Prostate cancer is an appropriate target for primary chemoprevention because of its ubiquity, disease-related mortality, treatment-related morbidity, and long latency period. The PCPT and REDUCE trials demonstrate that this cancer can be prevented by a relatively nontoxic oral pharmacologic agent (5α-reductase inhibitors). Evidence from the SELECT trial argues against the recommendation of the use of vitamins and micronutrients as chemoprevention of prostate cancer. Dietary modification may substantially alter a man’s risk of prostate cancer, but the specific dietary manipulations that are necessary are poorly defined and these may need to be instituted in early adulthood to be successful. 5α-reductase inhibitors represent an effective primary prevention strategy, and these agents should be used more liberally for the prevention of prostate cancer, particularly in high-risk patients.
In 2009, an estimated 192,000 men will be diagnosed with prostate cancer and over 27,000 will die from this disease. The ubiquity and mortality of prostate cancer make it an attractive and appropriate target for primary chemoprevention. Numerous observations in the epidemiologic literature suggest associations between various dietary and lifestyle factors and the risk for developing prostate cancer. However, many of the risk factors for prostate cancer (age, ethnicity, and genetic factors) are not modifiable, and as much as 40% of the risk of the disease is estimated to be genetic. Given the incidence, prevalence, disease-related mortality, substantial cost of treatment, and treatment-related morbidity of prostate cancer, chemoprevention has become an important public health approach to reduce the mortality and burden of therapy for this disease.
Chemoprevention is defined as the use of specific natural or synthetic agents to reverse, suppress, or prevent the carcinogenic process thereby preventing the development of clinically evident cancer. Primary chemoprevention targets the general population of healthy individuals at risk to prevent the development of prostate cancer. Secondary prevention strategies target individuals with premalignant lesions (eg, high-grade prostate epithelial neoplasia [HGPIN]) with the goal of preventing progression to frank cancer. Tertiary prevention aims to prevent the development of a second primary cancer in an affected individual. The challenge of primary chemoprevention is finding an effective intervention that has acceptable toxicity and cost as well as identifying a population of individuals at sufficiently increased risk for developing prostate cancer for which chemoprevention is appropriate and cost-effective.
Enthusiasm for chemoprevention of prostate cancer has heightened in recent years with the publication of several large, randomized trials (namely the Prostate Cancer Prevention Trial [PCPT]), demonstrating that this disease may be prevented by a relatively nontoxic oral agent. However, the failure to alter the incidence of prostate cancer using selenium and vitamin E in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a reminder that chemopreventive strategies supported by strong epidemiologic and biologic rationale may not always be effective. A listing of the completed and ongoing primary and secondary chemoprevention trials is listed in Table 1 . Epidemiologic evidence suggests the existence of several other pharmacologic agents and nutritional supplements that appear promising for large-scale studies. It is conceivable that these agents may be useful in different populations.
| Trial | Risk Group | Agent | Target | Results |
|---|---|---|---|---|
| Prostate Cancer Prevention Trial | Low (PSA level <3.0 ng/mL) | Finasteride | Type I 5α-reductase | Updated 2008 |
| Selenium and Vitamin E Cancer Prevention Trial | Low (PSA level <4.0 ng/mL) | Selenium, vitamin E | Oxidative stress | Reported 2008 |
| Reduction by Dutasteride of Prostate Cancer Events Trial | Intermediate (PSA level, 2.5–10 ng/mL) | Dutasteride | Type I and II 5α-reductase | Reported 2009 |
| Southwest Oncology Group 9917 | High (HGPIN) | Selenium | Selenium-mediated effects | 2010 |
| Toremifene | High (HGPIN) | Toremifene | Estrogen receptor | 2010 |
| National Cancer Institute of Canada | High (HGPIN) | Selenium, vitamin E, soy protein | Oxidative stress |
Rationale for chemoprevention of prostate cancer
Biologic Rationale
The molecular pathogenesis of prostate cancer lends itself to a primary prevention strategy. Prostate carcinogenesis is a multistep process induced by genetic and epigenetic changes that disrupt molecular pathways involved in cell proliferation, differentiation, apoptosis, and senescence. Several precursor lesions for prostate cancer have been described (HGPIN, proliferative inflammatory atrophy, and atypical small acinar neoplasia), which possess many genetic changes that are present in prostate cancer and represent intermediate stages between normal and malignant epithelium. These lesions may appear as early as 20 years before the appearance of clinically evident cancer, suggesting that the development of prostate cancer occurs over a protracted time interval. In theory, the prolonged carcinogenesis of prostate cancer provides an opportunity to intervene before a malignancy is established.
