Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12 | Lung Cancer | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.204.227.34. Please contact the publisher to request reinstatement.
1.
Smith AD, Kim YI, Refsum H. Is folic acid good for everyone?  Am J Clin Nutr. 2008;87(3):517-53318326588PubMedGoogle Scholar
2.
Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach.  Int J Cancer. 2005;113(5):825-82815499620PubMedGoogle ScholarCrossref
3.
Cho E, Hunter DJ, Spiegelman D,  et al.  Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies.  Int J Cancer. 2006;118(4):970-97816152626PubMedGoogle ScholarCrossref
4.
Slatore CG, Littman AJ, Au DH, Satia JA, White E. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer.  Am J Respir Crit Care Med. 2008;177(5):524-53017989343PubMedGoogle ScholarCrossref
5.
Stevens VL, Rodriguez C, Pavluck AL, McCullough ML, Thun MJ, Calle EE. Folate nutrition and prostate cancer incidence in a large cohort of US men.  Am J Epidemiol. 2006;163(11):989-99616554345PubMedGoogle ScholarCrossref
6.
Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis.  J Natl Cancer Inst. 2007;99(1):64-7617202114PubMedGoogle ScholarCrossref
7.
Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF,  et al.  Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.  Am J Clin Nutr. 2006;83(4):895-90416600944PubMedGoogle Scholar
8.
Maruti SS, Ulrich CM, White E. Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk.  Am J Clin Nutr. 2009;89(2):624-63319116331PubMedGoogle ScholarCrossref
9.
Kim YI. Folate and colorectal cancer: an evidence-based critical review.  Mol Nutr Food Res. 2007;51(3):267-29217295418PubMedGoogle ScholarCrossref
10.
Ulrich CM, Potter JD. Folate and cancer: timing is everything.  JAMA. 2007;297(21):2408-240917551134PubMedGoogle ScholarCrossref
11.
Centers for Disease Control and Prevention (CDC).  Trends in wheat-flour fortification with folic acid and iron—worldwide, 2004 and 2007.  MMWR Morb Mortal Wkly Rep. 2008;57(1):8-1018185494PubMedGoogle Scholar
12.
Pfeiffer CM, Johnson CL, Jain RB,  et al.  Trends in blood folate and vitamin B-12 concentrations in the United States, 1988-2004.  Am J Clin Nutr. 2007;86(3):718-72717823438PubMedGoogle Scholar
13.
Kalmbach RD, Choumenkovitch SF, Troen AM, D'Agostino R, Jacques PF, Selhub J. Circulating folic acid in plasma: relation to folic acid fortification.  Am J Clin Nutr. 2008;88(3):763-76818779294PubMedGoogle Scholar
14.
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art.  Am J Med Sci. 2009;338(1):48-4919593104PubMedGoogle ScholarCrossref
15.
Bønaa KH, Njolstad I, Ueland PM,  et al; NORVIT Trial Investigators.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  N Engl J Med. 2006;354(15):1578-158816531614PubMedGoogle ScholarCrossref
16.
Ebbing M, Bleie O, Ueland PM,  et al.  Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.  JAMA. 2008;300(7):795-80418714059PubMedGoogle ScholarCrossref
17.
Kelleher BP, Broin SD. Microbiological assay for vitamin B12 performed in 96-well microtitre plates.  J Clin Pathol. 1991;44(7):592-5951856292PubMedGoogle ScholarCrossref
18.
O'Broin S, Kelleher B. Microbiological assay on microtitre plates of folate in serum and red cells.  J Clin Pathol. 1992;45(4):344-3471577973PubMedGoogle ScholarCrossref
19.
Midttun Ø, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry.  Rapid Commun Mass Spectrom. 2009;23(9):1371-137919337982PubMedGoogle ScholarCrossref
20.
Meyer K, Fredriksen A, Ueland PM. MALDI-TOF MS genotyping of polymorphisms related to 1-carbon metabolism using common and mass-modified terminators.  Clin Chem. 2009;55(1):139-14918988749PubMedGoogle ScholarCrossref
21.
Cancer Registry of Norway.  Cancer in Norway 2007: Cancer Incidence, Mortality, Survival and Prevalence in Norway. Oslo, Norway: Cancer Registry of Norway (Kreftregisteret); 2008
