Introduction

Carcinogenesis is a multistep molecular process induced by genetic and epigenetic changes that disrupt the balance between cell proliferation, apoptosis, differentiation, senescence, and the pathways controlling these cellular processes. Precursor lesions that represent intermediate stages between normal and malignant cells can arise as long as 20 years before the appearance of cancer. This, coupled with the age-dependent incidence of most cancers, suggests that the carcinogenic process occurs slowly and during a protracted interval. In theory this provides the opportunity to intervene before a malignancy is established, using either lifestyle changes such as dietary alterations, smoking cessation, exercise, or chemoprevention, defined as the use of natural or synthetic agents that reverse, inhibit, or prevent the development of cancer. The goal of primary chemoprevention is to decrease the incidence of a given cancer, simultaneously reducing both treatment-related adverse events and mortality. Effective chemoprevention requires the use of nontoxic agents, usually administered orally, that inhibit specific molecular steps in the carcinogenic pathway.

Prostate cancer is an attractive and appropriate target for primary prevention because of its incidence, prevalence, and disease-related mortality. The molecular pathogenesis of prostate cancer also lends itself to a primary prevention strategy. Several histologic lesions, such as atypical small acinar proliferation , proliferative inflammatory atrophy , and prostatic intraepithelial neoplasia (PIN) , that contain both genetic and epigenetic changes intermediate between normal prostatic epithelium and prostate cancer have been described. Clinically evident prostate cancer is rare in men under 50 years of age, while PIN is apparent at autopsy in men younger than 30 years. Furthermore, the prevalence of PIN is similar across different populations, even those that have different levels of risk associated with developing clinically evident prostate cancer, suggesting that external environmental influences are important and potentially modifiable. There are numerous observations in the epidemiologic literature suggesting associations between various dietary, lifestyle, and genetic factors and the risk of developing prostate cancer. The Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT), two large-scale, population-based trials with the goal of preventing prostate cancer, have been launched by the National Cancer Institute and are two of the trials discussed in this review.

Finasteride in Prostate Cancer Prevention

The Prostate Cancer Prevention Trial: Background and Results

The PCPT was the first large-scale, population-based trial to test a primary chemopreventive strategy in men at risk of developing prostate cancer. The trial was based on the observations that androgens are required for the development of prostate cancer, and men with congenital deficiency of 5α-reductase type 2 are unaffected by benign prostatic hyperplasia and prostate cancer. The PCPT tested the hypothesis that treatment with finasteride, which induces an acquired deficiency of type-2 5α-reductase, would lower intraprostatic dihydrotestosterone (DHT) levels and thereby prevent prostate cancer. In PCPT, 18,882 men >55 years of age, with a normal digital rectal examination (DRE) and a prostate-specific antigen (PSA) level of <3.0 ng/ml were randomly assigned to treatment with finasteride (5 mg/day) or placebo for 7 years. Prostate biopsy was recommended if the subsequent annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng/ml or if the DRE result was abnormal. The primary end point was the prevalence of prostate cancer during the 7 years of the study, as diagnosed either by biopsies conducted as a result of abnormal DRE or PSA results ('for cause' biopsies) or by end-of-study biopsies.

There were four main findings of the PCPT:

The prevalence of prostate cancer was reduced by 24.8% (RELATIVE RISK [RR] = 0.75, 95% CI 18.6-30.6), from 24.4 to 18.4% in those randomized to finasteride compared with placebo.

The prevalence of tumors at GLEASON SUM 7-10 was higher in the finasteride group than with placebo (6.4 vs 5.1%, RR = 1.27, 95% CI 1.07-1.50).

The risk reductions associated with finasteride among risk groups defined by age, family history, race, and PSA were of the same general magnitude.

Adverse events relating to sexual dysfunction were more common with finasteride, whereas urinary symptoms were more common with placebo.

