By Abdul Sattar Sohrani
Folic acid and vitamin B supplementation was associated with an increase in cancer incidence, cancer mortality, and all-cause mortality in a new analysis with long-term follow-up of data from 2 trials conducted in Norway, where there is no folic acid fortification of foods.
The results are reported in the November 18 issue of the Journal of the American Medical Association.
The authors, led , say that these results, although in need of confirmation, suggest that there is a need for “safety monitoring” because there is now widespread folic acid fortification of foods and increasing use of folic acid in dietary supplements.
However, the authors of an accompanying editorial points out that data from the United States, where there has been mandatory folic acid fortification of flour and other foods since 1998, have been showing a significant decrease in cancer incidence. “These national incidence rates do not support a substantial population-wide adverse effect of the magnitude suggested in the study,” write the editorialists, Bettina F. Drake, PhD, MPH, and Graham Colditz, MD, DrPH, both from the Washington University School of Medicine in St Louis, Missouri.
“The population data from the United States do not suggest that there is a problem,” Dr. Drake said in an interview with Medscape Oncology. She pointed out that folate supplementation used in the study resulted in much higher blood levels than would be seen after eating foods fortified with folic acid. In addition, the study was conducted in individuals with heart disease and was of limited duration.
The findings from this study “do not nullify the potential long-term benefits that folic acid fortification may have on population health,” Dr. Drake explained. The measure was introduced to reduce neural tube defects in newborns (which arise from folate deficiency during pregnancy). A reduction was seen within a “few years,” the editorialists note.
Concerns about a link between cancer and folic acid supplementation have been raised previously, most recently with regard to colorectal cancer, as reported by Medscape Oncology. At that time, leading expert on nutrition and cancer Walter Willet MD, DrPH, from the Harvard School of Public Health in Boston, Massachusetts, said: “I am certain that we are not causing an epidemic of colorectal cancer with folic acid fortification of flour.” He added that there was a small increase in the incidence of this cancer soon after fortification was introduced, but this coincided with an increase in colonoscopy, and he pointed out that mortality rates from this cancer have been declining steadily.
LATEST RESULTS FROM NORWAY
The latest results come from 2 trials conducted in 6837 patients with ischemic heart disease, in which half the participants took supplements of vitamin B (including folic acid) to lower homocysteine levels to see if this would reduce cardiovascular outcomes. It did not, and these results are in line with other large trials. At the same time, both trials showed — independently — an increase in cancer in the supplementation group, compared with the placebo group, but this was not statistically significant.
In these 2 trials, participants took supplements containing folic acid (0.8 mg/d), vitamin B12 (0.4 mg/d), and B6 (40 mg/d), or various combinations of these. This dose of folic acid is 4 to 6 times higher than the average dose delivered by the mandatory fortification in the United States, and is twice the recommended daily allowance, the authors note, although they add that it is below the tolerable upper intake level of 1 mg/d set by the US Institute of Medicine.
The current analysis pooled results from the 2 trials, which had a median participation of 39 months, and added data from an observational posttrial follow-up of 38 months, giving a total duration of around 5.5 years. The authors note that pooling the data from the 2 trials is “justified” because they were nearly identical.
This pooled analysis found a statistically significant increase in cancer incidence, cancer mortality, and all-cause mortality.
These results for cancer outcomes are not supported by other studies of homocysteine-lowering vitamin B trials, the authors note.
INCREASED INCIDENCE DRIVEN BY LUNG CANCER
The increase in cancer incidence and mortality was “mainly driven by an increase in lung cancer incidence,” the authors write. They also pointed out that 94% of the subjects who developed lung cancer were either current or former smokers.
So the “real headline of this study should be that smoking increases the risk of lung cancer,” according to the Council for Responsible Nutrition, which issued a statement about the study.
CANCER DECREASING SIGNIFICANTLY
In their editorial, Drs. Drake and Colditz write that these results indicate an excess of approximately 3.5 new cases of cancer per 1000 people per year, and 1 excess case of lung cancer per 1000 people per year. The excess deaths correspond to 1.7 cancer deaths per 1000 people per year.
“These numbers, if generalizable to the United States, would be substantial at the overall levels of total cancer incidence and mortality,” they write. In addition, an increase in lung cancer incidence would be expected.
“However, the rates of total cancer incidence decreased significantly from 2001 to 2005, and the lung cancer incidence has also declined significantly,” they point out.
Although the study suggests there is an association between folic acidsupplementation and an increase in cancer, the US population data suggest that there isn’t a problem with folic acid fortification of foods and cancer, Dr. Drake told Medscape Oncology. Folic acid fortification has been mandatory in the United States for more than 10 years and, given the results of this study, we would have expected a significant increase in the incidence of cancer by now, she suggested.
One of the issues with clinical trials is that observations are reported with a short time frame after the implementation of an intervention, the editorialists note. This can often lead to “looking for effects that fit the time frame,” they add. “By analogy, when keys are missing it is common to look for them under the lamppost where the light is, rather than in the murky location where the keys were more likely to have been dropped.”
