Definition

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 newly diagnosed 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 hormonal therapy, termed androgen-independent prostate cancer, biochemically defined.”

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Prevalence

It was estimated that there would be 234,460 new prostate cancer diagnoses in 2006, with 27,350 men dying of the disease. Prostate cancer is the most commonly diagnosed neoplasm (excluding nonmelanoma skin cancer), and is the second most common cause of cancer death, after lung cancer, in American men. 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, and other environmental factors and the widespread use of prostate cancer screening in the United States. Various autopsy studies have shown that histologic evidence of prostate cancer increases with age, and that roughly 70% to 80% of men older than 80 years will have 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.

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Risk Factors

The causes of prostate cancer remain poorly understood. The main predictors of prostate cancer risk are age, race, 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 white men. Prostate cancer can be sporadic, hereditary, or familial, with the latter defined by a clustering of prostate cancer cases within members of a family. Men with a father or brother diagnosed with prostate cancer are twice as likely to develop the disease than are men without affected relatives. In those families with two or three affected first-degree relatives, the risk of developing prostate cancer increases 5- to 11-fold. ¹

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-I levels as significant risk factors. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, antioxidants, and various micronutrients, but the specific role of dietary agents in promoting or preventing prostate cancer remains controversial.

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Pathophysiology

The pathophysiology of prostate cancer is poorly understood and, for many years, was an underrepresented area of investigation, in contrast to work in colon and breast cancers. Over the past decade, there has been a significant increase in focus on this neoplasm, 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.

High-grade prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer. PIN is characterized by cellular proliferation within preexisting ducts and glands, with cytologic changes that mimic those of cancer. ¹ 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 high-grade PIN and cancer has led many investigators to propose its use as an intermediate marker in chemoprevention studies.

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 six prostate cancer susceptibility loci have been identified to date, with increasing evidence that there is no single major gene accounting for a large proportion of susceptibility to the disease. The proportion of prostate cancer cases caused by mutations in these genes is estimated to be 5% to 10%, with the hereditary form of the disease diagnosed, on average, approximately 7 years earlier than the sporadic form of the disease.

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Signs and Symptoms

The clinical manifestations of prostate cancer result from the effects of local growth of the tumor, the spread to regional lymph nodes via the lymphatics, and the hematogenous dissemination to distant metastatic sites.

Although most patients with early-stage prostate cancer are asymptomatic, locally advanced disease may 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 frequently spreads to bone, frequently leading to bone pain. A small but important subset of patients may 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.

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Diagnosis

With the introduction of PSA 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 (PSA plus digital rectal examination) has become widely used in the United States. Prostate cancer screening remains highly controversial, as evidenced by the wide array of screening recommendations (Table 1), because there is no prospective evidence demonstrating a decrease in prostate cancer-specific mortality. ²

Several prospective screening trials are ongoing in the United States and worldwide. Among the largest are the European Randomized Screening for Prostate Cancer (ERSPC) trial, with more than 160,000 men, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), sponsored by the National Cancer Institute, which completed enrollment of more than 154,000 participants, including 75,000 men, in the summer of 2001. It is hoped that the results of these trials may provide more definitive guidance to patients and clinicians about the impact of screening. Until more definitive data are available, many major medical societies have recommended a careful discussion with individual patients, before screening, regarding the potential risks and benefits. 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 one or more affected first-degree relatives, might be appropriate candidates for screening at an earlier age, 40 to 50 years.

Over the last decade, the penetration of PSA-based screening has caused a stage migration, with an increasing proportion of patients with normal rectal examination findings being diagnosed on the basis of an elevated PSA level (clinical stage T1c in the tumor, node, metastasis [TNM] staging classification). There has also been a concomitant dramatic decrease in the number of patients who present initially with evidence of metastatic disease.

Following a biopsy-proven diagnosis of prostate cancer, patients are clinically staged using the TNM system (Table 2) based on the extent of local tumor on rectal examination and the presence or absence of metastatic disease. In the last several years, a series of outcomes-based nomograms have been developed to improve the clinician's ability to predict the patient's pathologic stage (http://urology.jhu.edu/prostate/partintables.php) and his response to therapy (http://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.

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Treatment and Outcomes

Chemoprevention

Finasteride, an inhibitor of 5a-reductase, has been widely used to treat symptoms related to benign prostatic hyperplasia. A large randomized trial (over 18,000 participants) comparing finasteride with placebo has demonstrated a 25% decrease in the prevalence of prostate cancer over a 7-year period for men taking finasteride. In the original report of this study, one of the important caveats was the finding that tumors of Gleason grades 7 to 10 were somewhat more common in patients receiving finasteride. Finasteride has long been known to decrease the size of the prostate gland, and there is now compelling evidence that the sextant biopsies used as standard practice in this study are more likely to detect prostate cancer in smaller glands (finasteride-receiving patients) and, given that cancer is detected, it is more likely to be of high grade. ³

