporadic, hereditary, or familial; the familial type is defined by a clustering of prostate cancer cases within members of a family. Men with an affected first-degree relative (ie, father or brother) have a 2-fold increase in the risk of developing prostate cancer. Similarly, early age of onset in any family member also increases the risk. In families with 2 or 3 affected first-degree relatives, the risk of developing prostate cancer increases 5- to 11-fold.2
There are numerous purported molecular, genetic, environmental, and dietary factors, with varying degrees of supporting evidence. Studies have provided compelling data to support the role of elevated serum testosterone and insulin-like growth factor-1 levels as significant risk factors. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including animal fat, calories, fruits and vegetables, antioxidants, and various micronutrients, but the specific role of dietary agents in promoting or preventing prostate cancer remains controversial. Also controversial are the data from recent observational studies that have hypothesized statins and nonsteroidal anti-inflammatory drugs (NSAIDs) as agents capable of decreasing the risk of developing any malignancy, including prostate cancer.
The pathophysiology of prostate cancer is poorly understood and, for many years, was an underrepresented area of investigation, in contrast to work in other solid tumors. Over the past decade, there has been a significant increase in prostate cancer research, with a concomitant increase in funding for basic investigation. Among the challenges faced by investigators attempting to understand early steps in the carcinogenic pathway is the lack of a reliable animal model of prostate cancer.
Although prostate cancer typically manifests in men aged 65 years and older, a growing body of evidence suggests that prostatic carcinogenesis is initiated much earlier. Prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer. Although not all patients with high-grade PIN (HGPIN) progress to develop invasive disease, PIN is characterized by cellular proliferation within pre-existing ducts and glands, with cytologic changes that mimic those of cancer.2 PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer. The recognition of the strong association of HGPIN and cancer has led many investigators to propose its use as an intermediate marker in chemoprevention studies.
Prostate cancer progression has also been related to a number of genetic abnormalities that affect the androgen receptor (AR) and other molecules that are involved in cell survival and apoptosis. In fact, over the past decade, recognition of a hereditary form of prostate cancer has prompted a vigorous research effort into the molecular genetics of prostate cancer, with various research teams performing linkage studies leading to the identification of several chromosomal loci that may be the source of prostate cancer susceptibility genes. At least 6 prostate cancer susceptibility loci have been identified, with increasing evidence that there is no single major gene accounting for a large portion of susceptibility to the disease. The portion of prostate cancer cases caused by mutations in these genes is estimated to be between 5% and 10%, and the hereditary form of the disease is diagnosed, on average, approximately 7 years earlier than the sporadic form. Despite the heterogeneity of this tumor and the lack of appropriate model systems of prostate cancer progression, these studies are beginning to provide important insights into the pathogenesis of this neoplasm.
The clinical manifestations of prostate cancer result from the effects of local growth of the tumor, the spread to regional lymph nodes via the lymphatic system, and the hematogenous dissemination to distant metastatic sites.
Although most patients with early-stage prostate cancer are asymptomatic, locally advanced disease can lead to obstructive or irritative voiding symptoms that result from local tumor growth into the urethra or bladder neck, extension into the trigone of the bladder, or both.
Prostate cancer most often spreads to bone, commonly leading to bone pain. A small but important subset of patients develop spinal cord impingement from the epidural spread of disease, resulting in pain and neurologic compromise that, depending on the location of the spinal lesion, could include the irreversible loss of bowel and bladder function and the ability to walk. Other common sites of metastatic spread include lymph nodes, with some patients presenting with progressive lymphedema, renal insufficiency, or both as a consequence of obstruction of pelvic lymphatics and ureteral outlet obstruction.
With the introduction of PSA testing into clinical practice in the late 1980s and the subsequent influential recommendations of the American Urological Society and the American Cancer Society, prostate cancer screening has become widely used in the United States. Conventional screening consists of PSA testing plus digital rectal examination [DRE]. Prostate cancer screening, however, remains controversial and recent clinical trial data have added fuel to the ongoing debate.3,4
Two large prospective screening trials, one in the US and one in Europe, have been reported and recently updated. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial included 76,685 men (aged 55 to 74 years) who were randomly assigned to either screening or usual care (controls). Participants in the screening arm were offered annual PSA tests for 6 years and DREs for 4 years. A positive test was defined as a PSA value >4 ng/mL or a suspicious DRE. Prostate cancer screening was not associated with a mortality benefit at 7 to 10 years of follow-up. An update of the data at 13 years of follow-up also demonstrated no survival benefit from routine prostate cancer screening.3 This trial has been appropriately questioned as a result of the high contamination rate (ie, off-protocol PSA screening) in the control arm.
