Adjunct Faculty, Bastyr University, Seattle; Owner, Naturopathic Doctor, Harbor Integrative Medicine, Bellingham, WA

Dr. Pantuso reports no financial relationships relevant to this field of study.

SYNOPSIS: These researchers investigated the use of supplemental vitamin B6, folate, and B12 and the risk of lung cancer in 77,118 participants in the Vitamins and Lifestyle cohort, finding an increased risk of lung cancer in men, which was exacerbated by smoking.

SOURCE: 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;35:3440-3448.

Lung cancer is the leading cause of cancer deaths in both men and women each year in the United States, with an estimated 234,030 new cases expected to be diagnosed in 2018.¹ Smoking accounts for approximately 80% of lung cancer deaths. Lung cancer risk is higher in men than women and increases with age.² The results of previous studies investigating the association between B vitamin supplementation and lung cancer risk have been inconsistent.^3,4 In 2009, Ebbing et al published a study that demonstrated a 21% increased cancer incidence associated with the use of vitamin B12 and folate, which was driven mostly by increases in lung cancer.³ A recent meta-analysis found that B vitamin supplementation was associated with a lower risk of melanoma but not overall cancer incidence.⁵

In this observational study, the authors investigated the association between B vitamin supplementation and lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort, which included 77,118 men and women recruited between October 2000 and December 2002. Participants were considered eligible if they were 50-76 years of age at the time of recruitment/baseline and lived in a 13-county region in Western Washington State covered by the Surveillance, Epidemiology and End Results (SEER) registry. All incident cancer diagnoses in those 13 counties are reported to the SEER registry, with the exception of melanoma. Cohort participants were followed for incident lung cancer from baseline to Dec. 31, 2007, with a mean follow-up of six years. A total of 808 incident cases of lung cancer from the VITAL cohort were identified.

Participants with a prior medical history of an unknown lung cancer at baseline (n = 590), with lung cancer diagnosis that was noted only on the death certificate with no date of diagnosis (n = 8), and with lung lymphoma (n = 2) or in situ lung cancer (n = 1) were excluded from the study. The participants of the VITAL cohort self-reported their regular intake of multivitamins, individual B vitamin supplements, and mixtures such as B-complex over the 10 years before baseline.

To calculate the 10-year average daily doses for vitamin B6, folate, and vitamin B12, the authors summed the intakes from each of the multivitamin preparations, individual vitamin sources, and mixtures. Participants were categorized into five different groups based on their 10-year average daily doses for vitamin B6, folate, and vitamin B12. The groups included: 1) no use; 2) the first tertile among users; 3) more than the first tertile up to the amount of the nutrient that would be obtained from 10-year daily use of a common multivitamin formulation (Centrum Silver, Wyeth, Madison NJ); and two groups with more than the amount of that nutrient that would be obtained from 10-year daily use of that multivitamin. (See Tables 1 and 2.)

Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between supplemental B vitamins and lung cancer risk were calculated with multivariable adjusted Cox proportional hazards regression models. The study controlled for smoking, age, race, education, body mass index, alcohol consumption in the past year, history of chronic obstructive pulmonary disease, a personal history of cancer, number of first-degree relatives with a history of lung cancer, and use of nonsteroidal inflammatory drugs (NSAIDs). Cyclooxygenase-2 (COX-2) has been shown to be a factor in the progression of lung cancer, which NSAIDs are known to inhibit.⁶ Additional adjustments were performed to control for the use of combined hormonal therapy and duration in women.

The authors of this study were interested in the participants’ use of individual B vitamin supplementation and whether the participants previously had used vitamin B supplements, currently were using B vitamin supplements, and a 10-year use history, which all were calculated from baseline.

To investigate the risk of lung cancer and individual vitamin B supplements, the authors compared the men who previously had used individual vitamin B supplements to those in the non-use group. The authors found that there was an 84% increased risk of lung cancer in men who previously had used vitamin B6 as an individual supplement compared to the nonuse group (multivariable-adjusted HR, 1.84; 95% CI, 1.01-553.36). There also was a two-fold increased risk in men who formerly used B12 as an individual supplement compared with the nonuse group (HR, 2.42; 95% CI, 1.49-3.95).

The risk of lung cancer associated with current use of B6 and B12 at baseline was weaker (HR, 1.37; 95% CI, 1.03-1.84; HR, 1.22; 95% CI, 0.91-1.64 for vitamin B6 and B12, respectively).

However, when the authors compared the nonuse group to the 10-year average daily use groups, they found that men in the highest intake group had increased risk of lung cancer for both vitamin B6 (> 20 mg/day; HR, 1.82; 95% CI, 1.25-2.65) and vitamin B12 (> 55 mcg/day; HR,1.98; 95% CI, 1.32-2.97).

Among current male smokers, the increased risk of 10-year use of vitamin B6 and B12 was found to be even higher. In men who were in the 10-year vitamin B6 (> 20 mg/day) group, there was a near tripling of lung cancer risk (HR, 2.93; 95% CI, 1.50-5.72; P trend = 0.04). In the B12 (> 55 mcg/day) 10-year use group, there was an almost four-fold increased risk of lung cancer in current male smokers (HR, 3.71; 95% CI, 1.77-7.74; P trend < 0.01). These increases in the lung cancer risk in men with the highest 10-year supplemental B vitamin use were similar among histological subtypes of lung cancer. In addition, the study controlled for other confounding variables.

