The results of our literature synthesis show generally disappointing results for the efficacy of these antioxidant supplements in these doses to prevent, modify risks or treat cancer in these populations. The exceptions to this conclusion are a study in which vitamin C (along with other vitamins) was found to be beneficial in preventing new tumors in a single trial of bladder cancer when used in conjunction with BCG28
; a study in which vitamin E when used in combination with ω-3 fatty acid increased survival in patients with advanced cancer26
; and a study in which vitamin E for prevention of new tumors in subjects with prostate cancer.27
But, in the same study on reduction in new prostate cancer, no effect was seen when vitamin E and β-carotene were given together, and there was no effect on death from prostate cancer.
A number of issues potentially limit the effectiveness of this review. Methodologically, there was marked heterogeneity in the size of the population, the intent of the trial, the types of outcomes, and follow-up times. We identified a number of large primary prevention trials (α-Tocopherol, β-Carotene Group, Linxian General Population and Linxian Dysplasia Trials and the Heart Protection Study Collaborative Group) that each reported on a number of separate outcomes. The majority of remaining trials were studies of much smaller numbers of people. They included not only secondary prevention trials but also treatment trials. In addition, the populations varied greatly. The observed heterogeneity in study populations and designs deterred us from conducting a meta-analysis in 2 of our outcome domains—death and new tumors—and also excluded some studies from our colonic polyps analysis. In the face of this heterogeneity, we provide individual study risk ratios and discuss the studies descriptively. With only 2 studies in our primary analysis reporting statistically significant beneficial results, we could not perform any meaningful sensitivity analysis using study quality. Similarly, we cannot assess the relationship between the possible heterogeneity in treatment effects and study or population characteristics with such small numbers of studies available.
Clinically, a number of potential limitations could be identified as well. Few studies evaluated single agents for efficacy. There was no standard amount of vitamin C or E given, nor were the multivitamin formulas consistent from study to study. Some of this variation may be because of differences in the populations assessed; however, it also reflects lack of consensus on recommended doses of these vitamins to be used therapeutically. Given the small number of studies and the differences in doses and formulas, no assessment could be made regarding effectiveness of varying dosage levels or combinations of individual supplements.
During the submission and review of this paper, 2 new major randomized-controlled trials (RCTs) have been published. The first was a study by Lonn et al.45
of more than 4,000 patients randomized to receive a daily dose of 400 IU of vitamin E or placebo and followed for a median of 7 years. No evidence of beneficial effect was observed (incidence RR = 0.94, 95% CI: 0.84–1.06; death RR = 0.88, 95% CI: 0.71–1.09).
The second paper was part of the Women's Health Study by Lee et al.46
in which 40,000 women were randomized to receive vitamin E (600 IU on alternative days), aspirin or placebo in a factorial design trial. There was no significant effect on the incidence of total cancer (RR = 1.01), or for breast cancer (RR = 1.00), lung cancer (RR = 1.09), or colon cancers (RR = 1.00). These findings support the results of our review and metaanalysis.
In trying to resolve the randomized trial results with the cellular/molecular and the epidemiologic data there are several possible explanations: the type of antioxidants used in the trials was different (synthetic vs natural); the dose used was wrong; the results were because of something other than the single antioxidants or combinations that were tested in the trials; the duration of treatment was too short; and unaccounted for confounding means the observed epidemiologic association is not causal.
We conclude that there is no evidence that the antioxidants tested, in the doses tested, and for the populations tested, help prevent cancer. This does not constitute “proof” that antioxidants do not influence cancer, especially in light of the fact that some of the risk ratios were clinically significant but lacked power. This suggests, for these outcomes at least, further studies are needed. However, the generally negative results from the randomized trials do place the burden of proof on the proponents of antioxidant supplements to identify the specific supplement, the dosage, and the population combination that is efficacious.