Vitamin D and Cancer: Can We Believe the Evidence from Observational Studies?

Abstract

The article by Afzal et al. in this issue of Clinical Chemistry (1) presents data showing an association of low concentrations of vitamin D with risk of tobacco-related cancers. The authors found that vitamin D was not associated with other types of cancer, that the effect was stronger among smokers, and that it appeared to be independent of levels of tobacco consumption among smokers. Although these data suggest that increasing concentrations of plasma 25-hydroxyvitamin D [25(OH)D],2 especially among smokers, may lead to cancer protection, the data remain suggestive rather than conclusive. Science is rife with examples of promising hypotheses based on observational data that did not hold up under more rigorous randomized controlled trials. An early panacea was β-carotene, which was hypothesized to reduce cancer incidence (2). At the time, it was the exciting new theory and garnered much attention. When tested in randomized controlled trials, however, the promising hypothesis failed to hold up. The Physicians' Health Study, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial, the Beta-Carotene and Retinol Efficacy Trial (CARET), and other trials found no overall effect of β-carotene on cancer (3). Whereas observational analyses can carefully control for many confounders, residual confounding cannot be ruled out. There is a persistent and consistent association of consumption of fruits and vegetables with reduced cancer risk, but it is difficult to break down the food items into individual nutrients that may be causally related. The same has occurred for various other dietary nutrients, including vitamin E, vitamin C, and the B vitamins (4). All had been shown to be related to cancer or cardiovascular disease in observational data, but the results did not hold up to the more rigorous examination of a randomized trial. Vitamin E, in particular, enjoyed widespread public attention and was promoted as akin to a …