Prostate cancer remains the most common noncutaneous malignancy diagnosed in American men and is the second leading cause of cancer-related deaths in that group. In the year 2008, almost 187,000 will be diagnosed with prostate cancer and an estimated 29,000 men will die of the disease.

The only undisputed risk factors for prostate cancer are older age, African-American race, and positive family history. Prostate cancer is generally a disease of elderly men; risk increases exponentially with age, with a median age at presentation of 68 years. Eighty percent of prostate cancer diagnoses and 90% of prostate cancer deaths occur in men older than 65. The incidence rates of the disease among African-American men are higher than rates for men in any other racial or ethnic background. African-American men are more likely to be diagnosed with prostate cancer and to die from it than their Caucasian counterparts. The estimated lifetime risk of prostate cancer is 17.6% and 20.6% respectively for Caucasians and African-Americans, while the estimated lifetime risk of death is 2.8% and 4.7%. Studies suggest that early onset prostate cancer may be inherited in an autosomal dominant fashion, and it is estimated that approximately 10% of all prostate cancer cases are hereditary. A large twin study suggests that genetic factors may account for as much as 42% of prostate cancer risk, although the absence of clear, highly penetrant markers suggests that in the majority of men, prostate cancer risk involves a complex interaction of multiple genetic and environmental factors.

Additional factors such as diet, obesity, hormones, inflammation and sexually transmitted diseases, and occupational exposure have all been implicated in prostate carcinogenesis, but without consistent results. Dietary fat may be a risk factor for prostate cancer. Multiple epidemiological, case–control, and cohort studies have suggested a moderate to strong increased risk of developing prostate cancer, particularly advanced disease, associated with total dietary fat, saturated fat, alpha linolenic fatty acid, and cooked red meat. Two large prospective studies and a smaller case–control study suggest that fish intake may be protective, possibly owing to marine omega-3 fatty acids—known antagonists of arachidonic acid, which suppress the production of proinflammatory cytokines. Evidence for the association with dietary fat is further correlated with worldwide incidence patterns; prostate cancer is more common in the United States and northern European countries and is relatively rare in Asia and Africa. When Asian men migrate to the West and change from a low-fat to a high-fat diet, their risk of prostate cancer increases. These studies, however, are complicated by the fact that many of the men migrating from low-fat diet areas also consume green tea and soy products, which contain isoflavones and estrogen that may act as antioxidants and chemoprotectants against prostate-specific carcinogenesis. Several epidemiologic studies have suggested an inverse relationship between soy intake and prostate cancer risk.

Most studies have not demonstrated an association between obesity and prostate cancer incidence, but there is growing evidence to support an association between obesity and aggressive prostate cancer, recurrence after primary therapy, and death from prostate cancer. Data from the Prostate Cancer Prevention Trial (PCPT) suggest that obesity increases the risk of higher-grade cancers, but decreases the risk of low-grade prostate cancer. While BMI ≥30 was associated with an 18% decrease in low-grade cancers (Gleason grade < 7) there was a 29% increase in Gleason grade of 7 and above and a 78% increase in high-grade cancers (Gleason 8–10). These data suggest that obesity may differentially affect the development of aggressive and nonaggressive prostate cancer and may somehow play a role in the progression from latent to clinically significant prostate cancer. Although the specific role obesity plays in prostate cancer risk is unclear, it may be linked to other risk factors such as dietary fat and meat intake, hormone metabolism, and insulin metabolism. The prevalence of obesity also correlates with prostate cancer risk across populations and may provide a link between the increased risk of prostate cancer with westernization.

Although a diet rich in fruits and vegetables is associated with reduced risk in several cancers, their effect on prostate cancer risk is still unclear. Several studies have shown an inverse association with tomatoes and tomato products, presumably owing to the effects of lycopene, the most common carotenoid in the human body and one of the most potent carotenoid antioxidants. Data from the large Health Professionals Follow-Up Study (HPFS) suggest that frequent consumption of tomato products is associated with a decreased risk of prostate cancer, and in a meta-analysis of 21 case–control and cohort studies, a statistically significant 10% to 20% risk reduction was associated with high versus low intake of tomatoes. The majority of these studies also show a stronger effect for cooked versus raw tomatoes.