Biological Significance of 'Prevented' Tumors

There are several areas of debate over the results of the PCPT that have relevance to the question of whether finasteride is a useful preventive agent. One of these is whether the Gleason sum 6 cancers that were 'prevented' are biologically significant, a term which can be defined as destined to metastasize or to kill the patient. At present there are no biological, clinical, pathological, or radiographic markers that allow us to answer this question for an individual tumor. Either because of or in spite of this uncertainty, in the US, 95% of patients with newly diagnosed Gleason sum 6 tumors choose some form of definitive therapy instead of watchful waiting. This high treatment penetrance suggests that, even when lacking the ability to assign the biologic significance of a tumor for affected men, the tumors are 'clinically relevant' because they lead to treatment with attendant morbidity. Viewed in the context of 'clinical relevance' as defined by current urologic practice, preventing Gleason sum 6 tumors by administration of finasteride has the added advantage of avoiding the 'burden of cure'-the anxiety, cost and morbidity associated with their treatment. The magnitude of this burden has been quantified by the National Health Interview Survey, which demonstrated that prostate cancer survivors suffer lower overall health-related quality of life, higher levels of lost productivity (measured in days lost from work in past 12 months), and were more likely to report their health as fair or poor than control subjects that have not had cancer.

Prevalence of Tumors

Another question is whether the increased prevalence of higher grade tumors is real or artifactual. Finasteride is known to change the appearance of prostatic epithelium in a way that could bias interpretation, and the Gleason grading system has never been validated on prostate glands treated with antiandrogenic agents. There are also some plausible biological hypotheses that suggest the association of finasteride with higher grade tumors could be real. A group of pathologists and scientists have been convened by the PCPT Steering Committee to investigate this and other issues related to explanation of the trial results.

An additional potential confounder relates to the possibility of overdetection bias in the finasteride-treated prostate glands. Such a bias is suggested by the following observations: finasteride-treated glands were on average 25% smaller than those on the placebo arm; a similar number of tissue cores (mean of six per patient) were taken on end-of-study biopsy in both arms of the trial; previous observations that shorter term finasteride use causes a roughly equal volume reduction in both the transition and peripheral zones of the prostate; and the likelihood that, with equal sampling volumes, a greater proportion of the prostate is sampled in a smaller gland than in a larger one. Together, these observations suggest that there was an increased chance of detecting cancer in the finasteride-treated glands, and that the 25% risk reduction seen in this arm of the trial actually underestimates its protective effect.

It has also been suggested that the risk reduction with finasteride use in the PCPT was closer to 10% than 25%, based on the observation that fewer men in the finasteride arm underwent 'for cause' biopsies, and on the assumption that the end-of-study biopsies were not clinically relevant. Conclusions based only on 'for cause' biopsies should be interpreted cautiously, however, because of known biases in ascertainment of diagnosis, owing to differences induced by finasteride in DRE results, PSA levels, and prostate volume, and issues relating to adherence and unreported use of finasteride in the placebo arm (i.e. drop-in). Furthermore, the assumption that cancer detected by end-of-study biopsies is not clinically relevant is arguable given data from the placebo arm of the PCPT demonstrating that 15% of men with a normal DRE and PSA <4.0 ng/ml have prostate cancer and given the recommendation, by some advocates of screening, that the PSA cut-off for triggering biopsy should be lowered to <4.0 ng/ml.

Routine Use of Finasteride for Primary Prevention

Can finasteride prevent prostate cancer? The biologic answer from PCPT is a clear 'yes', but whether the use of finasteride should be adopted as routine clinical practice is debatable. Clinical trials in other settings illuminate this debate. The Breast Cancer Prevention Trial demonstrated that tamoxifen reduces the incidence of bone fractures and both invasive and noninvasive breast cancer in women at increased risk of developing breast cancer. Although these benefits occurred at the cost of an increased risk of endometrial cancer, thromboembolic disease, and cataracts, tamoxifen is now FDA-approved for prevention of breast cancer in women with a high risk of developing this cancer. More recently, the Women's Health Initiative concluded that routine estrogen and progesterone replacement in postmenopausal women had advantages in reducing the risks of bone fractures and colon cancer, but that the increased risks associated with breast cancer, heart attack, and stroke did not justify routine use. Ultimately, the adoption of a preventive strategy always hinges on its potential benefits weighed against the potential risks, and recommendations for use of finasteride for prostate cancer prevention depend on how the risks and benefits are weighed.