CLINICAL CONTEXT
Folic acid, a B vitamin that plays a role in cell growth and repair, has been linked with possible cancer risk, as reported by Smith and colleagues in the March 2008 issue of the American Journal of Clinical Nutrition. In the February 20, 2005, issue of the International Journal of Cancer, Sanjoaquin and colleagues noted that folic acid intake was inversely associated with colorectal cancer risk.
In Norway, where foods are not fortified with folic acid, 2 randomized double-blind placebo-controlled studies on homocysteine-lowering treatment with folic acid and vitamin B12 in patients with ischemic heart disease found a nonsignificant increase in cancer incidence: the Norwegian Vitamin (NORVIT) trial reported by Bonaa and colleagues in the April 13, 2006, issue of the New England Journal of Medicine and the Western Norway B Vitamin Intervention Trial (WENBIT) reported by Ebbing and colleagues in the August 20, 2008, issue of the Journal of the American Medical Association.
This study combines data from the NORVIT and WENBIT studies with extended follow-up to assess whether vitamin B supplementation is linked with cancer incidence, cancer mortality, or all-cause mortality.
STUDY HIGHLIGHTS
• The study analyzed data for 6837 patients with ischemic heart disease from the NORVIT and WENBIT studies between 1998 and 2005.
• Both studies had similar patients, same study design and treatment, and similar follow-up; both studies were also conducted in the same laboratory.
• Exclusion criterion was active, but not cured, cancer.
• 1708 patients received daily folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg.
• 1703 patients received daily folic acid 0.8 mg plus vitamin B12 0.4 mg.
• 1705 patients received daily vitamin B6 40 mg.
• 1721 patients received placebo.
• Mean age was 62.3 years, and 23.5% of patients were women.
• Fewer current smokers were in the folic acid groups vs the non–folic acid groups (38% vs 41%; P = .01).
• 297 (4.3%) of patients had been registered with cancer before study entry.
• Prevalence of TT homozygotes of the MTHFR 677C>T polymorphism was 8.2%, comparable to general Norwegian population.
• Patients were asked to not take over-the-counter vitamin B–containing supplements.
• Data and blood specimens were collected at baseline, after 1 to 2 months, and at final study visit.
• Patients received treatment for a median of 39 months.
• Adherence, defined as taking at least 80% of the study medication, was 84.7%.
• 6261 subjects (91.6%) participated in posttrial extended follow-up of 39 months through December 31, 2007, for total follow-up of 78 months.
• The main outcome measures were cancer incidence, cancer mortality, and all-cause mortality.
• Nonmelanoma skin cancers were not included.
• Data were obtained from the Cancer Registry of Norway and Cause of Death Registry at Statistics Norway.
• Folic acid groups showed increase in median serum folate levels from 3.9 to 27.5 ng/mL and an increase in serum cobalamin levels from 477 to 761 pg/mL.
• Vitamin B6 groups showed an increase in median plasma pyridoxal 5′ phosphate from 8.2 to 75.4 ng/mL.
• Median serum folate concentration for TT genotype of MTHFR 677C>T polymorphism subjects vs CC or CT genotype subjects was 17.7% lower at baseline, 11.7% lower in folic acid groups during study treatment, and 10.4% lower in the non–folic acid groups during study treatment.
• Cancer was diagnosed in 341 patients (10.0%) in the folic acid plus vitamin B12 group vs 288 (8.4%) in the non–folic acid groups (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03 – 1.41; P = .02).
• Basis for cancer diagnosis was histologic study in 90.5%, cytologic examination in 4.9%, and other examination in 4.1%.
• Cancer mortality occurred in 136 patients (4.0%) in the folic acid plus vitamin B12 groups vs 100 (2.9%) in the non–folic acid groups (HR, 1.38; 95% CI, 1.07 – 1.79; P = .01).
• All-cause mortality occurred in 548 patients (16.1%) in the folic acid plus vitamin B12 groups vs 473 (13.8%) in the non–folic acid groups (HR, 1.18; 95% CI, 1.04 – 1.33; P = .01).
• Total cancer incidence was similar in study vs general Norwegian population, except lung cancer incidence was 25% higher in study vs general population (HR, 1.25; 95% CI, 1.01 – 1.53).
• Lung cancer was more common in folic acid vs non–folic acid groups (56 vs 36 patients; HR, 1.59; 95% CI, 0.92 – 2.75).
• Of 236 cancer deaths, 75 were the result of lung cancer.
• Vitamin B6 was not linked with any effects on cancer incidence, cancer mortality, or all-cause mortality.
• Adjustment for age, sex, smoking status, and acetylsalicylic acid use did not significantly affect results.
• Study limitations included lack of data on family history of cancer, occupational or environmental exposures, and vitamin B supplement use during posttrial follow-up; in addition, all patients in the folic acid groups also received vitamin B12.
CLINICAL IMPLICATIONS
• In patients with ischemic heart disease, supplementation with folic acid plus vitamin B12, but not vitamin B6, is linked with increased cancer incidence, especially lung cancer, and cancer mortality rates.
• In patients with ischemic heart disease, supplementation with folic acid plus vitamin B12, but not vitamin B6, is linked with increased all-cause mortality rates.