Although it seems intuitive that testosterone levels may influence the incidence of prostate cancer, no evidence exists to confirm this association. Dihydrotestosterone, the active hormone produced from the conversion of testosterone by the enzyme 5α-reductase, is associated in some studies with increased risk. A prospective, population-based study of 1156 men showed no correlation between 17 different hormones and prostate cancer development, with the possible exception of androstanediol glucuronide. Importantly, no dose–response relationships were seen, suggesting that serum hormonal levels may not be useful even in risk stratification.

There is some evidence that chronic inflammation may increase prostate cancer risk. One meta-analysis of 11 studies on prostatitis and prostate cancer showed an overall relative risk of 1.6, while another meta-analysis of aspirin and cancer showed that regular aspirin use was associated with an approximately 15% decrease in prostate cancer risk. Population based studies have suggested an increased risk of prostate cancer in patients with STDs, including syphilis, recurrent gonorrhea, HPV, and HIV. A meta-analysis of 17 studies of prostate cancer and sexual patterns suggested that an increased number of sexual partners was associated with an increased prostate cancer risk, possibly through an increased exposure to STDs. There are currently no strong data to suggest a link between benign prostate hypertrophy (BPH) and prostate cancer risk.

Chemoprevention is an area of ongoing research, and in many ways, prostate cancer is an ideal disease for this approach—relatively slow growing, centered in the elderly population, yet with devastating effects and difficult management after the onset of metastasis.

Finasteride

Finasteride is a drug that blocks the actions of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone. The PCPT enrolled 18,000 men between January 1994 and May 1997 to study the efficacy of finasteride for decreasing the period prevalence of prostate cancer. The trial was based on two observations: androgens are required for prostate cancer development and men with congenital 5α-reductase deficiency develop neither BPH nor prostate cancer. This randomized, double-blind, placebo-controlled trial was closed early because of a perceived risk reduction with finasteride. After 7 years of treatment, prostate cancer was diagnosed in 18.4% of the men on finasteride and 24.4% of the men on placebo, a 6% absolute risk reduction and 24.8% relative risk reduction. The risk reduction associated with finasteride was apparent across all risk groups defined by age, family history, race, and PSA. Finasteride use was also associated with increased sexual dysfunction, but decreased lower urinary tract symptoms.

Results from the trial, however, were tempered by an apparent increase in high-risk cancers in the finasteride group; 6.4% of the cancers in the finasteride group were Gleason grade 8 to 10 versus 5.1% in the controls. This represented a statistically significant 1.3% absolute increase in the risk of high-grade cancer associated with finasteride. Since high-grade cancers are associated with a poorer prognosis after definitive therapy, the role of finasteride in the prevention of prostate cancer remains controversial at this time. Several experts, however, have questioned whether the increase in high-grade cancers associated with finasteride in the PCPT is real or artifact. If finasteride induced higher-grade tumors, the incidence of prostate cancer in the finasteride arm should increase at a greater rate, particularly as the trial progressed and the duration of prostate exposure to finasteride increased. This was not the case however. Furthermore, ultrasound evaluation showed a 24.1% decrease in prostate volume in the treatment arm (median volume 25.5 cm3 versus 33.6 cm3). There is evidence to suggest that the risk of missing high-grade cancers increases as prostatic volume increases; with a smaller volume, a larger proportion of the gland is biopsied and evaluated, increasing the chance of detecting cancer. Thus, some experts claim that the increased risk of high-grade cancer in the finasteride group could be because of increased sampling rather than a medication effect. Finally, there is new evidence to suggest that finasteride enhances the sensitivity of PSA for prostate cancer, by decreasing BPH and thus its effect on PSA levels.

Further evaluation of the role of 5α-reductase inhibitors in prostate cancer prevention will occur with The Reduction by Dutasteride of Prostate Cancer Events (REDUCE), a randomized, double-blind, placebo-controlled trial currently enrolling patients in Europe and the United States, randomizing men to Avodart, a new 5α-reductase inhibitor, versus placebo. Until these results are available, widespread use of finasteride for chemoprevention is currently not being advocated by most experts in the field. It remains, however, an effective treatment for BPH.

Vitamin E and Selenium

In recent years, the role of oxidative stress in the development of prostate cancer has been investigated. The damage caused by reactive oxygen species is not limited to deoxyribonucleic acid (DNA); it can encompass lipids and proteins as well. The association of prostate cancer and a high-fat diet may be secondary to the generation of increased fatty acids, which can cause lipid peroxidation. The two most exciting agents in the area of chemoprevention are selenium and vitamin E.

