The Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) Study was launched in the 1980s along with several other cancer chemoprevention trials and was predicated in part on epidemiological data showing that higher beta‐carotene blood levels and consumption of carrots and other vegetables were related to lower risk of lung cancer and other malignancies. Some investigations had observed stronger inverse associations in cigarette smokers, for example, and some laboratory research supported the findings. Following its planned closure in 1993, this large randomized controlled trial (RCT) of 29,133 male Finnish smokers demonstrated an unexpected 16% increase in lung cancer incidence (and 8% higher overall mortality) among participants supplemented with beta‐carotene, 20 mg daily for 5–8 years, as compared with those receiving placebo. The adverse effect was stronger in men who smoked at least 20 cigarettes daily (RR=1.25) and those who drank more than the median amount of alcohol daily (RR=1.35). One other RCT of high‐risk women and men, the Beta‐Carotene and Retinol Efficacy Trial (CARET), corroborated the ATBC Study findings with a 28% lung cancer excess (and 17% total mortality increase) in the trial arm supplemented with a combination of beta‐carotene (30 mg) and retinyl palmitate (25,000 IU). By contrast, the Physicians' Health Study showed no effect on cancer incidence for a different formulation of beta‐carotene (50 mg every other day), an outcome very recently supported by the Women's Antioxidant Cardiovascular Study (WACS) that tested beta‐carotene, and vitamins C and vitamin E, while the Nutritional Intervention Trial in China found 21% lower stomach cancer mortality rates in the trial arm supplemented with a combination of beta‐carotene (15 mg), alpha‐tocopherol (30 mg), and selenium (50 µg) daily. The latter finding highlighted the potential importance of background nutritional status of targeted populations. Taken together, the results of these trials led to a reexamination of several chemoprevention hypotheses and additional experimental investigation of the biological actions of beta‐carotene. The studies also raised important questions regarding the nutritional prevention of cancer and the role of RCTs. When is a trial of vitamin supplementation warranted and what data are necessary and sufficient to support one, including small clinical studies of efficacy for surrogate biomarkers? Can post‐intervention follow‐up shed additional light on the observed trial period effects? How to select the study population, agent(s), dosage, and intervention duration in order to optimize trial design and the potential to demonstrate efficacy? How can supplementation with such micronutrients lead to adverse effects when previous evidence points only to biologically plausible cancer inhibitory functions? What is the appropriate role of single synthetic phytochemicals versus consumption of whole foods that deliver all component compounds?

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PL04-02.