Selenium and Vitamin E in Prostate Cancer Prevention

Selenium's Source and Distribution

Selenium is an essential trace element occurring in both organic and inorganic forms. The organic form is found predominantly in grains, fish, meat, poultry, eggs, and diary products and enters the food chain via consumption of plants and plant-consuming animals. There is marked geographic variability of selenium content in food, which can be related to local soil content. Selenium is also widely available in over-the-counter supplements and multivitamins. It is widely distributed in body tissues and is an important constituent of many antioxidant enzymes.

Evidence for Selenium's Protective Effect

Many epidemiologic observations support selenium as a protective agent against the development of cancer. Both case-control and randomized placebo-controlled trials in humans also suggest that selenium can decrease the risk of developing prostate cancer. The strongest evidence for a protective effect of selenium comes from the Nutritional Prevention of Cancer Trial, a randomized study of selenized yeast, administered orally, in patients with nonmelanomatous skin cancer. In that trial, 1,312 participants took the equivalent of 200 µg yeast per day vs placebo, and with a mean follow-up of 4.5 years the incidence of prostate cancer was reduced in the selenium arm by two-thirds compared to placebo. Reanalysis of the effect of selenium supplementation with a mean follow up of 7.5 years continues to show a marked reduction of the incidence of prostate cancer, with an RR of 0.48 (95% CI 0.29 to 0.87), with the strongest effect for those with a PSA <4 ng/ml and the lowest serum levels of selenium at study entry.

Selenium inhibits tumorigenesis in a variety of experimental models, and a number of potential mechanisms have been proposed for its antitumorigenic effects. Accumulating evidence suggests that it works by inhibiting important early steps in carcinogenesis by inhibition of cellular proliferation, induction of apoptosis, and modulation of androgen-regulated genes.

In vivo studies also support the antitumorigenic role of selenium in prostate cancer. In a dog model, Waters demonstrated that oral selenium, in various forms, given over 7 months as a dietary supplement resulted in lower levels of DNA damage in prostatic epithelial cells and increased intraprostatic apoptosis compared with controls. A study comparing 200 µg oral selenium per day with placebo, in 51 men who underwent transurethral resection of the prostate for benign prostatic hyperplasia and who had normal pretreatment serum levels of selenium, demonstrated that selenium supplementation resulted in significantly higher levels of selenium in prostatic tissue. Together, these studies demonstrate that orally ingested selenium reaches the prostate gland and modulates markers of oxidative stress relevant to the proposed molecular mechanisms of its protective effects. 

Vitamin E

Vitamin E is a family of naturally occurring, essential, fat-soluble vitamin compounds that function as the major lipid-soluble antioxidants in cell membranes. The most active form of vitamin E is α-tocopherol. It is also among the most abundant, is widely distributed in nature, and is the predominant form in human tissues. α-tocopherol may influence the development of cancer through several mechanisms, but its molecular effects are less well elucidated than those of selenium. One study has demonstrated that the chromanol moiety of vitamin E has direct antiandrogenic activity. A large-scale, randomized, double-blind, placebo-controlled trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC), supports the role of vitamin E in the prevention of prostate cancer. ATBC studied the effects of α-tocopherol (50 mg synthetic dl -α-tocopheryl acetate daily) and beta-carotene (20 mg daily), alone or in combination, in 29,133 male smokers aged 50-69 years at entry. The primary endpoint was lung cancer incidence and mortality; there was a statistically significant 32% reduction in prostate cancer incidence and a 41% lower mortality in those receiving α-tocopherol. 

