This paper is part of NMJ's 2017 Oncology Special Issue. Read the paper or download the full issue here.
Brasky TM, White E, Chen CL. Long-term, supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the vitamins and lifestyle (VITAL) cohort. J Clin Oncol. 2017;35(30):3440-3448.
To examine the relationship between long-term supplemental B vitamin intake and lung cancer risk
Prospective cohort study in 13 counties around the Puget Sound in northwest Washington state (VITAL cohort)
Men and women, aged 50 to 76 at baseline and covered by the Surveillance, Epidemiology, and End Results (SEER) program cancer registry, were recruited from 364,418 baseline questionnaires from October 2000 to December 2002. Individuals with a history of lung cancer at baseline, lung cancer diagnosis on death certificate with no date of diagnosis, lung lymphoma and in situ lung cancer were excluded; after exclusions, 77,118 were available for study. Cohort members were followed from baseline to December 31, 2007, a mean follow-up of 6 years.
Study Parameters Assessed
Diet was assessed by food frequency questionnaire of 120 foods and beverages adapted from the Women’s Health Initiative, and the following demographic and health-related characteristics were collected: height, weight, computed BMI, education, family history of lung cancer, medical history, and cigarette smoking history, including age of onset of daily smoking, current smoking habits, cumulative years of smoking, number of years since quitting, and categorization as never smoked, former smoker (quit >10 years ago), recent smoker (quit <10 years ago), or current smoker.
…smokers may not be good candidates for vitamin A/beta-carotene and B6 or B12 supplementation until biochemical mechanisms are better understood.
Cohort members reported their regular intake (>1 per week for >1 year) of multivitamin, individual vitamin supplements, and mixtures in a closed-ended format including usual daily dose of B6, B9, and B12, use of a multivitamin formulation, and brand name.
Participants who developed lung cancer tended to be older, male, and less educated at baseline. They also had a lower BMI, consumed less alcohol, were more likely to be current smokers at baseline, had greater pack years, and were more likely to have a positive history of chronic obstructive pulmonary disease (COPD) and cancer.
Comparing men and women, women consumed more B vitamins from supplements (P<0.001), men tended to consume more B vitamins from diet (P<0.001), and women had lower overall B vitamin intake (food and supplements; P<0.001). Both groups exceeded the US recommended daily allowance (RDA) for each B vitamin.
There was no correlation of lung cancer risk with B vitamins in women. In men, compared to nonusers, intake of individual B vitamin supplements was associated with increased lung cancer risk for B6 (hazard ratio [HR]: 1.84; 95% confidence interval [CI]: 1.01-3.36) and B12 (HR: 2.42; 95% CI: 1.49-3.95). The 10-year average daily dose for men in the highest to lowest categories of B6 intake (>20 mg/d; HR: 1.82; 95% CI: 1.25-2.65) and B12 (>0.55 mcg/d; HR: 1.98; 95% CI: 1.32-2.97) was greater for current smokers compared to recent smokers or former smokers.
Among current male smokers, only B6 above 20 mg per day (HR: 2.93; 95% CI: 1.5 -5.72, P=0.04) and B12 above 55 mcg per day (HR: 3.71; 95% CI: 1.77 -7.74, P<0.01) were significant for lung cancer risk . There was no risk for lung cancer in former smokers who quit more than 10 years ago or less than 10 years ago. There were too few participants who had never smoked to evaluate associations. The association with increased use of B vitamins was similar across all histological subtypes of lung cancer except adenocarcinoma.
The relationship between B vitamins and cancer has been examined in a few prior studies. A randomized intervention study by Ebbing et al provided B vitamins to 6,837 patients with ischemic heart disease for 38 months, with another 39 months of follow-up. The study, which was conducted from 1998 to 2007, had 4 arms: 0.4 mg/d B12 plus 0.8 mg/d folic acid; 0.8 mg/d folic acid plus 40 mg/d B6; 40 mg/d B6 only; and placebo.1 Investigators found no effect of B6 on lung cancer. In the B12 plus folic acid arm, 10% developed cancer, while 8.4% of participants who did not receive that combination developed cancer (HR: 1.21; 95% CI: 1.03 -1.41, P=0.02). In this study, 40% were current smokers and 72% were current or former smokers. All-cause mortality was higher in the B12 with folic acid vs other treatments (16.1% vs 13.8%; HR: 1.18, P=0.01) and was mainly due to lung cancer. The cause of the increased cancer was unknown.
The Hordaland Health Studies were surveys performed in Hordaland County, Norway during the 1990s. The surveys were used to explore homocysteine in about 7,000 residents.2 An analysis of B6 metabolism found that the 4-pridoxic acid/pyridoxal + pyridoxal-5-phosphate ratio was a marker of B6 catabolism during inflammation and may be a marker of carcinogenesis. Smoking creates inflammation that can take years for the body to quell. Perhaps B6 during smoking and quelling of its inflammation will in some people lead to lung cancer.
