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Lung Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI] - Description of the Evidence


Interventions Associated With Increased Risk of Lung Cancer

Beta-carotene supplementation in smokers

Results of the National Cancer Institute (NCI) Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial were first published in 1994.[55] This trial included 29,133 Finnish male chronic smokers aged 50 to 69 years in a 2 x 2 factorial design of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day). Subjects were randomly assigned to one of the following four groups for 5 to 8 years: beta-carotene alone, alpha-tocopherol alone, beta-carotene plus alpha-tocopherol, or placebo. Subjects receiving beta-carotene (alone or with alpha-tocopherol) had a higher incidence of lung cancer (RR = 1.18; 95% CI, 1.03–1.36) and higher total mortality (RR = 1.08; 95% CI, 1.01–1.16). This effect appeared to be associated with heavier smoking (one or more packs/day) and alcohol intake (at least one drink/day).[56] Supplementation with alpha-tocopherol produced no overall effect on lung cancer (RR = 0.99; 95% CI, 0.87–1.13).

In 1996, the results of the U.S. Beta-Carotene and Retinol Efficacy Trial (CARET) were published.[57] This multicenter trial involved 18,314 smokers, former smokers, and asbestos-exposed workers who were randomly assigned to beta-carotene (at a higher dose than the ATBC trial, 30 mg/day) plus retinyl palmitate (25,000 IU/day) or placebo. The primary endpoint was lung cancer incidence. The trial was terminated early by the Data Monitoring Committee and NCI because its results confirmed the ATBC finding of a harmful effect of beta-carotene over that of placebo, which increased lung cancer incidence (RR = 1.28; 95% CI, 1.04–1.57) and total mortality (RR = 1.17; 95% CI, 1.03–1.33). In a follow-up study of CARET participants after the intervention discontinued, these effects attenuated for a period of time. After 6 years of postintervention follow-up, the postintervention RR for lung cancer incidence was 1.12 (95% CI, 0.97–1.31) and for total mortality was 1.08 (95% CI, 0.99–1.71). During the postintervention phase a larger RR among women, rather than men, emerged for both outcomes in subgroup analyses; the reason for this observation, if reliable, is not known.[58]

The overall findings from the ATBC [55,56] and CARET [57,59] studies, which include over 47,000 subjects, demonstrated that pharmacological doses of beta-carotene increase lung cancer risk in relatively high-intensity smokers. The mechanism of this adverse effect is not known. Lung cancer risks were not increased in subsets of moderate-intensity smokers (less than a pack per day) in the ATBC study, or in former smokers in the CARET study. Evidence from other studies, such as the Physicians' Health Study,[60] does not indicate that beta-carotene supplementation increases lung cancer risk in nonsmokers. Subsequent analyses of participants in these trials and cohorts suggest that the beneficial outcomes associated with high beta-carotene plasma levels may be due to increased dietary intake of fruits and vegetables. These findings show the importance of randomized controlled trials to confirm epidemiologic studies.


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
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