title: Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.
abstract: BACKGROUND
  A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects.
  
  
  METHODS
  We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival.
  
  
  RESULTS
  The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group.
  
  
  CONCLUSIONS
  FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).
authors.affiliation: From Azienda Ospedaliero-Universitaria Pisana and Università di Pisa, Pisa (F.L., C. Cremolini, G.M., L.S., A.F.), Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (S.L., V.Z.), Sapienza Università di Roma (E.C.) and Università Campus Biomedico (G. Tonini), Rome, Azienda Istituti Ospitalieri, Cremona (G. Tomasello), Ospedale San Raffaele, IRCCS, Milan (M.R.), Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Turin (R.S.), Fondazione Poliambulanza, Brescia (A.Z.), Centro di Riferimento Oncologico, IRCCS, Aviano (A.B.), Ospedale Versilia, Lido di Camaiore (D.A.), Ospedale San Martino, IRCCS, Genoa (S.C.), Azienda Ospedaliera Universitaria Federico II, Naples (C. Carlomagno), Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia (C.B.), Ospedale Felice Lotti, Pontedera (G.A.), and Azienda Ospedaliero-Universitaria Careggi and Istituto Toscano Tumori, Florence (L.B.) - all in Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Enrico
authors.initials: E
authors.lastname: Cortesi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tomasello
authors.forename: Monica
authors.initials: M
authors.lastname: Ronzoni
authors.forename: Rosella
authors.initials: R
authors.lastname: Spadi
authors.forename: Alberto
authors.initials: A
authors.lastname: Zaniboni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Angela
authors.initials: A
authors.lastname: Buonadonna
authors.forename: Domenico
authors.initials: D
authors.lastname: Amoroso
authors.forename: Silvana
authors.initials: S
authors.lastname: Chiara
authors.forename: Chiara
authors.initials: C
authors.lastname: Carlomagno
authors.forename: Corrado
authors.initials: C
authors.lastname: Boni
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.forename: Luca
authors.initials: L
authors.lastname: Boni
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin