Comments on Folic Acid and Cancer Incidence and Mortality in Relation to the “Simplified Treatment Approach” for Lifting the Methylation Cycle Block in Chronic Fatigue Syndrome By Rich Van Konynenburg, Ph.D. November 24, 2009 Introduction A recent paper published in the Journal of the American Medical Association reported on clinical trials conducted in Norway in which vitamin B12 and folic acid were given as supplements, and rates of cancer incidence and mortality were measured. The abstract of this paper is as follows: JAMA. 2009 Nov 18;302(19):2119-2126. Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. Department of Heart Disease, Haukeland University Hospital, Jonas Liesvei 65, Bergen, Norway 5021. firstname.lastname@example.org. 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 B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) 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 B(12) 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 B(12) 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 B(12) 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 B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION: Treatment with folic acid plus vitamin B(12) 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. PMID: 19920236 [PubMed - as supplied by publisher] As reported in this abstract, the study found that there were higher rates of cancer incidence and mortality, as well as mortality from all causes, in the patients who were given the vitamin B12 and folic acid treatment, and the study also found that increased incidence of lung cancer dominated the results. In addition, the complete paper states that “the observed associations between the primary end points and vitamin concentration measured during study treatment were confined to serum folate, suggesting that the adverse effects were mediated by folic acid.” In addition to this paper, there have been several other studies of folic acid or total folate consumption in relation to cancer in recent years. Because the “Simplified Treatment Approach” for treating chronic fatigue syndrome includes a form of vitamin B12 together with folates as its main components, it is important to consider whether this treatment, while offering benefits for those suffering from chronic fatigue syndrome, could also be producing greater risks of cancer incidence and mortality. This article therefore explores the issues involved. Discussion of the patient population in the paper by Ebbing et al. It is important first to consider the characteristics of the patient population that participated in the clinical trials that were reported, and to compare these characteristics to those of the chronic fatigue syndrome population. The patients in these clinical trials all had ischemic heart disease. Nearly half of them had had a heart attack, and most of the rest had chronic angina. The average age was between 62 and 63 years. Over three-quarters of the patients were male. More than 80% were taking lipid-lowering drugs and beta blockers. About 40% were currently smokers. Over one-third had high blood pressure. About one-sixth were obese. More than one tenth had diabetes mellitus. For comparison, ischemic heart disease is not often reported in CFS, at least in the U. S., though decreased stroke volume and cardiac output (Peckerman et al., 2003) found to be due to diastolic dysfunction of the heart (Cheney and Lucki, 2007) is apparently fairly common. The average age of PWCs is probably somewhat lower than the average in this study. In the epidemiological study by Jason et al. (1999), the highest prevalence of CFS was in the age range 40 to 49, and it was least prevalent in those 60 years old or older. The majority of PWCs are female. Beta blockers have been advocated for use in PWCs, but lipid-lowering drugs generally have not. (It should be noted that statin drugs block HMG CoA reductase, which is upstream of Coenzyme Q-10, which is already deficient in many cases of CFS.) A Dutch study (Goedendorp et al., 2009) found that 23% of 247 patients studied were smokers. A study of 233 female fibromyalgia patients (Yunus et al., 2002) found that 21.9% were smokers. Hypotension is much more common than hypertension in CFS (Newton et al., 2009). Obesity is fairly common in CFS (Vollmer-Conna et al., 2006). Diabetes mellitus is an exclusionary diagnosis for CFS, and hypoglycemia, rather than elevated blood sugar, is commonly observed. This comparison shows that the population studied by Ebbing et al. has several features that are different from those of the CFS population, including some that would tend to make these patients more susceptible to cancer and other causes of death. This raises questions about the applicability of the results of this study to CFS. A study of causes of death in CFS (Jason et al.,2006) found that cancer was one of the three most prevalent ones in the 166 PWCs they studied, and that the mean age at death of those who died from cancer was 47.8 years. Recent work on a cohort of CFS patients in Nevada (Mikovits, 2009) has found that an unusual form of lymphoma appears to have a relatively high prevalence in this group. Although high quality epidemiological studies with low uncertainties are lacking, these preliminary studies suggest that PWCs may be more vulnerable to developing cancer unless they can be cured of CFS. More work needs to be done on the epidemiology, but even moreso, on finding