The European Randomized Screening for Prostate Cancer (ERSPC) reported after 11 years of follow-up in 162,388 men (aged 55 to 69 years) from 8 European countries who were randomly assigned to receive either PSA screening or no screening. As in the initial report, PSA screening did not affect overall mortality, but it significantly reduced prostate-cancer mortality (the primary outcome; relative risk reduction, 21%; P = .001). To prevent 1 prostate cancer death, 1,055 men would have to be screened, and 37 cancers would have to be detected.4
In addition to these trials, the US Preventive Services Task Force (USPSTF) preliminary report on prostate cancer screening concluded by assigning a grade of D, defined as "The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.". The American Urologic Association has released a new clinical practice guideline on the role of screening in prostate cancer. The highlights of these guidelines include recommendations against routine screening of men less than 40 years of age, or those 70+ with less than a 10-15 year life expectancy. Additionally they note that there is insufficient evidence to recommend for or against routine screening in men ages 40-54 years of age, suggesting an informed consent discussion with patients/physicians.
Patients with significant comorbid conditions and those with life expectancies of less than 10 years are much less likely to benefit from therapeutic intervention and therefore should not be considered for screening. Alternatively, patients at potentially high risk, such as African Americans and those with 1 or more affected first-degree relatives might be appropriate candidates for screening at an earlier age, 40 to 50 years.
Over the past decade, the penetration of PSA-based screening has caused a stage migration, with an increasing percentage of patients with normal DRE findings receiving a diagnosis on the basis of an elevated PSA level (clinical stage T1c in the tumor, node, metastasis [TNM] staging classification). There has also been a dramatic decrease in the number of patients who initially present with evidence of metastatic disease.
Following a biopsy-proven diagnosis of prostate cancer, patients are clinically staged using the TNM system (Table 1) based on the extent of local tumor on rectal examination and the presence or absence of metastatic disease. In the past several years, a series of outcomes-based nomograms have been developed to improve the clinician's ability to predict the patient's pathologic stage (urology.jhu.edu/prostate/partintables.php) and his response to therapy (www.mskcc.org/mskcc/html/10088.cfm). These nomograms use clinically available parameters such as PSA, Gleason scores obtained from prostate biopsies or surgery, and other known prognostic factors, such as prostate capsule penetration, margin status, involvement of the seminal vesicles, and node status.
|T1a||Nonpalpable, with ≤5% of tissue with cancer, low grade (diagnosed by transurethral resection of the prostate)|
|T1b||Nonpalpable, with >5% of tissue with cancer, high grade (diagnosed by transurethral resection of the prostate), or both|
|T1c||Nonpalpable, but prostate-specific antigen level elevated|
|T2a||Palpable, ≤50% of 1 lobe|
|T2b||Palpable, ≥50% of 1 lobe, not both lobes|
|T2c||Palpable, involves both lobes|
|T3a||Palpable, unilateral capsular penetration|
Features such as a high prevalence rate, a long latency period, and identifiable risk factors have made prostate cancer a desirable tumor to test different chemopreventive strategies.
Work from a number of groups over the past several decades has provided hypothesis-generating data regarding the potential for selenium (S) and vitamin E (E) to lower prostate-cancer incidence and overall disease-related mortality. These data along with epidemiologic and preclinical data led an international group of investigators to conduct the phase-III, placebo-controlled, Selenium and Vitamin E Cancer Prevention Trial (SELECT). Eligible participants (n = 35,533) included black men aged 50 years and older and men of other races aged 55 years or older with no prior prostate-cancer diagnosis, PSA level ≤4, and unremarkable DRE. Participants were randomly assigned to receive either E (400 IU daily), S (200 mcg daily), E plus S, or placebo. All 4 groups were screened and followed based on community standards at 6-month intervals.
