Arizona Oncology - The US Oncology Network

Vitamin E Supplements May Raise Prostate Cancer Risk CME

10/21/2011

Vitamin E Supplements May Raise Prostate Cancer Risk CME

News Author: Roxanne Nelson
CME Author: Charles P. Vega, MD

Clinical Context

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was designed to test whether supplementation with vitamin E or selenium could reduce the risk for prostate cancer among average-risk men. However, the study was stopped early in 2008 after a median of 5.5 years of follow-up. A safety committee assigned to the study found that the active interventions could not significantly improve the main study outcomes. In fact, at that time, there was some suggestion that vitamin E increased the risk for prostate cancer compared with placebo, and selenium might be associated with a higher risk for incident type 2 diabetes. However, these differences were not statistically significant.

Nonetheless, researchers continued to observe men who participated in the SELECT trial. The current research describes findings from this group after an additional 3 years of follow-up.

Study Synopsis and Perspective

Vitamin E supplementation in men does not protect against prostate cancer; instead, it might increase risk.

The initial report of SELECT found that neither selenium nor vitamin E supplements reduced the risk for prostate cancer. However, an updated analysis, which appears in the October 12 issue of JAMA, shows that vitamin E supplementation can significantly increase the risk for prostate cancer.

Men who received a common dose and formulation of vitamin E (400 IU/d) had a significant 17% increased risk for prostate cancer than men who received placebo.

This observed increase in risk demonstrates "the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm," write the authors.

"This was a surprising finding and, at present, there is no biological explanation for why those who took vitamin E are at higher risk of developing prostate cancer," first author Eric Klein, MD, told Medscape Medical News. Dr. Klein is chair of the Glickman Urological and Kidney Institute, Cleveland Clinic, Ohio.

"We have made the SELECT biorepository available to the wider scientific community to test hypotheses that might explain the findings," he added.

Should vitamin supplementation be avoided until more is known about this possible link to prostate cancer?

There is no reason for otherwise healthy men to take vitamin E.

"As we point out in the paper, there are few if any studies that show any health benefits for taking vitamin E, and the SELECT findings suggest it could be harmful," said Dr. Klein. "It seems there is no reason for otherwise healthy men to take vitamin E as a dietary supplement."

Senior author Laurence H. Baker, DO, professor of internal medicine and pharmacology at the University of Michigan, Ann Arbor, agrees that the findings were unexpected.

"Vitamin E doesn't prevent prostate cancer; it doesn't prevent any cancer, despite the claims of some, and it doesn't promote cardiovascular health, despite the claims of many." he said in an interview.

"There is no evidence to support any of these claims, yet thousands or even millions of men include vitamin E in their supplementation," Dr. Baker continued. "What this tells us is that even though we assume something to be good, it may not be. In fact, it may be harmful. The assumption is that because vitamin E is an antioxidant, it's good for us. But that isn't the case."

On the basis of these results, Dr. Baker noted that there is "good reason to avoid the dose of vitamin E...that was used in the study."

"The onus of proof should always be on the people" who advocate the use of a product, he explained.

Despite the negative results, the study offers a unique opportunity to learn more about prostate cancer. In the biorepository, there are blood samples and tissue samples from the 3500 men who participated in the trial. "Even though we don't know why these men had a higher incidence of prostate cancer, I am optimistic that these results may teach us why men get prostate cancer," Dr. Baker noted. "That would be a very important benefit."

No Evidence to Support Benefit

The SELECT trial was conducted on the premise that selenium and vitamin E supplementation might reduce the risk for prostate cancer. This hypothesis stemmed from preclinical and epidemiologic studies that suggested that there might be a benefit. However, the use of the 2 supplements was halted in October 2008 because of an apparent lack of benefit and a possibility of harm.

