Neoadjuvant chemotherapy and bevacizumab for colorectal peritoneal metastases: clinical and translational outcomes of the phase II BEV-IP trial.

The addition of bevacizumab (BEV) to chemotherapy has shown survival benefits in metastatic colorectal cancer but may increase operative risks, potentially limiting applicability in cytoreductive surgery (CRS) for CRPM. We report the phase II BEV-IP trial investigating the feasibility, safety and potential efficacy of BEV with neoadjuvant chemotherapy (NACT) before CRS in CRPM patients. In this multicenter single-arm trial, 60 CRPM patients were enrolled to receive BEV and standard NACT prior to CRS. The primary endpoint was the 90-day major surgical morbidity rate.

Secondary endpoints included safety profile of perioperative BEV, progression-free survival (PFS), overall survival (OS) and identification of exploratory biomarkers predictive of BEV response. A total of 54 patients were eligible for analysis. The 90-day major morbidity and mortality rates were 29.4% (95% CI 18.7 - 43.0%) and 3.9% (95% CI 1.1 - 13.2%), respectively. With a median follow-up of 71.4 months, the median PFS was 16.1 months (95% CI 11.2 - 21.0) and the median OS was 40.6 months (95% CI 32.4 - 48.8).

A multivariable Cox-regression model identified peritoneal carcinomatosis index, BRAF mutation, peritoneal HbEGF levels and nuclear HIF1A staining as independent predictors of OS.

Notably, in contrast to published literature, nuclear HIF1A overexpression was associated with improved OS (HR 0.17, 95% CI: 0.04-0.65,p = 0.010). BEV-containing NACT for CRPM is safe and feasible in patients undergoing CRS. Peritoneal hbEGF concentrations and tumoral nuclear HIF1A staining emerge as potential biomarkers predictive of response to BEV, warranting further investigation of strategies targeting angiogenesis in CRPM.