Clinical Rationale
Mortality from prostate cancer may be reduced through early detection, prevention, and improvements in local and systemic therapy. The limitations of screening for prostate cancer were highlighted with the publication of 2 randomized trials in the United States (Prostate Lung Colorectal and Ovarian Cancer Screening Trial [PLCO]) and Europe (European Randomized Study of Screening for Prostate Cancer [ERSPC]). ERSPC randomized 162,433 men from 7 countries to screening at 4-year intervals versus no screening and reported a significant increase in the incidence of prostate cancer (8.2% vs 4.8%) and a 20% relative risk reduction in prostate cancer–specific mortality at 10 years. However, the investigators highlighted the problem of overdiagnosis with mass screening, as they estimated 48 men would need to be treated to prevent 1 death from prostate cancer at 10 years. In the PLCO trial, 76,693 men were randomized to annual screening versus no screening, and no significant difference in prostate cancer–specific mortality was reported. The PLCO trial has been criticized for substantial contamination of screening in the control, the low rate of prostate biopsy in men with indications for biopsy, and the low-risk nature of both populations at the time of randomization.
The risk of overdiagnosis has been estimated using cancer incidence rates from ERSPC and Surveillance, Epidemiology and End Results (SEER) Program registry. In these studies, overdiagnosis is defined as detection of cancers that would have otherwise remained undetected throughout a man’s lifetime in the absence of screening. Assuming annual screening beginning at age 55 years, the overdiagnosis rate of prostate cancer has been reported to be 30% to 50%. If overdiagnosis is defined as the detection of nonlethal prostate cancer, an estimated 84% of detected cancers would represent overdiagnosis. Based on these studies and the 2 randomized trials, prostate-specific antigen (PSA) screening is associated with (at best) a slight reduction in prostate cancer–specific mortality with a substantial risk of overdiagnosis.
Whereas the urologic community recognizes the overdiagnosis of prostate cancer at the population level, a diagnosis of prostate cancer in the United States generally leads to radical therapy of some form. The safety and feasibility of active surveillance has been demonstrated in several cohorts with low reported overall and cause-specific mortality with 10 years of follow-up. However, it is not widely embraced because of concerns that clinical staging and grading will underestimate the threat posed by cancers. In the United States, only 5% of low-risk patients choose active surveillance (including only 9% of men meeting the Epstein criteria for insignificant cancer), and an estimated 73% of those who do ultimately opt for radical therapy within 4 years. More than 70% of elderly men aged 65 to 80 years with low- and intermediate-risk prostate cancer received some form of therapy (surgery, radiation, or hormonal therapy) in a recent population-based study. Given the protracted natural history of screen-detected cancers, it is unlikely that many of these men benefited from treatment in terms of preventing metastasis and death from prostate cancer.
The burden of therapy for prostate cancer can also be measured by the effect of treatments on health-related quality of life (HRQOL). A recent study of complications after surgical therapy for localized disease in an unselected population-based cohort reported that at more than 18 months after radical prostatectomy, 8.4% of men were incontinent and 42% reported that their sexual performance was a moderate-to-large problem. In a prospective cohort study that compared outcomes in patients 5 years after radiation or surgery with those in age-matched controls, the authors concluded that “declines in urinary and sexual function domains after diagnosis and treatment of localized cancer far exceeded any effects from aging….” A multicenter, prospective, longitudinal study assessing HRQOL after local therapy found that all treatments had a significant effect on urinary, sexual, bowel, and/or hormonal function.
Two randomized trials have demonstrated that radical therapy (radical prostatectomy and external-beam radiotherapy) can significantly alter the natural history of prostate cancer in men diagnosed in the absence of screening. In an update of the Scandinavian Prostate Cancer Group-4 randomized trial of radical prostatectomy versus watchful waiting, a 5.4% absolute reduction in prostate cancer–specific mortality at 12 years was observed with radical prostatectomy (12.5% vs 17.9%). However, this study demonstrates that 70% of men with a lethal form of prostate cancer will ultimately die from prostate cancer despite radical local therapy.
