Effects of folic acid supplementation on overall and site-specific cancer inc...

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals
Prof Stein Emil Vollset MD a, Dr Robert Clarke FRCP b Corresponding AuthorEmail Address, Sarah Lewington DPhil b, Marta Ebbing MD c, Jim Halsey BSc b, Prof Eva Lonn FRCPC d, Prof Jane Armitage FRCP b, Prof JoAnn E Manson MD e, Prof Graeme J Hankey MD f, Prof J David Spence MD g, Pilar Galan MD h, Prof Kaare H Bønaa MD i, Prof Rex Jamison MD j, J Michael Gaziano MD k, Peter Guarino PhD l, Prof John A Baron MD m, Prof Richard FA Logan FRCP n, Prof Edward L Giovannucci MD o, Martin den Heijer MD p, Prof Per M Ueland MD q, Derrick Bennett PhD b, Prof Rory Collins FMedSci b, Prof Richard Peto FRS b, for the B-Vitamin Treatment Trialists' Collaboration†
Summary
Background
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 the randomised trials of folic acid supplementation, at doses higher than those from fortification.
Methods
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 on cancer 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 cancer incidence rate ratio (RR).
Findings
During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 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 1·06, 95% CI 0·99—1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). 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.
Interpretation
Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials.
Funding
British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.