New Study Suggests That Folic Acid Does Not Restrain Colorectal Tumours

07/06/07 A new US study suggests that folic acid supplementation does not reduce the risk of benign colorectal tumours and may even increase the risk of higher grade tumours.

The study is published in the Journal of the American Medical Association (JAMA).

Some epidemiological and animal studies have suggested that folic acid supplementation may prevent colorectal tumours.

Dr Bernard F Cole of Dartmouth Medical School, Hanover, New Hampshire and colleagues conducted a nine-centre trial in the US and Canada between 1994 and 2004 involving 1,021 patients of average age 57 who had recently had at least one colorectal adenoma removed within three months of enrollment but with no history of colorectal cancer.

Adenomas or polyps are benign growths that form singly or in clumps and may become malignant over time.

The patients were randomly assigned to receive either folic acid supplement (1 mg per day) or placebo and underwent colonoscopy about 3 years afterwards. 607 of the patients had a second colonoscopy at the 6 year mark.

Cole and colleagues were surprised to find more adenomas in the patients who had received folic acid although the risk did not differ significantly between the two groups.

At the first follow up, 44 per cent of the folic acid group had adenomas versus 42 per cent in the placebo group. At the second follow up, these figures were 42 versus 37 per cent respectively.

The folic acid group also showed a trend toward more advanced and multiple adenomas. In the first follow up 11 per cent of the folic acid group had advanced adenomas compared with 9 per cent in the placebo group and in the second follow up these figures were 12 and 7 per cent respectively.

The incidence of noncolorectal cancers in the folic acid group was significantly greater than in the placebo group ((11 versus 6 per cent). This was mainly due to an increase in prostate cancer.

Cole and colleagues concluded that:
"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."

And in regard to increased risk they said that the evidence was unclear and called for further research. However, they went to say that:

"In view of the fortification of the US 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."

In an accompanying editorial, Dr Cornelia M Ulrich and Dr John D Potter, from the Fred Hutchinson Cancer Research Center in Seattle, said that this study may be raising an issue of timing. If taken early, then perhaps folic acid prevents adenomas from forming, but if taken once they are formed, it could accelerate their development into cancer.

"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 of these patients (who are at increased adenoma risk), and that folic acid promoted growth of these lesions," they wrote.

They said this idea was supported by experimental studies where folic acid was given after lesions were present.

However, they said this study does not say anything about whether folic acid prevents adenomas in the first place, since all the patients had already had at least one when they were enrolled. It would cost a lot of money and take a long time, to prove that folic acid prevented tumours.

"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," said Ulrich and Potter.

This is not the first time that trials with single agents has thrown up these issues, and Ulrich and Potter draw comparisons with the problem of showing betacarotene benefits in lung cancer prevention. Lessons could be learned from chemotherapy, where multiple agents are used. They said the time has come 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."