To date no prospective studies have found an association between B12 and lung cancer risk. However, 2 prospective biomarker studies reported an elevated lung cancer risk in the highest versus the lowest categories of serum B12 in both sexes; methionine and B6 were associated with a lower risk.3,4 Hartman et al reported no association in men with high serum B6 levels; in this study, the highest serum levels had half the lung cancer risk (odds ratio [OR]: 0.51; 95% CI: 0.23-0.93, P=0.02).4
In the present study by Brasky et al, men who took individual B6 and B12 were at increased risk of lung cancer, and this association was almost two-fold among current smokers at baseline. No association was found in women who took multivitamins or individual vitamins, and no association was found with folate/B9 in men or women. The amount of B6 posing a hazard was >20 mg/d; the daily US RDA is 1.7 mg for men and 1.5 mg for women.5 The amount of B12 posing a hazard was 55 mcg/d; the daily US RDA is 2.4 mcg for men and women 14 years and older.6 However, this value is easily exceeded in the normal nonvegetarian standard North American diet; for example, a single double-cheeseburger or tuna sandwich at home, at a fast food establishment, or an upscale restaurant provides the RDA for B12.
So, depending on the study, B6 can increase or decrease the risk for lung cancer. Vitamin B12 has been reported to elevate the risk, but the mechanism is not reported. Cyanocobalamin, ubiquitous in the over-the-counter marketplace, is a suspect.
Cyanocobalamin provides 20 mcg of cyanide per 1,000 mcg of cobalmin. The structure of B12 contains a corrin ring, similar to the porphyrin ring of hemoglobin, chlorophyll, and cytochrome.7 Cyanocobalamin is easily synthesized in the laboratory and used in food and supplements because it is not oxidized air.5 Once ingested, cyanide is rapidly absorbed by the liver, lungs, blood, and brain in humans and rodents. Cyanide from tobacco has been implicated in tobacco-alcohol amblyopia, cyanide can prevent uptake of iodine into the thyroid, and long-term low-level exposure can produce neuropsychiatric symptoms and Parkinson-like motor symptoms.8 To date cyanocobalamin has been considered safe given that foods such as apricots, cherries, and cassava contain over 100 times more cyanide. This study may prompt a re-examination given its tendency to accumulate in the lungs, among other tissues.
Smoking is an inflammatory habit, with 85% of smokers developing COPD by ages 40 to 50.9 Perhaps this or related processes also alter the metabolism of B12 and B6 in some individuals. Vitamin A and beta-carotene pose risk in smokers as well.10 In summary, smokers may not be good candidates for vitamin A/beta-carotene and B6 or B12 supplementation until biochemical mechanisms are better understood.
A cohort self-reporting study encompassing 6 or more years carries accuracy risks associated with self-reporting regarding actual frequency of use, dose of the B vitamin used, and consistent use of the same brand manufactured with the same dose. Also, in the United States no agency regulates the manufacturing of B vitamins or certifies that the label and the contents are in agreement, which further muddies the waters. Companies often produce proprietary formulas that list ingredients but not the actual amounts of each ingredient. Consumer Labs is an independent company that tests many nutritional supplements and has reported label discrepancies in the past; actual amounts are generally less than the label claim.11,12
In clinical practice it is not unusual for patients to purchase supplements and use them at less than the suggested rate, or take a break on the weekend. Thus the doses claimed in the study by self-reporting may well be under or over the dose actually consumed. In this study, supplement consumption was counted if the participants took it one or more days per week for one or more years.
Accuracy of dietary recall is also unreliable, particularly when a study spans several years. Most of us realize that unless patients complete a diet diary each day, their recall of what they ate yesterday is poor and often selective.
An additional weakness of the study is that the form of the B vitamins is unknown. The authors cite Centrum Silver Adults as an example of a good multivitamin-mineral supplement but the label does not state the chemical form of B6 (3 mg) of which there are 6, of folic acid (400 mcg) of which there are 3 main forms encompassing 18 chemical structures, or of B12 (25 mcg) of which there are 4 forms.13 Individuals with diverse genetic polymorphisms may have difficulty converting to the active pyridoxal-5-phosphate or absorbing folic acid not in the methyl form, or utilizing cyanocobalamin, the most common form in over-the-counter supplements.
An unanswered question is why were members of this cohort taking individual B6, B9, B12, or a multivitamin. If they are smokers one might argue they were taking B vitamins to treat fatigue or to prevent cancer. With a quick search of the internet, patients may learn that B6 will benefit fatigue, mood, and depression. Folic acid is advertised for anemia, to build new cells, and to prevent cancer, and B12 is advertised for anemia, weakness and tiredness, and building nerve cells. It takes much further internet searching and nutritional biochemistry to determine which form of each vitamin is best absorbed or most bioavailable. The authors do not speculate or provide data on why the individuals in the SEER catchment took supplements.