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A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma^1,2,3

¹ From the Departments of Nutrition (KW, WCW, DJH, and EG), Epidemiology (WCW, DJH, and EG), and Biostatistics (BR), Harvard School of Public Health, Boston, MA; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (EAP); the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (WCW, CSF, BR, DJH, and EG); Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (JS); and the Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF).

² Supported by the National Cancer Institute grants CA 55075 and CA 95589 and NIH grants U54 100971 and R01 CA 67883. Folic acid and placebo pills were provided by the pharmaceutical company Lederle (now Wyeth Pharmaceuticals, Collegeville, PA).

³ Address correspondence to K Wu, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Boston, MA 02115. E-mail: kana.wu{at}channing.harvard.edu.

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, P_interaction = 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. This trial was registered at clinical trials.gov as NCT00512850.