title: 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.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: U.O. Oncologia Medica, Istituto Toscano Tumori, Livorno, Italy. a.falcone@med.unipi.it
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Sergio
authors.initials: S
authors.lastname: Ricci
authors.forename: Isa
authors.initials: I
authors.lastname: Brunetti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pfanner
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.forename: Cecilia
authors.initials: C
authors.lastname: Barbara
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.forename: Giovanni
authors.initials: G
authors.lastname: Benedetti
authors.forename: Walter
authors.initials: W
authors.lastname: Evangelista
authors.forename: Laura
authors.initials: L
authors.lastname: Fanchini
authors.forename: Enrico
authors.initials: E
authors.lastname: Cortesi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Picone
authors.forename: Stefano
authors.initials: S
authors.lastname: Vitello
authors.forename: Silvana
authors.initials: S
authors.lastname: Chiara
authors.forename: Cristina
authors.initials: C
authors.lastname: Granetto
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Porcile
authors.forename: Luisa
authors.initials: L
authors.lastname: Fioretto
authors.forename: Cinzia
authors.initials: C
authors.lastname: Orlandini
authors.forename: Michele
authors.initials: M
authors.lastname: Andreuccetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011788:Quality of Life; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin