Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12

doi:10.1001/jama.2009.1622

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B₁₂

Marta Ebbing, MD;
Kaare Harald Bønaa, MD, PhD;
Ottar Nygård, MD, PhD;
Egil Arnesen, MD;
Per Magne Ueland, MD, PhD;
Jan Erik Nordrehaug, MD, PhD;
Knut Rasmussen, MD, PhD;
Inger Njølstad, MD, PhD;
Helga Refsum, MD, PhD;
Dennis W. Nilsen, MD, PhD;
Aage Tverdal, PhD;
Klaus Meyer, PhD;
Stein Emil Vollset, MD, DrPH

Author Affiliations: Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (Drs Ebbing, Nygård, and Nordrehaug); Department of Heart Disease, University Hospital of North Norway, Tromsø (Drs Bønaa and Rasmussen); Departments of Community Medicine (Drs Bønaa, Arnesen, and Njølstad) and Clinical Medicine (Dr Rasmussen), University of Tromsø, Tromsø, Norway; Institute of Medicine, University of Bergen and Haukeland University Hospital, Bergen, Norway (Drs Nygård, Ueland, Nordrehaug, and Nilsen); Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (Dr Refsum); Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, England (Dr Refsum); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (Dr Nilsen); Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway (Drs Tverdal and Vollset); Bevital AS, Bergen, Norway (Dr Meyer); and Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway (Dr Vollset).

Abstract

Context Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk.

Objective To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials.

Design, Setting, and Participants Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007.

Interventions Oral treatment with folic acid (0.8 mg/d) plus vitamin B₁₂ (0.4 mg/d) and vitamin B₆ (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B₁₂ (0.4 mg/d) (n = 1703); vitamin B₆ alone (40 mg/d) (n = 1705); or placebo (n = 1721).

Main Outcome Measures Cancer incidence, cancer mortality, and all-cause mortality.

Results During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B₁₂ vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B₁₂ vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B₁₂ vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B₁₂. Vitamin B₆ treatment was not associated with any significant effects.

Conclusion Treatment with folic acid plus vitamin B₁₂ was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.

Trial Registration clinicaltrials.gov Identifier: NCT00671346

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