After being followed for up to 10 years after randomization, the hazard ratio for prostate cancer in SELECT trial participants assigned to vitamin E supplements was 1.17 (95% CI 1.004 to 1.36) relative to the study's placebo group, reported Eric A. Klein, MD, of the Cleveland Clinic, and colleagues.
The four-arm trial also included selenium supplements, given alone or in combination with vitamin E. Participants in those groups showed a smaller increase in prostate cancer risk that failed to reach statistical significance, Klein and colleagues indicated in the Oct. 12 issue of the Journal of the American Medical Association.
SELECT is an acronym for the Selenium and Vitamin E Cancer Prevention Trial, which randomized 35,553 men 50 and older to the four study arms from 2001 to 2004. Klein and colleagues noted that, whatever else may be gleaned from the results, the study demonstrated that these supplements do not prevent cancer.
The findings, they wrote, "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."
Physicians contacted by MedPage Today and ABC News suggested that the evidence of harm for vitamin E was relatively weak, but they agreed that, on the basis of this and other studies, that neither the vitamin nor selenium holds any benefit for patients.
Jack Cusick, PhD, of Queen Mary University in London, told MedPage Today and ABC News that the study had a very strong if limited interpretation.
"The evidence is very clear that vitamin E will not protect against prostate cancer and should not be taken for that purpose. Whether it constitutes an important risk when used for another purpose is unclear," he said in an email.
Tim Byers, MD, MPH, a cancer prevention specialist at the University of Colorado, was even less convinced there was proof of increased risk with the vitamin.
"Although I have been among those critical of hazards of high-dose supplementation, I view this finding as contributing to an overall pattern showing little or no association rather than to an overall conclusion of proven harm," Byers said in an email.
Results from SELECT were first reported in 2008, at which point there was a nonsignificant trend toward increased prostate cancer risk with vitamin E. The trial was stopped at that point, before the planned termination, because it was clear that the supplements were not reducing cancer risk.
Participants in the trial had been assigned to receive 400 IU/day of vitamin E, 200 mcg/day of L-selenomethionine, both supplements, or placebo in a double-blind, double-dummy fashion. Consequently, when the trial ended, participants had been taking the supplements for four to seven years.
Follow-up continued through July 2011. Because additional events were be expected, the investigators reviewed the data to determine if the trends seen in the earlier analysis were still evident or had disappeared.
Since the original report, an additional 54,464 person-years of follow-up were available and 521 new cases of prostate cancer were diagnosed. A total of 31,793 participants were still alive and being followed, although data for the new prostate cancer analysis were unavailable on about 1,100.
With follow-up data on almost equal numbers of patients in the placebo and vitamin E monotherapy groups, the researchers found that 529 men assigned to placebo had developed prostate cancer compared with 620 of those taking vitamin E.
A Kaplan-Meier curve showed that the difference in diagnosis rates between the vitamin E and placebo groups first appeared in the third year of follow-up and increased as time went on.
There was also a slight increase in risk among those taking selenium monotherapy (HR 1.09, 95% CI 0.93 to 1.27) and in the group receiving both supplements (HR 1.05, 95% CI 0.89 to 1.22).
Klein and colleagues calculated an excess prostate cancer risk of 1.6 cases per 1,000 person-years for vitamin E alone, 0.8 cases for selenium alone, and 0.4 cases for both supplements.
Rates of prostate cancers with Gleason scores of 7 or greater were similarly increased in all three active-treatment groups relative to placebo, but because there were relatively few of these (about one-quarter of all diagnoses), the differences did not reach statistical significance.
Participants had been screened before study entry to exclude those with high prostate-specific antigen readings or suspicious findings from digital rectal exams.
PSA tests and rectal exam rates were the same in all study groups, both before and after the study was unblinded, suggesting that surveillance bias was not a factor in the long-term results.
Klein and colleagues indicated that the findings for vitamin E constitute "an important public health concern," given that more than half of older men are believed to be taking some amount of vitamin E supplements, with about one-quarter taking at least 400 IU/day (18 times the recommended daily allowance of 22.4 IU).
"The fact that the increased risk of prostate cancer in the vitamin E group of participants in SELECT was only apparent after extended follow-up (allowing for additional events) suggests that health effects from these agents may continue even after the intervention is stopped," they added.
The researchers suggested that follow-up should continue indefinitely in all trials stopped prematurely in order to catch these late events.
They also cautioned against using so-called factorial designs in chemoprevention studies, in which a variety of secondary interventions are tested alongside the primary treatments. Such designs allow for more comparisons with fewer participants than would be possible in a straight randomized trial.
Some studies with such designs had previously suggested beneficial effects for vitamin E, selenium, and other compounds, which later were not confirmed in full-blown randomized trials.
Said Cusick, "Except for cases of clear deficiency, supplementation of vitamin E has not been shown to benefit any aspect of health, so there is no rationale for taking it unless a deficiency exists. Further clinical trials are needed if it is to be recommended for any use except in those with deficiencies."
This article was developed in collaboration with ABC News.
The SELECT study was funded by the National Cancer Institute and the National Center for Complementary and Alternative Medicine. Study agents were provided by Perrigo Company, Sabinsa Corporation, Tishcon Corporation, and DSM Nutritional Products.
Some study authors reported relationships with Pfizer, Merck, sanofi-aventis, AstraZeneca, Abbott, GlaxoSmithKline, Janssen, Amgen, Novartis, Firmagon, and Cancer Prevention Pharmaceuticals.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Journal of the American Medical AssociationSource Reference: Klein E, et al "Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)" JAMA 2011; 306: 1549-1556.