Hormonal Prevention
The Prostate Cancer Prevention Trial (PCPT), a large randomized placebo-controlled trial of finasteride (an inhibitor of alpha-reductase), was performed in 18,882 men aged 55 years or older. At 7 years, the incidence of prostate cancer was 18.4% in the finasteride group versus 24.4% in the placebo group, a relative risk reduction (RRR) of 24.8% (95% confidence interval [CI], 18.6%–30.6%; P .001). The finasteride group had more patients with Gleason grade 7 to 10, but the clinical significance of Gleason scoring is uncertain in conditions of androgen deprivation. High-grade cancers (Gleason score 7–10) were noted in 6.4% of finasteride patients, compared with 5.1% of men who received placebo, yielding a relative risk (RR) of 1.27 (95% CI, 1.07–1.50). The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase during this time period.
Finasteride decreases the risk of prostate cancer but may also alter the detection of disease through effects on prostate-specific antigen (PSA), prostate digital rectal examination (DRE), and decreased prostate volume (24%), creating a detection bias. Adjustment of PSA in men taking finasteride preserves the performance characteristics for cancer detection.
Examination of the outcomes of the PCPT found that finasteride significantly reduced the risk of high-grade prostatic intraepithelial neoplasia (HGPIN); HGPIN alone was reduced by 15% (RR, 0.85; 95% CI, 0.73–0.99) and HGPIN with prostate cancer was reduced by 31% (RR, 0.69; 95% CI, 0.56–0.85). The concern that finasteride may increase the risk of high-grade cancer prompted an examination of the rate of cancer development in the PCPT. While a gradual and progressive increase in the number of high-grade tumors would have been expected over the study duration of 7 years, when compared with placebo, this was not the case. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase during this time period. An analysis of the PCPT data adjusted for the sources of detection bias found that finasteride reduced the incidence of Gleason score 5 to 7 and Gleason score 3 to 4 prostate cancer, but not Gleason score 2 to 3 or Gleason score 8 to 10. The reduction in the incidence of Gleason score 7 (22%) was less than the reduction in the incidence of Gleason 5 score (58%) and Gleason score 6 (52%). An analysis using different methodologies found an overall reduction of both low-grade (Gleason score 6) and high-grade (Gleason score >7) cancers.
A follow-up analysis of the PCPT of finasteride mapped study participants with the National Death Index, allowing for an analysis of prostate cancer-specific mortality. With 296,842 person-years of follow-up and a median follow-up of 18.4 years, of the 9,423 men randomly assigned to the finasteride group, there were 3,048 deaths of which 42 were caused by prostate cancer; of the 9,457 men randomly assigned to the placebo group, there were 2,979 deaths of which 56 were caused by prostate cancer. The 25% reduction in risk of prostate cancer death with finasteride was not statistically significant (hazard ratio, finasteride vs. placebo, 0.75; 95% CI, 0.50–1.12). It was concluded that the early concern for an increased risk of high-grade prostate cancer with finasteride was not borne out. In this study, it was notable that, of the 61 prostate cancer deaths for which original Gleason grading was available, 23 (38%) of the prostate cancer deaths were seen in men whose original biopsy Gleason grade was less than or equal to 6
A retrospective, population-based, cohort study from the U.S. Department of Veterans Affairs health care system examined the impact of 5-alpha reductase inhibitor (5-ARI) use before prostate cancer diagnosis on prostate cancer-specific mortality. The authors found that prediagnostic use of 5-ARIs was associated with a delayed diagnosis (median time from first elevated PSA was 3.6 years for men who received 5-ARIs versus 1.4 years for non–5-ARI users) and worsened cancer-specific outcomes (e.g., higher grade, higher clinical stage, more with positive nodes, and higher rates of metastatic disease) in men with prostate cancer. A subsequent letter to the editor pointed out the following challenges with the analysis:
- A 39% improvement in prostate cancer mortality with a 2-year earlier diagnosis and with only 5.9 years of follow-up is implausible, given that the very best reduction in prostate cancer mortality in a randomized clinical trial was 20%.
- Because the study could not assess 5-ARI medication adherence, PSA misadjustment was a serious concern.
- Because men treated with 5-ARIs are very different than those not treated (i.e., more urinary symptoms, older, larger prostates, etc.), major differences in baseline characteristics, as reported in the study, prevented adequate adjustment in outcomes.
