How should we advise patients about the chemoprevention of prostate cancer?
Article first published online: 24 JUL 2005
Volume 96, Issue 3, pages 231–232, August 2005
How to Cite
Kirby, R. S. and Fitzpatrick, J. M. (2005), How should we advise patients about the chemoprevention of prostate cancer?. BJU International, 96: 231–232. doi: 10.1111/j.1464-410X.2005.05606.x
- Issue published online: 24 JUL 2005
- Article first published online: 24 JUL 2005
Prostate cancer represents in many ways an ideal candidate for chemoprevention, because of its high incidence and long latency to clinically significant disease . Because of this, increasingly many patients are asking their urologist directly what steps they can take to reduce their risk of being affected by the disease. If we as clinicians do not provide appropriate evidenced-based advice, then our patients are likely to end up taking an expensive cocktail of ‘natural’ preparations, often purchased at considerable expense from their local health-food store.
So what is the current evidence that there is anything now available that can safely and effectively reduce the risk of prostate cancer? This is an especially pertinent issue, as ever-increasing numbers of prostate biopsies are being taken, and urologists are seeing more men who are deemed ‘high-risk’, either as result of a raised PSA level, prostatic intraepithelial neoplasia, or a positive family history of prostate malignancy.
Selenium is a trace nutrient essential for the activity of glutathione peroxidase, which may reduce oxidative damage to DNA. Several studies suggest a useful effect, but the best (and still indirect) evidence for its chemopreventive activity comes from the Nutritional Prevention of Cancer Study Group's randomized trial of selenium to reduce the recurrence of skin cancer. After 10 years of follow-up (mean time on treatment 4.5 years), men taking selenium at a dose of 200 µg/day had a 63–74% reduction in the risk of prostate cancer .
Vitamin E is the other supplement for which there is reasonable, but again indirect, evidence for a genuine chemopreventative effect in this context. In the Alpha-Tocopherol Beta-Carotene Cancer Prevention Trial  there was a statistically significant reduction of both prostate cancer incidence and mortality of ≈ 40% in men receiving 50 IU of α-tocopherol daily.
Many clinicians have been in the habit of advising higher doses of vitamin E, often 400 IU/day, but recently published evidence suggests that the recommended dose should be ≤ 150 IU/day. Miller et al. reported a meta-analysis of 19 trials, recruiting 135 967 participants; nine of 11 trials testing high-dosage (<400 IU) vitamin E showed a greater risk for all-cause mortality for those on vitamin E than in controls. The difference in mortality risk in high-dosage vitamin E trials was 39 per 10 000 persons (95 CI, 3–74; P = 0.035). For low-dosage vitamin E trials, the risk difference was − 16 per 10 000 persons (CI − 41 to −10; P > 0.2). A dose–response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk for dosages of >150 IU/day (Fig. 1).
The true safety and effectiveness of selenium and vitamin E should become clearer when the results of the SELECT study become available. This trial, which is sponsored by the USA National Cancer Institute, is a randomized, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E either alone or combined . The target accrual is 32 400 individuals and the study duration is planned for 12 years. Unfortunately results are not expected until 2013 (SELECT details available at http://www.crab.org/select/).
In theory, some of the most logical chemopreventative agents for prostate cancer are the 5α-reductase inhibitors. Finasteride, the first compound developed in this class, which inhibits isoenzyme type 2, has been evaluated in the Prostate Cancer Prevention Trial . In that study 18 882 men with a normal DRE and a PSA level of <3.0 ng/mL were randomized to either finasteride 5 mg/day or placebo, for 7 years. Prostate biopsy was advised if the PSA was >4.0 ng/mL or the DRE became abnormal. Prostate cancer was detected in 18.4% of men in the finasteride group and 24.4% in the placebo group, a 24.8% reduction (P < 0.001). However, tumours were of Gleason score 7–10 in 6.4% of the finasteride-treated men, compared with 5.1% of the placebo group (P = 0.005), and sexual side-effects were more common in the finasteride arm. The explanation for the slight preponderance of less well-differentiated tumours in the men treated with finasteride so far remains elusive. Although the result could be artefactual, because of the known effect of finasteride on prostatic epithelial architecture, there remains the worrying possibility that the effect could be real. Until the position becomes clearer, finasteride should probably not be recommended as a chemopreventive agent for prostate cancer.
Dutasteride is a dual inhibitor of both 5α-reductase types 1 and 2. As such it results in suppression of dihydrotestosterone by >90%, compared with a suppression of ≈ 70% with finasteride. The Reduction of Prostate Cancer Events trial has just completed recruiting 8000 men to receive either 0.5 mg of dutasteride or placebo for 4 years . Biopsies must be negative within 6 months of accrual and repeat biopsies will be taken at 2 and 4 years. The results will not be available for some time yet, but should throw new light on the issue.
Encouragingly, it was recently proposed that the consumption of red wine might be protective against prostate cancer . Schoonen et al. interviewed 753 middle-aged patients newly diagnosed with prostate cancer, and 703 age-matched controls. Their lifelong alcohol habits, choice of beverage and prostate cancer history were assessed using an elaborate scoring process. Overall, total alcohol, beer, liquor and white wine consumption were not associated with the risk of prostate cancer. However, with red wine, every additional glass drunk per week showed a statistically significant 6% decrease in relative risk. Men drinking 4–7 glasses/week were almost 25% less likely to have the disease (a relative risk reduction of 48%).
So how should we advise patients while awaiting more data? A combination of selenium 200 µg and vitamin E at ≤ 150 IU per day may be effective, and seems unlikely to cause significant side-effects, provided appropriate doses are used. A glass or two of red wine may be helpful, and tastes good! A myriad of other remedies are promoted as being effective , but in the absence of firm evidence from randomized studies or adequate safety data, patients should be discouraged from using compounds that may do more harm than good, and that are also likely to damage the wallet!
- 2Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 1998; 90: 1219–24, , et al.
- 4Meta-analysis: high dosage vitamin E supplementation may increase all-cause-mortality. Ann Int Med 2005; 142: I40, , et al.