Although B vitamin supplement intake was higher among women than men (P < 0.001), women were found to have decreased dietary intake compared to men (P < 0.001). Although the total intake of B vitamins was lower in women compared to men (P < 0.001), participants exceeded the U.S. recommended daily allowance (RDA) for each B vitamin, on average. (See Tables 2 and 3.)

COMMENTARY

An estimated half of the U.S. population uses one or more dietary supplements. It is unclear whether B vitamin supplementation is necessary. Most Americans have adequate dietary intake of B vitamins, especially folate, as it is added to foods. In this study, the B6 vitamin daily dose of > 20 mg/day is greatly increased from the RDA of 1.3 mg/day in 19- to 50-year-old adult males; however, it is lower than the upper intake level of 100 mg/day.

In addition, the highest daily dose of B12 was 55 mcg/day contrasted with the RDA of B12, which is 2.4 mcg/day. The extremely high intakes in this study for both B6 and B12 may have the potential to alter DNA synthesis, DNA methylation, and repair, especially in precancerous and cancerous cells.

This study does not prove that B vitamins cause cancer, only that there is an association between high vitamin intake of B6 and B12 and increased lung cancer in men. The authors hypothesized that the finding that supplemental vitamin B6 and B12 increased the risk of lung cancer in men but not women may be a result of the effect of male hormones on the one carbon metabolism. Androgens such as testosterone bind to androgen receptors, which are known to alter one carbon metabolism and which may explain the increased risk of lung cancer in men taking B6 and B12 supplements. Smoking is a known risk factor for lung cancer, and combined with altered one carbon metabolism may explain the further increased risk.

The strengths of this study are the large number of participants in the VITAL cohort, the number of cases of incident lung cancer, and the baseline data collection. These characteristics help enforce the results because observational studies can follow a larger number of participants for a longer period than most randomized, controlled trials. Limitations of this study are the self-reporting of B vitamin intake, known to be inherently inaccurate, and the fact that the actual doses in the supplement may differ from label claims, affecting the quantity of vitamins ingested as calculated in this study. The authors also mentioned that they did not test for serum B-vitamin measurements, which further may have supported the self-reported B vitamin intake or demonstrated that true intake was less than the stated intake. In addition, the fortification of food with folic acid in the United States may have interfered with detecting any differences in lung cancer risk and folic acid supplementation.

The role of B vitamins in lung cancer risk is complicated and at this point is not fully understood. From this study, we learned that women tend to get more B vitamins from supplements than diet. This increased supplementation found in women may be the result of the recommendation that women of childbearing age supplement with folate. Although folate did not demonstrate an association with increased lung cancer risk, it may be due to higher background of folic acid intake from fortified foods and should not be interpreted as a reason to recommend high-dose folic acid.

Overall, these results corroborate some concerns surfacing with the use of vitamins above and beyond the RDA. For example, similar oncological concerns may exist with the ingestion of antioxidant supplements, such as vitamin A and beta-carotene in male smokers.^7,8 It makes one wonder about mechanisms that might overlap with the results of the study reviewed here.

Recommending a healthy diet, such as the Mediterranean dietary pattern, and a multivitamin is safe. Counseling patients who smoke about smoking cessation is the most important factor in preventing lung cancer. Also, counseling patients about the lack of safety and efficacy of individual supplemental B vitamins in the absence of documented deficiency is important, particularly in men who are currently smoking. B vitamin deficiencies are more common in certain populations. Individuals who follow a vegetarian or vegan diet may be at an elevated risk of B vitamin deficiencies if not consciously consuming B12-fortified foods. Individuals who have decreased gastrointestinal absorption of nutrients also should be evaluated for B vitamin deficiencies, including the elderly.

This study is quite convincing that B vitamin supplementation should be limited to individuals who are deficient and should not be a commonplace recommendation to current smokers.

REFERENCES

1. American Cancer Society. Key statistics for lung cancer. Available at: www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html. Accessed Jan.18, 2018.
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD. Available at: https://seer.cancer.gov/csr/1975_2014/. Based on November 2016 SEER data submission, posted to the SEER web site, April 2017.
3. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119-2126.
4. Gruber BM. B-group vitamins: Chemoprevention? Adv Clin Exp Med 2016;25:561-568.
5. Zhang SL, Chen TS, Ma CY, et al. Effect of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality: A PRISMA-compliant cumulative meta-analysis of randomized controlled trials. Medicine (Baltimore) 2016;95:e3485.
6. Liu R, Xu KP, Tan GS. Cyclooxygenase-2 inhibitors in lung cancer treatment: Bench to bed. Eur J Pharmacol 2015;769:127-133.
7. Schwingshackl L, Boeing H, Stelmach-Mardas M, et al. Dietary supplements and risk of cause-specific death, cardiovascular disease, and cancer: A systematic review and meta-analysis of primary prevention trials. Adv Nutr 2017;8:27-39.
8. Latino-Martel P, Cottet V, Druesne-Pecollo N, et al. Alcohol beverages, obesity, physical activity and other nutritional factors, and cancer risk: A review of the evidence. Crit Rev Oncol Hematol 2016;99:308-323.