LACK OF EFFECT OF LONG-TERM SUPPLEMENTATION WITH BETA CAROTENE ON THE INCIDENCE OF MALIGNANT NEOPLASMS AND CARDIOVASCULAR DISEASE

Background. Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. Methods. In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to followup, and compliance was 78 percent in the group that received beta carotene. Results. Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. Conclusions. In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes. (N Engl J Med 1996;334:1145-9.)  1996, Massachusetts Medical Society. From the Divisions of Preventive Medicine (C.H.H., J.E.B., J.E.M., N.R.C., C.B., F.L., J.M.G., P.M.R.) and Cardiovascular Medicine (J.M.G., P.M.R.) and the Channing Laboratory (M.S., B.R., W.W.), Department of Medicine, Brigham and Women’s Hospital; the Department of Ambulatory Care and Prevention, Harvard Medical School (C.H.H., J.E.B., N.R.C.); and the Departments of Epidemiology (C.H.H., J.E.B., M.S., W.W.), Biostatistics (B.R.), and Nutrition (M.S., W.W.), Harvard School of Public Health — all in Boston; and the Imperial Cancer Research Fund Clinical Trial Service Unit, University of Oxford, Oxford, England (R.P.). Address reprint requests to Dr. Hennekens at 900 Commonwealth Ave. E., Boston, MA 02215. Supported by grants (CA-34944, CA-40360, HL-26490, and HL-34595) from the National Institutes of Health. O BSERVATIONAL epidemiologic studies suggest that people who consume higher dietary levels of fruits and vegetables containing beta carotene have a lower risk of certain types of cancer 1,2 and cardiovascular disease, 3 and basic research suggests plausible mechanisms. 4-6 It is difficult to determine from observational studies, however, whether the apparent benefits are due to beta carotene itself, other nutrients in beta carotene– rich foods, other dietary habits, or other, nondietary lifestyle characteristics. 7 Long-term, large, randomized trials can provide a direct test of the efficacy of beta carotene in the prevention of cancer or cardiovascular disease. 8 For cancer, such trials should ideally last longer than the latency period (at least 5 to 10 years) of many types of cancer. A trial lasting 10 or more years could allow a sufficient period of latency and an adequate number of cancers for the detection of even a small reduction in overall risk due to supplementation with beta carotene. Two large, randomized, placebo-controlled trials in well-nourished populations (primarily cigarette smokers) have been reported. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study, a placebocontrolled trial, assigned 29,000 Finnish male smokers to receive beta carotene, vitamin E, both active agents, or neither, for an average of six years. 9 The BetaCarotene and Retinol Efficacy Trial (CARET) enrolled 18,000 men and women at high risk for lung cancer because of a history of cigarette smoking or occupational exposure to asbestos; this trial evaluated combined treatment with beta carotene and retinol for an average of less than four years. 10 Both studies found no benefits of such supplementation in terms of the incidence of Downloaded from www.nejm.org at UW MADISON on December 04, 2003. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 1146 THE NEW ENGLAND JOURNAL OF MEDICINE May 2, 1996 cancer or cardiovascular disease; indeed, both found somewhat higher rates of lung cancer and cardiovascular disease among subjects given beta carotene. The estimated excess risks were small, and it remains unclear whether beta carotene was truly harmful. Moreover, since the duration of these studies was relatively short, they leave open the possibility that benefit, especially in terms of cancer, would become evident with longer treatment and follow-up. 11 In this report, we describe the findings of the beta carotene component of the Physicians’ Health Study, a randomized trial in which 22,071 U.S. male physicians were treated and followed for an average of 12 years.