JAMA Study Links Vitamin E, Prostate Cancer

CHICAGOAccording to a trial including 35,000 men published in JAMA, men randomized 400 IU/d of vitamin E had a significantly increased risk of prostate cancer (2011;306(14):1549-56). Lifetime risk of prostate cancer in the United States is currently estimated to be 16 percent. Although most cases are found at an early, curable stage, treatment is costly and urinary, sexual and bowel-related adverse effects are common. There has been considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate cancer risk. The initial report [published December 2008] of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements, but a statistically non-significant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.

Therefore, Eric A. Klein, M.D., of the Cleveland Clinic, and colleagues examined the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. SELECT included a total of 35,533 men from 427 study sites in the United States, Canada and Puerto Rico who were randomized between August 2001 and June 2004. Eligibility criteria included a prostate-specific antigen (PSA) measure below a certain level, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men, and 55 years or older for other men. The primary analysis included 34,887 men who were randomly assigned to one of four treatment groups: 8,752 to receive selenium (200 micrograms/d); 8,737, vitamin E (400 IU/d); 8,702, both agents; and 8,696, placebo, with a planned follow-up of a minimum of seven years and maximum of 12 years. Analysis reflects the final data collected by the study sites on their participants through July 5, 2011.

Since the initial report, a total of 521 additional prostate cancers have been diagnosed: 113 in the placebo group, 147 in the vitamin E group, 143 in the selenium group, and 118 in the combination group. The researchers found the rate of prostate cancer detection was greater in all treatment groups when compared with placebo, but was statistically significant only in the vitamin E alone group (a 17-percent increased rate of prostate cancer detection). Compared with the placebo group, in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer, as did 575 in the selenium group, and 555 in the selenium plus vitamin E group. The difference in rates of prostate cancer between vitamin E and placebo became apparent during the participants third year in the trial. The elevated risk estimate for vitamin E was consistent across both low- and high-grade disease.

In this article, we report an observation of important public health concern that has emerged with continued follow-up of SELECT participants," according to the authors of the study. Given more than 50 percent of individuals 60 years or older are taking supplements containing vitamin E, and 23 percent of them are taking at least 400 IU/d despite a recommended daily dietary allowance of only 22.4 IU for adult men, the implications of our observations are substantial."

The researchers noted the fact increased risk of prostate cancer in the vitamin E group of this trial was only apparent after extended follow-up suggests that health effects from these agents may continue even after the intervention is stopped, emphasizing the need for long-term follow-up, adding, the findings of this and other studies illustrate the importance of large-scale, population-based, randomized trials in accurately assessing the benefits and harms of micronutrients as dietary supplements.

The observed 17-percent increase in prostate cancer incidence demonstrates the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm," the researchers noted. The lack of benefit from dietary supplementation with vitamin E or other agents with respect to preventing common health conditions and cancers or improving overall survival, and their potential harm, underscore the need for consumers to be skeptical of health claims for unregulated over-the-counter products in the absence of strong evidence of benefit demonstrated in clinical trials."

In response to JAMAs study, Duffy MacKay, N.D., vice president, scientific and regulatory affairs, Council for Responsible Nutrition (CRN), commented: Men shouldnt rush to judgment about vitamin E based on this study, but instead should consider the body of evidence, the amount being taken and their individual medical history. 

The study itself, in the confines of the drug model, appears to be well-designed and well-executed; however, it also evidences the risks of examining a nutrient in isolation. With a reductionist approach to the benefits of nutrition, the study showed a dose of 400 IU/d vitamin E was not likely to provide benefit for preventing cancer, and the authors found an increased risk for developing prostate cancer.  Interestingly, when vitamin E was combined with selenium, the risk was reduced to a non-significant statistic, perhaps even the result of chance. This reinforces the theory that vitamins work synergistically and that drug-like trials of nutrients, when used in isolation from other nutrients, may not be the most appropriate way to study them.

Because the results of this study are different from other studies, they are not a reason for men to stop using their vitamin E. The authors acknowledge other research has demonstrated the benefits of vitamin E for Alzheimers disease, and age-related macular degeneration. Even with respect to prostate cancer, two other studies (cited within the article) had different results: one demonstrated a 3- percent risk reduction for prostate cancer in men taking 50 mg/d (75 IU) vitamin E for six years and another resulted in no effect on risk.

This study provides an important addition to the knowledge base, but we should be reminded it is one study.  We will be interested to see the results of the serum level analysis, which the researchers have indicated will be published at a future date, as that will provide even further information about the role of vitamin E and prostate cancer.

Finally, at the end of the study, there is a gratuitous dig about dietary supplements being unregulated, which, aside from being false, forces us to engage in discussion that goes beyond what the study itself says. It concerns us that underlying bias from the publication about the dietary supplement industry and the fact that these products are not regulated like drugs may provide an ulterior motive for which studies are published and how study results are presented."