Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial.

// Antonio Avallone 1 , Biagio Pecori 2 , Franco Bianco 3 , Luigi Aloj 4 , Fabiana Tatangelo 5 , Carmela Romano 1 , Vincenza Granata 6 , Pietro Marone 7 , Alessandra Leone 8 , Gerardo Botti 5 , Antonella Petrillo 6 , Corradina Caraco 4 , Vincenzo R. Iaffaioli 1 , Paolo Muto 2 , Giovanni Romano 3 , Pasquale Comella 1 , Alfredo Budillon 8 , Paolo Delrio 9 1 Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 2 Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 3 Gastrointestinal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 4 Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 5 Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 6 Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 7 Endoscopy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 8 Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy 9 Colorectal Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy Correspondence to: Antonio Avallone, e-mail: a.avallone@istitutotumori.na.it Keywords: locally advanced rectal cancer, bevacizumab, preoperative chemo-radiotherapy, adjuvant chemotherapy, vessel normalization Received: May 17, 2015      Accepted: July 17, 2015      Published: July 30, 2015 ABSTRACT Background: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. Patients and methods: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. Results: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%–65%). Neutropenia was the most common grade ≥3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%–89%) and 85% (95%CI, 69%–93%), respectively, for the sequential-schedule. Conclusions: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.