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

Oncotarget. 2015 Oct 6;6(30):30394-407. doi: 10.18632/oncotarget.4724.

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.

Keywords: adjuvant chemotherapy; bevacizumab; locally advanced rectal cancer; preoperative chemo-radiotherapy; vessel normalization.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / administration & dosage*
  • Angiogenesis Inhibitors / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / administration & dosage*
  • Bevacizumab / adverse effects
  • Chemoradiotherapy, Adjuvant* / adverse effects
  • Chemoradiotherapy, Adjuvant* / mortality
  • Disease Progression
  • Disease-Free Survival
  • Drug Administration Schedule
  • Early Termination of Clinical Trials
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Italy
  • Kaplan-Meier Estimate
  • Leucovorin / administration & dosage
  • Magnetic Resonance Imaging*
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / adverse effects
  • Neoadjuvant Therapy* / mortality
  • Neoplasm Recurrence, Local
  • Organoplatinum Compounds / administration & dosage
  • Oxaliplatin
  • Predictive Value of Tests
  • Quinazolines / administration & dosage
  • Rectal Neoplasms / mortality
  • Rectal Neoplasms / pathology
  • Rectal Neoplasms / therapy*
  • Risk Factors
  • Thiophenes / administration & dosage
  • Time Factors
  • Treatment Outcome

Substances

  • Angiogenesis Inhibitors
  • Organoplatinum Compounds
  • Quinazolines
  • Thiophenes
  • Oxaliplatin
  • Bevacizumab
  • raltitrexed
  • Leucovorin
  • Fluorouracil