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  • Title: A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours.
    Author: Sastre J, Paz-Ares L, Carcas A, Alfonso R, Grávalos C, Frías J, Guerra P, Pronk L, Cortés-Funes H, Díaz-Rubio E.
    Journal: Cancer Chemother Pharmacol; 2005 May; 55(5):453-60. PubMed ID: 15818508.
    Abstract:
    PURPOSE: Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy. PATIENTS AND METHODS: Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m(2)) plus a fixed dose of 5-FU CI 250 mg/m(2) per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m(2). In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m(2), and then followed by 2-5 weeks rest. RESULTS: Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m(2) + 5-FU 250 mg/m(2) CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m(2) due to toxicity. The weekly schedule of CPT-11 75 mg/m(2) + 5-FU 250 mg/m(2) CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied. CONCLUSION: CPT-11 300 mg/m(2) + 5-FU 250 mg/m(2) protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.
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