Cancer Prevention

G.S. Omenn, G.E. Goodman, M.D. Thornquist, J. Balmes, M.R. Cullen, A. Glass, J.P. Keogh, F.L. Meyskens Jr., B. Valanis, J.H. Williams Jr., Scott Barnhart, Samuel Hammar, "Effects of a Combination of Beta-Carotene and Vitamin A on Lung and Cardiovascular Disease," New England Journal of Medicine, 334:1150-55, 1996. (Cited in at least 226 publications to date) Comments by Gilbert S. Omenn, Executive Vice President for Medical Affairs, University of Michigan, Ann Arbor HALTING FINDINGS: Michigan's Gilbert S. Omenn decided to prematurely end a vitamin A and beta-carotene supplementation trial when it was found that subjects receiving daily doses actually had an increased risk of acquiring lung cancer. Two decades ago, vitamin A and beta-carotene, a plant pigment converted to vitamin A by the liver, earned widespread attention as possible chemopreventative agents against lung cancer. Twenty-one out of 32 observational epidemiology studies found a statistically significant association between low dietary or serum beta-carotene and increased risk of cancer. By the early 1980s, the National Cancer Institute sought to test the results of the epidemiology studies. Three major prevention trials were launched by NCI, including the Beta-Carotene and Retinol Efficacy Trial (CARET) led by Gilbert S. Omenn, who was then an investigator in the division of public health sciences at the Fred Hutchinson Cancer Research Center in Seattle and dean of the School of Public Health at the University of Washington. Announcement of results of CARET would turn this promising preventive compound to a potential carcinogen almost overnight. The CARET trial tested the combination of daily doses of 30 mg of beta-carotene and 25,000 IU of retinyl palmitate (vitamin A) against a placebo in 18,314 men and women at high risk for developing lung cancer. In 1985, researchers in Seattle enrolled the first 1,800 subjects determined to be at risk for lung cancer. By 1994, about 4,000 asbestos-exposed workers and 14,000 heavy smokers from around the nation were enrolled in the trial, which was expected to go on until October 1997. But twenty-one months before the trial was to end, Omenn and the research team made an unprecedented move. They decided to end the trial based on preliminary data analysis, which showed that beta-carotene and Vitamin A supplementation produced no benefit on the incidence of cardiovascular disease or cancer in smokers, former smokers, and asbestos-exposed workers in CARET. Most startling, those subjects receiving daily doses of beta-carotene and retinyl palmitate actually had an increased risk of acquiring lung cancer. Compared to placebo groups, there were 28 percent more lung cancers and 17 percent more deaths in the intervention group. "This finding was alarming to us," Omenn recalls. "We had to end the intervention in the best interest of research participants." The study confirmed unexpected findings of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study involving more than 29,000 male smokers in Finland. Participants in that trial receiving beta-carotene had lung cancer in excess of 16 percent of control groups. Omenn and the research team submitted the article on the findings to the New England Journal of Medicine, and the editors agreed with Omenn and NCI that results of this research were too important to withhold from the public until publication. In January 1996, Omenn joined with NCI chief Richard D. Klausner in announcing the decision to end the trial. Soon after the announcement, beta-carotene was withdrawn from the ongoing Women's Health Study of more than 40,000 health-care professionals. Cereal manufacturers and some multivitamin makers also ended supplementation of their products with beta-carotene. "In light of our evidence, this was the right move to make," Omenn maintains. "Unfortunately, some supplement manufacturers simply replaced the synthetic compound with beta-carotene derived from algae. There is no basis to believe that the naturally derived compound is chemically and biologically different and, therefore, safe." Omenn says the study has gotten widespread attention because it put physicians and the public on guard against indiscriminate use of supplemental nutrients. In the past, not much concern was given to vitamins that didn't live up to health claims made for them. "The attitude was that nothing was gained, but no harm was done," he explains. "The beta-carotene study heightened our awareness that vitamins have adverse effects and that trials are necessary to ascertain safety as well as efficacy." The CARET trial also has invigorated research on the biochemical activity of antioxidants. Recent studies have found that beta-carotene actually can act as a pro-oxidant under conditions produced by smoking. Other researchers have demonstrated that retinyl palmitate could have adverse genomic effects in epithelial cells exposed to carcinogens. "Before the CARET study, research on the biochemistry of carotenoids was considered ho-hum," Omenn says. "But now the field is alive with activity. Basic scientists are just beginning to tell the biochemical and molecular story behind our findings."

Cancer Prevention

The Scientist Staff

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