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Meta-Analysis
. 2013 Mar 23;381(9871):1029-36.
doi: 10.1016/S0140-6736(12)62001-7.

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals

Stein Emil Vollset  1 , Robert Clarke, Sarah Lewington, Marta Ebbing, Jim Halsey, Eva Lonn, Jane Armitage, JoAnn E Manson, Graeme J Hankey, J David Spence, Pilar Galan, Kaare H Bønaa, Rex Jamison, J Michael Gaziano, Peter Guarino, John A Baron, Richard F A Logan, Edward L Giovannucci, Martin den Heijer, Per M Ueland, Derrick Bennett, Rory Collins, Richard Peto; B-Vitamin Treatment Trialists' Collaboration
Collaborators, Affiliations
Meta-Analysis

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals

Stein Emil Vollset et al. Lancet. .

Abstract

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.

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Conflict of interest statement

Conflicts of interest Sources of funding for individual trials are described in their separate publications. The Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), where the BVTT secretariat is located, has a policy of not accepting fees, honoraria, or paid consultancies directly or indirectly from any industry. It receives its core funding from the British Heart Foundation, UK Medical Research Council and Cancer Research UK. Support for this project was also provided by a grant from the UK Food Standards Agency (N05072).

Figures

Figure 1
Figure 1. Effects of folic acid allocation on overall first cancer incidence
The black squares denote the rate ratios (RRs) and horizontal lines the 99% confidence intervals (CIs). Each square has area inversely proportional to the variance of the log of the rate ratio. The diamonds represent the summary estimates and their corresponding 95% CIs.
Figure 2
Figure 2. Effects of folic acid on cancer incidence in all available trials, by year of follow-up
The black squares denote the rate ratios (RRs) and horizontal lines the 99% confidence intervals (CIs). Each square has area inversely proportional to the variance of the log of the rate ratio. The diamonds represent the summary estimates and their corresponding 95% CIs.
Figure 3
Figure 3. Effects of folic acid on first cancer incidence, by type and duration of treatment
The black squares denote the rate ratios (RRs) and horizontal lines the 99% confidence intervals (CIs). Each square has area inversely proportional to the variance of the log of the rate ratio. The diamonds represent the summary estimates and their corresponding 95% CIs.
Figure 4
Figure 4. Colorectal cancer mortality trends, 1950–2008, in the United States at ages 35–69
Male (upper line) and female annual mortality rates: rates at ages 35–69 are calculated as the mean of the annual rates in the seven component 5-year age groups. Source: WHO mortality database and UN population tables. Mortality rates at ages 35–69 years were standardised for age by averaging the seven component 5-year age groups. If the annual rate per 100,000, standardised in this way, is R, then the 35-year death rate from colorectal cancer, ignoring competing risks, is 1−exp(−35R/100,000).
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