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25 Jan 2013

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

[Source: The Lancet, full text: (LINK). Abstract, edited.]

The Lancet, Early Online Publication, 25 January 2013


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

Original Text

Prof Stein Emil Vollset MD a, Dr Robert Clarke FRCP b, 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†




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.


a Norwegian Institute of Public Health and Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway; b Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK; c Department of Heart Disease, Haukeland University Hospital, Bergen, Norway; d Population Health Research Institute and Department of Medicine, Division of Cardiology, McMaster University, Hamilton, ON, Canada; e Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA; f Department of Neurology, Royal Perth Hospital, Perth, WA, Australia; g Department of Neurology, Robarts Research Institute, University of Western Ontario, London, ON, Canada; h Research Unit on Nutritional Epidemiology, INSERM U557, Inra, CNAM Université Paris 13, CRNH Idf, Bobigny, France; i Department of Heart Disease, University Hospital of Northern Norway, Tromsø, Norway; j Department of Medicine, Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, CA, USA; k Massachusetts Veterans Epidemiology Research and Information Centre, VA Boston Healthcare System, Boston, MA, USA; l Cooperative Studies Program, Department of Veterans Affairs, Connecticut VA Healthcare System, West Haven, CT, USA; m Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; n Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK; o Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA; p Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; q Institute of Medicine, University of Bergen, and Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway

Correspondence to: Dr Robert Clarke, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Richard Doll Building, University of Oxford Old Road Campus, Oxford OX3 7LF, UK

† Collaborators listed at end of report