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Two large, double-blind, placebo-controlled randomised trials fail to demonstrate a benefit of selenium, vitamin E or vitamin C in preventing prostate cancer.
Action:
Clinicians should not recommend the use of supplements of selenium, vitamin E or vitamin C to patients for the prevention of prostate cancer.
What is the background to this?
Some observational studies, supported by data from some earlier cancer prevention studies (e.g. NPC study, ATBC study), suggested the hypothesis that selenium and vitamin E might reduce the incidence of prostate cancer as well as other cancers. Two large randomised controlled trials (RCTs) were designed to test this hypothesis; SELECT considered selenium and vitamin E, alone or in combination, while PHS II considered vitamin E and vitamin C alone.
What do the studies claim claim?
SELECT found that over a median of 5.5 years, selenium and vitamin E, alone or in combination, did not reduce the incidence of prostate cancer in men who were 55 years of age or older (50 years of age or older for African American men) compared with placebo. PHS II found that, over a mean of 8 years, vitamin E or vitamin C did not reduce the incidence of cancer in male physicians (aged 50 years or older) compared with placebo. Neither study showed a benefit for any of the supplements for cancer overall or for any specific type of cancer.
How does this relate to other studies?
As pointed out in an editorial accompanying the two articles, although previous cancer prevention studies have identified reductions in the incidence of prostate cancer with the taking of selenium supplements and antioxidant vitamins, none have pre-specified prostate cancer as an endpoint in the trials. SELECT, which included over 35,000 men, is probably the largest individually randomised cancer prevention trial ever conducted. Together with PHS II, which included more than 14,000 men, it provides high-quality evidence regarding the supplements examined and surpasses previous evidence from observational and secondary analyses of other studies. It now appears likely that the benefits reported in some earlier trials were due to bias or chance.
So what?
The studies provide no support for the taking of selenium or vitamin E or C supplements for the purpose of preventing cancer, and clinicians should not recommend their use for this purpose. The studies provide a good example of why observational data or secondary analysis of unspecified endpoints of RCTs should only be considered as hypothesis generating.
Both SELECT and PHS II, though providing high quality evidence, do have limitations which are discussed by the authors of the two publications. For example, they did not consider different doses and formulations of the supplements or assess the effects in reducing advanced or fatal prostate cancer. However, these would seem relatively minor in comparison with the limitations of previous studies. The accompanying editorial discusses other, perhaps more important, limitations of the study, which are an issue for any prostate cancer prevention study these days, i.e. the widespread use of off-study prostate-specific antigen (PSA) testing by the participants, which may remove patients from the study before there prostate cancer progresses. This is supported by the lower than expected incidence of prostate cancer reported in the studies. Nevertheless, despite its limitations, the editor felt the power of the studies was such that if there had been any benefit of the supplements, this would have been detected.
Study details
Design: Randomised, double-blind, placebo-controlled trial.
Patients: 35,533 men in the USA, Canada and Puerto Rico, aged 55 years or older (or 50 years or older in African American men), with a serum prostate specific antigen level of 4ng/ml or less, and a digital rectal examination not suspicious of prostate cancer.
Interventions: Randomised to one of four groups: selenium (200 micrograms/day from L-selenomethionine); vitamin E (400 IU/d of all rac-{alpha}-tocopheryl acetate); selenium plus vitamin E, and placebo.
Outcomes: Prostate cancer and pre-specified secondary outcomes, including lung, colorectal and overall primary cancer.
Results: During a median overall follow-up of 5.46 years, the hazard ratios (HRs) for prostate cancer were 1.13 (99%CI 0.95 to 1.35, P=0.06; n=473) for vitamin E, 1.04 (99%CI, 0.87 to 1.24, P=0.62; n=432) for selenium, and 1.05 (99%CI, 0.88 to 1.25, P=0.52; n=437) for selenium plus vitamin E vs. 1.00 (n=416) for placebo. There were no significant differences (all P>0.15) in any of the other pre-specified cancer endpoints.
Sponsorship: This work was supported by a grant awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by the National Center for Complementary and Alternative Medicine (National Institutes of Health). Study agents and packaging were provided by Perrigo Company, Sabinsa Corporation, Tishcon Corporation, and DSM Nutritional Products Inc., USA.
Design: Randomised, double-blind, placebo-controlled trial.
Patients: 14,641 male physicians in the USA aged 50 years or older, including 1307 men with a history of prior cancer at randomisation.
Interventions: 400 IU of vitamin E every other day and 500 mg of vitamin C daily.
Outcomes: Prostate and total cancer.
Results: During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years, respectively; HR 0.97; 95%CI, 0.85 to 1.09; P=0.58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years, respectively; HR 1.04; 95%CI, 0.95 to 1.13; P=0.41). There was no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years, respectively; HR 1.01; 95%CI 0.92 to 1.10; P=0.86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years, respectively; HR 1.02; 95%CI 0.90 to 1.15; P=0.80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results.
Sponsorship: This work was supported by grants from the National Institutes of Health, USA and an investigator-initiated grant from BASF Corporation. Study agents and packaging were provided by BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products Inc (formerly Roche Vitamins), USA.
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