The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping β-Carotene and Retinol Supplements

ARTICLES The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping ␤-Carotene and Retinol Supplements Gary E. Goodman, Mark D. Thornquist, John Balmes, Mark R. Cullen, Frank L. Meyskens, Jr., Gilbert S. Omenn, Barbara Valanis, James H. Williams, Jr. Background: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily ␤-carotene (30 mg) and retinyl palmitate (25 000 IU) on the incidence of lung cancer, other cancers, and death in 18 314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly as- signed to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group. Methods: After the intervention ended, CARET par- ticipants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self- reported cancer endpoints were confirmed by review of pa- thology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two- sided. Results: With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all- cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] ⴝ 0.97 to 1.31) and 1.08 (95% CI ⴝ 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the interven- tion was stopped. During the post-intervention phase, fe- males had larger relative risks of lung cancer mortality (1.33 versus 1.14; P ⴝ .36), cardiovascular disease mortality (1.44 versus 0.93; P ⴝ .03), and all-cause mortality (1.37 versus 0.98; P ⴝ .001) than males. Conclusions: The previously reported adverse effects of ␤-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to as- bestos persisted after drug administration was stopped al- though they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung can- cer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smok- ers. [J Natl Cancer Inst 2004;96:1743–50] Lung cancer is the leading cause of cancer death in the United States, accounting for 29% of deaths from cancers and 9% of all deaths (1). In 2004, an estimated 90 000 men and 67 000 women will die from lung cancer. Although there has been a small but detectable improvement in lung cancer treatment over the past 20 years, the 5-year survival among individuals who received a lung cancer diagnosis between 1989 and 1996 was only 14% (1). The National Cancer Institute (NCI) has encouraged an active research program in chemoprevention, i.e., the use of agents to prevent, arrest, or reverse lung cancer carcinogenesis. In the early 1980s, the dietary constituent ␤-carotene was one of the agents with the strongest supportive evidence suggesting that it was a chemoprevention agent. Results of observational epidemiologic studies as well as those of less numerous animal studies (2) led to the initiation of the large intervention trials designed to test the effect of supplemental ␤-carotene. The Physicians’ Health Study Trial tested the effect of ␤-carotene and aspirin on cancer and cardiovascular disease in a healthy male population. The Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Trial, which was conducted in Finland, and the Beta-Carotene and Retinol Efficacy Trial (CARET), which was conducted in the United States, were designed to test the effect of ␤-carotene on lung cancer incidence. ATBC used a 2 ⫻ 2 study design to test the combination of 20 mg of ␤-carotene and 50 mg of alpha-tocopherol in 29 133 male current cigarette smokers (3). CARET compared the combination of 30 mg of ␤-carotene and 25 000 IU of retinyl palmitate (retinol) with placebo in 18 314 male and female current and recent ex- smokers and male asbestos-exposed workers (4). In 1994, after a mean follow-up of 6.1 years, ATBC reported that subjects in the treatment arms that received ␤-carotene had a 16% increased incidence of lung cancer (relative risk [RR] ⫽ 1.16, 95% con- fidence interval [CI] ⫽ 1.02 to 1.33; P ⫽ .02) and an 8% increase in all-cause mortality (RR ⫽ 1.08, 95% CI ⫽ 1.01 to Affiliations of authors: Fred Hutchinson Cancer Research Center, Seattle, WA (GEG, MDT); Swedish Cancer Institute, Seattle (GEG); Department of Medi- cine, University of California at San Francisco (JB); Yale School of Medicine, Yale University, New Haven, CT (MRC); UC Irvine Medical Center, Orange, CA (FLM, JHW); University of Michigan Medical School, Ann Arbor (GSO); Kaiser Permanente Center for Health Research, Portland, OR (BV). Correspondence to: Gary E. Goodman, MD, MS, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Bldg. M, M1-B514, Seattle, WA 98109 (e-mail: gary.goodman@swedish.org). See “Notes” following “References.” DOI: 10.1093/jnci/djh320 Journal of the National Cancer Institute, Vol. 96, No. 23, © Oxford University Press 2004, all rights reserved. Journal of the National Cancer Institute, Vol. 96, No. 23, December 1, 2004 ARTICLES 1743