irinotecan. The starting dose of biweekly irinotecan was 215 mg/m 2 for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.
ResultsThe dose of irinotecan was escalated to 370 mg/m 2 in patients with the *1/*28 genotype and to 420 mg/m 2 in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m 2 and in two of three of *1/*1 patients at 420 mg/m 2 . No DLTs were observed in 10 *1/*28 patients at 310 mg/m 2 and in 10 *1/*1 patients at 370 mg/m 2 ; 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.
ConclusionThe recommended dose of 180 mg/m 2 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.
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