Another randomized, double-blind, placebo-controlled lung cancer prevention trial, the beta-Carotene and Retinol Efficacy Trial (CARET), lends support to the epidemiologic evidence that α-tocopherol may prevent prostate cancer. Analysis of serum micronutrients in CARET participants has shown that low serum levels of α-tocopherol were associated with a higher risk of prostate cancer, demonstrated by a higher incidence of prostate cancer in this group. A recent meta-analysis of selected vitamin E trials concluded, however, that higher doses of vitamin E may be associated with a slightly increased risk of mortality. Of the three studies that used 400 IU of vitamin E, one showed no effect, one showed a slight increase, and one showed a slight decrease in mortality.

The Selenium and Vitamin E Cancer Prevention Trial

The accumulated epidemiologic and biologic evidence that selenium and vitamin E may prevent prostate cancer led to the design and launch of SELECT, a National Cancer Institute (NCI)-sponsored phase III, randomized, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E, alone and in combination, in the prevention of prostate cancer. The study has a 2 × 2 factorial design with a target accrual of 32,400 subjects. Eligibility criteria include age >50 years for African American men, >55 years for men of other races and ethnicities, a DRE that is not suspicious for cancer, serum PSA <4 ng/ml, and normal blood pressure. Randomization will be equally distributed among four study arms: selenium with placebo, vitamin E with placebo, selenium with vitamin E, and placebo with placebo. The planned study duration is 12 years, with a minimum of 7 years and maximum of 12 years of intervention depending on the time of randomization. The supplements used in the study consist of 200 µg l-selenomethionine, 400 mg of racemic α-tocopheryl, and an optional multivitamin containing no selenium or vitamin E.

The primary endpoint for SELECT is the clinical incidence of prostate cancer. Prostate biopsy will be performed at the discretion of study physicians according to local community standards based on abnormalities in DRE or elevations in serum PSA. Secondary endpoints will include prostate-cancer-free survival, mortality from any cause, and the incidence and mortality of other cancers and diseases potentially affected by the chronic use of selenium and vitamin E. Other trial objectives include periodic quality of life assessments, assessment of serum micronutrient levels and prostate cancer risk, and studies of the association of biological and genetic markers with the risk of prostate cancer. The study design permits detection of a 25% reduction in the incidence of prostate cancer for selenium or vitamin E alone, with an additional 25% reduction for the combination of selenium and vitamin E compared to either agent alone. Since neither oral selenium nor vitamin E is known to affect serum PSA, no PSA adjustments are planned. SELECT reached full accrual of 32,400 men in April 2004, and initial data analysis is anticipated in 2006, with complete results in 2013.

Other Potential Agents in Prostate Cancer Prevention

Epidemiological, preclinical, and molecular data also support the potential role of other agents, including dutasteride (another 5α-reductase inhibitor), in the prevention of prostate cancer. A brief review of the rationale and supportive evidence for some of these is presented below.

Vitamin D

Interest in Vitamin D as a preventive agent for prostate cancer comes from several epidemiologic observations. Reduced levels of active vitamin D result in a higher incidence of and a higher mortality rate from prostate cancer. This reduction can occur as a result of several factors: less exposure to UV light, through either geographic location, increased age resulting in decreased outdoor activity, or high levels of skin pigmentation (melanin blocks the effects of UV light) age-related declines in the levels of hydroxylases responsible for synthesis of the active vitamin; and dietary intake of dairy products rich in calcium, which depresses serum levels of vitamin D. In contrast, native Japanese men, whose diet is rich in vitamin D derived from fish, have a low incidence of prostate cancer.

In addition, preclinical work has indicated that vitamin D exerts an antiproliferative effect on prostate cancer cells. Use of vitamin D analogs in humans has been limited by their hypercalcemic effects, but newer analogs with more tolerable toxicity are currently being tested in phase I and II trials.

