expert opinion

Folic Acid and the Risk of Prostate Cancer ─ A Comment on the Results from a Randomized Clinical Trial

March 1, 2009

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Prof. Dr. med. vet. K. Pietrzik, Institute for Nutrition and Food Sciences Dept. of Nutritional Pathophysiology, Rheinische Friedrich-Wilhelms-University Bonn, Germany

“On March 10, 2009, a summary of a study was published which reports a higher incidence of prostate cancer after several years’ (up to 10.8 years, median 7 years) intake of vitamin B9 (folic acid) (1). This was a follow-up to the Aspirin/Folate Polyp Prevention Study (AFPP) (2). The primary goal of the AFPP study was to determine whether the risk of colon polyps could be reduced by giving aspirin or folic acid. This study had already been published in 2007 and indicated that giving folic acid resulted in a trend toward a higher rate of colon polyps; an increased risk of prostate cancer was also reported. The present publication reports on the findings of a secondary analysis which specifically evaluated the impact of folic acid supplementation (1 mg/day), as compared to placebo administration, on prostate cancer. According to this analysis, 25 out of 327 subjects in the group given folic acid (9.7%) developed prostate carcinoma, while only 9 out of 316 subjects in the placebo group (3.3%) developed the condition.

This result is in clear contradiction to all previously published observations, according to which a good long-term folate status reduces the risk of cancer. Paradoxically this is also the finding of the authors of this newly published study. According to the study those subjects with good baseline levels of folate who did not receive extra folic acid are at considerably less risk of developing prostate cancer than those with a poor baseline folate status. The authors emphasize that the risk of cancer is more likely to rise when folic acid is given in the form of synthetic supplements. They discuss the difference in bioavailability and metabolization of the different folate forms and surmise that possible differences between natural dietary folates (preferably 5-methyl-tetrahydrofolate) and synthetic folic acid (pteroyl-monoglutamate) are responsible for this. The possibility cannot be excluded that consumption of folic acid at Tolerable Upper Intake Levels (UL=1 mg, the daily dose given here) over several years might result in folic acid, including unmetabolized folic acid, circulating continuously in the body and possibly affecting metabolic pathways which could lead to cancer. However, the result of the study does keep the option open that lower dosages, e.g., within the recommended range (200 μg folic acid/day), could actually have positive effects.

Finally, even the authors of the study find it unclear why dietary and plasma levels among non-multivitamin users may be inversely associated with risk. This is why they also discuss the possible limitations of their study, pointing out that this is a secondary analysis which has nothing to do with the primary goal of the study. One criticism is that no screening in the form of rectal examination was undertaken for prostate enlargements already present at the start of the study (in contrast to the prostate cancer analysis, the original AFPP study used colonoscopy to screen for the incidence of adenoma at the start of the study). If there was indeed a variance in the distribution of prostate tumors present at the start of the study the result would have to be re-evaluated accordingly. Without more specific details on this point, however, it is impossible to do this retrospectively.

Furthermore, the authors point out that the estimates of risk may not be precise given the small number of prostate cancers observed (see above). Although these limitations were discussed frankly by the authors of the publication as well as by the journal’s publishers, readers of recent reports in the media (Deutsche Ärzteblatt of 12 March 2009 "Folsäure erhöht Prostatakarzinomrisiko” [Folic Acid Increases Risk of Prostate Carcinoma], Hamburger Abendblatt of 14March, 2009 “Vorsicht bei Folsäurepräparaten” [Beware of Folic Acid Preparations], Ärzte Zeitung of 16 March 2009 “Mit Folsäure mehr Prostatakarzinome” [More Prostate Carcinomas with Folic Acid]) learn nothing of the reservations the authors of the study have about their own results.

The critical reader will also note that trial subjects given folic acid supplements had significantly lower levels of vitamin B12 than the people in the placebo group. Since vitamin B12 together with folic acid guarantees the adequate production of methionine and it is activated methionine in the form of S-adenosyl methionine (SAM) that is responsible for a number of methylation processes, it might be debated whether the significantly lower vitamin B12 levels in the group given folic acid supplementation may have resulted in increased hypomethylation, which could in turn have increased the incidence of cancer. The difference in vitamin B12 status in the groups was not, however, discussed in more detail by the authors.

The design of the study cannot be described as first rate (secondary analysis without proper preliminary rectal examination to find pre-existing prostate enlargements or biochemical risk assessment using prostate-specific antigen). Further research into possible differences between natural dietary folates and synthetic folic acid should be undertaken so that speculation can make way for facts. This publication challenges scientists to continue to explore and report on the complex role of folates in relation to risk reduction or risk increase and to follow up the subject critically.

However, it is indisputable that folic acid/folate has a recognized preventive effect with regard to the reduction of neural tube defects in newborns and that good folate levels can reduce not only the risk of developing cancer but also the risk of strokes and neurodegenerative diseases.

Conclusion

  • The study has basic flaws in its design – this could mean that the results are simply chance findings.
  • There is no explanation for the observation that a good intake of folate reduces the risk of developing prostate cancer, notwithstanding the phenomenon that the cancer risk increases when folic acid is given. Given the dearth of facts, the discussion about the possibly different effects of dietary folates and natural folic acid must remain speculative. The