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Folic Acid for the Prevention of Colorectal Adenomas: A Randomized Clinical Trial.
Cole, Bernard F. PhD; Baron, John A. MD; Sandler, Robert S. MD; Haile, Robert W. DrPh; Ahnen, Dennis J. MD; Bresalier, Robert S. MD; McKeown-Eyssen, Gail PhD; Summers, Robert W. MD; Rothstein, Richard I. MD; Burke, Carol A. MD; Snover, Dale C. MD; Church, Timothy R. PhD; Allen, John I. MD; Robertson, Douglas J. MD; Beck, Gerald J. PhD; Bond, John H. MD; Byers, Tim MD, MPH; Mandel, Jack S. PhD, MPH; Mott, Leila A. MS; Pearson, Loretta H. MPhil; Barry, Elizabeth L. PhD; Rees, Judy R. BM, BCh, MPH, PhD; Marcon, Norman MD; Saibil, Fred MD; Ueland, Per Magne MD; Greenberg, E. Robert MD; Polyp Prevention Study Group
[Article] JAMA. 297(21):2351-2359, June 6, 2007.

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Context: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine.

Objective: To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas.

Design, Setting, and Participants: A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma.

Intervention: Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later).

Main Outcome Measures: The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (>=25% villous features, high-grade dysplasia, size >=1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or >=3 adenomas).

Results: During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation.

Conclusions: Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia.

Trial Registration: clinicaltrials.gov Identifier: NCT00272324