It seems self-evident that an effective prevention strategy would spare many men the burden of diagnosis and cure and reduce the overdiagnosis problem associated with widespread opportunistic PSA screening. When combined with aggressive early detection and treatment, chemoprevention also has the potential to reduce the mortality from prostate cancer, which remains the second leading cause of cancer deaths among men in the United States.
Chemoprevention trials in prostate cancer
5α-Reductase Inhibitors
Prostate Cancer Prevention Trial
PCPT was the first large-scale primary chemoprevention trial in men at risk for prostate cancer. The study randomized 18,882 men aged 55 years or older with a normal digital rectal examination (DRE) and a PSA level of 3.0 ng/mL or less to finasteride, 5 mg/d, or placebo for 7 years. The rationale for finasteride (a selective type II 5α-reductase inhibitor [5ARI]) as a chemopreventive agent is based on the absence of prostate cancer in men with congenital deficiency of 5α-reductase (the enzyme that converts testosterone to dihydrotestosterone) and the critical role of androgens in the development of prostate cancer. In PCPT, prostate biopsy was recommended at the end of study for all participants or for those “on-trial” if men had a PSA level of 4 ng/mL or more (adjusted for the effect of finasteride) or an abnormal DRE. The primary end point was the prevalence of prostate cancer during the 7 years of the study, as diagnosed by biopsy for-cause or end-of-study biopsy. Ultimately, 9060 participants (48%) were evaluable for the primary endpoint.
The main finding of PCPT was a 25% (95% confidence interval [CI], 19–31) reduction in the period prevalence of prostate cancer in men randomized to daily finasteride (18.4%) compared with placebo (24.4%). The relative benefit of finasteride versus placebo in reducing the risk of prostate cancer was apparent across all groups defined by age (55–59, 60–64, and ≥65 years at randomization), ethnicity (white, black, Hispanic, other), family history of prostate cancer, and PSA level at the beginning of the study (≤1, 1.1–2, and 2.1–3 ng/mL), with hazard ratios (HRs) between 0.66 and 0.81. The risk reduction in the finasteride arm was seen in both clinically apparent tumors (those diagnosed “for cause” because of an elevated PSA or abnormal DRE) and end-of-study biopsies (men with PSA level<4.0 ng/mL and normal DRE at study termination). Finasteride also reduced the risk of HGPIN (without associated prostate cancer) compared with placebo (HR, 0.85; 95% CI, 0.73–0.99; P = .04). However, a significant increase in the prevalence biopsy Gleason score 7 to 10 cancers was observed in men receiving finasteride (280 [37%]) compared with placebo (237 [22%]), particularly for biopsy Gleason score 8 to 10 cancers (90 [12%] in the finasteride arm vs 53 [5%] in the placebo arm). There were an equal number of deaths resulting from prostate cancer (5) in each study arm. Sexual side effects were also more common with finasteride, whereas urinary symptoms were more common with placebo.
Several relevant observations can be made about the results of the trial. Most surprising was the 24.4% prevalence of prostate cancer in the placebo arm, 4 times higher than the 6% assumed for the trial design. This discrepancy can be explained by the fact that the 6% assumption was based on SEER incidence estimates, which are derived from clinically evident cases, and not on the prevalence in men with PSA level less than 4 ng/mL and normal DRE who underwent biopsy. The incidence of clinically evident cancers detected “for cause” by elevations in PSA levels or abnormal PSA was 7.2% at 7 years, similar to the incidence of cancer in the screening arms of ERSPC (8.2%) and PLCO (7.4%). Another observation was a marked effect of finasteride on the prevalence of biopsy Gleason score 2 to 6 tumors, no effect on the prevalence of biopsy Gleason score 7 tumors, and a slight increase in the prevalence of biopsy Gleason score 8 to 10 tumors. The higher incidence of biopsy Gleason score 8 to 10 tumors was restricted to those men undergoing for-cause biopsy, although this is partly explained by the low prevalence of these high-grade cancers in men with PSA level less than 4.0 ng/mL and with normal DRE (20 of 3652 in finasteride arm vs 8 of 3820 in placebo arm).