22.
Statistics Norway.  Causes of deaths, 2007. http://www.ssb.no/dodsarsak_en/. Accessed September 22, 2009
23.
Larsen IK, Småstuen M, Parkin DM, Bray F. Data quality at the Cancer Registry of Norway. In: Bray F, ed. Cancer in Norway 2006: Cancer Incidence, Mortality and Prevalence in Norway. Oslo, Norway: Cancer Registry of Norway (Kreftregisteret); 2007:S1-S51
24.
Cleves M, Gutierrez R, Gould W, Marchenko Y. The Cox Model: Diagnostics: An Introduction to Survival Analysis Using Stata. 2nd ed. College Station, TX: Stata Press; 2008:197-202
25.
Fredriksen A, Meyer K, Ueland PM, Vollset SE, Grotmol T, Schneede J. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism.  Hum Mutat. 2007;28(9):856-86517436311PubMedGoogle ScholarCrossref
26.
Timbo BB, Ross MP, McCarthy PV, Lin CT. Dietary supplements in a national survey: prevalence of use and reports of adverse events.  J Am Diet Assoc. 2006;106(12):1966-197417126626PubMedGoogle ScholarCrossref
27.
Hoey L, McNulty H, Askin N,  et al.  Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults.  Am J Clin Nutr. 2007;86(5):1405-141317991653PubMedGoogle Scholar
28.
Clarke R, Sherliker P, Hin H,  et al.  Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK.  Br J Nutr. 2008;100(5):1054-105918341758PubMedGoogle ScholarCrossref
29.
Quinlivan EP, Gregory JF III. Effect of food fortification on folic acid intake in the United States.  Am J Clin Nutr. 2003;77(1):221-22512499345PubMedGoogle Scholar
30.
Institute of Medicine.  Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline: A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and Its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, DC: National Academies Press; 1998
31.
Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK.  Br J Nutr. 2007;98(4):667-67517617936PubMedGoogle ScholarCrossref
32.
Troen AM, Mitchell B, Sorensen B,  et al.  Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.  J Nutr. 2006;136(1):189-19416365081PubMedGoogle Scholar
33.
Peto R, Emberson J, Landray M,  et al.  Analyses of cancer data from three ezetimibe trials.  N Engl J Med. 2008;359(13):1357-136618765432PubMedGoogle ScholarCrossref
34.
Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells.  Proc Natl Acad Sci U S A. 1998;95(22):13217-132209789068PubMedGoogle ScholarCrossref
35.
Ulrich CM, Neuhouser M, Liu AY,  et al.  Mathematical modeling of folate metabolism: predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis.  Cancer Epidemiol Biomarkers Prev. 2008;17(7):1822-183118628437PubMedGoogle ScholarCrossref
36.
Cole BF, Baron JA, Sandler RS,  et al; Polyp Prevention Study Group.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.  JAMA. 2007;297(21):2351-235917551129PubMedGoogle ScholarCrossref
37.
Lonn E, Yusuf S, Arnold MJ,  et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  N Engl J Med. 2006;354(15):1567-157716531613PubMedGoogle ScholarCrossref
38.
Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial.  JAMA. 2008;300(17):2012-202118984888PubMedGoogle ScholarCrossref
39.
Centers for Disease Control and Prevention (CDC).  Tobacco use among adults—United States, 2005.  MMWR Morb Mortal Wkly Rep. 2006;55(42):1145-114817065979PubMedGoogle Scholar
40.
Rosenberg IH. Science-based micronutrient fortification: which nutrients, how much, and how to know?  Am J Clin Nutr. 2005;82(2):279-28016087969PubMedGoogle Scholar
Original Contribution
November 18, 2009

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

Author Affiliations

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).

JAMA. 2009;302(19):2119-2126. doi:10.1001/jama.2009.1622
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

×