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

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

Helena Taflin  1 , Elisabeth Odin  1 , Göran Carlsson  1 , Roger Tell  2 , Bengt Gustavsson  1 , Yvonne Wettergren  3
Affiliations
Clinical Trial

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

Helena Taflin et al. Cancer Chemother Pharmacol. 2021 Jan.

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.

PubMed Disclaimer

Conflict of interest statement

RT is an employee of Isofol. BG and EO are stockholders of Isofol. BG and HT are immediate family members. Other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Thymidylate synthase (TS) inhibitory effect on the pathway of thymidine nucleotides. Ternary complex formation with 5-fluorodeoxyuridine monophosphate (FdUMP) blocks the binding of deoxyuridine monophosphate (dUMP) to TS. Dephosphorylation of dUMP to deoxyuridine (dUr) leads to subsequent efflux of dUr into the blood circulation. 5-FU, 5-fluorouracil; dTMP, deoxythymidine monophosphate; FdUr, 5-fluorodeoxyuridine; THF, tetrahydrofolate
Fig. 2
Fig. 2
Comparison of the toxicity scores of female and male patients. As shown, females had higher toxicity scores than males. The scores were significantly different for total toxicity (p = 0.0004) and haematological toxicity (p = 0.0089), but not for gastrointestinal toxicity (p = 0.14). Mean values and standard deviations (within parenthesis) are presented to the right of each plot, and confidence intervals are shown as blue- and red-shaded areas. Each dot represents one patient
Fig. 3
Fig. 3
Mean dUr levels at C1-24 h and C4-24 h by arfolitixorin dose. As shown, the dUr C1-24 h levels increased by increasing arfolitixorin dose (p = 0.023). At C4-24 h, the plasma dUr level was higher in patients receiving 120, compared to 30 and 60 mg/m2 arfolitixorin but the difference did not reach significance (p = 0.31). Mean values and standard deviations (within parenthesis) are presented to the right of each plot, and confidence intervals are shown as blue- and red-shaded areas. Each dot represents one patient
Fig. 4
Fig. 4
Changes in plasma dUr levels over time in individual patients (n = 21) with mCRC, where samples were available at four time points (C1-0 h, C1-24 h, C4-0 h, C4-24 h). Patients were divided into groups based on the dUr alteration patterns. The arfolitixorin dose (mg/m2), gender (M or F), age (years), haematological toxicity score (0–12), clinical response (PR, SD, or PD), treatment line (1 or 2), and cytotoxic drugs [5-FU (FU), 5-FU/oxaliplatin (FU/OX), or 5-FU/irinotecan (FU/IR)] of each patient are presented in tables below the graphs. a Three patients increased the dUr levels at each time point. b Seven patients had a higher dUr level at C4-24 h compared to C1-24 h. c Five patients had a lower dUr level at C4-24 h compared to C1-24 h. d Six patients had a higher dUr value at C4-24 h compared to C1-24 h, but the dUr level was low over the entire range. It is striking that 9 out of 10 patients with haematological toxicity had PR, whereas 9 out of 11 patients without haematological toxicity had SD/PD
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