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Ann Oncol. 2015 Apr;26(4):724-30. doi: 10.1093/annonc/mdv012. Epub 2015 Jan 18.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.

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Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa
Division of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa.
Clinical Trials Coordinating Center, AOU Careggi/Istituto Toscano Tumori, Firenze.
Division of Medical Oncology, Azienda USL 2 di Lucca, Istituto Toscano Tumori, Lucca.
Division of Medical Oncology, Azienda USL 6 di Livorno, Istituto Toscano Tumori, Livorno.
Division of Medical Oncology, Azienda USL 6 di Livorno, Presidio Ospedaliero di Piombino, Istituto Toscano Tumori, Piombino.
Division of Medical Oncology, Ospedale S. Croce e Carle, Cuneo.
Division of Medical Oncology 1, Azienda Ospedaliero-Universitaria Careggi, Istituto Toscano Tumori, Firenze.
Division of Medical Oncology, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia.
Division of Medical Oncology, Azienda USL 5 di Pisa, Ospedale Felice Lotti, Istituto Toscano Tumori, Pontedera.
Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria San Martino-Istituto Nazionale Ricerca Cancro, Genova.
Division of Medical Oncology, Ospedale della Versilia, Istituto Toscano Tumori, Lido di Camaiore.
Division of Medical Oncology, AULSS 21 Legnago, Ospedale Mater Salutis, Legnago, Italy.



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.


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.


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.


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. number: NCT00720512.


bevacizumab; beyond progression; metastatic colorectal cancer; second-line

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