Abstract
PurposeThe 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.MethodsThirty-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.ResultsThe 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).ConclusionThe 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 registrationNCT02244632, first posted on ClinicalTrials.gov on September 19, 2014
Highlights
Colorectal cancer (CRC) is ranked as the third most common cancer worldwide, and in 2018, approximately 1.8 million people were diagnosed with the disease [1]
The results showed that more females than males needed to reduce the dose of chemotherapy during treatment (p = 0.013)
There was a negative correlation between the gastrointestinal toxicity score and age (r = −0.35, p = 0.044), no significant correlation was seen between total toxicity score or haematological toxicity score and age
Summary
Colorectal cancer (CRC) is ranked as the third most common cancer worldwide, and in 2018, approximately 1.8 million people were diagnosed with the disease [1]. Isofol Medical AB, Göteborg, Sweden treatment with curable intent for CRC is radical surgery, and for selected rectal tumors, surgery in combination with radiotherapy [2]. Chemotherapy is used in all settings, both neoadjuvant, with the intent of reducing the tumor burden and making the tumor resectable/less advanced; in the adjuvant setting after radical surgery to reduce the risk of recurrence; and in a pure palliative setting with the purpose of prolonging life [3, 4]. Novel combination treatments have been developed during the last years, 5-fluorouracil (5-FU) plus the folate leucovorin ([6R,S]-5-formyltetrahydrofolate) is still a cornerstone in treatment of CRC [5]. 5-FU is an analogue of uracil in which the hydrogen at position 5 is replaced by fluorine. Using the same mechanism to enter the cell as uracil, 5-FU is converted into the active metabolite fluorodeoxyuridine monophosphate (FdUMP), which forms an inhibitory ternary complex with
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