title: Cancer incidence and mortality after treatment with folic acid and vitamin B12.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721).
  
  
  METHODS
  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 B(12) 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 B(12) 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 B(12) 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 B(12). Vitamin B(6) treatment was not associated with any significant effects.
  
  
  CONCLUSIONS
  Treatment with folic acid plus vitamin B(12) 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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00671346.
authors.affiliation: Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, Bergen, Norway 5021. marta.ebbing@helse-bergen.no
authors.forename: Marta
authors.initials: M
authors.lastname: Ebbing
authors.forename: Kaare Harald
authors.initials: KH
authors.lastname: Bønaa
authors.forename: Ottar
authors.initials: O
authors.lastname: Nygård
authors.forename: Egil
authors.initials: E
authors.lastname: Arnesen
authors.forename: Per Magne
authors.initials: PM
authors.lastname: Ueland
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Nordrehaug
authors.forename: Knut
authors.initials: K
authors.lastname: Rasmussen
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.forename: Helga
authors.initials: H
authors.lastname: Refsum
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Nilsen
authors.forename: Aage
authors.initials: A
authors.lastname: Tverdal
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.forename: Stein Emil
authors.initials: SE
authors.lastname: Vollset
mesh_terms: D000368:Aged; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D017202:Myocardial Ischemia / Q000517:prevention & control; D009369:Neoplasms / Q000453:epidemiology* / Q000401:mortality; D009664:Norway; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D014805:Vitamin B 12 / Q000097:blood / Q000627:therapeutic use*; D025101:Vitamin B 6 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12