Comparison of a Thymine Challenge Test and Endogenous Uracil-dihydrouracil Levels for Assessment of Fluoropyrimidine Toxicity Risk

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2021 Mar 9

PMID 33687515

Authors

Kathryn E Burns

Ottiniel Chavani

Soo Hee Jeong

John A Duley

David Porter

Michael Findlay

R Matthew Strother

Nuala A Helsby

Affiliations

Soon will be listed here.

Abstract

Purpose: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity.

Methods: Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC-MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases.

Results: There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), U p = 0.0004; U/DHU p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%).

Conclusions: The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

Citing Articles

Thymine as potential biomarker to predict 5-FU systemic exposure in patients with gastro-intestinal cancer: a prospective pharmacokinetic study (FUUT-trial).

Hanrath M, Banken E, van den Wildenberg S, van de Kerkhof D, Moes D, Boisdron-Celle M Cancer Chemother Pharmacol. 2025; 95(1):34.

PMID: 39955449 PMC: 11829899. DOI: 10.1007/s00280-025-04759-8.

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