After a median overall follow-up of 5.46 years, supplementation with selenium, vitamin E, or both did not prevent prostate cancer in a population of relatively healthy men. There was a statistically nonsignificant increased risk for prostate cancer among men who received vitamin E only (P = .06) and a statistically nonsignificant increased risk for type 2 diabetes mellitus in the men who received selenium only (P = .16) (JAMA. 2009;301:39-51).

Only the use of supplements was stopped by the Data and Safety Monitoring Committee, not the trial. The authors planned on following the study participants for 3 additional years to determine if there was any benefit or harm.

Contradicts Early Data

Much of the evidence that vitamin E is protective came from epidemiologic studies, explained James R. Marshall, PhD, who was approached by Medscape Medical News for independent comment. "In spite of the publicity these studies received, it is very difficult — virtually impossible — to evaluate causality, and to disentangle causes from confounding factors, such as tobacco and alcohol use, physical activity, obesity, and other nutritional factors, in observational epidemiologic studies," he said.

Dr. Marshall, who is chair of the Department of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York, explained that he was on the Institute of Medicine committee that developed the 2000 guidelines for antioxidants, including vitamin E and selenium. "Some members of the committee proposed that the daily recommended intake of vitamin E be raised to 400 IU per day, which was the dose tested in the SELECT trial," he said. "That recommendation did not become a part of the guidelines."

One of the major pieces of evidence that justified the SELECT study was the Alpha-Tocopherol, Beta-Carotene trial that was conducted in Finland. In that study, beta-carotene was expected to decrease lung cancer risk but did not, and vitamin E was expected to decrease heart disease risk but did not, although it was associated with a largely unanticipated 40% decrease in prostate cancer incidence, Dr. Marshall explained.

"We don't to this day understand how that decrease in prostate cancer risk appeared, other than to attribute it to chance — a statistical fluke," he said. "Often, there are unanticipated outcomes from observational epidemiologic studies — generally, most of the outcomes of these studies are unanticipated — and from clinical trials."

"We probably need to be more careful than we have been of the common practice of paying attention to these unanticipated outcomes," Dr. Marshall continued. "This new result, from the analysis of SELECT by Klein and colleagues, should be seen as definitive. It is drawn from a huge, well-designed, -managed, and -analyzed trial."

"The likelihood that vitamin E in the dose studied in SELECT confers health benefits has to be, at this point, seen as 0," he added.

Elevated Risk Observed

The SELECT trial involved 35,533 healthy men from 427 study sites in the United States, Canada, and Puerto Rico who were randomized from 2001 and 2004. All participants had a prostate-specific antigen level of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and were 50 years or older (black men) or 55 years or older (all others).

The men were randomized to 1 of 4 treatment groups: 8752 received selenium (200 μg/d from L-selenomethionine), 8737 received vitamin E (400 IU/d of all-rac-alpha-tocopheryl acetate), 8702 received both agents, and 8696 received placebo.

After 5.56 years of follow-up, there were 473 cases of prostate cancer in the vitamin E group (hazard ratio [HR], 1.13); 432 in the selenium group (HR, 1.04); 437 in the selenium plus vitamin E group (HR, 1.05); and 416 in the placebo group (HR, 1.0).

The current analysis reflects the final data collected by the study sites up to July 5, 2011, and includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer — 113 in the placebo group, 147 in the vitamin E group, 143 in the selenium group, and 118 in the combination group.

Findings showed that the rate of prostate cancer detection was higher in all groups that received active treatment than in the placebo group, but only the vitamin E group reached statistical significance (HR, 1.17; P = .008).

Secondary End Points

The initial findings of the SELECT study showed a nonsignificant increased risk for type 2 diabetes mellitus in the selenium group; in the updated results, this finding was still not statistically significant (P = .34).

The authors also updated findings on prespecified secondary end points, including lung, colorectal, and total other cancers, deaths, and grade 4 cardiovascular events. They found no statistically significant differences in the hazard ratios of any group, which suggests that for these end points, there is neither benefit nor harm related to the use of these supplements.

