Originally published as JCO Early Release 10.1200/JCO.2009.23.6125 on December 28 2009

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Genotype-Driven Phase I Study of Irinotecan Administered in Combination With Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer

From Experimental and Clinical Pharmacology, Medical Oncology and Scientific Direction, Centro di Riferimento Oncologico National Cancer Institute, Aviano; Medical Oncology, San Filippo Neri Hospital, Rome; Medical Oncology, Ospedale "Pierfortunato Calvi," Noale; Medical Oncology, Istituto Oncologico Veneto, National Cancer Institute Padova, Padova; Department of Pharmacology, University of Florence, Florence; Medical Oncology, "Ca' Foncello" Hospital Treviso, Treviso; Medical Oncology, "S. Maria degli Angeli" Hospital, Pordenone, Italy; and Department of Medicine, Cancer Research Center, Committee on Pharmacology and Pharmacogenomics, the University of Chicago, Chicago, IL.

Corresponding author: Giuseppe Toffoli, MD, Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico National Cancer Institute, via Pedemontana Occidentale 12, Aviano 33081, Italy; e-mail: gtoffoli{at}cro.it.

Purpose We aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan.

Patients and Methods Patients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m² for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.

Results The dose of irinotecan was escalated to 370 mg/m² in patients with the *1/*28 genotype and to 420 mg/m² in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m² and in two of three of *1/*1 patients at 420 mg/m². No DLTs were observed in 10 *1/*28 patients at 310 mg/m² and in 10 *1/*1 patients at 370 mg/m²; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics.

Conclusion The recommended dose of 180 mg/m² for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

Sponsored by the Centro di Riferimento Oncologico National Cancer Institute. The Institute has received funds from Pfizer for this study. F.I. received royalties from the Mayo Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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