Do Leucopenia Rates Change After Widespread Folic Acid Fortification in Randomized Controlled Trials of Breast Cancer Chemotherapy?

Folate is an essential nutrient functioning in a variety of one-carbon transfer reactions, is necessary for red blood cell formation and growth, and deficiency is known to cause megaloblastic anemia. The role of folate in prevention of neural tube defects has been the driving force in public health measures leading to large-scale food fortification in the United States starting in 1996. It is not known if folate fortification has an impact on hematologic toxicities of patients undergoing chemotherapy. The goal of this study is to compare rates of leucopenia reported in pre and post folic acid fortification randomized clinical trials of Adriamycin and Cyclophosphamide (AC) chemotherapy in breast cancer.

Randomized trials of breast cancer chemotherapy with AC conducted in the United States were searched for in the Medline database, bibliographies, and using Google Scholar. Studies were included if AC was used alone in any arm of study, at standard dosing. Only studies that included disease free survival (DFS), overall survival (OS), and rates of grade III/IV leucopenia for the AC group were included. Studies were eliminated if they included patients with known metastatic disease, “dose dense” or nonstandard AC regimens, or included growth factor support. Rates of phase III/IV leucopenia were grouped in pre and post 1996 folate fortification groups, and meta-analyzed in a random effects model using MIX, a comprehensive free software for meta-analysis of causal research data.

Seven studies involving 14,386 patients were identified using the defined search methodology. There was no significant difference in phase III/IV leucopenia rates between prefolate (4.36% 95%CI 2.31-6.42%) and postfolate studies (7.07% 95%CI 5.41-8.73%).

This review disclosed no statistically significant difference in the rates of leucopenia in patients given AC for breast cancer before or after 1996. Postfolate studies did have 46% more leucopenia than those prior to folate fortification. The confidence intervals of the leucopenia rates overlapped but approached significance. This is contradictory to our theory that increased dietary folate might mitigate hematologic toxicities of chemotherapy. Further studies using individual patient data from institutions administering AC pre and post fortification would further elucidate the role of dietary folate in hematologic toxicities.

No relevant conflicts of interest to declare.