Vitamin Supplements and Cancer Prevention: Where Do Randomized Controlled Trials Stand?

Cancer chemoprevention as a concept and research methodology that examines inhibition of human carcinogenesis by nutritional, phytochemical, and other pharmacological substances dates to at least the early 1980s ( 1 , 2 ). At that time, a flurry of chemoprevention trials was launched predicated on epidemiological observations regarding potential protective roles for a wide range of foods and nutrients, including retinoids, beta carotene, calcium, and lower dietary fat in several cancers, and on basic research that provided both corroboration of the hypotheses through tumor inhibition in experimental models and evidence relevant to the responsible biological mechanisms. However, only a few of the randomized controlled studies, or RCT’s, have demonstrated the hoped- for reductions — or even unanticipated benefits — in incidence or recurrence of neoplasia from nutrient supplementation or dietary modification. For example, the Nutritional Prevention of Cancer Study, which aimed to prevent nonmelanoma skin cancers with selenized yeast, failed to do so, but unexpected yet statistically significant reductions in prostate, lung, and colorectal cancers were observed ( 3 ). Similarly, the Nutritional Intervention Trial targeted a high esophageal cancer incidence area and found a 21% reduction in gastric (but not esophageal) cancer mortality in response to a selenium, beta carotene, and vitamin E combination ( 4 ). In the Calcium Polyp Prevention Study, daily supplementation with calcium carbonate did lead to a 15% reduction in colorectal adenomatous polyp recurrence ( 5 ). The majority of similar cancer trials demonstrated no chemopreventive efficacy for their primary neoplastic endpoints [eg, ( 6 – 9 )], and in some there was evidence of unexpected harmful effects, such as an increased number of lung cancers in those receiving beta carotene in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study ( 10 , 11 ) and Beta-Carotene and Retinol Efficacy Trial (CARET) ( 12 , 13 ), and an increased number of colorectal neoplasias in participants receiving folic acid in the Aspirin/ Folate Polyp Prevention Study ( 14 ). Other nonsupplementation trials of dietary modification including two that assessed the effect of lower fat intake yielded statistically null results for their primary hypotheses ( 15 , 16 ), although the latter study showed a small breast cancer incidence reduction. The fi ndings of Lin et al. ( 17 ) in this issue of the Journal fall into the well-populated category of null trials. Using a factorial design, the Women’s Antioxidant Cardiovascular Study, or WACS, tested supplementation for 8 – 10 years with beta carotene (50 mg daily), vitamin C (as ascorbic acid, 500 mg daily), and vitamin E (as RRR-alpha-tocopherol, 600 IU every other day) in more than 7600 women who at study entry were at least 40 years old and at elevated risk of cardiovascular disease. Based on 624 cancer diagnoses (41% of which were breast cancers) and 176 cancer deaths, the investigators observed relative risks (RRs) for the beta carotene, vitamin C and vitamin E trial arms of 1.00, 1.11, and 0.93, respectively, for overall cancer incidence, and 0.84, 1.28, and 0.87, respectively, for relative mortality. The investigators concluded that the vitamins had no effect, singly or in combination. Duration of active supplementation within the range studied, compliance, and “drop-in” use of extrastudy supplements did not appear to account for the fi ndings. By contrast, the “lack of complete follow-up” alluded to by the investigators as a methodological limitation [presumably the 93% follow-up completeness through January 31, 2005 ( 18 ), and/or exclusion of approximately 40 unconfi rmed cases] or the high cardiovascular disease (CVD) risk of the study population which might overshadow other health benefi ts may have contributed to the lack of effi cacy for the cancer endpoints. Neither the antioxidants nor the fourth intervention added later — a combination of folic acid and vitamins B 6 and B 12 – had any statistically signifi cant effects in terms of cardiovascular disease endpoints ( 18 , 19 ). Their just- reported fi ndings for folic acid – B vitamins and cancer were that overall rates and breast cancer rates were comparable in the active and placebo arms ( 20 ). Thus, taken as a whole, WACS provides little or no evidence that such vitamin supplementation as tested offers any measurable preventive impact on cancer in women. Despite the trial’s conclusion that there were no overall benefi ts for primary cancer prevention, two of the specifi c fi ndings reported by Lin et al. ( 17 ) deserve additional mention because they corroborate previous trial results and demonstrate the potential for site-specifi c effi cacy. The fi rst is the possible effect of vitamin E supplementation in preventing colorectal cancer (RR = 0.63), similar to what was observed in the ATBC Study ( 20 ) and in a pooled analysis of serum tocopherol levels in cohort studies ( 21 ). The second is the elevated lung cancer risk in the beta carotene arm, along with modest excess overall cancer risk in smokers and heavier drinkers. The suggested harmful effects from vitamin C for lung and pancreatic cancers, with the former effect achieving statistical signifi cance, are also noteworthy and raise questions concerning the chemopreventive potential of ascorbic acid. All these observations, based on the randomized design, represent value-added data that will contribute to a better understanding of cancer etiology and prevention and the appropriate role of these micronutrient supplements.