Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2009
Publication Date: 12/20/2009
Citation: Selhub, J., Wu, K., Platz, E., Willet, W., Fuchs, C., Rosner, B., Hunter, D., Giovannucci, E. 2009. A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. American Journal of Clinical Nutrition. 90(6):1623-1631. Interpretive Summary: Animal and human studies have suggested that the B vitamin folate may protect against colorectal cancer. To find the result of folic acid supplementation on colorectal tumors, we conducted a trial of participants from 2 large studies: the Health Professionals Follow-Up Study and the Nurses’ Health Study. Subjects were randomly assigned to receive 1 mg/day folic acid or placebo for 3–6.5 y. Having at least one recurrent tumor was not associated with folic acid supplementation. Among study subjects with low blood folate levels at the beginning of the study, those randomly assigned to receive folic acid had a significant decrease in tumor recurrence. However, on subjects with high folate levels at the beginning of the study, supplemental folic acid had no significant effect. Different from findings from another clinical trial, there was no evidence for a higher risk of advanced or multiple tumors. In conclusion, our results do not support a protective effect of folic acid on the recurrence of colorectal tumors. Adding folic acid to the diet of those with lower folate levels may still have some benefits.
Technical Abstract: Background: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. Objective: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conducted a cost-efficient, double-blind, randomized trial among participants of 2 large prospective cohorts, the Health Professionals Follow-Up Study and the Nurses’ Health Study. Design: Participants were randomly assigned to receive folic acid (1 mg/d) (n = 338) or placebo (n = 334) for 3–6.5 y. The primary endpoint was any new diagnosis of adenoma during the study period (May 1996–March 2004). Secondary outcomes were adenoma by site and stage and number of recurrent adenomas. Associations were also examined by plasma folate concentrations at baseline. Results: Incidence of at least one recurrent adenoma was not significantly associated with folic acid supplementation [relative risk (RR): 0.82; 95% CI: 0.59,1.13; P = 0.22]. Among participants with low plasma folate concentrations at baseline ( 7.5 ng/mL), those randomly assigned to receive folic acid experienced a significant decrease in adenoma recurrence (RR: 0.61; 95% CI: 0.42, 0.90; P = 0.01), whereas for subjects with high folate concentrations at baseline (>7.5 ng/mL), supplemental folic acid had no significant effect (RR: 1.28; 95% CI: 0.82, 1.99; P = 0.27, Pinteraction = 0.01). Contrary to findings from another clinical trial, there was no evidence for an increased risk of advanced or multiple adenomas. Conclusions: Our results do not support an overall protective effect of folic acid supplementation on adenoma recurrence. Folic acid supplementation may be beneficial among those with lower folate concentrations at baseline.