Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.
BACKGROUND
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.


METHODS
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.


METHODS
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).


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


BACKGROUND
clinicaltrials.gov Identifier: NCT00272324.
Cole
Bernard F
BF
Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH, USA. bernard.cole@dartmouth.edu
Baron
John A
JA
Sandler
Robert S
RS
Haile
Robert W
RW
Ahnen
Dennis J
DJ
Bresalier
Robert S
RS
McKeown-Eyssen
Gail
G
Summers
Robert W
RW
Rothstein
Richard I
RI
Burke
Carol A
CA
Snover
Dale C
DC
Church
Timothy R
TR
Allen
John I
JI
Robertson
Douglas J
DJ
Beck
Gerald J
GJ
Bond
John H
JH
Byers
Tim
T
Mandel
Jack S
JS
Mott
Leila A
LA
Pearson
Loretta H
LH
Barry
Elizabeth L
EL
Rees
Judy R
JR
Marcon
Norman
N
Saibil
Fred
F
Ueland
Per Magne
PM
Greenberg
E Robert
ER
D000236:Adenoma / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000209:etiology; D012306:Risk; D017211:Treatment Failure
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005492:Folic Acid; D001241:Aspirin