RESEARCH - Folic acid for the prevention of colorectal adenomas

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JAMA

Vol. 297 No. 21, June 6, 2007

Original Contribution

Folic Acid for the Prevention of Colorectal Adenomas

A Randomized Clinical Trial

Bernard F. Cole, PhD; A. Baron, MD; S. Sandler, MD;

W. Haile, DrPh; Dennis J. Ahnen, MD; S. Bresalier, MD; Gail

McKeown-Eyssen, PhD; W. Summers, MD; I. Rothstein, MD;

Carol A. Burke, MD; Dale C. Snover, MD; R. Church, PhD;

I. , MD; J. on, MD; Gerald J. Beck, PhD; H.

Bond, MD; Tim Byers, MD, MPH; Jack S. Mandel, PhD, MPH; Leila A. Mott,

MS; Loretta H. Pearson, MPhil; L. Barry, PhD; Judy R. Rees,

BM, BCh, MPH, PhD; Norman Marcon, MD; Fred Saibil, MD; Per Magne

Ueland, MD; E. Greenberg, MD; for the Polyp Prevention Study

Group

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.

http://jama.ama-assn.org/cgi/content/abstract/297/21/2351

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