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

Abstract

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.

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

“…For chronoIFL, irinotecan (180 mg/m²) was infused from 02:00 to 08:00 with peak delivery at 05:00 on day 1, then followed by chronoFL (garufi et al,2006). The chronoIFLO schedule combined day1 chronomodulated irinotecan (180mg/m²) with day2-5 chronoFLO (5-fluorouracil, 2800 mg/m², leucovorin, 1200 mg/m², oxaliplatin, 85 mg/m²) every 3 weeks (Gholam et al, 2006). The characteristics of the patients in Cohorts I and II were previously reported (Mormont et al, 2000;Innominato et al, 2009a).…”

“…All the patients had rest-activity recorded with a wrist watch "Mini-motion Logger" for a minimum of 48 h up to 7 days. The patients subsequently received at least one course of conventional or circadian-based chemotherapy (chronotherapy) involving oxaliplatin (O), irinotecan (I) or both, eventually combined with 5-fluorouracil (F) and Leucovorin (L) (Levi et al, 1997;Gholam et al, 2006). ChronoFL consisted in four consecutive daily chronomodulated infusions of 5-fluorouracil (cumulative dose per course, 2800-3200 mg/m²) and leucovorin (1200 mg/m²) from 22:15 to 9:45, with peak delivery rate at 4:00 at night every 2 weeks .…”

“…Chronotherapy included chronoFLO (266 patients) (Levi et al, 1997;Giacchetti et al, 2006), chronoFL (38 patients), or irinotecan-based chronotherapy (56 patients) (Mormont et al, 2000, Gholam et al, 2006Garufi et al, 2006).…”

Modelling Physiological and Pharmacological Control on Cell Proliferation to Optimise Cancer Treatments

“…Combinations of chemotherapy and surgery have proved successful in the treatment of metastatic colorectal cancer [108].…”

“…This has been in use for the last 15 years or so in the clinic of cancer, by delivering cytotoxic drugs 5-fluorouracil and oxaliplatin according to variable infusion flow time schedules, in the treatment of colorectal cancer, and combination with surgery, yielding successful results, see e.g., [108] for a recent study. The explanation of the mechanisms by which chronotherapeutics works seem to involve both chronopharmacokinetic and chronopharmacodynamic components.…”