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.
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).
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.
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.
British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards
Agency.