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

BackgroundWe 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 methodsThis 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.ResultsThe 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.ConclusionsThese results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.

Revisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non‐Small Cell Lung Carcinoma

“…The optimal lag we identified in our study is in line with other experimental studies that explored the normalization window after bevacizumab or other anti‐angiogenics administration, most of these reporting an optimal delay ranging between 2 and 5 days , . In patients, Avallone et al . showed that giving bevacizumab 4 days prior to chemotherapy yielded better efficacy compared to concomitant administration.…”

“…The optimal lag we identified in our study is in line with other experimental studies that explored the normalization window after bevacizumab or other anti-angiogenics administration, most of these reporting an optimal delay ranging between 2 and 5 days. 18,33,41 In patients, Avallone et al 19 showed that giving bevacizumab 4 days prior to chemotherapy yielded better efficacy compared to concomitant administration. Intriguingly, two clinical studies in NSCLC and metastatic colorectal cancer showed reduced tumor drug delivery of cytotoxic agents when administered 1 and 4 days after bevacizumab, 42 which contrasts with our preclinical findings and direct clinical observation of vessel normalization after bevacizumab administration by means of interstitial fluid pressure measurements and functional computed tomography.…”

“…Another recent study showed that bevacizumab followed 24 hours later by paclitaxel potentiated its antitumor activity in an ovarian cancer model. 17 At bedside, Avallone et al 19 showed that administering bevacizumab 4 days prior to chemotherapy in patients with locally advanced rectal cancer led to better OS and progression-free survival compared to concomitant administration. Although promising, most attempts to revisit bevacizumab scheduling have been made on an empirical basis and a trial-and-error mode.…”

18F-FDG PET/CT Is an Early Predictor of Pathologic Tumor Response and Survival After Preoperative Radiochemotherapy with Bevacizumab in High-Risk Locally Advanced Rectal Cancer

“…We have recently reported the final results of a non-randomized phase 2 study, to assess the safety and efficacy of traditional "concomitant" versus experimental "sequential" (4 days before chemoradiotherapy) administration of bevacizumab, with preoperative chemotherapy, in magnetic resonance imaging (MRI)-defined high-risk LARC patients (BRANCH Trial) (9). The primary endpoint, pathological complete tumor regression (TRG1), was reached with the sequential schedule and the final TRG1 rate was 50% (95% CI 35%-65%).…”

Mir‐483 inhibits colon cancer cell proliferation and migration by targeting TRAF1

“…Colorectal cancer is one of the most common malignancies in the gastrointestinal tract [1]. The morbidity and mortality rate have increased year by year due to changes in lifestyle, diet, as well as living conditions [2]. Surgery and chemotherapy are the routine treatments of colorectal cancer.…”