Localized Prostate Cancer

For appropriately selected patients with clinically organ-confined prostate cancer, potential curative approaches include radical prostatectomy and radiation therapy. 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. 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. Using biochemical failure—PSA recurrence following radical prostatectomy or three consecutive rising PSA levels after a nadir in patients receiving radiotherapy—as an intermediate end point and after adjustment for stage and grade of tumors, outcomes with external beam radiotherapy and radical prostatectomy at 8 years' follow-up are equivalent. ⁴ Among the challenges in identifying the most beneficial therapy for localized disease is the relatively rapid evolution of radiotherapy techniques over time. Over the last 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 dosages of 72 to 78 Gy. This increase in dosage has been made possible by technologic improvements in radiotherapy delivery systems using three-dimensional conformal techniques (computer-guided dosing techniques that attempt to minimize radiation dosage outside the target field), such as intensity-modulated radiotherapy. Evidence from prospective, randomized, clinical trials has also demonstrated that for select patients undergoing external beam radiotherapy who have poor-risk disease features, such as large tumor size, high Gleason grade, and more elevated PSA levels a survival benefit is gained when they receive concomitant and adjuvant androgen deprivation therapy for periods ranging from 6 months to 3 years.

Prostate brachytherapy with ¹²⁵I or ¹⁰³Pd 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 will receive 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 helping guide their decision is the potential side effects of radiotherapy and surgery (Table 3). 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. ⁵ Although, historically, reports of these side effects in the literature were typically those reported to the treating physicians in retrospective reviews, there has been a large effort by numerous investigators using “modern” quality-of-life assessment tools to quantitate more precisely the impact of local therapies on long-term quality of life. ⁶ These assessments should be used by patients and physicians to help guide treatment decisions.

Metastatic Prostate Cancer

Hormonal therapy—androgen ablation—has for more than 60 years been the primary initial treatment of 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 human males, 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, with meta-analysis evidence of only a modest improvement in survival, with some added toxicity and significant expense. ⁷ It is important to remember that approximately 10% patients started on LHRH therapy will 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 (e.g., bicalutamide, flutamide) for 2 to 3 weeks to obviate this possibility.

Unfortunately, the vast majority of patients with metastatic prostate cancer will have evidence of disease progression on hormonal therapy (median response duration to hormonal therapy, 24 to 36 months). 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 may develop significant lymphedema or ureteral obstruction. Spinal cord compression is relatively common, and a high index of suspicion must be maintained for 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 bony destruction), magnetic resonance imaging (MRI) of the thoracic and lumbosacral spine, with and without gadolinium, should be the minimum study performed. Given the high frequency of involvement of both the lumbar and thoracic spines, failure to image both areas may compromise radiotherapy if untreated lesions become symptomatic and are detected at a later time.

Historically, management of advanced disease consisted of second-line hormonal therapies and palliative radiotherapy. The latter remains an important component of patient management. 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. ⁸ Over the past decade, there has been compelling evidence that chemotherapy has the potential to provide meaningful palliation for select patients, with improvement in pain and other disease-related symptoms. 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 modestly. ⁹ Current research efforts are underway to integrate a large number of targeted agents into the management of this disease. However, 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.

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Summary

• Prostate cancer is the most commonly diagnosed neoplasm (excluding nonmelanoma skin cancer), and is the second most common cause of cancer death, after lung cancer, in American men.
• Prostate cancer screening with PSA testing and a digital rectal examination is widely performed, but data supporting an impact on survival are not yet available.
• Chemotherapy for advanced prostate cancer has the ability to palliate the disease and modestly improve survival.

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Suggested Readings

• American College of Physicians . Screening for prostate cancer. Ann Intern Med. 126: 1997; 480-484.
• Bianco FJ, Riedel ER , Begg CB. Variations among high-volume surgeons in the rate of complications after radical prostatectomy: Further evidence that technique matters. J Urol. 173: 2005; 2099-2103.
• Bostwick DG. High-grade prostatic intraepithelial neoplasia: The most likely precursor of prostate cancer. Cancer. 75: 1995; 1823-1836.
• Goodman PJ, Thompson IM , Tangen CM. The Prostate Cancer Prevention Trial: Design, biases and interpretation of study results. J Urol. 175: 2006; 2234-2242.
• Harlan LC, Potosky A , Gilliland FD. Factors associated with initial therapy for clinically localized prostate cancer: Prostate Cancer Outcomes Study. J Natl Cancer Inst. 93: 2001; 1864-1871.
• Kupelian PA, Elshaikh M , Reddy CA. Comparison of the efficacy of local therapies for localized prostate cancer in the PSA era: A large single-institution experience with radical prostatectomy and external beam radiotherapy. J Clin Oncol. 20: 2002; 3376-3385.
• Maximum androgen blockade in ad-vanced prostate cancer: An overview of the randomised trials. Lancet. 355: 2000; 1491-1498.
• Saad F, Gleason DM , Murray R. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 94: 2002; 1458-1468.
• Tannock I, de Wit R , Berry W. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 351: 2004; 1502-1512.