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

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).

Corresponding Author: Bernard F. Cole, PhD, Dartmouth-Hitchcock Medical Center, 7927 Rubin Bldg, Lebanon, NH 03756 ([email protected]).

Author Contributions: Drs Cole and Baron had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cole, Baron, Sandler, Ahnen, Bresalier, Burke, Snover, Allen, Beck, Bond, Byers, Mandel, Pearson, Greenberg.

Acquisition of data: Baron, Sandler, Haile, Ahnen, Bresalier, McKeown-Eyssen, Summers, Rothstein, Burke, Snover, Church, Allen, Beck, Bond, Byers, Mandel, Barry, Rees, Marcon, Saibil, Ueland.

Analysis and interpretation of data: Cole, Baron, Sandler, Haile, Ahnen, Bresalier, McKeown-Eyssen, Church, Allen, Robertson, Beck, Byers, Mott, Greenberg.

Drafting of the manuscript: Cole, Baron, Allen, Byers, Mott, Saibil, Greenberg.

Critical revision of the manuscript for important intellectual content: Baron, Sandler, Haile, Ahnen, Bresalier, McKeown-Eyssen, Summers, Rothstein, Burke, Snover, Church, Allen, Robertson, Beck, Bond, Byers, Mandel, Pearson, Barry, Rees, Marcon, Ueland, Greenberg.

Statistical analysis: Cole, Baron, Haile, Church, Byers, Mott, Greenberg.

Obtained funding: Cole, Baron, Ahnen, Bresalier, Church, Byers, Mandel.

Administrative, technical, or material support: Cole, Baron, Sandler, Bresalier, McKeown-Eyssen, Rothstein, Burke, Snover, Church, Beck, Bond, Mandel, Pearson, Barry, Saibil.

Study supervision: Cole, Baron, Haile, Bresalier, Summers, Church, Allen, Beck, Mandel, Marcon.

Financial Disclosures: Dr Cole reported being a consultant to Schering-Plough. Dr Baron reported being a consultant to Merck and Bayer. Dartmouth College and Dr Baron hold a use patent for calcium supplementation, which is licensed to Wyeth Consumer Health Care. Dr Sandler reported receiving research support from Merck and being a consultant to Merck, Bayer, GlaxoSmithKline, and Procter & Gamble. Ms Mott reported that she has equity interest in Wyeth. No other authors reported any financial disclosures.

Polyp Prevention Study Group Investigators, Study Coordinators, and Coordinating Center Staff (listed alphabetically within study site):Cleveland Clinic Foundation, Cleveland, Ohio: J. Bauman, H. Hasson; University of Colorado Health Sciences Center, Denver: L. Richman, R. Reveille, R. Roller (Rocky Mountain Gastroenterology Associates, Lakewood, Colo), J. Levine (University of Colorado Hospital, Denver), P. Baker, P. Hanna, D. Hruza (South Denver Endoscopy, Denver, Colo), A. Triebling (Arapahoe Gastroenterology, Littleton, Colo), S. Lawrence, V. Jakribettuu (Denver Veterans Affairs Medical Center, Denver, Colo), S. Frederick, S. Rein; Dartmouth-Hitchcock Medical Center, Lebanon, NH: D. Howell (Portland Gastroenterology Associates, Portland, Me), P. Moses (University of Vermont College of Medicine, Burlington), A. Robinson (Claremont, NH), A. Warner (Lahey Clinic, Burlington, Mass), D. Chamberlain, M. Hynes, L. Wetteman; Henry Ford Health Sciences Center, Detroit, Mich: B. Zonka; University of Iowa College of Medicine, Iowa City: D. Abramson, D. Purdy, R. Silber, G. Weinman (Gastroenterologists, P.C.I., Cedar Rapids, Iowa), N. Dusdieker (Internists, P.C., Cedar Rapids, Iowa), J. Ewing, B. O'Meara (Gastroenterology Associates of Iowa City, Iowa City, Iowa), R. Thompson; University of Minnesota, Minneapolis: the physicians of Minnesota Gastroenterology P.A., J. Blomquist; University of North Carolina School of Medicine, Chapel Hill: S. Levinson (Chapel Hill Internal Medicine, Chapel Hill, NC), R. McCall, M. Pate (Mid-Carolina Gastroenterology, Sanford, NC), R. Schwarz (Raleigh Medical Group, Raleigh, NC), R. Buccini (Eagle Gastroenterology, Greensboro, NC), J. Weissman (Tannenbaum Associates, Greensboro, NC), B. Schliebe; University of Southern California, Los Angeles: B. Batra, D. Berkowitz, E. Lever (Kaiser-Bellflower, Bellflower, Calif), C. Conteas, T. Teller (Kaiser-Sunset, Los Angeles, Calif), L. Gerstmann, P. Harmon, A. Montes, N. Uk.; University of Toronto, Toronto, Ontario: E. Irvine (McMaster University Hamilton Health Sciences Centre, Hamilton, Ontario), L. Cohen, M. Cooper, T. Devlin, D. Hemphill, E. Hurowitz, H. Price, S. Stafford (Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario), N. Bassett, V. Jazmaji, M. Morgan, L. Vernich; Dartmouth Medical School, Hanover, NH: B. Beaulieu, D. Carmichael, P. Courtney, J. Dykes, S. Ewell, J. Hebb, S. Raymond, S. Rovell-Rixx, B. Thomas.

Data and Safety Monitoring Committee: F. Giardiello (Johns Hopkins University School of Medicine, Baltimore, Md), J. Lachin (George Washington University, Washington, DC), J. Neaton (University of Minnesota, Minneapolis), L.J. Roberts (Vanderbilt University School of Medicine, Nashville, Tenn), W. Willett (chairman; Harvard University, Boston, Mass).

Funding/Support: This work was supported in part by grants 5 R01 CA059005 and U54 CA100971 from the National Institutes of Health. Study tablets were provided by Wyeth Consumer Health Care, Madison, NJ.

Role of the Sponsor: The funding organizations played no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Acknowledgment: We thank all the individuals who participated in this clinical trial.

JAMA: The Journal of the American Medical Association 297(21):p 2351-2359, June 6, 2007.

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