Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study

Dieuwertje E. Kok*, Fränzel J.B. van Duijnhoven, Floor J.E. Lubberman, Jill A. McKay, Anne-Sophie van Lanen, Renate M. Winkels, Evertine Wesselink, Henk K. van Halteren, Johannes H.W. de Wilt, Cornelia M. Ulrich, Arve Ulvik, Per M. Ueland, Ellen Kampman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. Objective: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. Methods: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. Results: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. Conclusions: 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. Clinical trial details: This trial was registered at as NCT03191110.

Original languageEnglish
Pages (from-to)294-301
JournalAmerican Journal of Clinical Nutrition
Issue number2
Early online date7 Dec 2023
Publication statusPublished - Feb 2024


  • biomarker
  • capecitabine
  • chemotherapy
  • colorectal cancer
  • diet
  • dietary supplements
  • folate
  • folic acid
  • toxicity


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