RISK-FACTORS FOR LUNG-CANCER AND FOR INTERVENTION EFFECTS IN CARET, THE BETA-CAROTENE AND RETINOL EFFICACY TRIAL

Background: Evidence has accumulated from observational studies that p eople eating more fruits and vegetables, which are rich in beta-carote ne (a violet to yellow plant pigment that acts as an antioxidant and c an be converted to vitamin A by enzymes in the intestinal wall and liv er) and retinol (an alcohol chemical form of vitamin A), and people ha ving higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested t he combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18 314 men and women at hig h risk of developing lung cancer. The CARET intervention was stopped 2 1 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 25% more lung cancers and 17% m ore deaths in the active intervention group (active = the daily combin ation of 30 mg beta-carotene and 25 000 IU retinyl palmitate). Promptl y after the January 18, 1996, announcement that the CARET active inter vention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. Purpose: We pre sent for the first time results based on the pre-specified analytic me thod, details about risk factors for lung cancer, and analyses of subg roups and of factors that possibly influence response to the intervent ion. Methods: CARET was a randomized, double-blinded, placebo-controll ed chemoprevention trial, initiated with a pilot phase and then expand ed 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Seru m tvas collected from the participants at base line and periodically a fter randomization and was analyzed for beta-carotene concentration. A n Endpoints Review Committee evaluated endpoint reports, including pat hologic review of tissue specimens. The primary analysis is a stratifi ed logrank test for intervention arm differences in lung cancer incide nce, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitat ive interactions between the intervention and smoking status or alcoho l intake, O'Brien-Fleming boundaries were used for stopping criteria a t interim analyses. Statistical significance was set at the .05 ct val ue, and all P values were derived from two-sided statistical tests. Re sults: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% Cr = 1.13-2.23; P = .01) for we ighted lung cancer mortality. All subgroups, except former smokers, ha d a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histol ogy (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histo logic categories has P = .35), but not with base-line serum beta-carot ene concentrations. Conclusions: CARET participants receiving the comb ination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are hi ghly consistent with those found for beta-carotene in the Alpha-Tocoph erol Beta-Carotene Cancer Prevention Study in 29 133 male smokers in F inland. Implications: Individuals at high risk of developing lung canc er, i.e., current smokers and asbestos-exposed workers, should be disc ouraged from taking supplemental beta-carotene (and the combination of beta-carotene with vitamin A). Safety and efficacy should be demonstr ated before recommending use of vitamin supplements in any population.