Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

• Published in: Cancer chemotherapy and pharmacology 2021-01, Vol.87 (1), p.31-41
• Main Authors: Taflin, Helena, Odin, Elisabeth, Carlsson, Göran, Tell, Roger, Gustavsson, Bengt, Wettergren, Yvonne
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; age; association; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer Research; Chemotherapy; Colorectal cancer; Colorectal carcinoma; dihydrouracil levels; fluorouracil; Folate; Gastrointestinal toxicity; Gender; Haematological toxicity; Hematology; leucovorin; Markers; Medicine; Medicine & Public Health; Metastases; Metastasis; Metastatic; Oncology; Original; Original Article; Patients; Pharmacology & Pharmacy; Pharmacology/Toxicology; Plasma; pretherapeutic uracil; sex; Thymidylate synthase; Toxicity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-020-04173-2

Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores ( p  = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males ( p  = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity ( p  = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity ( p  = 0.026). Haematological toxicity was predicted by gender and age ( p  = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response ( p  = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014