Folic acid and prevention of colorectal adenomas: A combined analysis of randomized clinical trials

Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women with a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo, and who had a follow-up endoscopy 6 to 42 months after randomization (mean=30.6 (standard deviation=8.1) months). We used random-effects meta-analysis to estimate risk ratios (RR’s) and 95% confidence intervals (CI). The RR comparing folic acid vs. placebo was 0.98 (95% CI=0.82–1.17) for all adenomas and 1.06 (95% CI=0.81–1.39) for advanced lesions. Folic acid was associated with a non-significant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤11 nmol/L) and no effect among individuals in the highest quartile (>29 nmol/L, p for trend = 0.17). There was a non-significant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow-up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% vs. 0.5%, p=.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma.