Folic acid may induce toxicities in capecitabine-treated CRC patients

The presence of folic acid in plasma and intake of folic acid supplements appear to contribute to chemotherapy-induced toxicities in patients treated with capecitabine for colorectal cancer (CRC), reports a recent study.

“This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment,” the investigators said.

Overall, 290 patients with stage II to III CRC being treated with capecitabine were identified from the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort.

Using questionnaires, the investigators assessed dietary and supplemental intake of folate and folic acid at diagnosis and during chemotherapy. They then determined plasma folate and folic acid levels using liquid chromatography tandem mass spectrometry.

Toxicities were characterized by toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Cox proportional hazards regression, adjusted for age and sex, was used to examine the associations of intake and biomarkers of folate and folic acid with toxicities.

More than half of the patients (n=153, 53 percent) had toxicities leading to modification of capecitabine treatment. [Am J Clin Nutr 2024;119:294-301]

Folate intake and plasma folate levels did not increase the risk of toxicities, but the use of folic acid-containing supplements during treatment (hazard ratio [HR], 1.81, 95 percent confidence interval (CI), 1.15‒2.85) and the presence of folic acid in plasma at diagnosis (HR, 2.09, 95 percent CI, 1.24‒3.52) and during treatment (HR, 2.31, 95 percent CI, 1.29‒4.13) correlated with increased toxicity risk.

Excessive intake

Folic acid is often detected because of the saturation of the enzyme dihydrofolate reductase, while high intake of folic acid is usually driven by taking supplements. As such, circulating folic acid may be used as a substitute for an overall higher folate status.

“Indeed, we observed higher folate levels in patients with versus those without plasma folic acid,” the investigators said. “We have now shown for the first time that folic acid, as a supplemental intake or circulating marker, is associated with risk of capecitabine-related toxicities.”

Capecitabine

The B-vitamin folate is essential in the mode of action of many anticancer medications, including fluoropyrimidines such as capecitabine and 5-fluorouracil (5-FU).

Capecitabine is an oral chemotherapeutic drug used for treating CRC. After conversion to 5-FU, capecitabine restrains the enzyme thymidylate synthase (TS), leading to disturbed nucleotide pools and damaging DNA synthesis and repair, which then results in antitumour effects. [Nat Clin Pract Oncol 2009;6:17-24; Clin Colorectal Cancer 2018;17:156-163; Pharmacogenomics 2005;6:673-689]

“Reduced folate species can contribute to the stability of a ternary complex formed with TS and active fluoropyrimidine drug metabolites, which could theoretically enhance the efficacy but also toxicity and, thus, side effects of treatment,” the investigators said. [Clin Therapeutics 2005;27:23-44; Nat Rev Cancer 2003;3:330-338]

“Results of this study may contribute to awareness on this topic for researchers and healthcare professionals and provide an evidence base for future studies on diet-drug interactions,” they noted.