Secondary analyses of the PCPT have demonstrated an overall improved sensitivity of DRE and a higher accuracy of PSA for the diagnosis of prostate cancer in the finasteride arm. Finasteride-treated glands were also 28% smaller on average compared with those in the placebo arm. Data suggest that having a smaller prostate enhanced the detection of cancer and proportionately more diagnosed cancers are high-grade. These effects of finasteride on the detection of prostate cancer should bias PCPT in favor of the placebo arm and lead to a greater detection of all grades of prostate cancer with finasteride, further strengthening the results of the trial.
Following the original publication of PCPT, there were 2 areas of intense debate over the trial’s findings. The first was that critics argue that finasteride prevents insignificant cancers and does little to prevent potentially lethal cancers. This criticism was based on the fact that the incidence of cancers in control arm (24.4%) was significantly higher than a man’s lifetime risk of developing prostate cancer (18%) and 4 times higher than the cancer incidence in screening trials over a similar period. Finasteride also reduced the prevalence of low-grade cancers and did not appear to reduce the risk of high-grade cancers. However, in a secondary analysis of 93.4% of biopsy specimens that were subject to central pathology review, the rate of insignificant cancers (as defined by the Epstein criteria ) among the biopsy Gleason 2 to 6 cancers detected in the finasteride (38%) and placebo arms (36%) was not significantly different. Most of the cancers detected in PCPT were clinically significant (80% in finasteride arm and 72% in the placebo arm). Viewed in the context of clinical relevance as defined by current urologic practice, preventing biopsy Gleason 2 to 6 cancers by finasteride also prevents the anxiety, cost, and morbidity associated with their treatment. From a public health perspective, preventing the burden of cure in newly diagnosed patients should be added as a positive to the 25% reduction in risk of diagnosis and significant reduction in urinary symptoms associated with finasteride use.
The second question raised by PCPT was whether finasteride induces the development of high-grade or aggressive cancers. Androgen deprivation therapy is known to change the appearance of prostatic epithelium in a way that could bias interpretation. Thus, the apparent increase in high-grade cancers in men treated with finasteride may be an artifact of these morphologic changes. However, when this was examined in PCPT, there appeared to be no morphologic effect of finasteride on prostate cancer grading when specimens were reviewed by a panel of expert pathologists blinded to treatment arm. Another potential explanation for the observed increase in high-grade tumors in the finasteride group is ascertainment bias. As stated earlier, finasteride has been shown to increase the sensitivity of PSA and DRE and to decrease prostate volume by 28%, leading to a higher probability of finding the high-grade component of cancer (among men with pathologic Gleason 7–10 cancer) on biopsy. Indeed, the rate of upgrading from biopsy Gleason score 2 to 6 to pathologic Gleason score 7 to 10 among men treated by radical prostatectomy was higher in the placebo arm compared with the finasteride arm.
If finasteride induces high-grade cancers, one would expect a higher proportion of cancers with adverse features by biopsy criteria or at radical prostatectomy in the finasteride arm. No significant difference in the proportion of cancers with perineural invasion, length of cancer in biopsy specimens, and bilaterality of cancer on biopsy was identified between the arms, and men on finasteride with biopsy Gleason 2 to 7 cancers had fewer positive biopsy scores compared with men on placebo. Among the 528 men who were treated by radical prostatectomy, no significant difference in the rate of extraprostatic extension, seminal vesicle invasion, or lymph node metastasis was observed between the 2 arms, and there were fewer pathologic Gleason 7 to 10 cancers among men treated with finasteride versus placebo (89 vs 105).
In a secondary analysis of PCPT that adjusted for the effects of finasteride on the detection of prostate cancer, the adjusted prostate cancer rates were estimated to be 21.1% in the placebo group and 14.7% in the finasteride group, a 30% risk reduction for all cancers (HR, 0.70; 95% CI, 0.64–0.76) and a nonstatistically significant 14% increase in high-grade cancer. Accounting for the increased probability of upgrading to pathologic Gleason 7 to 10 cancer at radical prostatectomy among men with biopsy Gleason 2 to 6 cancers in the placebo arm, the investigators estimated the rate of true high-grade cancer to be 6% in the finasteride arm and 8.2% in the placebo arm, representing a 27% relative risk reduction in the rate of true high-grade cancers in men treated with finasteride (HR, 0.73; 95% CI, 0.56–0.96). Using different methodology in an independent analysis, Pinsky and colleagues concurred that the rate of true high-grade disease may have been lower in the finasteride group compared with the placebo group.
