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Gastrointestinal Cancer

Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer

^a INSERM U776 "Rythmes Biologiques et Cancers" and ^b Department of Medical Oncology, Hôpital Paul Brousse, Villejuif, France; ^c Faculté de Médecine, University of Paris XI, Le Kremlin Bicêtre, France; ^d INSERM U569 – National Institute for Demographic Studies, Hôpital Le Kremlin Bicêtre, Le Kremlin Bicêtre, France

Key Words. Metastatic colorectal cancer • Salvage treatment • Chronotherapy • Irinotecan • Oxaliplatin • Circadian rhythm

Correspondence: Francis Lévi, M.D., Ph.D., INSERM U776 "Rythmes Biologiques et Cancers," Paul Brousse Hospital, 14-16 Avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France. Telephone: 00-33-1-45-59-38-55; Fax: 00-33-1-45-59-36-02; e-mail: levi-m{at}vjf.inserm.fr

Purpose. To evaluate the activity and tolerability of salvage chronomodulated chemotherapy combining irinotecan (I), 5-fluorouracil/leucovorin (5-FU/LV), and oxaliplatin (O) (chronoIFLO) in patients with metastatic colorectal cancer (MCRC) and prior progression on four drugs.

Patients and Methods. Seventy-seven nonhospitalized MCRC patients received chronoIFLO every 3 weeks, with day 1: I (180 mg/m² over 6 hours, with peak infusion rate at 05:00) and days 2–5: 5-FU/LV (700/300 mg/m² per day over 12 hours, with peak flow rate at 04:00), and O (20 mg/m² per day over 12 hours, with peak flow rate at 16:00). Toxicity and response were assessed every 3 weeks and every 2 months, respectively.

Results. Three or more prior chemotherapy lines were given to 75% of the patients. Two or more organs had metastatic disease in 65% of the patients. A median number of six courses of chronoIFLO was given. The main grade 3–4 toxicities were diarrhea (39% of the patients, 9% of the courses) and neutropenia (30% of the patients and 7% of the courses). Grade 3 peripheral sensory neuropathy occurred in 14% of the patients. Two patients achieved a partial response and 61 had stable disease, resulting in disease control for 82% of the patients. The median time to progression (TTP) was 5.5 months (95% confidence interval, 3.7–6.0). The median overall survival time was 14.2 months (9.8–17.3). Baseline performance status, serum carcinoembryonic antigen (CEA) level, and CEA doubling time were independent prognostic factors of TTP.

Conclusions. ChronoIFLO safely and durably halted tumor progression in most extensively pretreated MCRC patients.

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