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N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.

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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.



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.


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.


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.


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; number, NCT00719797.).

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