Although the concerns raised by the original publication of PCPT regarding the apparent increased risk of high-grade cancer in men receiving finasteride were valid, these subsequent studies indicate that finasteride does not induce the development of Gleason 7 to 10 cancers and may reduce a man’s risk of high-grade cancer. In March 2009, the American Urological Association and the American Society of Clinical Oncology jointly published guidelines based on expert review of the available evidence stating that use of finasteride for the prevention of cancer should be discussed with at-risk men.
In addition to the prevention of prostate cancer, 5ARIs have other benefits that need to be considered. As mentioned earlier, finasteride improves the sensitivity of PSA and DRE for prostate cancer detection. Furthermore, randomized, placebo-controlled trials of men with symptomatic benign prostatic hyperplasia (BPH) have demonstrated that finasteride reduces the severity of lower urinary tract symptoms, risk of acute urinary retention, and need for surgical intervention.
On the other hand, adverse effects more common with finasteride than placebo include impaired sexual or erectile function and endocrine effects. Pooled data from randomized trials indicate absolute differences of 2% (95% CI, 1–2) for gynecomastia, 3% (95% CI, 1–6) for decreased libido, 4% (95% CI, 1%–8%) for erectile dysfunction, and 4% (95% CI, 8–17) for reduced volume of ejaculate. Sexual dysfunction was also assessed in the PCPT participants during the 7-year trial period using the Sexual Activity Scale. Compared with baseline scores, over the course of 7 years finasteride was associated with a slight increase in sexual dysfunction relative to placebo, equivalent to about half the effect of being 6.5 years older at randomization.
Reduction by Dutasteride of Prostate Cancer Events Trial
The REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial is another large-scale, randomized, placebo-controlled primary chemoprevention trial using a different 5ARI called dutasteride, which is an inhibitor of both type 1 and type 2 isoforms of 5ARI. Dutasteride has been shown to reduce the risk of prostate cancer in men treated for lower urinary tract symptoms related to BPH compared with placebo. The REDUCE trial completed accrual in 2005, and the initial results have been presented in abstract form only at this time. Eligibility for REDUCE included men with a prior negative prostate biopsy within 6 months of enrollment who were aged 50 to 75 years and had baseline PSA levels of 2.5 to 10 ng/mL and prostate volume of 80 cm 3 or less. The primary endpoint of REDUCE is the prevalence of cancer on study-mandated prostate biopsies performed at 2 and 4 years after randomization.
The trial accrued 8231 men, of which 6726 (82.6%) underwent at least 1 biopsy and 1516 (22.5%) were diagnosed with prostate cancer. Dutasteride reduced the risk of prostate cancer during 4 years by 23% (857 in the placebo arm vs 659 in the dutasteride arm, P <.001). Interestingly, no significant increase in biopsy Gleason 8 to 10 cancers was observed in the study (19 in placebo vs 29 in dutasteride, P = .15). As with finasteride in PCPT, the benefit of dutasteride in prostate cancer risk versus placebo was apparent across all subgroups, including age (<65 vs ≥65 years), family history, and PSA level at study entry (relative risk reduction, 22%–32%). Dutasteride also demonstrated beneficial effects on BPH outcomes (acute urinary retention and BPH-related surgery) and was generally well tolerated (15% drug-related adverse events in placebo vs 22% in dutasteride arm).
PCPT and REDUCE confirm the consistency of the effect of 5ARI at reducing the risk of prostate cancer, with a similar magnitude of risk reduction across all subgroups without any apparent increase in the risk of high-grade cancers. The fact that the results of the REDUCE trial were congruent with those of the PCPT with respect to the magnitude of risk reduction, benefits on BPH endpoints, minimal toxicity, and absence of issues related to tumor grade suggest that 5ARIs represent an effective primary prevention strategy and these agents should be used more liberally for prevention of prostate cancer. However, deciding whether or not the advantages outweigh the potential disadvantages of 5ARI for prostate cancer chemoprevention is not a simple task ( Table 2 ). A recently published decision analysis model for 5ARIs as chemopreventive agents found that widespread use of these agents are unlikely to be cost-effective because of the usually indolent natural history of treated prostate cancer, but these agents may be cost-effective in high-risk populations.