At a median follow-up of 5.46 years (range, 7-12 years), no significant differences were found between groups in terms of prostate-cancer incidence (the primary endpoint), as determined by routine clinical assessment. However there were 2 concerning trends: a small increase in the number of prostate cancer cases in men taking only vitamin E, and a small increase in the number of cases of diabetes in men taking only selenium. Updated data from SELECT show that after an average of 7 years (5.5 years on supplements and 1.5 off supplements), there were 17% more cases of prostate cancer among men who were taking only vitamin E than in men taking only placebos. This difference, an absolute increase of 11 cases per 1,000 men, was statistically significant.5
Several studies have evaluated different agents thought to be capable of reducing the risk of prostate cancer. Although agents such as retinoids and toremifene have failed to show statistical benefits in this setting, finasteride, an inhibitor of 5-alpha-reductase (5-AR) widely used to treat symptoms related to benign prostatic hyperplasia, appears to reduce the risk for developing prostate cancer. A large randomized trial with more than 18,000 participants comparing finasteride with placebo in men with a normal DRE and normal serum PSA values but with an elevated risk for prostate cancer (aged 55 or older, African American ethnicity, or a first-degree relative having prostate cancer) demonstrated a 25% decrease in the incidence of prostate cancer over a 7-year period for men taking finasteride. Despite this result, the controversy about a possible increase in the incidence of high-grade tumors (Gleason scores >7) initially dampened enthusiasm for the use of this agent as a chemopreventive strategy. Subsequent explanations for these findings suggest a diagnostic bias due to the effect of finasteride on prostate size. In fact, when prostate size was included in the analysis, the risk for high-grade tumors disappeared.6
The potential role of dutasteride a more potent 5-AR dual inhibitor was assessed in a multicenter, randomized, double-blind, placebo-controlled trial that evaluated its efficacy in preventing prostate cancer progression in men with low-risk disease who opted to be followed with active surveillance. The study involved 320 men (aged 48 to 82 years) with low-risk (T1c–T2a) prostate cancer, a Gleason score of ≤6 (no Gleason pattern score of ≥4), and a serum PSA level of ≤11 ng/mL. At 3 years, fewer men taking dutasteride experienced pathologic or therapeutic disease progression compared with men in the control group (38% vs. 48%; hazard ratio, 0.62; P = .009). The incidence of adverse effects was similar in both groups, and no patients developed metastatic disease or died of prostate cancer.7
For appropriately selected patients with clinically organ-confined prostate cancer, potential curative options include radical prostatectomy (RP) and radiation therapy (external-beam radiation therapy [EBRT], brachytherapy, or both). Other options include active surveillance, androgen-deprivation therapy (ADT), and cryotherapy. The optimal treatment for localized prostate cancer remains undefined, in part because of the absence of prospective randomized clinical trials comparing outcomes of surgery and radiotherapy. To date, only one randomized phase III trial has directly compared RP and watchful waiting in men with clinically localized disease. This study demonstrated a significant improvement in disease-specific survival as well as overall survival in men undergoing surgery.
Other factors that complicate our understanding of the impact of these therapies include the stage migration resulting from screening and the long natural history of localized prostate cancer. Biochemical relapse (BCR)—PSA recurrence following radical prostatectomy (PSA >0.2) or the nadir PSA value +2 ng/mL in patients receiving radiotherapy—is used as an intermediate clinical end point. Using BCR, after adjustment for stage and grade of tumors, outcomes with EBRT and radical prostatectomy at 8 years' follow-up were found to be equivalent.8
The relatively rapid evolution of radiotherapy techniques over time creates an additional challenge in identifying the most beneficial therapy for localized disease. Over the past 5 to 10 years, there has been increasing evidence of a dose-response relationship for prostate cancer, leading to an increase in conventional radiotherapy dosages for localized disease from the upper 60-Gy range to current doses of 72 Gy to 78 Gy. This increase in dosage has been made possible by technologic improvements in radiotherapy delivery systems using 3-dimensional conformal radiation therapy (3D-CRT). Various types of 3D-CRT, such as intensity-modulated radiotherapy, are computer-guided dosing techniques intended to minimize radiation dosage outside the target field.