Selenium is an essential trace nutrient, which enters the food chain via consumption of plants and plant eating animals. Since there is marked geographic variability in foods, linked to local soil content, selenium intake cannot be easily linked to dietary sources. Selenium was initially investigated in the prevention of recurrent basal and squamous cell skin cancers, and although it did not affect the incidence of recurrent skin cancer, an unexpected finding was a decrease in the risk of prostate, colorectal, and lung cancer. Remarkably, the incidence of prostate cancer decreased by 65%. Subsequently, both case–control and randomized placebo-controlled trials have demonstrated a decrease in the risk of developing prostate cancer associated with selenium supplementation.

Alpha tocopherol is the most active and abundant source of vitamin E, and its antioxidant properties have been studied extensively in a variety of prostate cell lines and animal models. Results from human studies are conflicting. In one prospective study, there was no protective association between increased serum levels of vitamin E and the risk of prostate cancer, while other studies have shown a statistically significant positive effect. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) randomized 29,133 male smokers to either α-tocopherol (50 mg daily), beta carotene (20 mg daily), both or placebo. Although the primary endpoint was lung cancer incidence and mortality, the trial demonstrated a statistically significant 32% decrease in prostate cancer incidence and a 41% decrease in prostate cancer mortality in the groups taking α-tocopherol supplements. A recent meta-analysis of 19 randomized clinic trials, however, suggested that long-term supplemental vitamin E ≥400 IU daily was associated with an increase in mortality from all causes. This has caused many to question the long-term use of this supplement as a chemoprotectant in the absence of data demonstrating clear benefit.

SELECT (Selenium and Vitamin E Cancer Prevention Trial) is an NCI sponsored, randomized, prospective, double-blind trial designed to determine whether selenium and vitamin E decrease the risk of prostate cancer in healthy men. It will enroll 32,400 healthy men with a normal digital rectal examination and a prostate-specific antigen (PSA) ≤4 ng/mL. The 2 × 2 factorial design includes four study arms: vitamin E + placebo, selenium + placebo, vitamin E + selenium, and placebo + placebo. The primary end point of the trial is the clinical incidence of prostate cancer; secondary endpoints include prostate cancer-free survival, mortality from any cause, and the incidence and mortality of other cancers or diseases affected by chronic supplementation with vitamin E and/or selenium. The planned duration of the study is 12 years with a minimum 7 years of treatment, and final results are expected by 2013. As prostate cancer incidence increases with age, it is important to enroll as many geriatric patients as possible, as the greatest risk reduction may be possible in this group.

Most men who present with prostate cancer are asymptomatic, particularly in the era of PSA testing, which detects many cancers long before they are clinically apparent. Patients rarely have urinary symptoms, as the majority of cancers arise in the posterior aspect of the prostate. Most men undergo evaluation after routine screening reveals either an elevated PSA or abnormal digital rectal examination (DRE). Since the advent of PSA testing and regular screening, there has been a demonstrated risk migration, and presently in the United States, the majority of patients have clinically localized, intermediate-risk prostate cancer at diagnosis. A minority of patients are diagnosed when they present with symptomatic metastatic disease, usually manifested as bony pain; CapSure data demonstrate that while in 1988, 14% of new prostate cancer patients presented with metastatic disease, that number had fallen to 3.3% by 1998. Although screening has strongly influenced this downward stage migration, there are no data to suggest that it has significantly decreased prostate cancer–specific mortality; there is some concern that screening may detect a significant number of clinically insignificant cancers. The wide discrepancy between incidence and mortality attributed to prostate cancer demonstrates that some slow growing cancers may never be life threatening. Published guidelines do exist, notably from the NCCN (National Comprehensive Cancer Network). Currently, there are two large scale, long-term, randomized clinical trials ongoing in the United States and Europe evaluating whether screening decreases mortality; these trials may ultimately provide evidence for the validity of wide-based screening.