Proceed With Caution

Matthew R. Smith, MD, PhD, associate professor of medicine at Harvard University Medical School in Boston, Massachusetts, reiterated that this study highlights the need to be skeptical of claims attributed to over-the-counter products, although he noted that vitamin E, per se, is not specifically marketed to prevent cancer.

"The cautionary part is that if you look at the background information, it is a compelling narrative," said Dr. Smith. "Unfortunately, the definitive trial has now been done, and shows it is not true."

He agrees that there is no basis for recommending these products to prevent prostate cancer. "On a larger scale, we should be careful about claims. They may not be harmful; they may just be neutral," he said in an interview. Dr. Smith was not involved in the study.

Dr. Smith also pointed out that although the reason for the increased risk for prostate cancer observed with vitamin E supplementation is unclear, the dose given was much higher than would normally be found in food. "These are nonphysiologic doses and methods of delivery," he said. "With food, you don't get a 400 IU slug of vitamin E. The biology of these vitamins is very complex, and this is not how they are normally taken in the diet."

The study was funded in part by the National Cancer Institute and the National Center for Complementary and Alternative Medicine (National Institutes of Health). Dr. Klein and Dr. Baker have disclosed no relevant financial relationships, but several coauthors report financial relationships with several pharmaceutical companies.

JAMA. 2011;306:1549-1556. Abstract

Study Highlights

  • Men eligible for study participation were at least 50 years old (for black men) or 55 years old (for all other participants) and had a prostate-specific antigen (PSA) value of 4.0 ng/mL or less. They also had normal digital rectal examination for prostate cancer.
  • Participants were randomly assigned to 1 of 4 placebo-controlled treatment groups: selenium 200 µg/day, vitamin E 400 IU/day, both selenium and vitamin E, or double placebo.
  • Participants underwent a limited history and physical examination every 6 months during the study and were encouraged to receive prostate cancer screening according to the community standard.
  • The main study outcome was incident prostate cancer. Researchers also followed the incidence rates of other types of cancer, along with incident type 2 diabetes mellitus and cardiovascular disease.
  • Active study treatment was discontinued after approximately 5.5 years.
  • 35,533 men underwent randomization between 2001 and 2004. The median age of men was 63 years, and nearly 80% of participants were white. The mean PSA level at baseline was 1.1 ng/mL.
  • The current report provides another 54,464 person-years of follow-up. There was no difference regarding the intensity of PSA testing during follow-up in comparing the study intervention groups.
  • 521 additional prostate cancers were recorded since the initial report. Treatment with vitamin E was associated with a significant increase in the risk for prostate cancer (hazard ratio, 1.17; 99% confidence interval, 1.004 - 1.36).
  • However, treatment with selenium alone or selenium plus vitamin E was not associated with a significant change in the risk for prostate cancer.
  • Gleason 6 prostate cancer was the most common cancer grade overall. However, the association between vitamin E and the risk for prostate cancer appeared to span the spectrum of cancer grades.
  • The difference in the risk for prostate cancer between vitamin E and placebo became apparent by study year 3 and gradually increased thereafter, including after the discontinuation of active treatment.
  • Selenium was not associated with a significant change in the risk for incident type 2 diabetes during the longer follow-up period. There were no other significant associations between study treatments and the risks for types of cancer other than prostate cancer, or in the risks for cardiovascular events or overall mortality.

Clinical Implications

  • SELECT was halted early after it was determined that neither vitamin E nor selenium would improve the risk for incident prostate cancer. In fact, vitamin E was associated with a nonsignificant increased risk for prostate cancer at that time, and selenium was associated with a nonsignificant risk for incident type 2 diabetes mellitus.
  • The current study suggests that treatment with vitamin E alone can increase the risk for prostate cancer among older men. However, coadministration with selenium might negate this risk, and treatment with selenium alone did not alter the risk for prostate cancer.