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A Randomized Clinical Trial

Bernard F. Cole, PhD; John A. Baron, MD; Robert S. Sandler, MD; Robert W. Haile, DrPh; Dennis J. Ahnen, MD; Robert S. Bresalier, MD; Gail McKeown-Eyssen, PhD; Robert W. Summers, MD; Richard I. Rothstein, MD; Carol A. Burke, MD; Dale C. Snover, MD; Timothy R. Church, PhD; John I. Allen, MD; Douglas J. Robertson, MD; Gerald J. Beck, PhD; John H. Bond, MD; Tim Byers, MD, MPH; Jack S. Mandel, PhD, MPH; Leila A. Mott, MS; Loretta H. Pearson, MPhil; Elizabeth L. Barry, PhD; Judy R. Rees, BM, BCh, MPH, PhD; Norman Marcon, MD; Fred Saibil, MD; Per Magne Ueland, MD; E. Robert Greenberg, MD; for the Polyp Prevention Study Group

JAMA. 2007;297:2351-2359.

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

Author Affiliations: Departments of Community and Family Medicine (Drs Cole, Baron, Barry, Rees, and Greenberg, and Mss Mott and Pearson) and Medicine (Drs Baron, Rothstein, and Greenberg), Dartmouth Medical School, Hanover, NH; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (Dr Sandler); Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles (Dr Haile); Departments of Medicine (Dr Ahnen) and Preventive Medicine and Biometrics (Dr Byers), University of Colorado, Denver; Department of Gastrointestinal Medicine and Nutrition, MD Anderson Cancer Center, Houston, Tex (Dr Bresalier); Departments of Public Health Sciences and Nutritional Sciences (Dr McKeown-Eyssen) and Medicine (Drs Marcon and Saibil), University of Toronto, Toronto, Ontario; Division of Gastroenterology/Hepatology, University of Iowa Carver College of Medicine, Iowa City (Dr Summers); Departments of Gastroenterology (Dr Burke) and Quantitative Health Sciences (Dr Beck), The Cleveland Clinic Foundation, Cleveland, Ohio; Department of Pathology, Fairview Southdale Hospital, Edina, Minn (Dr Snover); Division of Environmental Health Sciences, University of Minnesota School of Public Health, Minneapolis (Dr Church); Department of Medicine, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minn (Dr Bond); Minnesota Gastroenterology PA, Plymouth (Dr Allen); Section of Gastroenterology, Department of Veterans Affairs Medical Center, White River Junction, Vt (Dr Robertson); Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Ga (Dr Mandel); and Section of Pharmacology, Institute of Medicine, University of Bergen and Haukeland University Hospital, Bergen, Norway (Dr Ueland).

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