Irinotecan and chronomodulated infusion of 5-fluorouracil and folinic acidin the treatment of patients with advanced colorectal carcinoma - A phase I study

BAGKGROUND. Irinotecan (CPT-11) is an active drug in the treatment of patie nts with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-F U) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was t o establish the maximum tolerated dose (MTD) of CPT-11 together with a chro nomodulated infusion of 5-FU and the I-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL). METHODS. Twenty-six patients with advanced colorectal carcinoma who had rec eived previous treatment with 5-FU were entered on this Phase I study. At l east three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m(2) per dose level . A daily administration of chronomodulated 5-FU (400 mg/m(2); peak deliver y rate at 04:00) and FA (175 mg/m(2); peak delivery rate at 04:00) for 5 da ys every 3 weeks nas given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m(2) per day due to toxicity. No intrapati ent dose escalation was allowed. RESULTS. One hundred sixty-one courses were delivered. Dose-limiting toxici ty was observed during the first course in seven patients (27%). Four patie nts developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m(2) when a toxic death was obs erved with a recommended dose of 325 mg/m(2). Six partial responses were ob served (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment. CONCLUSIONS. The recommended dose for Phase II trials is 325 mg/m(2) CPT-11 on Day I, which is similar to the dose given as a single agent, together w ith a 5-day chronomodulated infusion of 700 mg/m(2) 5-FU and 175 mg/m(2) FA . Intensification of this schedule every 2 weeks should be achievable. (C) 2001 American Cancer Society.