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Cancer Chemotherapy and Pharmacology

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Open Access 01-01-2021 | Colorectal Cancer | Original Article

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

Authors: Helena Taflin, Elisabeth Odin, Göran Carlsson, Roger Tell, Bengt Gustavsson, Yvonne Wettergren

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2021

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

Available only for authorised users

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Title: 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
Authors: Helena Taflin
Elisabeth Odin
Göran Carlsson
Roger Tell
Bengt Gustavsson
Yvonne Wettergren
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04173-2

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