De-SELECT? Vitamin E, Selenium, and Prostate Cancer
De-SELECT? Vitamin E, Selenium, and Prostate Cancer
By Russell H. Greenfield, MD, Editor
Synopsis: Results of the SELECT trial, a large randomized, placebo-controlled, double-blind trial designed to help determine whether selenium, vitamin E, or both could safely prevent prostate cancer in middle-aged and older men, were not to be published for another four years. Interim analyses, however, revealed no benefit from therapy, and even some potential health concerns.
Source: Lippman S, 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.
The authors of this large phase 3 randomized, placebo-controlled, double-blind trial were interested in determining whether selenium, vitamin E, or both could safely prevent prostate cancer and other diseases in middle-aged and older men who were relatively healthy at time of study initiation. A total of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico participated in the trial and were to be followed for 7-12 years. Subjects had to be older than age 50 years if African American, or older than age 55 (all other men), have no prior history of prostate cancer, have a PSA < 4 ng/mL and normal findings on digital rectal examination. Participants were randomly assigned to one of four groups: selenium (200 mg/d from L-selenomethionine) and matched placebo; vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate [a synthetic racemic mixture of eight vitamin E stereoisomers]) and matched placebo; selenium and vitamin E; or placebo and placebo. Subjects were followed regularly by their doctor. The main outcome of interest was development of prostate cancer. Secondary outcomes of interest included development of other cancers including lung and colorectal cancer, cardiovascular events, and overall mortality. An independent data and safety monitoring committee met annually and reviewed existing data from the trial. Interim analyses had been planned for years 5, 7, 9, 10, and 11 after the first participant was randomized.
The safety and data monitoring committee met last September to review data as of Aug. 1, 2008, and determined that there was no evidence of benefit from either study agent, and no apparent research benefit to continuing follow-up for subjects enrolled in SELECT. The study was stopped in its seventh year.
The committee reached their decision on the basis of a median 5.46 years of follow-up. There were no statistically significant differences between the four groups for either primary or secondary outcomes of interest. A non-statistically significant increased risk of prostate cancer in the vitamin E group was identified, as was a mildly increased risk for Type 2 diabetes in the selenium group (relative risk = 1.07). Similar risks were not seen in the combined selenium + vitamin E group. The researchers concluded that selenium and vitamin E, alone or in combination, and at the doses and formulations used, did not prevent prostate cancer in a heterogeneous population of relatively healthy older men during a median of 5.5 years follow-up.
Commentary
The study authors state that the genesis of SELECT was the findings from secondary analyses of the Nutritional Prevention of Cancer (NPC) study and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study that showed significant prostate cancer risk reductions with selenized yeast or alpha-tocopherol. Further data suggesting chemopreventive effects of selenium and vitamin E came from epidemiologic evidence and preclinical data. At the SELECT study's initiation there were high hopes that an effective method of helping prevent the most common non-skin epithelial malignancy in U.S. men might be found. Many anxiously awaited the year 2013 when results were to be published and we'd learn if the early promise of selenium and vitamin E bore fruit; we gained access to the data early, unfortunately. The results are certainly disappointing, but the negative conclusions drawn from this trial need not be overly broad when considering issues of timing and the specific agents employed.
First, it's important to comment on the strengths of this trial, and they are many. From the very large sample size, to unique methods of pre-trial compliance assessment, to supplement quality measures, to intensive statistical analyses and a study population that included a large proportion (13%) of African-American men, the research team put together an exemplary model of research methodology.
Now, a word of caution in interpreting the results. The subjects enrolled in SELECT were all older than age 50 years at the time of supplement regimen initiation, so we don't know whether earlier administration of selenium, vitamin E, or both might have offered chemoprotective effects against much later development of prostate cancer. The authors point out the next area of concern themselvesthey chose one specific formulation each of selenium and vitamin E, and results are tied specifically to the formulations employed. This is an important consideration, as the NPC trial used high selenium yeast, and some researchers suggest that gamma-tocopherol might offer the most active chemoprotective effects, and that all rac-alpha-tocopheryl acetate may be significantly less potent than other forms of vitamin E.
Prior studies suggested that selenium's effects might be more noticeable in selenium-deficient populations, but the subjects in SELECT were largely selenium-replete. Other data point to more of a protective effect against prostate cancer for vitamin E in smokers, but subgroup analysis of smokers in SELECT did not reveal a protective benefit for vitamin E.
Concerns about an association between high levels of selenium intake and later development of Type 2 diabetes have been raised previously, but there is no consensus yet, as data are conflicting. The results presented in SELECT merit additional concern in this regard. The nonsignificant increase in prostate cancer in the vitamin E group also warrants close attention. The authors do state, however, that 400 IU vitamin E appears to be safe in otherwise healthy men, since they detected no increased incidence of cardiovascular events or overall mortality in the vitamin E group.
What are practitioners to make of these data? It seems clear that vitamin E alone, selenium alone, or the two in combination should not be recommended to middle-aged and older men for the specific purpose of preventing prostate cancer. Whether administration of selenium and vitamin E earlier in life, or the use of other formulations, might have benefits in this regard remains unknown.
For the conclusions that can be safely drawn from this trial, it is an exquisite piece of research, one worthy of a place in your file cabinet.
Results of the SELECT trial, a large randomized, placebo-controlled, double-blind trial designed to help determine whether selenium, vitamin E, or both could safely prevent prostate cancer in middle-aged and older men, were not to be published for another four years. Interim analyses, however, revealed no benefit from therapy, and even some potential health concerns.Subscribe Now for Access
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