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

Cancer Chemother Pharmacol. 2021 Jan;87(1):31-41. doi: 10.1007/s00280-020-04173-2. Epub 2020 Oct 24.

Abstract

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.

Keywords: 5-Fluorouracil; Folate; Gastrointestinal toxicity; Gender; Haematological toxicity; Metastatic.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Biomarkers / blood
  • Chromatography, Liquid
  • Colorectal Neoplasms / drug therapy*
  • Deoxyuridine / blood*
  • Dose-Response Relationship, Drug
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Male
  • Middle Aged
  • Sex Factors
  • Tandem Mass Spectrometry
  • Tetrahydrofolates

Substances

  • Biomarkers
  • Tetrahydrofolates
  • 5,10-methylenetetrahydrofolic acid
  • Fluorouracil
  • Deoxyuridine

Associated data

  • ClinicalTrials.gov/NCT02244632