- As demonstrated by the PCPT, because finasteride (a 5-ARI) prevents a substantial proportion of low-grade tumors, a greater proportion of high-grade tumors would be expected.
- Because national treatment guidelines recommend 5-ARIs for men with larger prostates, which have higher PSA values, and as prostate cancers are more commonly missed in larger prostates (and may be identified at a subsequent biopsy, often with a magnetic resonance imaging-directed biopsy), a later diagnosis would be common in this patient population.
- The authors' analysis did not adjust for survival bias; men not receiving a 5-ARI had an earlier diagnosis, and therefore, an inherent longer survival.
When taken together, these biases call into question the conclusions, which appear to be at odds with the prostate cancer–specific mortality outcomes of the randomized PCPT.
The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial randomly assigned 8,231 men aged 50 to 75 years at higher risk of prostate cancer (i.e., PSA 2.5–10.0 ng/mL) with one recent negative prostate biopsy to dutasteride at 0.5 mg daily or to placebo. The primary end point was prostate cancer diagnosed by prostate biopsy at 2 years and 4 years after randomization. After 4 years, among the 6,729 men (82% of initial population) who had at least one prostate biopsy, 25.1% of the placebo group and 19.9% of the dutasteride group had been diagnosed with prostate cancer, a statistically significant difference (absolute risk reduction, 5.1% and RRR, 22.8% [95% CI, 15.2%–29.8%]). The RRR in years 3 to 4 was similar to the RRR in years 1 to 2. The difference between the groups was entirely due to a reduction in prostate cancers with Gleason score 5 to 7. For years 3 to 4 there was a statistically significant increase in the dutasteride group compared with the placebo group in prostate cancers with Gleason score 8 to 10 (12 cancers in the dutasteride group vs. 1 cancer in the placebo group).
Overall, there was no statistically significant difference in high-grade tumors for Gleason score 8 to 10 cancers in years 1 to 4 (29 tumors in the dutasteride group vs. 19 tumors in the placebo group, 0.9% vs. 0.6%; P = .15). However, in a retrospective analysis there was a statistically significant difference between years 3 to 4. Because this is a small retrospective subgroup, the finding of an increase in Gleason score 8 to 10 cancers is of uncertain validity. However, the finding of no reduction in these cancers is more significant.
While long-term data are unavailable for dutasteride as a cancer prevention agent, evidence is now available that finasteride does not have a significant effect on overall survival or prostate cancer–specific survival. Its effect is primarily in preventing the diagnosis of prostate cancer and the subsequent events (staging, treatment, follow-up, and management of treatment-related side effects) after diagnosis.
Agents that are used for hormonal therapy of existing prostate cancers would be unsuitable for prostate cancer chemoprevention because of the cost and wide variety of side effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot flushes). Newer antiandrogens may play a role as preventive agents in the future.
A Cochrane systematic review of all published studies of clinical outcome investigations of the prostate preventive effects of 5-ARIs through 2010 that were at least 1 year in duration concluded that finasteride and dutasteride reduce the risk of being diagnosed with prostate cancer among men who are screened regularly for prostate cancer. The review also concluded that mortality effects could not be assessed from these studies and that persistent use of these agents increased sexual and erectile dysfunction. The review was based on MEDLINE and Cochrane Collaboration Library computerized searches through June 2010 using the Medical Subject Headings terms and text words finasteride, dutasteride, neoplasms, azasteroids, reductase inhibitors, and enzyme inhibitors to identify randomized trials. Eight studies met the inclusion criteria. Only the PCPT and the REDUCE study were designed to assess the impact of 5-ARIs on prostate cancer period prevalence. Reviews of all eight studies concluded that compared with placebo, 5-ARIs resulted in 25% RR reduction in prostate cancers detected for cause (RR, 0.75; 95% CI, 0.67–0.83 and 1.4% absolute risk reduction [3.5% vs. 4.9%]). Six trials of 5-ARIs versus placebo assessed prostate cancers detected overall. Among these there was a 26% RR reduction favoring 5-ARIs (RR, 0.74; 95% CI, 0.55–1.00 and 2.9% absolute risk reduction [6.3% vs. 9.2%]). There were reductions across age, race, and family history. One placebo-controlled trial of men considered at greater risk for prostate cancer based on age, elevated PSA, and previous suspicion of prostate cancer leading to a prostate biopsy reported that dutasteride did not reduce prostate cancers detected for cause based on needle biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23% (RR, 0.77; 95% CI, 0.7–0.85 and absolute risk reduction, 16.1% vs. 20.8%). There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. The Cochrane review defined for cause cancers as follows:
- Suspected clinically from symptoms, abnormal DRE, or PSA and confirmed on biopsy.
