Effects of a combination of beta carotene and vitamin a on lung cancer and cardiovascular disease

Background. Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of followup (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P 0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. Conclusions. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos. (N Engl J Med 1996;334:1150-5.)  1996, Massachusetts Medical Society. From the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle (G.S.O., G.E.G., M.D.T., S.B.); the Departments of Environmental Health and Medicine, University of Washington, Seattle (G.S.O., G.E.G., S.B., S.H.); the Swedish Hospital Tumor Institute, Seattle (G.E.G.); the Department of Medicine, University of California at San Francisco, San Francisco (J.B.); the Department of Medicine, Yale University, New Haven, Conn. (M.R.C.); Kaiser Permanente Center for Health Research, Portland, Oreg. (A.G., B.V.); the Department of Medicine, University of Maryland, Baltimore (J.P.K.); and the Department of Medicine and Cancer Center, University of California at Irvine, Orange (F.L.M., J.H.W.). Address reprint requests to Dr. Omenn at the Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, 1124 Columbia–MP859, Seattle, WA 98104. Supported by grants (U01 CA63673, U01 CA63674, U01 CA47989, U01 CA48200, U01 CA48203, U01 CA48196, and U01 CA52596) from the National Cancer Institute. *Other contributing authors were Carl Andrew Brodkin, M.D. (University of Washington, Seattle), Martin G. Cherniack, M.D. (Yale University, New Haven, Conn.), James E. Grizzle, Ph.D. (Fred Hutchinson Cancer Research Center, Seattle), Marjorie Perloff, M.D. (National Cancer Institute, Bethesda, Md.), and Linda Rosenstock, M.D., M.P.H. (University of Washington, Seattle). L UNG cancer is the leading cause of death from cancer in the United States, accounting for approximately 29 percent of deaths from cancer and 6 percent of all deaths. 1 New approaches are essential to prevent lung cancer in persons who have smoked cigarettes or who have had occupational exposure to asbestos. Twenty-nine percent of men and 25 percent of women who are 45 to 64 years of age currently smoke, 2 and at least 40 percent of men and 20 percent of women in this age group are former smokers. 3 An estimated 4000 to 6000 deaths from lung cancer per year are attributed to exposure to asbestos. 4,5 On the basis of epidemiologic observations and laboratory studies, beta carotene and vitamin A have attracted wide interest as agents that may prevent lung cancer. 6-9 The Beta-Carotene and Retinol Efficacy Trial (CARET) is one of several recent trials to assess the chemopreventive efficacy and safety of beta carotene and related agents. 10-13 This report presents interim efficacy results of the CARET study, which coincided with the announcement of the steering committee’s decision on January 11, 1996, to stop the trial’s active intervention. Follow-up for additional end points is expected to continue for another five years.