a cure. Discussion of the treatment used in the Ebbing et al. study The treatment given in the clinical trials described in this study was oral folic acid at 800 micrograms per day, together with oral cyanocobalamin at 400 micrograms per day. The patients were treated for a median time of 39 months, and were then followed up for an additional median time of 38 months. It is apparently not known whether they continued to take supplements during the additional followup period. The median level of total folates reached in the blood serum was 62.3 nmol/L. The fraction of this that was folic acid was not measured. For comparison, the Simplified Treatment Approach at the suggested dosages includes about 100 mcg/day of oral folic acid, 67 mcg/day of oral folinic acid, and 267 mcg/day of oral 5-methyl tetrahydrofolate. It also includes 2,000 mcg/day of sublingual hydroxocobalamin. In a clinical study of this treatment, the mean total plasma folate level after six months was 55.7 nmol/L, and the folic acid part of this was 27.7 nmol/L. It should be noted that many PWCs have reported that they use smaller dosages than those suggested. Discussion of folic acid The Ebbing et al. study found that the elevated risk of cancer was associated with supplementing folic acid. The naturally occurring chemically reduced forms of folate (folinic acid and 5-methyl THF) were not used as treatments in the trials they described. Folic acid is the oxidized form of folate. It does not occur significantly in natural foods. It is used as the common commercial supplement form of folate because it is easier to synthesize and has a longer shelf life, and is therefore lower in cost. When taken into the body as a supplement, it must be chemically reduced by the enzyme dihydrofolate reductase (DHFR) by two successive reactions in order to be used in the metabolism. The range in activity of DHFR for the initial reaction with folic acid is almost a factor of five among different people, because of genetic polymorphisms (Bailey and Ayling, 2009). People with a low DHFR activity due to the 19-base pair deletion polymorphism have a higher folic acid level in their blood for the same folic acid dosage (Kalmbach et al., 2008), and may therefore be more vulnerable to any deleterious effects of folic acid. Women who have this polymorphism and take multivitamin supplements (which contain folic acid) may be at elevated risk for developing breast cancer (Xu et al., 2007). Another recent study (Troen et al., 2006) found that unmetabolized folic acid in blood plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. Since one of the roles of natural killer cells is to kill cancer cells, this may explain an association between elevated folic acid and cancer risk. Another possible link between folic acid and cancer (which would apply to all forms of folate, not only folic acid) is that reduced folate, which is produced from folic acid in the body, is essential for the synthesis of DNA and RNA, and cancer presents a particular demand for these because of its more rapid proliferation of new cells than normal tissues. It is relevant to note that for this reason, some cancer chemotherapy agents (such as methotrexate) are designed to interfere with the folate metabolism. Discussion of other studies involving folate and cancer According to Ebbing et al., “Most epidemiological studies have found inverse associations between folate intake and risk of colorectal cancer. For example (Sanjoaquin et al, 2005), “In cohort studies, the association between folate consumption and colorectal cancer risk was stronger for dietary folate (folate from foods alone; relative risk for high vs. low intake = 0.75; 95% CI = 0.64-0.89) than for total folate (folate from foods and supplements; relative risk for high vs. low intake = 0.95; 95% CI = 0.81-1.11).” This suggests that the naturally occurring folate forms may be more beneficial in preventing colorectal cancer than is folic acid, the dominant supplemental form. According to Y.I. Kim (2007), “Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on the progression of established colorectal neoplasms. In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa.” Studies of the effect of folate intake on the risk of other types of cancer (including lung cancer) have shown no association or have had inconsistent results (Cho et al., 2006; Slatore et al., 2008; Stevens et al., 2006; Larsson et al., 2007; Stolzenberg-Solomon et al., 2006; and Maruti et al., 2009). Conclusions The conflicting results between the Ebbing et al. study and the other studies that have been done concerning the relationship of folic acid and natural forms of folate to cancer risk suggest that more study needs to be done in order to reach conclusions. In particular, possible differences between the effects of folic acid and natural, chemically reduced forms of folate should be explored. In the meantime, it does not appear that the results of the Ebbing et al. study are directly applicable to the treatment of chronic fatigue syndrome using the Simplified Treatment Approach, because of the differing characteristics of the populations involved and the differences between the treatments. Although there are some indications that the reduced forms of folate are less likely to present an increased risk of cancer than is folic acid for the same folate dosage, there is not yet enough evidence to reach this conclusion.