Beta-Carotene Supplements Confirmed as Harmful to Those at Risk for Lung CancerKey Words
Lung cancer, beta-carotene, dietary supplements, CARET, ATBC Study. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
People who took dietary supplements of the nutrient beta-carotene while enrolled in a large cancer prevention trial continued to have increased rates of lung cancer six years after the trial was stopped early and the supplements discontinued, long-term follow-up of trial participants has shown.
The results add to earlier evidence from this study and a second large prevention trial that, contrary to earlier expectations, not only do beta-carotene supplements not prevent lung cancer in people at high risk for the disease, they appear to increase rates of the disease, particularly among smokers.
Source
Journal of the National Cancer Institute, December 1, 2004 (see the journal abstract).
Background
In the 1980s, findings from observational studies suggested that dietary supplements of beta-carotene and vitamin A might reduce the incidence of cancer, particularly lung cancer. Beta-carotene and vitamin A are both antioxidants, compounds that may prevent carcinogens from damaging DNA and other components of cells.
Two large clinical trials were set up to test whether supplements of these nutrients could prevent lung cancer in people at high risk for the disease. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, conducted in Finland, enrolled more than 29,000 male smokers (see the NCI press release). Participants were randomly assigned to take daily supplements of beta carotene, vitamin E, both, or a dummy pill (placebo).
The Beta-Carotene and Retinol Efficacy Trial (CARET), conducted in the United States, enrolled more than 18,000 men and women who were smokers, former smokers, or workers exposed to asbestos. Participants in CARET were randomly assigned to take daily supplements of beta-carotene and vitamin A (also called retinol) or a placebo.
Both CARET and the ATBC trial were double-blinded, which means that neither the participants nor their doctors knew until afterward who got the supplements and who got the placebo.
In 1994, the ATBC researchers reported that, after a follow-up period averaging six years, the incidence of lung cancer was 16 percent higher among participants who took the supplements than among those who took a placebo. The rate of death from all causes was 8 percent higher in those who received the beta-carotene supplements.
CARET researchers reported similar findings in 1996: After a follow-up period averaging four years, lung cancer incidence was 28 percent higher among participants who took beta-carotene supplements and the rate of death from any cause was 17 percent higher. As a result of these and the ATBC Study findings, CARET was halted early and participants stopped taking the supplements.
Although both trials have now ended, researchers continued to follow the participants to learn about the supplements’ long-term effects on lung cancer rates and overall death rates. In July 2003 the ATBC Study researchers published the results of eight years of post-trial follow-up of their participants. They found that the increased risk of lung cancer declined soon after participants stopped taking the beta-carotene supplements. However, participants who had taken the beta-carotene supplements still had an overall death rate 7 percent higher than that for those who had taken a placebo, and this effect took longer to disappear. Most of the extra deaths were due to heart disease or stroke.
The Study
The present study reports the findings of six-year post-trial follow-up of CARET participants. The research team was led by Gary E. Goodman, M.D., of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Results
CARET participants who had taken supplements of beta-carotene and vitamin A had a 12 percent higher risk of developing lung cancer during the post-trial follow-up period than those who had taken a placebo. People in the supplement group also had an 8 percent higher risk of dying from any cause than those in the placebo group. These higher risks persisted after six years of post-trial follow-up, although by then they were not statistically significant - that is, they could have occurred by chance.
Supplement-takers were at no elevated risk of death from heart disease or stroke during the post-trial period. These findings contrasted with those of the ATBC trial, which found that the increased risk of lung cancer declined after the supplements were discontinued but that supplement-takers still had a 7 percent elevated risk of death, mostly from heart disease or stroke.
The persistent elevation in lung cancer risk seen in CARET participants could result from cellular changes caused by beta-carotene, the study authors suggest - changes that persist even after blood levels of the nutrient return to normal.
Limitations
Beta-carotene supplements have not been shown to be harmful to nonsmokers, says Demetrius Albanes, M.D., of the National Cancer Institute’s (NCI’s) Division of Cancer Epidemiology and Genetics. (Since 1984, Albanes has been a principal investigator for the ATBC Study, which NCI sponsored.) This is based in part on another large trial, the Physicians’ Health Study, which found no benefit or harm from beta-carotene supplements in healthy men.
Furthermore, he notes, clinical trial findings have demonstrated the limitations of beta-carotene supplements, not of a diet rich in beta-carotene and other carotenoids, which are found in fruits and vegetables that are yellow, orange, or red in color. Many studies point to the health benefits of such a diet.
Comments
The collective results of the ATBC trial and CARET “provide strong evidence of the adverse effect of beta-carotene supplement use on lung cancer incidence in smokers,” write Anna J. Duffield-Lillico and Colin B. Begg of Memorial Sloan-Kettering Cancer Center in New York in an accompanying editorial.
The post-trial CARET findings add to the earlier findings from the two trials by showing that beta-carotene supplements may cause more prolonged harm in some people at high risk for lung cancer, says Albanes, possibly women in particular.
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