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Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

Alfredo Falcone, Sergio Ricci, Isa Brunetti, Elisabetta Pfanner, Giacomo Allegrini, Cecilia Barbara, Lucio Crinò, Giovanni Benedetti, Walter Evangelista, Laura Fanchini, Enrico Cortesi, Vincenzo Picone, Stefano Vitello, Silvana Chiara, Cristina Granetto, Gianfranco Porcile, Luisa Fioretto, Cinzia Orlandini, Michele Andreuccetti, Gianluca Masi

From the U.O. Oncologia Medica, Istituto Toscano Tumori, Livorno; S.C. di Oncologia Medica, Ospedale S. Maria della Misericordia, Perugia; U.O. Oncologia Medica, Ospedale di Macerata, Macerata; Centro Oncologico ed Ematologico Subalpino, ASO Ospedale S. Giovanni Battista Le Molinette, Torino; Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma; U.O. Oncologia Medica, Ospedale S. Elia, Caltanissetta; Istituto Nazionale per la Ricerca sul Cancro, Genova; S.C. di Oncologia, Azienda Ospedaliera S. Croce e Carle, Cuneo; Oncologia Medica, P.O. S. Lazzaro, Alba; Oncologia Medica, Ospedale S. Maria Annunziata, Istituto Toscano Tumori, Firenze, Italy; U.O. Oncologia Medica, Azienda Ospedaliero-Universitaria, Istituto Toscano Tumori; and Dipartimento di Oncologia, dei Trapianti e Nuove Tecnologie in Medicina, Università degli Studi, Pisa, Italy

Address reprint requests to Alfredo Falcone, MD, Cattedra di Oncologia Medica, University of Pisa, Department of Oncology, Azienda USL-6 of Livorno, Viale Alfieri, 36, 57124 Livorno, Italy; e-mail: a.falcone{at}med.unipi.it

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m² day 1, oxaliplatin 85 mg/m² day 1, leucovorin 200 mg/m² day 1, fluorouracil 3,200 mg/m² 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR).

Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032).

Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Supported in part by a research grant of the Associazione Italiana Ricerca Cancro (A.I.R.C.) and by the Fondazione A.R.C.O.

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006, and at the American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, San Francisco, CA, January 24-27, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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