In this large cohort of patients with stage III colon cancer treated with surgery and adjuvant chemotherapy, neither multivitamin use during or after adjuvant therapy was significantly associated with improved DFS, RFS, or overall survival. Moreover, multivitamin use did not improve chemotherapy-related gastrointestinal toxicity, although there was a potential benefit on fatigue. Importantly, multivitamin use was not found to be detrimental to patient outcome. To our knowledge, this is the first study to examine the impact of multivitamin use on survival among patients with established colon cancer.
Several observational studies have investigated the association between multivitamin use and colorectal cancer incidence, with conflicting results. A case-control analysis using the Surveillance, Epidemiology, and End Results registry found a 51% reduction in the risk of colorectal cancer in those who used multivitamins for 10 years (P
trend < .001).13
Similarly, in a prospective cohort study using the Nurses' Health Study, there was no benefit of multivitamin use on colorectal cancer until 15 years of use, at which time a 75% reduction in risk was observed (P
trend < .001).15
In contrast, a prospective cohort study using the Women's Health Study showed no association between multivitamin use and colorectal cancer during 10 years of follow-up,26
and participants in the Women's Health Initiative who used multivitamins did not have a lower risk of several cancers, including colorectal cancer (HR, 0.99; 95% CI, 0.88 to 1.11).12
Multivitamins consist of several vitamins and micronutrients that have been purported to influence colorectal carcinogenesis. Among these, folate is thought to be the micronutrient most likely responsible for any potential benefit of multivitamins. Folate acts as a cofactor in single-carbon transfer in nucleic and amino acid metabolism, therefore a deficiency could lead to disturbances in DNA replication, methylation, and repair.2,3
The amount of folic acid in multivitamins was increased in 1973 from 100 to 400 μg,27
a level considerably higher than median dietary intake. Numerous epidemiologic studies have demonstrated that higher folate intake is associated with a lower risk of colorectal adenoma and cancer.28,29
However, a placebo-controlled trial demonstrated a 67% increase in the risk of advanced colorectal lesions and a more than two-fold increase in the risk of developing at least three adenomas with supplemental folic acid among subjects with prior adenomas.30
Animal studies have suggested that the timing of folic acid supplementation may be critical; administration before the existence of neoplastic lesions may prevent tumor development, whereas administration afterwards may promote tumor progression.31
Of note, in another analysis of stage I to III colorectal cancer patients, higher plasma folate levels were not associated with inferior survival.32
Higher circulating plasma 25-hydroxyvitamin D3
[25(OH)D] has been associated with a reduced risk of colorectal cancer,33
and in a cohort of 304 patients with stage I to IV disease, we observed a significant reduction in overall mortality with increasing plasma 25(OH)D.34
However, given the limited quantity of vitamin D in standard multivitamin tablets (200 to 400 U), regular multivitamin use is unlikely to materially increase 25(OH)D levels.35
In our secondary subset analyses, multivitamin use was associated with improved DFS in patients ≤ 60 years of age, but not in those older than 60. Of note, this exploratory finding may simply reflect chance. Nonetheless, the Nutrition Intervention Trials conducted in Linxian County, China, found that the benefit of beta-carotene, vitamin E, and selenium in reducing cancer mortality was greater in participants younger than 55 years of age.36
In addition, we observed a significant benefit from multivitamin use among obese patients, who often have greater levels of oxidative stress.37
It is possible that one or several of the micronutrients with antioxidant properties in multivitamins is contributing to improved outcomes in this subgroup of patients. These interactions with younger age and higher BMI require confirmation in other studies.
There are several advantages to using a cohort within a NCI-sponsored clinical trial. First, all patients had stage III cancer, reducing the impact of heterogeneity by disease stage. Second, treatment and follow-up were standardized, and the date and nature of recurrence were recorded prospectively. Finally, detailed information on prognostic factors was collected routinely.
Several potential limitations deserve comment. Patients who enroll in randomized trials may differ from the population at large. However, the prevalence of multivitamin use in our cohort falls within the range reported for patients with cancer overall.16
Moreover, since the study included patients from both community and academic centers throughout North America, our findings should reflect the general population.
Because we relied on self-reported multivitamin use, misclassification of the exposure is possible. However, prior studies have demonstrated such data to be reliable.38
Moreover, multivitamin use was recorded before any knowledge of cancer-related outcomes, thus reducing the likelihood of reporting biases. Finally, patients who consume supplements often engage in other healthful behaviors. In this study, we controlled for physical activity, BMI, and performance status, among other factors. However, residual confounding from unknown variables is possible.
In conclusion, our large prospective study of patients with stage III colon cancer found no significant benefit for multivitamin supplementation on patient outcome. These results are consistent with a conference statement from the National Institutes of Health that concluded there was insufficient evidence to recommend either for or against the use of multivitamins for chronic disease prevention.1
Nonetheless, further research is needed to assess the utility of individual vitamins in patients with established colorectal cancer.