Update on Safety Profiles of Vitamins B1, B6, and B12: A Narrative Review.
"One of the few studies proposing an association between B vitamins and lung cancer risk was published by Brasky et al34 in 2017. The Vitamins and Lifestyle (VITAL) cohort included 77,118 subjects aged 50–76 from the US and examined the association between the long-term use of supplemental B vitamins and lung cancer risk.34 In the 6-year follow-up on average, 808 lung cancer cases occurred. The 10-year average daily doses from individual and multivitamin supplements as well as mixtures were retrospectively documented at baseline by self-assessment questionnaires. When trying to establish associations, the authors found the long-term use of high-dose vitamin B6 (defined as >20 mg/day) or B12 (defined as >55 µg/day) from individual supplement sources, but not multivitamins, to be associated with a 30–40% increase in lung cancer risk among male smokers.34 However, in our opinion, the study does not prove causality between B vitamin intake and lung cancer risk and has significant limitations, as already pointed out by Obeid and Pietrzik.60 When reviewing patient characteristics of the VITAL study, 42% of lung cancer cases were ≥70 years, while only 19% of controls belonged to this age group.34 The percentage of smokers was almost four times higher for cases than controls.34 This imbalance was even more evident for smoking duration: 71% of lung cancer cases had smoked for >35 years vs 16% of controls. Likewise, 70% of cases and only 19% of controls had smoked >25 pack-years of cigarettes.34 Finally, the history of COPD was 5-times more frequent in cases than controls,34 and it is well known that this condition increases the risk of lung cancer – especially squamous cell carcinoma – by the factor five.61,62 Because these determinants of lung cancer, such as advanced age, cigarette smoking, and COPD history, were much more prevalent in cases than controls,34 it is much more likely that the authors estimated the effect of these well-known risk factors instead of the effect of B vitamins on this outcome.34,60
Without measuring serum levels over time, Brasky et al34 started from the premise that a self-reported intake above the RDA reflects disturbed vitamin homeostasis, but self-reported intakes should not be taken as surrogate markers for vitamin levels. As mentioned before, age, smoking status, smoking duration, smoking intensity, COPD history, and some genetic variants are well-known lung cancer risk factors.63 The fact that these factors were also associated with vitamin usage raises the suspicion that the association between vitamin intake and cancer was due to confounding, despite the authors’ attempts to compensate for it through adjustment for known or suspected risk factors. Like Obeid and Pietrzik,60 we consider a reverse causality more likely; ie, knowing to have an increased risk (which every smoker does) can trigger healthier behaviors in other areas of life, including taking vitamin supplements. Therefore, we do not believe that the VITAL study uncovered a causal relationship between supplement intake and lung cancer. Apart from our own assumptions, many studies contradict the findings from a scientific point (Table 3). For example, several authors reported inverse relationships between vitamin B6 levels and lung cancer risk,64–66 and Yang et al67 even consider a possible protective effect of vitamin B6 in a systematic review and meta-analysis, including 14 studies and >8,000 patients. This protective effect of vitamin B6 has also been described in gastrointestinal cancer, pancreatic cancer, and breast cancer.68–70
Taken together, the current evidence from (almost exclusively epidemiological) studies on a relationship between vitamin B6 and/or B12 intake and lung cancer risk is not conclusive.34,–59,–64–67,80–89 The results of Brasky et al34 regarding vitamins B6 and B12 should be interpreted with caution. The potential role of B vitamins in lung cancer carcinogenesis should be regarded in a bigger context and consider the complex interaction in OCM, folate cycle, etc., which we believe requires further intense research. However, the focus should still be on the actual high-risk factors such as smoking, which increase the risk many times."
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