title: 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.
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.
  
  
  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.
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Antonio
authors: A
authors: Avallone
authors: Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Biagio
authors: B
authors: Pecori
authors: Gastrointestinal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Franco
authors: F
authors: Bianco
authors: Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Luigi
authors: L
authors: Aloj
authors: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Fabiana
authors: F
authors: Tatangelo
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Carmela
authors: C
authors: Romano
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Vincenza
authors: V
authors: Granata
authors: Endoscopy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Pietro
authors: P
authors: Marone
authors: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Alessandra
authors: A
authors: Leone
authors: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Gerardo
authors: G
authors: Botti
authors: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Antonella
authors: A
authors: Petrillo
authors: Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Corradina
authors: C
authors: Caracò
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Vincenzo R
authors: VR
authors: Iaffaioli
authors: Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Paolo
authors: P
authors: Muto
authors: Gastrointestinal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Giovanni
authors: G
authors: Romano
authors: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Pasquale
authors: P
authors: Comella
authors: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Alfredo
authors: A
authors: Budillon
authors: Colorectal Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, 80131, Napoli, Italy.
authors: Paolo
authors: P
authors: Delrio
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000401:mortality; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000008:administration & dosage; D012004:Rectal Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012307:Risk Factors; D013876:Thiophenes / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; D000068258:Bevacizumab; C068874:raltitrexed; D002955:Leucovorin; D005472:Fluorouracil
keywords: adjuvant chemotherapy; bevacizumab; locally advanced rectal cancer; preoperative chemo-radiotherapy; vessel normalization