Health Professionals:

Research on Folic Acid

The relationship between folate and colon cancer and precancerous colorectal adenomas has been investigated in epidemiologic studies and randomized controlled trials.

In a study of two large cohorts (Nurses' Health Study and the Health Professionals Follow-up Study), highest folate intake (>700 micrograms/day) from diet and supplements was associated with a 30-40% decreased risk for colorectal adenomas compared to lower intakes (166-241 micrograms/day for women and men, respectively) (Giovannucci et al. 1993). In a large cohort of women, total folate intakes ≥ 400 micrograms/day was associated with a 30% reduced risk for colon cancer compared to folate intake < 200 micrograms/day (Giovannucci et al. 1998). In this study, a high percentage of women in the highest folate intake group were taking multivitamins.

An evaluation based on duration of vitamin use reported a 75% reduced risk for colon cancer in women who had used a multivitamin for at least 15 years, while there was no benefit in women taking multivitamins for shorter periods of time. A prospective study of the Swedish Mammography Cohort reported approximately a 30% reduced risk of colon cancer in women with each 100 microgram/day increase in dietary folate above 130 micrograms/day (Larsson et al. 2005). The significant results persisted even when controlling for fruit and vegetable intake and use of vitamin supplements.

The potential benefits of folic acid with regard to colon cancer risk may be especially dramatic in those with a family history of colon cancer (Fuchs et al. 2002).

The effects of folic acid on recurrence of colorectal adenomas has been investigated in several randomized controlled trials.
Cole and colleagues (Cole et al. 2007) evaluated the effect of 1 mg/day folic acid or placebo on adenoma recurrence in over 1,000 men and women with a recent history of adenomas using a double-blind randomized placebo-controlled study design. Folic acid did not reduce adenoma risk in study subjects who had previously been diagnosed with adenoma and of concern was an observed trend for an increased risk for recurrence of adenoma with folic acid use.

In 2008, a double-blind, placebo controlled trial with 94 patients with adenomatous polyps examined whether folic acid supplementation would reduce the recurrence of colorectal adenomas. Patients received either a daily 5 milligram dose of folic acid or a placebo for 3 years. The mean number of recurrent polyps at 3 years was 0.36 for folic acid treated patients compared to 0.82 for placebo treated. The authors concluded that folic acid may be an effective chemopreventive agent for colorectal neoplasia (Jaszewksi et al. 2008).

A study including participants from two large prospective cohort studies investigated the effect of folic acid (1 milligram/day for 3-6 years) on recurrent colorectal adenoma. The results from this study did not support an overall protective effect of folic acid supplementation on adenoma recurrence, but found that folic acid supplementation may be beneficial among those with lower folate concentrations at baseline (Wu et al. 2009). These differences in study results may be due to the dose of folic acid given, duration of supplementation, or disease state.

A report from researchers from Tuft’s University and the University of Aberdeen (United Kingdom) noted an increase in the number of colorectal cancer cases in the US and Canada coinciding with the introduction of folic acid fortification of cereal grains (Mason et al. 2007). The authors hypothesized that the increased rates could be a result of folic acid fortification. The increase was surprising because it followed a steady, downward trend in colorectal cancer rates observed in both countries since 1985 and could not be accounted for by an increase in screening rates or other factors. Since the post-fortification increase, the downward trend in colorectal cancer cases has resumed.

It is postulated that folate assumes different guises depending on the circumstances, and folic acid fortification has been termed a “double-edged sword” by some (Lucock and Yates 2009). This apparent dual effect role of folate caused pause among researchers and others who are trying to establish guidelines for folate intake or fortification programs, or evaluate fortification efforts.

The consensus from over 30 case-control and prospective cohort studies indicate that habitual intake of the greatest quantities of dietary folate are associated with a 40-60% reduction in the risk of developing a precursor lesion for colorectal cancer. However, there is evidence that for individuals who have existing neoplastic lesions and who have higher intakes of the vitamin, folate may be associated with a greater risk for tumorigenesis (Mason 2009). Newer research continues to be inconsistent.

The results from two meta-analyses and two prospective cohort studies suggest that higher folate intake is associated with lower colorectal (CRC) risk (initiation or early development) (Sanjoaquin et al 2005; Kim et al. 2010, Lee et al. 2011; Stevens et al. 2011). A meta-analysis comparing folic acid supplementation to placebo in more than 35,000 participants, reported no increase in cancer incidence or mortality among the supplement group (Clarke et al. 2010).