| Advantages | Disadvantages |
|---|---|
| 23%–30% reduction in risk of prostate cancer | No proven effect on mortality |
| May reduce risk of Gleason 7–10 cancers | May increase risk of Gleason 7–10 cancers |
| Reduction of overdiagnosis and overtreatment (burden of cure) | Increased sexual side effects |
| 20% reduction in risk of HGPIN | Cost |
| Improves the performance of PSA and DRE for early detection of prostate cancer | |
| Reduces symptoms, complications, surgical interventions for BPH |
Vitamins and Micronutrients
Selenium and Vitamin E Cancer Prevention Trial
SELECT was a randomized, placebo-controlled, population-based primary chemoprevention trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer. The rationale for selenium was based on a secondary analysis of the Nutritional Prevention of Cancer Trial of oral selenized yeast for nonmelanoma skin cancer, in which men randomized to selenium versus placebo had a 65% reduction in the prostate cancer incidence during a mean follow-up of 4.5 years. Selenium is an essential trace element occurring in both organic and inorganic forms, with marked geographic variability of selenium in food related to local soil content.
The rationale for vitamin E as chemopreventive agent for prostate cancer was based on the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial for lung cancer incidence and mortality, in which male smokers were randomized to alpha-tocopherol (50 mg/d) and beta carotene (20 mg/d) alone or in combination versus placebo. On secondary analysis, the ATBC trial found a statistically significant 32% reduction in prostate cancer incidence in those receiving alpha-tocopherol. Vitamin E is a family of naturally occurring, essential, fat-soluble vitamin compounds, which functions as the major lipid-soluble antioxidant in cell membranes. The most active form of vitamin E is alpha-tocopherol; it is also among the most abundant, is widely distributed in nature, and the predominant form in human tissues. Alpha-tocopherol may influence the development of cancer through several mechanisms, including induction of cell cycle arrest and through direct antiandrogen activity.
The SELECT was the largest cancer prevention trial ever performed, and it randomized 35,533 men to 4 treatment arms (selenium + placebo, vitamin E + placebo, selenium + vitamin E, and placebo + placebo). Eligibility criteria included age 50 years or more for African Americans, 55 years or more for Caucasians, a DRE not suspicious for cancer, serum PSA level of 4 ng/mL or less, and normal blood pressure. The primary endpoint was biopsy-confirmed prostate cancer, although the indications for biopsy were not dictated by protocol. Although the study duration was planned for 12 years, the independent data and safety monitoring committee recommended discontinuation of the study after the second interim analysis at 7 years because the data convincingly demonstrated no effect on the risk of prostate cancer by either agent alone or in combination and no chance of a beneficial effect of the hypothesized magnitude with continued supplementation. HRs for prostate cancer were 1.13 (99% CI, 0.95–1.13) for vitamin E, 1.04 (99% CI, 0.87–1.24) for selenium, and 1.05 (99% CI, 0.88–1.25) for selenium and vitamin E. Secondary analyses also showed no effect on the risks of lung, colorectal, or overall cancer incidence, no effect on cardiovascular events, and no effect on overall survival.
Null results for the effect of vitamin E on prostate cancer risk were also reported in the Physicians’ Health Study II, a randomized trial of vitamin E (400 IU every other day) and vitamin C (500 mg/d) versus placebo in the prevention of prostate and other cancers. Together, these results suggest that neither selenium nor vitamin E should be used in the hope of preventing prostate or other cancers.
Other Agents
Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs) possess both agonistic and antagonistic estrogen-like activity and have been shown to repress prostate cancer growth in several transgenic mouse models. In the transgenic adenocarcinoma of mouse prostate (TRAMP) model, toremifene reduces the incidence of HGPIN and cancer in an estrogen-dependent, androgen-independent mechanism. Toremifene is currently approved for the management of breast cancer and was tested in a phase 2b trial for decreasing the prostate cancer risk in which 514 men with HGPIN were randomized to toremifene, 20, 40, or 60 mg/d, or placebo. Although the 40- and 60-mg doses did not affect the risk of prostate cancer, the 20-mg dose was associated with a 48% decrease in the risk of prostate cancer at 12 months. A phase 3 trial is currently ongoing to assess toremifene’s activity against HGPIN and prostate cancer incidence.
