Folic acid does not decrease the risk of benign colorectal tumors

New research indicates that folic acid supplementation does not decrease the risk of benign colorectal tumors, but may possibly increase the risk for some types of colorectal tumors, according to a study in JAMA: The Journal of the American Medical Association.

Some previous studies have suggested that folate supplementation may help to prevent colorectal tumors.

Bernard F. Cole, Ph.D., of Dartmouth Medical School, Hanover, N.H., and colleagues evaluated the effect of folate for the prevention of new colorectal adenomas (benign tumors, precursors of most colorectal cancers) in persons with a history of these types of lesions. The trial was conducted at nine clinical centers in the U.S. and Canada between July 1994 and October 2004 and included 1,021 men and women with a recent history of colorectal adenomas but no previous large intestine cancerous tumor. Participants were randomly assigned to receive 1 mg/day of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/day) or placebo. Follow-up consisted of two colonoscopic examination cycles (the first interval was at 3 years and the second at 3 or 5 years later).

Contrary to what the researchers expected, more adenomas were seen in people who received folic acid. In the first follow-up interval, adenomas occurred in 42.4 percent of the participants in the placebo group and 44.1 percent of the participants in the folic acid group. In the second follow-up interval, adenomas occurred in 37.2 percent of the participants in the placebo group and 41.9 percent of the participants in the folic acid group.

In both follow-up intervals, participants in the folic acid group tended to have higher rates of advanced adenomas and multiple adenomas. Advanced adenomas have features, such as larger size, that increase the risk that they will develop into colorectal cancer. In the first follow-up interval, advanced adenomas occurred in 8.6 percent of the participants in the placebo group and 11.4 percent of the participants in the folic acid group. The respective numbers in the second follow-up interval were 6.9 percent and 11.6 percent for both groups, a 67 percent (but non-statistically significant) increased risk of advanced adenomas. Participants in the folic acid group (30 individuals, 9.9 percent) had more than twice the risk of having three or more adenomas than those in the placebo group (13 individuals, 4.3 percent).

"In conclusion, our study indicates that folate, when administered as folic acid for up to 6 years, does not decrease the risk of adenoma formation in the large intestine among individuals with previously removed adenomas. The evidence for an increased risk of adenomas is equivocal and requires further research. In view of the fortification of the U.S. food supply with folate, and some suggestions that folate could conceivably increase the risk of neoplasia even outside the colorectum, this line of investigation should have a high priority," the authors write.

(JAMA. 2007;297:2351-2359. Available pre-embargo to the media at

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Folate and Cancer-Timing Is Everything

In an accompanying editorial, Cornelia M. Ulrich, M.S., Ph.D., and John D. Potter, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, discuss the findings of Cole and colleagues.

"How should the unexpected results of this study be interpreted? The most likely explanation for the increased risk of advanced and multiple adenomas in the intervention group is that undetected early precursor lesions were present in the mucosa [a type of membrane] of these patients (who are at increased adenoma risk), and that folic acid promoted growth of these lesions. This hypothesis is consistent with experimental studies showing increased colorectal neoplasia when folic acid is administered after lesions are present."

"Nonetheless, by the nature of the design, the results do not provide information on primary prevention by folic acid (the potential for folic acid to reduce the incidence of first adenomas). The question of efficacy of folate in cancer prevention is not resolved, and animal experiments showing chemopreventive effects of folate, as well as the strong observational epidemiological evidence, speak to the potential of folate as a chemopreventive agent, if taken early. Unfortunately, primary prevention trials that start in childhood would be lengthy, expensive, and logistically nearly impossible."

"The results of the clinical trial by Cole et al illustrate, yet again, the principle that chemoprevention with single agents is problematic. Similar to the increased risk of lung cancer observed with beta carotene supplementation, selection of resistant clones is as plausible an outcome of the use of single-agent chemoprevention as it is of single-agent chemotherapy," they write. "It is time to be as thoughtful about the need for multiagent chemoprevention, not forgetting that diet is one version of this, as about the use of multiagent chemotherapy."


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