Table 3.
Characteristics of Included Studies on an Association Between Vitamin B6 and/or B12 Treatment and Lung Cancer Risk
| Reference | Study Type and Country | Sample Size | Main Findings | Comment |
|---|---|---|---|---|
| Takata et al, 201980 | Prospective cohort study, US | N=1,064 lung cancer cases among 68,236 participants | Neither the use of folic acid-containing supplements nor food intake of vitamin B6, vitamin B12 and riboflavin were associated with lung cancer risk | Study was designed to assess folic acid from food or supplements; vitamin B6 and B12 intake from supplements was not assessed |
| Fanidi et al, 201959 | Case-control study nested within LC3 study, international | N=5,183 case-control pairs Genetic data from N=29,266 cases and N=56,450 controls from the TRICL-ILCCO study |
Circulating vitamin B12 was positively associated with overall lung cancer risk in a dose–response fashion; findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer | Study has several weaknesses: secondary analysis of data from 20 cohorts that were not designed to study such association; reference groups of the different cohorts were the ones with the lowest levels of circulating vitamin B12; B12 not measured but “estimated“ in the TRICL-ILCCO study |
| Zuo et al, 201981 | Case control study nested within LC3, international | N=5,232 case-control pairs | Increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer | Conclusions are based on measurements at a single time point (regression dilution bias possible) |
| Yang et al, 201867 | Meta-analysis of 14 case-control studies/nested case-control studies, international | N=8,097 lung cancer patients and N=10,008 healthy controls | Serum folate and vitamin B6 might be protective factors against lung carcinogenesis and Hcy could contribute to lung cancer risk | Included cohorts were designed for such analysis; blood samples were used instead of intake estimates; three studies with reliable evidence, 11 studies with less certain evidence |
| Zuo et al, 201882 | Nested case-control study, Europe | N=892 incident lung cancer cases and N=1,748 controls from the EPIC study cohort | Increased vitamin B6 catabolism is independently associated with a higher risk of future lung cancer | Conclusions are based on measurements at a single time point (regression dilution bias possible); median time between blood draw and lung cancer diagnoses was 5.2 years |
| Fanidi et al, 201864 | Nested case-control study, international | N=5,364 incident case-control pairs (NCI cohorts) | Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall | Conclusions are based on measurements at a single time point (regression dilution bias possible); median time between blood draw and lung cancer diagnoses was 6.3 years |
| Brasky et al, 201734 | Prospective cohort study, US | N=77,118 participants (VITAL cohort) | Use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30–40% increase in lung cancer risk among men; no association in women | Study has several limitations (see Vitamin B6 and /or B12 and risk of lung cancer) |
| Zuo et al, 201583 | Prospective cohort study, Norway | N=6,539 participants (Hordaland Health Study) | Associations of vitamin B6 with cancer may be related to increased catabolism of vitamin B6 captured by plasma PAr, in particular for lung cancer where inflammation may be largely involved in carcinogenesis; the active B6 vitamer PLP was not significantly associated with overall cancer risk | Study investigated certain types of cancer (including but not limited to lung cancer); findings based on relatively small case numbers per cancer type; included a comprehensive panel of vitamin B6 markers |
| Tastekin et al, 201584 | Case-control study, Turkey | N=40 males with lung cancer, N=40 healthy controls | Plasma folate levels significantly lower in lung cancer cases compared with controls (P<0.001) but no significant difference with regard to B12 levels | Small sample size |
| Baltar et al, 201385 | Nested case-control study, Europe | N=891 cases; N=1,747 controls (EPIC cohort) | Structural equation modeling (including vitamins B2, B6, folate, B12) indicated roles of methionine-Hcy metabolism and immune activation in lung cancer risk; of the measured B vitamins, only folate and B6 were significantly (P<0.01) lower in cases than controls; tobacco smoking remained exposure with strongest impact on lung cancer risk | Authors emphasize that complex pathways (OCM, folate cycle, and immune system) rather than activities of single vitamins or nutrients should be considered in lung cancer carcinogenesis |
| Takata et al, 201286 | Prospective cohort study, China | N=74,941 women (Shanghai Women’s Health Study) | Dietary riboflavin intake was inversely associated with lung cancer risk while intakes of other B vitamins (eg, B6, B12) were not associated | Large study of female never-smokers with lung cancer; population had lower intakes than other populations; intakes of B6 and B12 only estimated; no information on serum levels |
| Bassett et al, 201287 | Prospective cohort study, Australia | N=41,514 people (Melbourne Collaborative Cohort Study) | Little evidence of an association between intake of B vitamins or methionine and lung cancer risk; weak inverse association between riboflavin and lung cancer risk in current smokers needs further investigation | Information on intake (self-reporting questionnaire) and potential confounding variables was only collected at baseline; no information on serum levels |
| Johansson et al, 201065 | Case-control study, Europe | N=899 lung cancer cases; N=1,770 controls (EPIC) | Serum levels of vitamin B6 and methionine were inversely associated with risk of lung cancer | Measurements of serum levels only at baseline (regression dilution bias possible) |
| Ebbing et al, 200988 | Combined data from two RCTs (NORVIT, WENBIT), Norway | N=6,837 participants with ischemic heart disease | While treatment with vitamin B6 alone was not associated with any significant effects, treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality | Study has limitations since both RCTs originally were not designed or powered to study lung cancer risk; authors point out that observed associations were confined only to serum folate, suggesting that the adverse effects were mediated by folate, not by vitamin B12 |
| Tsao et al, 200789 | Case-control study, China | N=27 patients and N=23 controls | RBC levels of vitamins B2 and B6 were reduced in NSCLC patients | Small sample size |
| Hartman et al, 200166 | Nested case-control study, Finland | N=300 male case-control pairs | No significant associations were seen between serum folate, vitamin B12 or Hcy and lung cancer risk; significantly lower risk of lung cancer among men who had higher serum vitamin B6 levels | Correlations between dietary intake and serum markers of B vitamins were not strong; many males had inadequate serum levels of folate and B6 |
Abbreviations: EPIC, European Prospective Investigation into Cancer and Nutrition; Hcy, homocysteine; LC3, Lung Cancer Cohort Consortium; NCI, National Cancer Institute; NORVIT, Norwegian Vitamin Trial; NSCLC, non-small cell lung cancer; OCM, one-carbon metabolism; PAr, 4-pyridoxic acid/(pyridoxal 1 pyridoxal 5ʹ-phosphate) ratio; PLP, pyridoxal 5ʹ phosphate; RBC, red blood cell; RCTs, randomized controlled trials; TRICL-ILCCO, Transdisciplinary Research Into Cancer of the Lung-International Lung Cancer Consortium; US, United States; VITAL, vitamins and Lifestyle; WENBIT, Western Norway B Vitamin Intervention Trial.