A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer

E. Marcuello, D. Páez, L. Paré, J. Salazar, A. Sebio, E. Del Rio, M. Baiget

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    Abstract

    Background:Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10- hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1 28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.Patients and methods:Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m 2 for the 1/ 1, 110 mg m 2 for the 1/ 28 and 90 mg m 2 for the 28/ 28 genotypes.Results:The dose of irinotecan was escalated to 450 mg m 2 in patients with the 1/ 1 genotype, to 390 mg m 2 in those with the 1/ 28 genotype and to 150 mg m 2 in those with the 28/ 28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.Conclusions:Our results demonstrated that the recommended dose of 180 mg m2- for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 1/ 1 and 1/ 28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 28/ 28 genotype is 30% lower than the standard dose of 180 mg m-2. © 2011 Cancer Research UK All rights reserved.
    Original languageEnglish
    Pages (from-to)53-57
    JournalBritish Journal of Cancer
    Volume105
    Issue number1
    DOIs
    Publication statusPublished - 28 Jun 2011

    Keywords

    • colorectal cancer
    • irinotecan
    • pharmacogenetics
    • UGT1A1

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