The overall findings from the ATBC [62,63] and CARET [64,66] 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, 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.
Interventions With Adequate Evidence That They Do Not Reduce Risk
Studies have examined whether it is possible to prevent cancer development in the lung using chemopreventive agents. Chemoprevention is defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy. So far, agents tested for efficacy in lung cancer chemoprevention have been micronutrients, such as beta-carotene and vitamin E.
Beta-carotene supplementation in nonsmokers
Two other randomized controlled trials of beta-carotene were carried out in populations that were not at excess risk of lung cancer. The Physicians' Health Study was designed to study the effects of beta-carotene and aspirin in cancer and cardiovascular disease. The study is a randomized, double-blind, placebo-controlled trial begun in 1982 involving 22,071 male physicians aged 40 to 84 years. After 12 years of follow-up, beta-carotene was not associated with overall risk of cancer (RR = 0.98) or lung cancer among current (11% of study population) or former (39% of study population) smokers.
In the Women's Health Study (WHS) approximately 40,000 female health professionals were randomly assigned to 50 mg beta carotene on alternate days or placebo. After a median of 2.1 years of beta-carotene treatment and 2 additional years of follow-up, there was no evidence that beta-carotene protected against lung cancer, as there were more lung cancer cases observed in the beta-carotene (n = 30) than placebo (n = 21) group. The strong evidence from rigorous randomized, placebo-controlled trials clearly indicate that beta-carotene supplementation does not lower the risk of lung cancer in populations that are not high-risk for lung cancer.