Abstract
BackgroundIrinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group.Methods/DesignThis trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups.DiscussionPatients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice.Trial registrationNCT02256800. Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015
Highlights
Irinotecan is approved and widely administered to metastatic colorectal cancer patients; it can cause severe toxicities including neutropenia and diarrhea
Our previous retrospective study showed that the clinical response rate of patients with metastatic colorectal cancer (mCRC) treated with chemotherapy of 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) plus bevacizumab under uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping and irinotecan dose escalation was significantly higher than that of those without UGT1A1 genotyping and dose escalation [8]
We will evaluate the efficacy and safety profile of FOLFIRI plus bevacizumab when the irinotecan dosage is adjusted on the basis of the blood UGT1A1 genotype through a prospective, multicenter, randomized controlled study
Summary
Irinotecan is converted into SN-38 by a carboxylesterase and metabolized by the enzyme UGT (predominantly by the UGT1A1 isoenzyme). The addition of bevacizumab improved the pathological response and protection against hepatic injuries in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases [19] This trial is performed to demonstrate the prognostic advantage of UGT1A1 genotyping and irinotecan dose escalation before systemic chemotherapy to patients with mCRC. A combination of bevacizumab and FOLFIRI as a first-line therapy for mCRC patients was retrospectively demonstrated to have a favorable response rate and acceptable toxicity. 70 % of the patients (55 of 79) with mCRC who had undergone pretherapeutic UGT1A1 genotyping and received an escalated dose of irinotecan responded clinically to bevacizumab-plus-FOLFIRI chemotherapy [8]. We are prospectively conducting a clinical trial to demonstrate that irinotecan dose escalation can achieve more favorable responses and outcomes without a significant increase in toxicities while using the FOLFIRIplus-bevacizumab regimen. All of the authors read and approved the final version of the manuscript
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