Pretreatment Serum Folate Levels and Toxicity/Efficacy in Colorectal Cancer Patients Treated With 5-Fluorouracil and Folinic Acid

Abstract

Background5-Fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients. 5,10-Methylenetetrahydrofolate and 5-fluorodeoxyuridine monophosphate bind to thymidylate synthase and together inhibit its function, resulting in cytotoxicity. We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in the serum components of folate metabolism affecting intracellular 5,10-methylenetetrahydrofolate levels. Patients and MethodsA prospective cohort of chemotherapy-naive colorectal cancer patients scheduled to receive intravenous 5-FU and folinic acid for 5 consecutive days every 4 weeks in both adjuvant and palliative settings was studied. Pretreatment clinical and laboratory data were collected. Biochemical data associated with folate metabolism were also collected. The primary endpoint was the occurrence of grade ≥ 3 toxicity and/or toxicity mandating dose delay or reduction. ResultsFor the 78 eligible patients studied, multivariable analyses identified only a greater pretreatment serum folate level as an independent predictor of grade ≥ 3 toxicity and/or mandating schedule modification (P = .016). Comparing the patient cohorts among the folate quartile groups revealed increasing toxicity trends in the highest quartile with an odds ratio of 2.58 (P = .19) compared with the combined lower quartiles, and superior relapse-free and overall survival for patients treated in the adjuvant setting. Log-rank analysis showed a significant association between higher folate levels and relapse-free and overall survival. ConclusionThe pretreatment serum folate level did not conclusively influence 5-FU toxicity and antitumor efficacy. However, high folate levels showed a trend toward a greater incidence of severe toxicities but also lower rates of disease recurrence and mortality. These results provide promising hypothesis-generating data warranting further investigation. The predictive value of pretreatment folate status should be a priority for study in cancer patients receiving 5-FU–based chemotherapy and should be considered a potentially confounding factor in clinical trials and a modifiable parameter in treatment.