Evidence from contemporary prospective, randomized clinical trials has also demonstrated that for selected patients, survival benefits—disease-free survival, time to the development of progressive disease, and overall survival—are gained when patients are treated with ADT. Appropriate patients include those with locally advanced disease (large tumor size, high Gleason grade, and high PSA levels. The addition of ADT has been prospectively studied in several settings, including neoadjuvant, concurrent, and adjuvant for periods often persisting for 6 to 36 months.
Prostate brachytherapy with 125I or 103Pd, which involves placing radioactive, rice-sized pellets directly into the prostate gland, has increasingly been used in the management of appropriately selected patients opting for radiotherapy. Compared with external beam radiotherapy, it has some important patient advantages, including a single outpatient treatment versus the typical 7-week course of external beam treatment. Some patients undergo brachytherapy followed by supplemental external beam radiotherapy. Whether the addition of supplemental external beam therapy improves outcomes and can justify increases in patient toxicity and cost remains controversial.
Given the lack of definitive evidence of the optimal therapy for localized prostate cancer, an important consideration for patients and the physicians are the potential side effects of radiotherapy and surgery (Table 2). The major side effects of therapy for localized prostate cancer affect urinary, bowel, and sexual function. Recent evidence has suggested that for patients undergoing radical prostatectomy, urologists with high-volume prostatectomy practices may have better patient outcomes.9 Although historically, reports of these side effects in the literature were typically those reported to the treating physicians in retrospective trials, there has been a large effort by numerous investigators using “modern” quality-of-life assessment tools to quantitate more precisely the effect of local therapies on long-term quality of life.10 These assessments should be used by patients and physicians to help guide treatment decisions.
|Treatment Modality||Impotence||Urinary Function||Rectal Injury|
|Brachytherapy||Variable||Acute bladder irritation, common; incontinence, rare||—|
|External beam radiotherapy||Common||Acute cystitis, common; late cystitis, infrequent||Acute diarrhea, common; rectal bleeding, infrequent; rectal perforation, rare|
|Radical prostatectomy||Variable||Incontinence (variable)||—|
Cryotherapy is another modality of local treatment for prostate cancer that initially had been abandoned because of its high rate of complications. Recently this modality of treatment has regained momentum as new and improved instruments and techniques have allowed reductions in toxicities and possibly greater efficacy. Currently, cryotherapy remains experimental in the United States.
Hormonal therapy—androgen deprivation therapy—has for more than 70 years been the primary initial treatment for patients with metastatic prostate cancer. Androgen ablation options for patients with advanced prostate cancer include bilateral orchiectomy, luteinizing hormone–releasing hormone (LHRH) analogues and antagonists, and combined androgen blockade, a combination of either an orchiectomy or LHRH analogue plus an antiandrogen. Although orchiectomy remains the historical gold standard, LHRH therapy is equivalent therapeutically, and patients are increasingly opting for medical therapy, in part because of the psychological implications of surgical castration. Orchiectomy remains an important option for patients presenting with spinal cord compression or diffuse, painful bone metastases, because it leads to the rapid achievement of castrate levels of testosterone (hours) compared with the 14 to 21 days required for LHRH analogues.
In men, 5% to 10% of circulating testosterone originates from the conversion of adrenal steroid precursors. Nonsteroidal antiandrogens act at the level of the androgen receptor to inhibit the stimulatory effects of testosterone. The use of an antiandrogen, in addition to LHRH or orchiectomy, is referred to as combined androgen blockade. The role of combined androgen blockade remains controversial. Evidence from a meta-analysis suggests only a modest improvement in survival, with some added toxicity and significant expense.11 Approximately 10% of patients started on LHRH therapy have an initial testosterone flare, so patients at risk–such as those with known bone or nodal metastases or at risk for urinary outlet problems–should be started concomitantly on an antiandrogen (eg, bicalutamide, flutamide) for 2 to 3 weeks to minimize this possibility.
Unfortunately, the vast majority of patients with metastatic prostate cancer have evidence of disease progression on hormonal therapy (median response duration to hormonal therapy, 24-36 months). Rapid progress in the understanding of the biology of the androgen receptor has led to the recognition that prostate cancer remains driven by this receptor even in the clinical context of progression following initial androgen deprivation therapy.12 Patients with clinical, radiographic, or PSA evidence of progression, and with evidence of castrate levels (testosterone levels <50 ng/dL), are referred to as having castration-resistant disease.
