In this randomized trial of vitamins C and E and beta carotene supplementation among women at high risk for cardiovascular events, we observed no overall associations of the three antioxidant supplements, taken singly or combined, with total cancer incidence or mortality. Duration of supplementation also did not appear to alter the associations of these supplements with risk of cancer or mortality due to cancer.
In melanoma cells, vitamin C treatment effectively decreased the expression of cyclooxygenase-2 and type I insulin-like growth factor receptor, resulting in suppression of cell proliferation (10
). Treatment with antioxidants such as vitamin E and beta carotene was also shown to induce cell apoptosis in breast cancer cells by restoring transforming growth factor-β and Fas (or CD95) signaling pathways (11
) or increasing the expression of peroxisome proliferator–activated receptor gamma (12
). Antioxidants also counterbalance the production of ROS and thus prevent the harmful effects of these oxygen intermediates on cellular nucleic acids, lipids, and proteins (13
). Growth regulatory pathways that are involved in cell proliferation and apoptosis are sensitive to ROS, and these unavoidable byproducts of aerobic respiration may in some circumstances lead to inappropriate cell signaling and carcinogenesis (14
Previous observational studies that assessed the relationship between total intakes of antioxidant nutrients and cancer prevention have yielded inconsistent results. Several case–control studies have reported an inverse association between antioxidant intakes and cancer risk, but cohort studies have generally observed little association. A meta-analysis that reported risk reduction for esophageal and gastric cardia adenocarcinoma with higher intakes of vitamins E and C and beta carotene was based primarily on case–control studies (52
). Similarly, another meta-analysis concluded that vitamin C or beta carotene intakes were inversely associated with breast cancer risk, but the inverse association was mainly driven by case–control studies (6
). By contrast, other pooled analyses of prospective studies have not shown an association of vitamins E and C or beta carotene intakes with risk of incident cancers of the breast (53
), colorectum (54
), lung (55
), or ovary (56
). Therefore, the cumulative data from observational studies offer limited, if any, support for an inverse association between antioxidant intakes and risk for cancer development.
Numerous randomized trials have also been conducted to investigate the effects of antioxidants in the prevention of cancers, but the findings have been mostly disappointing (16
). A meta-analysis that pooled data from 12 randomized trials of antioxidants and primary cancer prevention showed no reduction in risk for total cancer incidence with antioxidant supplementation (RR = 0.99, 95% CI = 0.94 to 1.04) (35
). With respect to individual types of antioxidants, the authors of this meta-analysis concluded that vitamin E did not reduce overall cancer (RR = 0.99, 95% CI = 0.94 to 1.04), but beta carotene supplementation was associated with a slight increase in cancer incidence (RR = 1.06, 95% CI = 1.00 to 1.12), with the increased risk mostly seen in smokers (RR = 1.10, 95% CI = 1.03 to 1.18) (35
). Similarly, meta-analyses of the association of antioxidants and minerals with incidence of cancer at specific sites indicated no beneficial effects of antioxidants or minerals. Two meta-analyses (31
) on incident gastrointestinal cancers found no statistically significant effects of supplementation with beta carotene; vitamins A, C, and E; and selenium (alone or in combination) [from Bjelakovic et al. (31
), pooled RRs = 0.90, 95% CI = 0.77 to 1.05; and from Bjelakovic et al. (32
), pooled RRs = 0.94, 95% CI = 0.83 to 1.06]. Another meta-analysis of eight randomized trials also reported no statistically significant effects of beta carotene; vitamins A, C, or E; or selenium supplements, alone or in combination, on the prevention of colorectal adenoma (pooled RR = 0.82, 95% CI = 0.60 to 1.1) (33
). Consistent with these analyses, we also found no effects of vitamins C and E and beta carotene supplementation in reducing the risk for total cancer events.
Systematic reviews of antioxidant trials also found no reduction in cancer mortality with antioxidant supplementation. The meta-analysis of 12 randomized trials of vitamin or mineral supplements described above reported no association between antioxidants and cancer mortality (pooled RR = 1.03, 95% CI = 0.92 to 1.15) (35
). Specifically, no reduction in cancer mortality was found with vitamin E (RR = 1.04, 95% CI = 0.94 to 1.04) or beta carotene (RR = 1.16, 95% CI = 0.98 to 1.37) supplementation (35
). However, a possible risk reduction in cancer mortality was observed for the mineral supplement selenium (RR = 0.78, 95% CI = 0.65 to 0.94) (35
). A pooled analysis of five studies from the two Linxian trials (the Linxian General Population Trial and the Linxian Dysplasia Trial) also did not present strong evidence that vitamin C combined with molybdenum improves cancer survival (RR = 1.06, 95% CI = 0.92 to 1.21) (34
). Two recent meta-analyses have concluded that there may be an increase in total mortality with increasing antioxidant use (31
). A review of 19 clinical trials reported a dose–response relationship between vitamin E and risk for total death (57
). A later review comprising 47 low-bias risk (high methodological quality) trials reported that supplementation with vitamin E or beta carotene increased total mortality (RR = 1.04, 95% CI = 1.01 to 1.07, and RR = 1.07, 95% CI = 1.02 to 1.11, respectively), but a modification of risk estimates by dosage was evident only with beta carotene supplementation (58
). By contrast, supplementation with vitamin C did not influence total mortality (58
). In this population, we observed no association of supplementation with vitamin C or E or beta carotene with fatal cancer events.
