Vitamin E and Prostate Cancer

Abstract and Commentary

By Howell Sasser, PhD, Dr. Sasser is a scientific review coordinator with Manila Consulting Group, and an adjunct member of the faculty of New York Medical College. He reports no financial relationships relevant to this field of study.

Synopsis: The SELECT Trial investigators report on nearly 10 years of follow-up of participants in a study of selenium and vitamin E and the risk of prostate cancer. A small but statistically significant increased risk of prostate cancer appears to be associated with taking vitamin E supplements. These results are in disagreement with others in the literature, and the authors present no plausible biological explanation for them. Nonetheless, the balance of evidence does not appear to support any recommendation that physicians advise their middle-aged and elderly patients to begin vitamin E supplementation for prostate cancer prevention.

Source: Klein EA, et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556.

The role of antioxidants in the prevention of a var-iety of diseases has been an active and controversial area of research for many years. Findings have been mixed and methodological issues have often affected their interpretation. Among these problems has been a lack of appropriately powered randomized studies with long enough periods of follow-up to permit assessment of clinically relevant endpoints. Such studies are especially important for cancer research because of the — usually — long latency period between initiation and the development of detectable disease. The newly published results of the SELECT trial go some way to meet this need in the case of prostate cancer.1

Briefly, 34,887 men were assigned in a parallel fashion to selenium (200 µg/d) plus placebo, vitamin E (400 IU/day) plus placebo, both active agents, or neither (double placebo). All had prostate-specific antigen (PSA) levels of no more than 4 ng/ml and normal digital rectal exam (DRE) findings. Recruitment began in 2001 and blinded follow-up continued through October 2008. At that point, an interim analysis of the study findings showed a small (13%) excess in the hazard (time-adjusted risk) of prostate cancer among those receiving vitamin E. This finding was not statistically significant (HR = 1.13, 99% CI, 0.95 to 1.35), but was of adequate concern to lead the investigators to end the experimental component of the study, inform all parties of study treatment assignments, and continue follow-up.2

The newest results update follow-up through July 2011. All treatment combinations (selenium, vitamin E, and selenium plus vitamin E) now show elevated hazards of prostate cancer as compared with placebo, and the hazard associated with vitamin E is statistically significant (HR = 1.17, 99% CI = 1.004 to 1.36). The authors interpret their findings as adding weight to the argument that consumers should be skeptical of the health claims made for products not regulated as medications.

There are a number of methodological reasons why these findings are compelling. First, the sample size is very large, and follow-up is lengthy. The SELECT study recruited on a population basis, from numerous sites in the United States, Canada, and Puerto Rico. This increases confidence that selection bias was minimized. The study's use of National Cancer Institute and Department of Veterans' Affairs research networks as mechanisms for recruitment also adds confidence that the study had access to a diverse group of potential participants. The original study design envisioned follow-up of between 8 and 12 years. The combined blinded and unblinded follow-up intervals cover nearly 10 years. Given that all participants were between 58 and 68 years of age on enrollment, follow-up included much of the period in the life course when prostate cancer is of greatest clinical significance.

Also worth noting is the study's naturalistic design and — paradoxically — its apparent lack of impact on the findings. Physicians were not instructed to perform PSA tests or DREs at specific intervals, but rather to do these and other tests as indicated by normal clinical protocol based on the patient's age and the presence of other risk factors. Replication of typical clinical conditions improves the study's generalizability. This would have been especially important had the experimental interventions shown a beneficial effect, but is worth noting even in the absence of such a result. Equally important is the reported finding that the rates of PSA and DRE tests did not change after unblinding. It might have been assumed that unblinding, combined with the nature of the study's initial findings, would have led to more frequent testing among men known to have been in the experimental treatment arms. Greater testing frequency, in turn, might have led to an apparent excess of new cases among those being tested more often. Because this does not seem to have been the case, it is possible to combine the blinded and unblinded phases of follow-up, adding to the study's case-finding power.

It is also important to note a few limitations of the latest SELECT results. First, the authors' finding of an increased risk of cancer with vitamin E supplementation is in disagreement with other published findings and the authors are not able to present a biological rationale for it. As noted in the present paper, the Alpha-Tocopherol, Beta Carotene (ATBC) trial and the second Physicians' Health Study (PHS II) reported a reduction in risk and no change in risk with supplementation, respectively.3,4 The ATBC dose was considerably smaller (roughly 75 IU/day as compared with 400 IU/day in SELECT) and the study population were all smokers. PHS II used the same dose as SELECT, but it was given only every other day. Nonetheless, all had populations of similar ages and studied supplementation of a similar duration, if not of the same intensity. This mix of similarities and differences makes a direct comparison of risk across studies difficult, but it does seem reasonable to conclude that the balance of evidence does not support the use of vitamin E in prostate cancer prevention.

A second issue also relates to biology and the theoretical model underlying the research question. All of these studies (SELECT, ATBC, PHS II) recruited participants who were at least 50 years of age — at least 58 in the case of SELECT. The most common proposed mechanism for antioxidants in cancer involves their role in preventing DNA damage through the scavenging of reactive oxygen species, a process that arguably begins much earlier in the life course. The role that antioxidants play late in the natural history of cancer may not be the same as, or as pronounced as, their role earlier on. SELECT did not collect information on earlier use of supplements or on diet, although care was taken to assure that participants were not taking concomitant doses of the agents in the study supplements.

This picture is further complicated by the apparent interaction of selenium and vitamin E observed in SELECT in the form of a smaller increased risk of cancer among those in the vitamin E plus selenium group as compared to that among those in the vitamin E only group. The authors hypothesized that selenium mitigated the negative effect of vitamin E but could offer no biological explanation for this either.

It can be argued that random assignment should have made most pre-trial and peri-trial factors irrelevant, but expected findings in any study should prompt questions about the assumptions on which it was built and around which randomization methods are designed.

Finally, from a statistical perspective, the finding of increased risk associated with vitamin E is significant but only by the smallest margin. In a large study, great precision is possible, but results must also be interpreted in light of the effect of the sample size on statistical outcomes. The lower bound of the relevant confidence interval (1.004) is expressed to a greater number of significant figures than any other in the paper. This undoubtedly represents an abundance of caution on the authors' part, but it should be noted that this would have been interpreted as a non-significant finding for any other reported measure.

Given all of this, what should a clinician recommend to his or her patients? There seems to be little evidence to suggest that vitamin E, consumed by men in the 50s and 60s, has much beneficial effect in preventing prostate cancer. The small, but marginally statistically significant, increase in risk associated with vitamin E in this study is of concern, but in the absence of a plausible biological rationale, should not be seen as alarming. If a patient is already taking vitamin E supplements for some other reason, it would be wise to discuss the potential risk it carries. If a patient is not taking vitamin E, this study provides no argument for why he should start, and at least a precautionary argument for why he should not.

References

1. Klein EA, et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556.

2. Lippman SM, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301:39-51.

3. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.

4. Gaziano JM, et al. Vitamins E and C in the prevention of prostate and total cancer in men: The Physicians' Health Study II randomized controlled trial. JAMA 2009;301:52-62.