A difficult task for primary physicians is thus deciding which patients should undergo screening for prostate cancer. In the absence of definitive data, a reasonable approach to screening should involve an active discussion between the physician and patient, taking into consideration the patient’s overall health and treatment preferences. Men with a life expectancy of 10 to 15 years (owing to age or comorbidities) should be informed that screening may not be beneficial. Younger men with a family history of prostate cancer and African-American men should be encouraged to undergo screening, as the disease prevalence is high in these groups. Any patient with symptoms that may be referable to prostate cancer (bone pain, hypercalcemia, symptomatic pelvic lymphadenopathy) warrants a PSA evaluation as a part of his initial evaluation, since symptomatic patients can enjoy significant improvement with the institution of hormonal therapy. An ongoing challenge for the geriatrician is the need to remain current on the development of new treatments. In the future, as more targeted and less toxic therapies are identified, PSA screening may become a routine part of health maintenance for all men.

The appropriate screening examinations for prostate cancer include a serum PSA and DRE. PSA is a protein produced and secreted by both normal prostate and prostate cancer cells. It provides a sensitive but not highly specific screening test, as it is also elevated with BPH, inflammation, and infection of the prostate. The proposed cutoff is 4.0 ng/mL, but studies have shown that 15% of men with normal PSA levels will have prostate cancer and 2% will have high-grade prostate cancer. PSA is, however, more sensitive than DRE, detecting more cancers and earlier stage and smaller sized cancers than rectal examination alone. PSA-doubling time is also a significant factor in prostate assessment, and any patient with a rapid PSA-doubling time should be sent for further evaluation, even if the absolute value of the PSA is below the normal cutoff level. DRE yield alone is low; estimates are that only 3% to 6% of examinations yield suspicious results. On the basis of an elevated PSA or an abnormal DRE, the patient should be referred for a transrectal ultrasound-guided prostate biopsy. In general, six to twelve cores are taken for evaluation; areas that are abnormal on DRE may receive more biopsy attempts.

If the biopsy is positive, a Gleason score is assigned. This score is one of the most important determinants of prognosis. The pathologist assigns a numerical value (on a scale of 1 to 5) to the most prevalent and the second most prevalent grades of cancer seen in the specimens. The score is then reported on a scale of 2 to 10, with 10 being the most aggressive cancer. Gleason scores should be reported separately, for example, 3 + 4 = 7, as the primary pathology has prognostic implications.

Risk stratification plays an important role in both the selection and timing of treatment and is an important part of the initial evaluation. After diagnosis, the natural course of prostate cancer can be estimated from tumor volume, aggressiveness, PSA level, and extent of disease. Tumor volume assessment includes local stage, the number of positive biopsy cores, and the extent of cancer in affected cores. Gleason score is currently the standard measurement of aggressiveness with Gleason 5 to 6 cancers considered low grade, Gleason 7 intermediate grade, and Gleason 8 to 10 high grade. Taking all of these prognostic factors into effect, newly diagnosed patients are classified as having low-, intermediate-, or high-risk disease. In addition to these broad risk groups, multiple nomograms are available to help clinicians estimate an individual patient’s probability of localized disease, risk of progression without intervention, and risk of recurrence after definitive therapy. Several of these tools are available online, and they can sometimes be more helpful than the broad categories in assessing an individual’s risk, as they allow integration of discordant factors (e.g., high PSA with low Gleason score). PSA velocity prior to diagnosis may also provide valuable information in risk assessment; a PSA velocity ≥2.0 ng/mL in the year prior to radical prostatectomy is predictive of greater risk of biochemical recurrence, cancer-specific mortality, and overall mortality.

The staging evaluation for men with known prostate cancer or symptoms that could be attributable to metastatic prostate cancer includes serum chemistries, PSA, bone scan, and computed tomography (CT) scan of the abdomen and pelvis. These initial tests provide evaluation of the most likely sites of metastatic disease to avoid inappropriate surgical intervention or radiation therapy. The extent of evaluation for metastatic disease relates to the likelihood of finding disease. A recent prospective survey of 3690 men described the positive yield of bone scan, and CT was <5% and 12%, respectively, for men with a PSA of 4 to 20 ng/mL. The yield decreased to 2% and 9% for those who also had a Gleason score of ≤6. Only the combination of a Gleason score of 8 to 10 and a PSA >20, or a PSA >50 alone, identified a group of men who had a >10% yield on bone scan and a 20% yield on CT scan. To stage in an appropriate and cost-effective manner, patients with low PSAs and low to intermediate Gleason scores do not require evaluation. More risk factors increase the degree of preoperative evaluation. Table 96-1 provides guidelines for preoperative staging. These studies also provide a baseline for follow-up. Figure 96-1 illustrates a stepwise approach to evaluation, monitoring, and treatment.