Opportunities for 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 were noted in 6.4% of finasteride patients, compared with 5.1% of men receiving a placebo. 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, and decreased prostate volume (24%), creating a detection bias. Adjustment of PSA in men taking finasteride preserves the performance characteristics for cancer detection.
It is possible that finasteride induced the development of high-grade epithelial neoplasia, but this has not been demonstrated. With a finasteride-induced development of high-grade prostate cancer, a gradual and progressive increase in the number of high-grade tumors would have been expected for more than 7 years, compared with placebo; however, 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 5 to 7 and Gleason 3 to 4 prostate cancer, but not Gleason 2 to 3 or Gleason 8 to 10. The reduction in the incidence of Gleason 7 (22%) was less than the reduction in the incidence of Gleason 5 (58%) and Gleason 6 (52%). An analysis using different methodologies found an overall reduction of both low-grade (Gleason <6) and high-grade (Gleason >7) cancers.
The Reduction by Dutasteride of Prostate Cancer Events trial randomly assigned 8,231 men aged 50 to 75 years at higher risk of prostate cancer (i.e., PSA 2.5–10.0) with one recent negative prostate biopsy to dutasteride at 0.5 mg daily or to placebo. The primary endpoint 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 dutasteride group vs. 1 cancer in placebo group).
Overall, there was no statistically significant difference of high-grade tumors for Gleason 8 to 10 cancers in years 1 to 4 (29 vs. 19, 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 8 to 10 cancers is of uncertain validity. However, the finding of no reduction in these cancers is more significant.
There are several plausible explanations for the failure of finasteride or dutasteride to reduce the incidence of Gleason 8 to 10 cancers. Because of this uncertainty, the evidence is currently insufficient to determine the effect of prophylaxis with these drugs on prostate cancer mortality.
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-alpha-reductase (5AR) inhibitors through 2010 that were at least one year in duration concluded that finasteride and dutasteride reduce the risk of being diagnosed with prostate 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 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 Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events study were designed to assess the impact of 5AR inhibitors on prostate cancer period prevalence. Reviews of all eight studies concluded that compared with placebo, 5AR inhibitors resulted in 25% relative risk (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 5AR inhibitors versus placebo assessed prostate cancers detected overall. Among these there was a 26% RR reduction favoring 5AR inhibitors [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:
- Suspected clinically from symptoms, abnormal digital rectal exam (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.
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 gleaned by such a diet, to include 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,[13-17] vitamin D,[18-20] and isoflavonoids,[21,22] have shown potential in either clinical or laboratory studies for chemoprevention of prostate cancer, the correlations of cancer prevention with these agents are increasingly of concern given the statistically increased risk of prostate cancer with alpha-tocopherol in the SELECT trial and the lack of preventive effect (actually, a non-significant increase in prostate cancer risk) with selenium.Chemoprevention with selenium and vitamin E
The Selenium and Vitamin E Cancer Prevention Trial (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 prolonged 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.[25-28] 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.[30,31] 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 Prostate Cancer Prevention Trial, 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.[33,34]References
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