A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

Abstract

The combination of irinotecan (CPT-11), oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) is one of the possibilities to overcome chemoresistance in advanced colorectal cancer (ACRC) patients. The aim of this study was to determine the tolerability and activity of CPT-11 plus chronomodulated infusion of L-OHP, 5-FU and FA in ACRC patients. A total of 35 patients (91% pretreated, 77% with CPT-11, 54% with L-OHP, 42% with both) were treated every 3 weeks with CPT-11, 180 mg m À2 day 1 i.v., plus L-OHP, 20 mg m À2 day À1 , 5-FU, 700 mg m À2 day À1 and FA, 150 mg m À2 day À1 , all three drugs from day 2 to day 5 by chronomodulated infusion. The patients' (pt) data were as follows: male/female 21/14; median age 58 years (range: 38 -70); PS 0: 26 pts (74%), PS 1: 8 pts (23%), PS 2: 1 pt (3%); primary tumour colon/rectum 26/9; involved organs: 1, 14 pts (40%); 2, 17 pts (48%); X3: 4 pts (11%); previous chemotherapy lines 1: 12 pts (34%), 2: 10 pts (28%), X3: 10 pts (28%). A total of 221 courses (c) were performed; no grade 4 toxicity was observed with only one grade 3 (G3) neutropenia and thrombocytopenia (3%) in one out of 221 courses (o1%). Maximal toxicity (G3) was nausea and diarrhoea in 10 pts (28%), occurring in 14 out of 221 c (6%) and 12 out of 221 c (5%) respectively. Seven patients achieved a partial response (20%, confidence interval (c.i.) 6.8 -33.3) and one patient a complete response (2.9%, c.i. 0 -8.4), for a total overall response rate of 22.9% (c.i. 9 -36.8); 15 out of 35 (42.9%, c.i. 26.5 -59.3) had stable disease and 12 out of 35 (34.3%, c.i. 18.6 -50) patients underwent a progression. In conclusion, this four-drug regimen is feasible in advanced pretreated ACRC patients with no significant haematological toxicity and acceptable diarrhoea. The activity of this combination is currently studied in EORTC 05011 study. In the last few years, prospective randomised phase III trials comparing both continuous infusion and bolus 5-FU plus folinic acid (FA) vs the same schedule plus CPT-11 or L-OHP showed significant increase of response rate (RR), time to progression (TTP), overall survival (OS), no quality of life (QoL) detriment with acceptable toxicity profile (De Gramont et al, 2000;Douillard et al, 2000; Saltz et al, 2000;Goldberg et al, 2002).These results suggest that combination of infusional 5-FU plus L-OHP or CPT-11 can now be considered as the standard treatment in this setting of patients.Drug delivery according to circadian rhythm showed an impact on toxicity profile and activity both in preclinical and in clinical setting (Lévi, 2001). It was demonstrated in phase III trials that the combination of L-OHP plus 5-FU and FA delivered by chronomodulated infusion, the FFL regimen, provides more activity and a better toxicity profile when compared to the flat infusion of the same drugs with a five-fold greater mucositis rate due to 5-FU and the double of peripheral neurotoxicity due to L-OHP in the constant infusion regimen (Lévi et al, 1994(Lévi et al, , 1997. Circadian changes in drug...

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

“…That regimen produced an objective response rate of 22.9% and disease stabilization in 42.9% of the patients. However, only 42% of the patients had previously received irinotecan, 5-FU/LV, and oxaliplatin; a stabilization rate of 53.3% and no objective responses were obtained in this patient subset [35]. In our study, all the patients had previously progressed on 5-FU/LV, irinotecan, and oxaliplatin.…”

“…The association of all four drugs [7,30] and the chronomodulation of their delivery most likely accounted for this tumor control in such a patient population. In a phase II study involving 35 MCRC patients, chronomodulated 5-FU/LV and oxaliplatin were combined with a 1-hour morning infusion of irinotecan [35]. That regimen produced an objective response rate of 22.9% and disease stabilization in 42.9% of the patients.…”

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

“…Other studies have evaluated the combination of FU with l-OHP and/or IRI administered as chronomodulated infusion. These trials also reported interesting response rates and optimal toxicity profiles, but raised questions about the feasibility of chronomodulated chemotherapy (Garufi et al, 2003). However, the analysis of seven phase III trials in advanced CRC suggested that exposure to all three drugs, regardless of their sequence, is a key element able to extend the overall survival of patients to 18 -21 months (Grothey et al, 2004).…”

Implications of circadian clocks for the rhythmic delivery of cancer therapeutics

“…In particular, this is the reason why we are presently developing more elaborate models of cell proliferation, for healthy or tumour tissues. These new models take into account several physiological events in the cell cycle, which are targeted by anti-cancer drugs (Bekkal-Brikci et al 2008;Clairambault 2008), so as to deal jointly with the circadian regulation of cell cycle determinants and therapeutic optimization of control flows for several drugs, such as 5-FU, oxaliplatin and irinotecan, which are used as triplets for treating colorectal cancer (Garufi et al 2003;Falcone et al 2007). …”