Soy
Legumes play an important role in the traditional diets of Asian countries where the incidence of prostate cancer is low, but they play only a minor role in diet of the West where the incidence is highest worldwide. Soybeans are unique among the legumes because they are a concentrated source of isoflavones, which have weak estrogenic activity. The major isoflavone components of soy, including genistein, daidzein, and their metabolites, inhibit benign and malignant prostatic epithelial cell growth, downregulate androgen-regulated genes, and reduce tumor growth in animals. Migration studies and lower prostate cancer rates in Asian men with higher soy intake also support the role of soy as an anticancer agent. A combination of vitamin E, selenium, and soy protein is being investigated in a randomized phase 2, placebo-controlled secondary chemoprevention trial in men with HGPIN, and this study is funded by the National Cancer Institute of Canada.
Lycopene
Lycopene is a red-orange carotenoid found primarily in tomatoes and tomato-derived products and other red fruits and vegetables. Lycopene is a highly unsaturated acyclic isomer of beta carotene, 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. A nested case-control study in PLCO prospectively examined the intake of more than 25 tomato-containing foods by 29,361 men and found no correlation with the incidence of prostate cancer. Currently, no phase 3 trials examining the role of lycopene in prostate cancer prevention are being conducted.
Green tea (Camellia sinensis)
Green tea has been suggested to prevent prostate cancer based on epidemiologic observations of a low incidence of prostate cancer among Asians with a high dietary intake. Previous work has focused on the effects of polyphenols (ie, flavanols, also know as catechins), which account for 30% to 40% of extractable solids from dried green tea leaves. In vitro studies of (−)-epigallocatechin-3-gallate (the major polyphenolic constituent of green tea) have shown that it induces apoptosis, cell-growth inhibition, and cell cycle dysregulation of prostate cancer. In a small randomized, placebo-controlled, secondary chemoprevention trial of green tea catechin tablets in 60 men with HGPIN, 9 men in the placebo arm were diagnosed with prostate cancer at 1 year compared with only 1 in the treatment group. Confirmatory trials are needed to better assess the role of green tea consumption in the prevention of prostate cancer.
Statins
Statins are widely used cholesterol-lowering drugs given for the treatment and prevention of atherosclerotic cardiovascular disease. They inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate-limiting enzyme in cholesterol biosynthesis. Statins may prevent the development of prostate cancer through anti-inflammatory effects, inhibiting angiogenesis, altering steroid hormone biosynthesis or metabolism, cell cycle regulation, or promoting apoptosis. Several observational studies have shown an inverse association between statin use and risk of prostate cancer, although others found no association, and 2 studies showed an increase in overall prostate cancer risk. Randomized trials of the use of statin to prevent cardiovascular disease reported no association with prostate cancer incidence, although such trials were limited by short durations of statin use, brief follow-up periods, and relatively young participants who develop few cancers. A meta-analysis of 6 randomized clinical trials, 6 cohort studies, and 7 case-control studies found no association between statin use and overall prostate cancer incidence but did find a protective association with advanced prostate cancer (HR, 0.77; 95% CI, 0.64–0.93). This finding suggests an effect of statins at a late stage in carcinogenesis (eg, tumor progression). Long-term statin users are generally healthier and more adherent to therapy and to screening for disease (and possibly earlier prostate cancer detection) than nonusers. Long-term statin users are generally healthier and more adherent to therapy and screening (leading to possibly earlier detection of prostate cancer) than non-users. Statin users have been shown to have lower serum PSA levels than nonusers. Although this result suggests an anticancer effect, decreased PSA levels could reduce the apparent incidence of prostate cancer in statin users, as there would be fewer individuals with elevated PSA levels to prompt prostate biopsy. Further research is needed to help determine the role, if any, of statins in the prevention of prostate cancer. The unexpected, nonstatistically significant increase in prostate cancer risk in men taking vitamin E in SELECT should caution against the use of statins as chemopreventive agents until there is evidence of a benefit from randomized trials.
Related posts:
Prostate Cancer: To Screen or Not to Screen?
Update on Prostate Imaging
Primary and Salvage Cryotherapy for Prostate Cancer
Neoadjuvant and Adjuvant Therapies in Prostate Cancer
Current Topics in the Treatment of Prostate Cancer with Low-Dose-Rate Brachytherapy
Immunotherapy for Prostate Cancer: An Emerging Treatment Modality
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