Oncotarget

Clinical Research Papers:

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 _, Biagio Pecori, Franco Bianco, Luigi Aloj, Fabiana Tatangelo, Carmela Romano, Vincenza Granata, Pietro Marone, Alessandra Leone, Gerardo Botti, Antonella Petrillo, Corradina Caracò, Vincenzo R. Iaffaioli, Paolo Muto, Giovanni Romano, Pasquale Comella, Alfredo Budillon and Paolo Delrio

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Oncotarget. 2015; 6:30394-30407. https://doi.org/10.18632/oncotarget.4724

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Abstract

Antonio Avallone1, Biagio Pecori2, Franco Bianco3, Luigi Aloj4, Fabiana Tatangelo5, Carmela Romano1, Vincenza Granata6, Pietro Marone7, Alessandra Leone8, Gerardo Botti5, Antonella Petrillo6, Corradina Caracò4, Vincenzo R. Iaffaioli1, Paolo Muto2, Giovanni Romano3, Pasquale Comella1, Alfredo Budillon8, Paolo Delrio9

1Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

2Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

3Gastrointestinal Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

4Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

5Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

6Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

7Endoscopy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

8Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, 80131, Napoli, Italy

9Colorectal 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.


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