Patients with advanced prostate cancer typically have progressive bone pain, cancer cachexia, and fatigue. Significant anemia is common, although transfusion dependency is rare. Some patients with primarily nodal involvement develop significant lymphedema or ureteral obstruction. Spinal cord compression is relatively common, and advanced disease should be considered in patients presenting with back pain, even in the absence of neurologic findings. In prostate cancer patients with suspected spinal cord compression (without cervical spine symptoms, clinical findings, or plain film evidence of bone destruction), magnetic resonance imaging (MRI) of the thoracic and lumbosacral spine, with and without gadolinium, should be performed. Given the high incidence of involvement of both the lumbar and thoracic spines, failure to image both areas can compromise radiotherapy if untreated lesions become symptomatic and are detected later.
Historically, management of advanced disease consisted of second-line hormonal therapies and palliative radiotherapy. Palliative radiotherapy remains an important component of patient management although its role has diminished as more effective systemic therapies have been developed. There has been evidence, similar to findings for breast cancer and multiple myeloma, that bisphosphonate therapy with zoledronic acid can decrease skeletal progression rates and complications in patients with androgen-independent metastatic bone disease.13 Chemotherapy has the potential to provide meaningful palliation for selected patients, with reduced pain and improvement in other disease-related symptoms.
Over the past several years there have been unprecedented therapeutic developments in the management of castration-resistant disease. Two important phase III studies have evaluated docetaxel-based therapies in patients with advanced prostate cancer and demonstrated, for the first time, the ability to improve the survival of patients with advanced disease, albeit modestly.14 New drugs in development are targeting the androgen receptor directly with androgen-receptor antagonists and by inhibition of androgenic steroid synthesis.
Abiraterone is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 (CYP17), a critical enzyme in testosterone synthesis, thereby blocking androgen synthesis by the adrenal glands and testes and within the prostate tumor. A large phase III trial of abiraterone and prednisone in patients with castration-resistant prostate cancer was followed by a second study in chemotherapy-naïve patients demonstrated that patients receiving abiraterone plus prednisone had clinical and statistically significant improvement in progression-free survival. Following chemotherapy, patients treated with abiraterone and prednisone had a significant improvement in overall survival.15 Over-all survival was also demonstrated, but this did not meet statistical significance.16
Enzalutamide is a novel second-generation anti-androgen, developed in bicalutamide-resistant pre-clinical models. In a phase III trial similar in design to the abiraterone trial noted above, a statistically significant improvement in overall survival was demonstrated with a very favorable side effect profile.17 Trials of this agent in earlier stages of prostate cancer are ongoing.
Sipuleucel-T the first, and currently only, FDA-approved therapeutic vaccine is an autologous active cellular immunotherapy product that consists of autologous peripheral blood mononuclear cells (PBMCs) pulsed ex vivo and activated in vitro with a recombinant fusion protein (PA2024). Although a phase III trial testing the utility of the vaccine demonstrated a survival benefit in patients treated with vaccine compared to placebo, the lack of objective anti-tumor activity of the vaccine in most patients treated has limited the broad use of this therapy.18
Cabazitaxel, a second-generation taxane, has demonstrated a survival benefit in patients with advanced prostate cancer following therapy with docetaxel. Its primary toxicity is myelosuppression which requires careful patient monitoring.19
Radium-223 is a targeted alpha emitter that selectively binds to areas of bone turnover in bone metastases. It is administered as an outpatient IV infusion. A large multicenter phase III trial randomized patients with castration resistant metastatic prostate cancer- patients both docetaxel naïve and treated patients were enrolled. Patients treated with Radium-223 had both a statistically significant improvement in survival as well as a decrease in symptomatic skeletal events.20
Although recent progress has been made and new agents are on the horizon, advanced prostate cancer remains an incurable disease. Vigorous efforts to manage pain and other disease-related symptoms through the appropriate use of opioids and palliative radiotherapy are essential for the optimal management of patients with progressive disease.