In a trial that included about 35,000 men, those who were randomized to receive daily supplementation with vitamin E had a significantly increased risk of prostate cancer, according to a study in the October 12 issue of JAMA. "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 costly¹ and urinary（泌尿的） , sexual, and bowel-related adverse² effects are common," according to background information in the article. There has been considerable preclinical（临床前的） and epidemiological（流行病学的） evidence that selenium（硒） 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 statistically³ nonsignificant 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."

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 relatively⁴ 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. Eligibility⁵ criteria⁶ included a prostate-specific antigen (PSA) measure below a certain level, a digital rectal（直肠的） 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 randomly⁷ assigned to 1 of 4 treatment groups: 8,752 to receive selenium (200 micrograms/day); 8,737, vitamin E (400 IU/day); 8,702, both agents; and 8,696, placebo⁸, with a planned follow-up of a minimum of 7 years and maximum of 12 years. Analysis reflect 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 that 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," the authors write. "Given that more than 50 percent of individuals 60 years or older are taking supplements containing vitamin E and that 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 note that the fact that the 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 intervention⁹ is stopped, emphasizing the need for long-term follow-up. They add that the findings of this and other studies illustrate¹⁰（阐明） the importance of large-scale, population-based, randomized trials in accurately¹¹ 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（无害的） yet biologically active substances such as vitamins to cause harm. 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 skeptical¹²（怀疑的） of health claims for unregulated over-the-counter products in the absence of strong evidence of benefit demonstrated in clinical trials."