Using a population-based cohort, we found no evidence that use of multivitamins, supplemental vitamin C, vitamin E, or folate is associated with a lower incidence of lung cancer. These estimates were adjusted for confounding factors, including tobacco, and were consistent using different analytic techniques. In contrast to the often assumed benefits or at least lack of harm, supplemental vitamin E was associated with a small increased risk of lung cancer that was most prominent in current smokers and in those with NSCLC.
Many of the previous studies of supplemental multivitamins, vitamin C, vitamin E, and/or folate have not found associations with lung cancer but were only able to analyze use dichotomously, as either current or no use (36
). Current use of supplemental vitamin C and folate was shown to be associated with a decreased risk of lung cancer for men only, whereas vitamin E did not affect the risk in either sex (27
). Only Voorrips and colleagues analyzed longer term use of supplements; they studied 939 men with lung cancer and found no association between lung cancer and use of supplemental vitamin C and E as measured dichotomously for the previous 5 years (35
). In contrast, the VITAL cohort was designed to assess the long-term intensity of supplement intake. We hypothesized that longer, higher dose exposures to supplements may be required to modify lung cancer risk and thus our measure of supplements focused on exposure over 10 years.
In addition to these observational studies, clinical trials of supplemental multivitamins, vitamin C, vitamin E, and/or folate do not suggest a benefit of supplemental vitamins for lung cancer chemoprevention. For example, a study using four different combinations of vitamin supplementation found no difference in lung cancer mortality (18
). The 6-year follow-up to the Alpha Tocopherol and Beta-Carotene (ATBC) study found a relative risk of 1.03 (95% CI, 0.91–1.16) for lung cancer in the group using 50 mg/day of α-tocopherol (49
). The Heart Protection Study, using a combination of antioxidant vitamins, 250 mg vitamin C, 20 mg β-carotene, and 600 mg of vitamin E, showed a nonsignificant increased lung cancer risk of relative risk (RR) 1.1 for the combination regimen (19
). Likewise, the Women's Health Study showed a nonsignificant increased risk of lung cancer of 1.09 (95% CI, 0.83–1.44) using 600 IU of vitamin E (~270 mg) every other day (20
Although long-term use of multivitamins and supplemental vitamin C and folate was not associated with lung cancer, supplemental vitamin E was associated with a small increased risk. Our results show a possible U-shaped association, with subjects using a medium dose for 10 years having a decreased risk whereas those using a high dose for 10 years showed an increased risk (). Because the HR modeled continuously is significant, the mildly increased risk of 1.05 for every 100-mg/day increase in supplemental vitamin E is heavily influenced by subjects using high-dose vitamin E supplementation.
It is interesting that the HR of incident lung cancer with high doses and prolonged use of supplemental vitamin E was greater for patients with NSCLC and current smokers. Cho and colleagues did not find differences in risks for different morphologies of lung cancer or by smoking status when they examined dietary vitamin C, E, and folate (17
). The ATBC study participants, all of whom were smokers at study initiation, did show a nonsignificant increased risk of lung cancer among those randomized to α-tocopherol supplementation in heavy smokers (50
). Watkins and coworkers found an increased risk of lung cancer mortality for men who currently smoke and who use multivitamins along with supplemental vitamins A, C, and E (RR, 1.17; 95% CI, 1.03–1.32) (51
). One possible mechanism is that, although vitamin E is considered an antioxidant, it might act as a prooxidant as well (52
Our study has several strengths. We were able to analyze the dose–response relationship of supplement use over a long period of time, which is likely necessary for biological plausibility. Our study examines the effect of individual supplements and our measure of supplement use has been validated (41
). We controlled for the strong confounding effect of tobacco and examined multiple other variables that affect the risk of incident lung cancer. Finally, the SEER database is complete and accurate.
Residual confounding might bias our results. For example, although an association with lung cancer has been reported for education and BMI, even when adjusted for tobacco exposure and/or physical activity and dietary variables (53
), residual confounding may still affect these results. However, when we adjusted for BMI and education, together with other potential confounders, the HRs and statistical significance for multivitamin, vitamin C, vitamin E, and folate supplementation did not substantively change. Thus, it is unlikely residual confounding significantly biases our results.
Our study has some potential limitations. Even with this very large cohort, the ability to detect a non-null result is limited to at least a 30% difference in incidence. The VITAL cohort was predominantly white and there were fewer current smokers than the proportion in the United States as a whole. Although these demographic factors may limit generalizability, they increase our internal validity by providing a wide range of supplement intensity and duration. In addition, because this is a prospective cohort study, we avoid selection bias.
Given the large population of current and former smokers at risk, the wide use of supplemental vitamins, and the extensive mortality and morbidity burden of lung cancer, evaluating the potential effects of vitamin supplementation has significant public health and resource implications. Although early detection is currently of great interest (55
), it is as yet unproven (6
) and chemoprevention remains an essential avenue to explore. This study of supplemental multivitamins, vitamin C, vitamin E, and folate did not show any evidence for a decreased risk of lung cancer. Indeed, increasing intake of supplemental vitamin E was associated with a slightly increased risk of lung cancer. Future studies may focus on other components of fruit and vegetables that may explain the decreased risk that has been associated with fruit and vegetables (56
). Our results, in combination with other intervention and cohort studies that have not found a decreased risk of incident lung cancer for users of supplemental multivitamins, vitamin C, vitamin E, and folate, should prompt clinicians to counsel patients that these supplements are unlikely to reduce the risk of lung cancer and may be detrimental.