Multiple-target chemotherapy (LV-modulated 5-FU bolus and continuous infusion, oxaliplatin, CPT-11) in advanced 5-FU-refractory colorectal cancer : Mtd definition and efficacy evaluation. A phase I-II study

Aims and background: To identify the maximum tolerated doses and to define the activity of a regimen incorporating leucovorin (LV)-modulated 5-fluorouracil (5-FU) bolus and continuous infusion, oxaliplatin (I-OHP) and irinotecan (CPT-11) in patients with advanced, 5-FU-refractory colorectal cancer (CRC). Patients and methods: Starting doses: LV 100 mg/m 2 as a 2-hour infusion followed by 5-FU 300 mg/m 2 bolus administration followed by 5-FU 500 mg//m 2 as a 22-hour infusion on days 1 and 2; I-OHP 65 mg/m 2 as a 2-hour infusion concomitantly with LV on day 1; CPT-11 90 mg/m 2 concomitantly with LV on day 2. Planned cycle interval: 2 weeks. Results: Two hundred twenty-six cycles were administered to 27 patients. Recommended doses were 5-FU bolus 300 mg/m 2 , 5-FU protracted infusion 500 mg/m 2 , 1-OHP 75 mg/m 2 , and CPT-11 150 mg/m 2 . Among 25 patients evaluable for response we observed 13 disease stabilizations (52%; 95% Cl: 33-71%), 6 instances of disease progression and 6 responses (24%; 95% Cl: 7-41%). Median time to progression and overall survival were 24 and 60 weeks, respectively. A cycle delay >3 days was observed in 134/199 cycles (67%). Conclusions: This study confirms the feasibility of triplet chemotherapy in patients with advanced 5-FU-refractory CRC.