A recent meta-analysis of four large randomized trials suggested that beta carotene supplementation may be associated with elevated lung cancer risk among current smokers (RR = 1.24, 95% CI = 1.10 to 1.39) but not among past smokers (RR = 1.10, 95% CI = 0.84 to 1.45) (59
). In our population with a low prevalence of smoking, we observed no effect of beta carotene on lung cancer. Nonetheless, we found that vitamin C was associated with an elevated risk for lung cancer incidence. Two previous trials of vitamin C combined with other antioxidants reported no effects on incidence of respiratory cancers (16
). The Linxian General Population Trial also reported no statistically significant effect of vitamin C combined with molybdenum on lung cancer death (RR = 1.01, 95% CI = 0.73 to 1.39) (60
). In observational studies, no association between total vitamin C intake and lung cancer risk was reported in a pooled analysis of nine prospective studies (RR comparing the highest vs lowest quintile = 0.97, 95% CI = 0.78 to 1.22, P
for trend = .82) (55
). It has been suggested that vitamin C may act as a pro-oxidant and promote oxidative damage to DNA when its local concentrations are high (61
). However, the overall evidence thus far suggests that there is no substantial oxidative DNA damage in humans who ingest high amounts of vitamin C (63
). Our results that indicate an association between vitamin C supplementation and lung cancer may be due to chance. Nevertheless, a possible increase in lung cancer risk among women with vitamin C supplementation warrants further investigation in analyses of data from other completed randomized trials.
In our trial, neither duration of treatment nor combination of the three antioxidant supplements had effects on overall fatal or nonfatal cancer events. Thus, our results are in agreement with the recent review of randomized trials indicating that total mortality was not affected by duration of supplementation and single or combined antioxidant regimens (58
Several other factors besides duration and the combination of supplements could affect the efficacy of antioxidants. For instance, lifestyle behaviors may modify an individual's response, in terms of cancer risk, to antioxidant supplementation. Findings from the Linxian General Population Trial (65
), which showed a possible reduction in cancer incidence with vitamin and mineral supplementation in a poorly nourished population, suggest that antioxidant supplementation is most likely beneficial for individuals who are low or deficient for various nutrients. By contrast, most studies, including ours, were conducted among well-nourished populations that had sufficient intakes of antioxidants (58
). In addition, there may be a sex-specific difference in the effect of antioxidants on cancer risk. In the Supplémentation en Vitamines et Minéraux Antioxydants (SUVIMAX) trial, antioxidant supplementation was associated with a lower cancer incidence in men, but not in women (16
). Although men in the SUVIMAX trial may have benefited from antioxidant supplements due to their lower baseline levels of antioxidants (16
), subsequent findings of an inverse association between baseline serum antioxidant levels and total cancer incidence in men but not in women suggest that factors other than baseline antioxidant levels may play a role in mediating any effects on carcinogenesis (66
). Different antioxidant effects attributable to gender also could have contributed to the null results in trials conducted among female populations, including ours.
Limitations of the WACS trial include the lack of complete follow-up and compliance. However, when we conducted sensitivity analyses that excluded women who did not meet the compliance criteria, we observed no major changes in the results. Another limitation of this study is that it may not be appropriate to apply our results, obtained from a population at high risk for CVD, to the general population. Nevertheless, our results are mostly consistent with previous findings from high-risk populations. We also had limited power to evaluate the combined effects of the three antioxidants on site-specific incident cancers. For example, there was less than 40% power to detect a 30% reduction in the risk for major site-specific cancers such as the breast, colorectum, or lung with supplementation with the three antioxidants. However, we have tested the combined effects on total cancer incidence with nearly 80% power for detection of the same magnitude of risk reduction and did not find any statistically significant effects resulting from the combined supplements. Finally, although this randomized trial of antioxidants is one of the few trials with long duration of treatment, it may still be of insufficient duration to assess effects on cancer incidence, given the long latency for cancer.
In conclusion, findings from the WACS trial suggest that there are no overall benefits or risks of vitamins C and E and beta carotene supplementation in the primary prevention of total cancer incidence or cancer mortality.