Vollset SE1 et al.
Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in therandomised trials of folic acid supplementation, at doses higher than those from fortification.
In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data oncancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials(ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancerincidence rate ratio (RR).
During a weighted average scheduled treatment duration of 5กค2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57กค3 nmol/L for the folic acid groups vs 13กค5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1กค06, 95% CI 0กค99จC1กค13, p=0กค10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0กค23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0กค13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site.
Folic acid supplementation does not substantially increase or decrease incidence of site-specificcancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acidthat are, on average, an order of magnitude smaller than the doses used in these trials