No statistically significant risks seen for prostate cancer or diabetes ...

Thousands of men and their loved ones may have been frightened this week by news that the National Cancer Institute had announced it was halting a major multi-center prostate cancer study due to safety concerns. It was a randomized clinical trial of vitamin E and selenium and its suspension brought others to fear their vitamins could be putting them at risk for prostate cancer or diabetes. While the precise findings which led to the decision to prematurely end this trial have not been made public, a better understanding of the science and what is known may help lessen fears and put things into perspective.

Background

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a major, phase III, randomized, placebo-controlled, double-blind clinical trial of selenium and vitamin E (individually or together). Its goals are to see if the vitamins have an effect on preventing prostate cancer, as well as lung cancer, colon cancer, Alzheimer’s disease, age-related macular degeneration and cataracts, and to determine if the supplements have any affect on lung function and chronic obstructive lung disease, serious cardiovascular events and overall survival. SELECT is registered at ClinicalTrials.gov (NCT00006392) and began in July 2001.

This study is the largest prostate cancer prevention trial ever conducted. It was designed to enroll a total of 32,400 men, 55 years of age and over (50 years and over for African American men) who were free of prostate cancer or elevated PSA levels. The study randomized the men into four arms to receive selenium (200 micrograms/day of L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) or a placebo. The men’s medical conditions were to be closely followed for a minimum of 7 years and up to 12 years.

This study has been conducted at more than 400 medical centers in the United States, Puerto Rico and Canada. It is coordinated by the Southwest Oncology Group (SWOG), one of the largest cancer clinical trials cooperative groups in the United States. Funding for this study included about $114 million from the NCI and $4.5 million from the National Center for Complementary and Alternative Medicine (NCCAM). The ancillary studies have each received additional funding. For example, the National Institute on Aging granted $7 million to evaluate Alzheimer’s and cognitive affects; the National Eye Institute provided $2 million to evaluate age-related macular degeneration and cataracts; and the National Heart, Lung and Blood Institute (NHLBI) gave more than $3 million for the lung function evaluations. The point being, a lot is riding on this study and it is inconceivable it would be discontinued lightly.

Available information on the study’s suspension

According to SWOG, the Data and Safety Monitoring Committee for the SELECT trial met last month to review the blinded data since the trial commenced, along with the study investigators and the National Cancer Institute. Together, it was decided to stop the trial due to concerns that the vitamins could slightly raise the men’s’ chances of getting diabetes and prostate cancer. The NCI provided more details on the SELECT page, saying that independent reviews of the study were done in September and October and reported:

[S]elenium and vitamin in E supplements, taken either alone or together for an average of five years, did not prevent prostate cancer. The data also showed two concerning trends: a small increase in the number of prostate cancer cases in men taking only vitamin E and a small increase in the number of cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance. Additional analyses of the data are under way and the investigators will produce a peer-reviewed publication of these initial results soon.

While no specifics have yet been published on precisely what the safety data showed, the key points highlighted on the NCI’s SELECT Q&A page is where we learn the risks would appear to be minimal, and may not even be real at all. There, they state that the trends were not even statistically significant.

The SELECT data showed two concerning, but not statistically significant, trends: there were slightly more cases of prostate cancer in men taking only vitamin E and slightly more cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance.

With no demonstrated benefit of the antioxidants in reducing prostate cancer (the study’s primary endpoint), they said that as a precaution they told all of the men to stop taking their study supplements yesterday. The men will continue to have their health monitored by the researchers for about three years. The NCI says that the study will continue to be blinded during these follow-up years to attempt to preserve reliable evaluations of the study objectives, but men will be told what supplements or placebo they were receiving if they request.

Balancing unknowns with what we know

With unknowns, it’s natural to feel worried or to let suspicions get the better of us, even when we’ve been told the risks aren’t beyond what might have surfaced by random chance. But examining the body of evidence to date will hopefully provide some additional reassurance and help to put things into perspective.

The NCI’s SELECT Q&A page provides little information on the entire body of evidence, noting only the inconclusiveness in studies of selenium or vitamin E published since SELECT began. That’s probably left many feeling even more unsettled about the unknowns and their possible risks.

The NCI notes that each of the observational (epidemiological) papers examining the correlations between selenium supplementation and blood sugars had reached different conclusions (increased risk, no association and lower risk for diabetes).

It notes only one published paper of a clinical trial of selenium supplementation, but it was a secondary analysis of a randomized, double-blind, placebo-controlled trial of selenium supplements taken by 1,202 people being seen at a dermatology clinic and reported only self-reported cases of type 2 diabetes. The authors published their findings last year in Annals of Internal Medicine and said that after an average of 7.7 years of follow-up, type 2 diabetes was seen in 1.26% people/year of those with the highest selenium blood levels compared to 0.84% among those with the lowest selenium levels. Because the study wasn’t designed to evaluate diabetes or determine the presence of diabetes at the beginning of the trial period, the authors urged caution in generalizing the findings but said a clinical trial to examine the potential risk for diabetes was warranted. The NCI said that the SELECT study will examine its data to evaluate this potential risk.

Finally, the NCI cites only one randomized, double-blind, placebo-controlled trial of vitamin E. This was a report of the international HOPE trials, which had enrolled 9,541 older adults with heart disease or diabetes, following them for 4.5 years, with HOPE-TOO following 7,030 of the participants for an additional 2.5 years. These trials saw no affect with natural vitamin E supplementation on the incidences of cancer or cancer deaths, on major cardiovascular events or death from any cardiovascular cause, or in deaths from any cause. It did report slightly higher rates of heart failure (14.6% in vitamin group versus 12.6% in placebo). The NCI said that the SELECT study will also examine its data for this potential risk.

