title: Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.
abstract: BACKGROUND
  The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy.
  
  
  METHODS
  In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and β error of 0.05 and 0.20, respectively, 262 patients were required.
  
  
  RESULTS
  In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data.
  
  
  CONCLUSIONS
  This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa. Electronic address: gl.masi@tin.it.
authors.forename: G
authors.initials: G
authors.lastname: Masi
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
authors.forename: L
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Clinical Trials Coordinating Center, AOU Careggi/Istituto Toscano Tumori, Firenze.
authors.forename: L
authors.initials: L
authors.lastname: Boni
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
authors.forename: F
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
authors.forename: C
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Division of Medical Oncology, Azienda USL 2 di Lucca, Istituto Toscano Tumori, Lucca.
authors.forename: L
authors.initials: L
authors.lastname: Fornaro
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
authors.forename: M
authors.initials: M
authors.lastname: Schirripa
authors.affiliation: Division of Medical Oncology, Azienda USL 6 di Livorno, Istituto Toscano Tumori, Livorno.
authors.forename: S
authors.initials: S
authors.lastname: Cupini
authors.affiliation: Division of Medical Oncology, Azienda USL 6 di Livorno, Istituto Toscano Tumori, Livorno.
authors.forename: C
authors.initials: C
authors.lastname: Barbara
authors.affiliation: Division of Medical Oncology, Azienda USL 6 di Livorno, Presidio Ospedaliero di Piombino, Istituto Toscano Tumori, Piombino.
authors.forename: V
authors.initials: V
authors.lastname: Safina
authors.affiliation: Division of Medical Oncology, Ospedale S. Croce e Carle, Cuneo.
authors.forename: C
authors.initials: C
authors.lastname: Granetto
authors.affiliation: Division of Medical Oncology, Ospedale S. Croce e Carle, Cuneo.
authors.forename: E
authors.initials: E
authors.lastname: Fea
authors.affiliation: Division of Medical Oncology 1, Azienda Ospedaliero-Universitaria Careggi, Istituto Toscano Tumori, Firenze.
authors.forename: L
authors.initials: L
authors.lastname: Antonuzzo
authors.affiliation: Division of Medical Oncology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia.
authors.forename: C
authors.initials: C
authors.lastname: Boni
authors.affiliation: Division of Medical Oncology, Azienda USL 5 di Pisa, Ospedale Felice Lotti, Istituto Toscano Tumori, Pontedera.
authors.forename: G
authors.initials: G
authors.lastname: Allegrini
authors.affiliation: Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria San Martino-Istituto Nazionale Ricerca Cancro, Genova.
authors.forename: S
authors.initials: S
authors.lastname: Chiara
authors.affiliation: Division of Medical Oncology, Ospedale della Versilia, Istituto Toscano Tumori, Lido di Camaiore.
authors.forename: D
authors.initials: D
authors.lastname: Amoroso
authors.affiliation: Division of Medical Oncology, AULSS 21 Legnago, Ospedale Mater Salutis, Legnago, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bonetti
authors.affiliation: Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D019233:Retreatment; D015996:Survival Rate
keywords: bevacizumab; beyond progression; metastatic colorectal cancer; second-line