- Study protocol recommended biopsy, but it was not done and the end-of-study biopsy showed prostate cancer.
- The end-of-study biopsy with PSA less than 4 ng/mL and/or suspicious DRE showed prostate cancer.
Dietary Prevention With Fruit, Vegetables, and a Low-fat Diet
Results from studies of the association between dietary intake of fruits and vegetables and risk of prostate cancer are not consistent. A study evaluated 1,619 prostate cancer cases and 1,618 controls in a multicenter, multiethnic population. The study found that intake of legumes and yellow-orange and cruciferous vegetables was associated with a lower risk of prostate cancer.
The European Prospective Investigation into Cancer and Nutrition examined the association between fruit and vegetable intake and subsequent prostate cancer. After an average follow-up of 4.8 years, 1,104 men developed prostate cancer among the 130,544 male participants. No statistically significant associations were observed for fruit intake, vegetable intake, cruciferous vegetable intake, or the intake of fruits and vegetables combined.
One study of dietary intervention over a 4-year period with reduced fat and increased consumption of fruit, vegetables, and fiber had no impact on serum PSA levels. It is unknown whether dietary modification through the use of a low-fat, plant-based diet will reduce prostate cancer risk. While this outcome is unknown, multiple additional benefits may be observed in patients following such a diet, including a lower risk of hyperlipidemia, better control of blood pressure, and a lower risk of cardiovascular disease—all of which may merit adoption of such a diet.
Chemoprevention
While several agents, including alpha-tocopherol, selenium, lycopene, difluoromethylornithine, vitamin D, and isoflavonoids, have shown potential in either clinical or laboratory studies for chemoprevention of prostate cancer. However, the correlations of cancer prevention with these agents are increasingly of concern given the statistically significant increased risk of prostate cancer with alpha-tocopherol in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the lack of preventive effect (actually, a nonsignificant increase in prostate cancer risk) with selenium.
Chemoprevention with selenium and vitamin E
The SELECT (NCT00006392) was a large randomized placebo-controlled trial of vitamin E and selenium. It showed no reduction in prostate cancer period prevalence, but an increased risk of prostate cancer with vitamin E alone.
Compared with the placebo group in which 529 men developed prostate cancer, there was a statistically significant increase in prostate cancer in the vitamin E group (620 cases), but not in the selenium plus vitamin E group (555 cases) or in the selenium group (575 cases). The magnitude of increase in prostate cancer risk with vitamin E alone was 17%. Of interest, the statistically increased risk of prostate cancer among men receiving vitamin E was seen after study supplements had been discontinued suggesting a longer-term effect of this agent.
Chemoprevention with lycopene
Evidence exists that a diet with a high intake of fruits and vegetables is associated with a lower risk of cancer. Which, if any, micronutrients may account for this reduction is unknown. One group of nutrients often postulated as having chemoprevention properties is the carotenoids. Lycopene is the predominant circulating carotenoid in Americans and has a number of potential activities, including an antioxidant effect. It is encountered in a number of vegetables, most notably tomatoes, and is best absorbed if these products are cooked and in the presence of dietary fats or oils.
The earliest studies of the association of lycopene and prostate cancer risk were generally negative before 1995 with only one study of 180 case-control patients showing a reduced risk. In 1995, an analysis of the Physicians’ Health Study found a one-third reduction in prostate cancer risk in the group of men with the highest consumption of tomato products when compared with the group with the lowest level of consumption, which was attributed to the lycopene content of these vegetables. This large analysis prompted several subsequent studies, the results of which were mixed. A review of the published data concluded that the evidence is weak that lycopene is associated with a reduced risk because previous studies were not controlled for total vegetable intake (i.e., separating the effect of tomatoes from vegetables), dietary intake instruments are poorly able to quantify lycopene intake, and other potential biases. Specific dietary supplementation with lycopene remains to be demonstrated to reduce prostate cancer risk. In the largest prospective study to date, the PCPT, lycopene was not associated with any reduction in risk of prostate cancer among 9,559 men studied. Similarly, there was no relationship between lycopene serum concentrations and risk of prostate cancer.