Not included on the NCI Q&A webpage was mention of the largest review of every available randomized, placebo-controlled, double-blind clinical trial of antioxidant vitamins conducted since 1945. This meticulous undertaking was recently published by Cochrane Database of Systematic Reviews, the world’s most respected source of systematic reviews of the evidence. Evaluating each trial for the quality of its methodology and to ensure it was unbiased, the experts found that no clinical trial done in over 60 years has found a credible benefit for taking antioxidant supplements. Similarly, there was no significant difference in mortality among those taking the antioxidant supplements compared to a placebo — regardless of the doses, antioxidants taken individually or in combination, in any population studied or after14 years of follow-up. As reviewed here, every relative risk hugged either side of null (1:1 = same risk of death in those taking supplements and in those not), all within the range of random chance and margin of error.

In other words, men, the best clinical trial evidence to date suggests that the overall risks of taking vitamin supplements at the dosages in this study are not significant. Going to the Cochrane report itself where the clinical trials of vitamin E and selenium, used singly or with other antioxidants, were specifically examined, the findings are similarly reassuring. The reviewers found no significant effect of vitamin E on mortality when including all 54 trials and after excluding high-bias trials. Some of these trials had used doses of 1,000IU and higher, many times higher than those used in the SELECT study. Selenium also had no significant effect on mortality in all of the low-bias risk trials.

Nor is there any evidence that any vitamins or antioxidant supplements offer any health benefits when a specific deficiency doesn’t exist, as reviewed last year. Yet, beliefs continue that antioxidants, as in lots of fruits and vegetables or super foods, can prevent cancers and chronic diseases of aging. The scientific expert review of anti-aging medicine done for the National Institutes of Aging emphatically concluded “there are no lifestyle changes, surgical procedures, vitamins, antioxidants, hormones or techniques of genetic engineering available today that have been demonstrated to influence the processes of human aging.”

Antioxidant and free radical myths

Both the reasons for the continued failure of antioxidant vitamins to demonstrate health benefits for degenerative diseases of aging in clinical trials, and for some studies to even suggest possible risks at doses above normal dietary levels, has to do with popularized misconceptions of the benefits of antioxidants and dangers of free radicals. Things aren’t as black and white as that. Free radicals actually play a role in normal, healthy physiological processes like our immune system and promote beneficial oxidation; while in excess they can produce harmful oxidation that causes cell damage. Similarly, many vitamins and supplements classified as antioxidants are actually redox agents, meaning they act as antioxidants in some instances and pro-oxidants in others and can produce harmful levels of free radicals.

An editorial in the Journal of the American Medical Association accompanying the HOPE trials, written by researchers at the University of Washington School of Medicine in Seattle, said that the HOPE trials add to a growing list of null clinical trials of vitamin E and effectively closes the door on the prospect of a major protective effect of this supplement for heart disease or cancer. More importantly, the carefully done HOPE trial “reemphasizes the importance of controlled clinical trials for testing important hypotheses deriving from basic biological findings or from epidemiological observations. The latter can mislead; well designed clinical trials rarely do.”

They added that this is a teaching opportunity:

HOPE-TOO allows physicians to educate their patients as with the following response to inquiries about vitamin E, “In nearly 68,000 patients studied to date, there is no compelling evidence that higher doses of vitamin E reduce cardiovascular risk or cancer; there are even some hints that vitamin E, in excess of normal daily intake, may slightly increase the risk of ischemic events or of heart failure. You may hear that vitamin E is a ‘natural,’ yet effective, way to prevent heart disease or cancer, but this has proven to be a false hope.

The continued resistance to accepting the null findings of many of these clinical trials on vitamin and antioxidant supplements originates in another misconception of vitamins and supplements: that only natural sources of vitamins work and that they’re different from synthetic versions. As explained in more depth here, this is a marketing concept, but has no scientific basis or biological plausibility. The molecular structure of a synthetic vitamin molecule is identical to one from natural sources and indistinguishable in all respects to our body.

Names can lead us to wrongly believe that one type of vitamin is less bioactive than another, such as vitamin E. The d-form (most often termed ‘d-alpha tocopherol’) comes form vegetable oils and other ‘natural’ sources. It’s different from the dl-form (dl-tocopherol) commonly called the ‘synthetic’ type of vitamin E. But biologically, one isn’t better than the other. That’s because, to put it simply, the dl-form is a combination of d-form and l-form, but the body only uses the d-form. The l-form is just excreted by the body. So the dosages will be different on the labels of dl-form and d-forms (half) — but the bioeffective vitamin dose is the same.

‘Natural’ vitamins are said to have hundreds of other, unknown substances found in whole foods that aren’t found in synthetic vitamins, but there are no credible clinical studies supporting such claims that these ingredients potentiate or improve the action or absorption of the vitamins or offer any special benefits. Vitamin pills extracted from foods undergo a process that changes their place in that food and it’s implausible that the miniscule amount of some unknown factor that might survive that process in a tiny pill has any special vital essences or health promoting properties.

For men and their loved ones who may have had their lives shaken up this week by news of the SELECT study being halted because of safety concerns, hopefully, realizing that the risks weren’t even statistically significant and seeing the bigger picture and the scientific evidence to date has helped.

© 2008 Sandy Szwarc