Vitamin D and cancer: can we believe the evidence from observational studies?

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], 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 -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 -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 wonder drug for cardiovascular disease. In trials, however, no effect was found, and a slight increase in mortality has even been suggested though not proven (5). Arguments have arisen, however, regarding the form of vitamin E, since there are several forms in addition to the -tocopherol used in most trials (6). Antioxidant effects may also differ between natural and synthetic sources. Several observational studies have now been conducted on vitamin D, the nutrient with the current most widespread appeal, that have suggested a possible protective effect for both cancer and cardiovascular disease. An effect on cancer has biologic plausibility on the basis of animal studies and studies of effects on cells. Residual confounding may still occur, however, since concentrations of 25(OH)D are related to factors such as obesity, physical activity, and diet (7). Reverse causation must also be considered when evaluating dietary exposures. Data from trials of vitamin D so far have been limited. An early trial suggested a protective effect of a combination of vitamin D and calcium on total cancer (8 ) but was based on a relatively small number of events. There was also little difference between the combination of vitamin D and calcium and the calcium-only arms. There have been few trials to date directly testing vitamin D alone, and results were null for 3 trials that did compare vitamin D interventions and total cancer in secondary analyses (7 ). In 2011, the Institute of Medicine released a new report on dietary reference intakes for vitamin D (9 ). The panel concluded that although vitamin D plays a role in bone health, evidence for other outcomes, including cancer, was inconsistent and inconclusive. Several observational studies found an association between 25(OH)D concentrations and cancer risk, but these also were inconsistent and could not prove causality. Several new trials of vitamin D are now ongoing, however. One is the Vitamin D and Omega-3 Trial (VITAL) (10 ), which will include 20 000 men and women across the US. VITAL will test the effects of 2000 IU/day of vitamin D3 (cholecalciferol) over a 5-year follow-up period. Although this level has generally been recognized as safe, there must be careful monitoring for any adverse effects, especially among individuals with high baseline values of vitamin D. Of course, not all questions can be answered with randomized trials. Trials are generally restrictive in their eligibility requirements and test a single dose or a 1 Division of Preventive Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA. * Address correspondence to the author at: Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave. East, Boston, MA 02215. Fax 617-264-9194; e-mail: [email protected]. Received February 20, 2013; accepted February 20, 2013. Previously published online at DOI: 10.1373/clinchem.2013.203158 2 Nonstandard abbreviations: 25(OH)D, 25-hydroxyvitamin D; ATBC, AlphaTocopherol, Beta-Carotene Cancer Prevention; CARET, Beta-Carotene and Retinol Efficacy Trial; VITAL, Vitamin D and Omega-3 Trial. Clinical Chemistry 59:5 000 – 000 (2013) Editorials