Antioxidant Supplementation and Risk of Skin Cancers

In a recent analysis of the VITAL (VITamins And Lifestyle) study cohort,¹ Asgari et al² failed to identify an association between antioxidant supplementation and the risk of incident melanomas. On this basis, they question the association previously observed in the SU.VI.MAX study (Supplementation en Vitamines et Mineraux Antioxydants).^{3 - 4} However, the 2 studies do not address the same question. The SU.VI.MAX study was a prospective randomized clinical trial testing the hypothesis that supplementation would influence cancer risk.⁴ The VITAL study was an observational study testing the hypothesis that individuals who use antioxidant supplementation would differ in their cancer risk from those who do not. The reasons why this does not directly address whether supplementation influences cancer risk are clearly explained in the discussion of the original article describing the VITAL study.¹ The individuals who used supplementation may have had a healthier lifestyle or cultivated more health-oriented behavior than those who did not. For example, those using supplementation also exercised more and had a lower body mass index and a healthier diet. Although these confounders can to some extent be accounted for in the risk determination, and certain confounders were indeed included in the reported analysis, the 2 populations are different. It is thus impossible to attribute any difference observed to supplementation or to inherent between-group differences. The only way to study supplementation reliably is through a randomized prospective study where between-group differences are minimized through randomization. This was the strategy pursued in the SU.VI.MAX study. In addition, failure to reject the null hypothesis (no difference between groups) in the VITAL study analysis does not mean that no such difference exists but only that one was not observed (absence of proof is not the same as proof of absence).

Asgari et al² also make 2 statements about the SU.VI.MAX study⁴ that are misleading and that we would like to rectify. First, they state that melanoma risk factors were not recorded in the SU.VI.MAX study. This is incorrect: participants completed 2 questionnaires including a number of items related to lifetime and previous-year sun exposure, and skin phototype was determined at the first medical visit. These factors did not differ between groups (consistent with the randomization) and thus cannot explain the difference in melanoma risk observed.

Second, Asgari et al² suggest that case ascertainment could be incomplete. However, care was taken to optimize ascertainment by collecting data from multiple sources, including the participants themselves, primary care physicians, hospital records, and laboratory test results, all reviewed by an expert adjudication committee. Indeed, the number of cases identified is consistent with the known incidence of skin cancers in the French general population.

Asgari et al² rightly point out that the confidence limits of the incidence rates determined in the SU.VI.MAX trial are wide owing to the low number of incident cases. However, the only way to improve the precision of the estimate of the skin cancer risk associated with antioxidant supplementation would be to perform an even larger or longer randomized clinical trial. In contrast, observational studies cannot address this issue adequately.

Correspondence: Dr Ezzedine, UMR U 557 INSERM, U 1125 INRA, CNAM, Paris 13 University, CRNH-IdF, 74 rue Marcel Cachin, F-93017 Bobigny, France (khaled.ezzedine@chu-bordeaux.fr).

Financial Disclosure: None reported.