For those with a history of colorectal adenomas (CRA), the results of three intervention trials reported mixed results, with one study reporting a higher risk for CRA and advanced lesions in the folic acid group 6 to 8 years after treatment (Cole et al 2007); one study detecting no effect of folic acid on CRA recurrence (Logan et al2008); and a third showing no overall protective effect on recurrence unless folate status was low (<7.5 ng/ml). These studies suggest that in individuals with a history of CRC/CRA, the impact of folic acid is unclear.

A meta-analysis examined 3 trials conducted in North America, the UK and Europe. All of the studies had at least 945 patients and a range of folate supplementation from 0.5 to 2.5 milligrams/day. Follow-up for the studies were conducted over 3 to 5 years. Results indicated that the risk of an adenomatous lesion among patients receiving folic acid supplementation was not increased for less than 3 years of follow-up. However, in relation to longer follow-up, results indicate that the risk of adenomatous lesions may be significantly increased (30%) with folate supplementation. This study supports the hypothesis that folate may possess a dual effect on colorectal carcinogenesis depending on the timing and dose of folic acid supplementation (Fife et al. 2010).

A systematic review and meta-analysis were conducted that included 27 studies, both case control and cohort studies, conducted in 11 countries with follow-up ranging from 5.3 to 22 years. The results indicated that there was an inverse relationship between folate intake and CRC incidence (a 15%-18% protective effect with high intakes in case control or cohort studies) (Kennedy et al. 2011).

A large prospective cohort study in the U.S. looked at the association between folate intake and CRC risk pre- and post-fortification (8.5 years post-fortification). The cohort consisted of 525,488 individuals from the NIH-AARP Diet and Health Study. Results indicated an inverse relationship between dietary folate intake and CRC risk in both pre- and post-fortification periods.
Those taking a folic acid supplement dose of 400 micrograms/day (equivalent to the amount in most multivitamins) in the post-fortification period had a modestly reduced risk (9%) compared to those not taking supplements. Researchers observed a 30% risk reduction with the highest folate intake compared to the lowest folate intake for the post-fortification phase. The researchers acknowledged that an 8.5 year follow-up may not be sufficient to observe development of CRC, as other studies have indicated that at least a 10 year follow-up may be needed (Gibson et al. 2011).

A meta-analysis of data from more than 50,000 individuals who participated in randomized trials reported that there was no significant effect of folic acid on the incidence of several types of cancer, including CRC (Vollset et al. 2013). This analysis included 13 trials that met the inclusion criteria of comparing folic acid to a placebo, lasted at least one year, and included at least 500 participants. The trials included in this meta-analysis used folic acid doses ranging from 500 micrograms to 40 milligrams/day, with a median intake of 2.0 milligrams/day.

A meta-analysis of cohort studies reported a significant 12% risk reduction for CRC when comparing highest versus lowest folate intake (Liu et al. 2015). A 2015 meta-analysis of 8 randomized trials concerning folic acid supplementation and CRC risk reported no association in the total population or in various subgroups based on gender, ethnicity, and body mass index (Qin et al. 2015). A meta-analysis evaluating circulating folate concentrations and CRC risk (8 publications) reported a null association (Chuang et al. 2013).

Although the possibility exists that folic acid supplementation could be associated with an increased risk for CRC as supported by some research studies, these recent meta-analyses seem to suggest otherwise. Regardless, the question of whether higher consumption of folic acid at levels typically achievable through the intake of supplements and fortified foods results in the acceleration of carcinogenesis remains a highly controversial topic (Kim 2008, Mason 2009, Mason and Tang 2017). Consequently, folic acid supplementation or use of other supplements is not recommended as a chemopreventive measure against colorectal or other cancers especially if nutrient needs are being met through dietary intake (Kim 2008, Ulrich 2008).

Clinicians should be sure to inquire about the use of supplements among cancer patients, especially those who may be taking folic acid at amounts higher than daily recommendations. In terms of dietary folate, epidemiological studies are strongly supportive of a protective effect against CRC, so adequate intake of folate from folate rich foods should be encouraged. Use of supplements of any kind may not be warranted especially when the diet is already supplying adequate nutrients, including folate (Ulrich 2008). In addition, individuals who are at higher risk for colorectal cancer or adenomas because of their age, family history, or previous diagnosis of adenomas or colorectal cancer, should consult their doctor to discuss having regular screenings for detection of adenomas, which can reduce their chance of developing colorectal cancer.

Top