COX-2 Inhibitors

COX-2 is one of two inducible isoforms of cyclo-oxygenase which convert arachidonic acid to prostaglandins, thereby mediating acute and chronic inflammation, pain, and cellular repair mechanisms. Inhibition of COX-2 expression blocks its proinflammatory effects and reduces expression of androgen receptors and androgen-inducible genes. In contrast, selective expression of COX-2 has been shown preclinically in high grade PIN, suggesting a role early in carcinogenesis. These results support the hypothesis that inhibition of COX-2 may be an effective preventive strategy; however, an industry-sponsored large scale trial of rofecoxib was closed after the drug was withdrawn from the market because of concerns over its cardiovascular safety. 

Selective Estrogen-Receptor Modulators (SERMs)

Interest in SERMs as preventive agents is stimulated by an apparent role of estrogens in the pathogenesis of prostate cancer, through promotion of cell growth. Furthermore, age-related prostatic disease rates parallel increases in serum estrogen levels and there is a low incidence of prostate cancer in cultures with diets rich in phytoestrogens.

Soy

Several studies have demonstrated a consistent anticancer effect of soy-based diets compared with controls in a variety of prostate cancer animal models. Epidemiologic evidence also supports the role of soy as an anticancer agent. A prospective study of 12,395 Seventh Day Adventists in California demonstrated that frequent consumption of soy milk (at least daily) was associated with a 70% reduction in the risk of developing prostate cancer. No large-scale clinical trials using soy or soy-based products as preventive or therapeutic agents in prostate cancer have been reported.

Lycopene

Lycopene is a red-orange, highly unsaturated, acyclic isomer of β-carotene found primarily in tomatoes and tomato-derived products and in other red fruits and vegetables. It is the predominant carotenoid in human plasma and possesses potent antioxidant activity. There is mixed epidemiologic evidence that lycopene consumption is associated with a lower risk of prostate cancer. In an in vivo rat model of induced prostate cancer, a protective effect was observed both for calorie restriction and tomato powder, but not pure lycopene. This study suggests that reduced caloric consumption and a diet rich in tomato-based foods may be more beneficial than taking oral lycopene supplements in reducing the risk of prostate cancer in humans. 

Two nonplacebo-controlled prospective clinical trials examining the effect of lycopene on known prostate cancer have been reported. Both trials involved men with clinically localized prostate cancer scheduled for radical prostatectomy. In the first trial, 26 men were randomized to oral lycopene vs no lycopene preoperatively for 3 weeks.

Statistically significant reductions in serum PSA and in the rate of positive margins were observed in the lycopene group, with no differences seen in various biological endpoints. The study was limited by a small sample size and significant differences in tumor burden between the intervention and control groups. In the second trial, 32 men ate tomato-sauce-based pasta dishes for the 3 weeks before surgery (achieving the same daily dose as in the first trial). Serum and prostate lycopene concentrations were statistically significantly increased in the intervention group. Compared with preintervention levels, both leukocyte and prostate oxidative DNA damage were also reduced significantly after intervention. A small but statistically significant reduction in serum PSA was also observed.

Green Tea

On the basis of epidemiologic observations of a low incidence of prostate cancer among native Asian men with a high dietary intake of green tea, it has been suggested that green tea might be a prostate cancer preventive agent. Work has focused on the effects of polyphenols contained in green tea, but the molecular mechanism of their action has not been elucidated. Prostate cancer cell culture and gene expression experiments have demonstrated that the major polyphenolic constituent of green tea inhibits cell growth and dysregulates the cell cycle.

Conclusion

Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between appearance of premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The results of the PCPT are the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. New trials designed to test additional agents (many of which are antioxidants with antiandrogenic effects) are currently being, or are about to be, tested in large-scale clinical trials. These trials might provide sufficient evidence for making a routine recommendation of dietary or nutritional supplements for the prevention of prostate cancer.

Review Criteria

PubMed and Medline were searched for records from January 2000 to November 2004, using the terms "prostate cancer" and "prevention". Of the citations identified by the searches, papers were selected on the basis of their clinical relevance to prevention of prostate cancer. Only papers published in English have been cited in this review.