Neoadjuvant Bevacizumab and Chemoradiotherapy for Locally Advanced Rectal Cancer: Long-Term Outcomes of a Multicentre Study

Background: Neoadjuvant treatment for locally advanced rectal cancer (LARC) evolves rapidly, and targeted agents could play a relevant role. Patients and Methods: In the phase II RAX study, we investigated the efficacy and safety of neoadjuvant chemoradiotherapy (CRT, 25 × 2 Gy with twice daily 825 mg/m² capecitabine) combined with bevacizumab (5 mg/kg, day: 14, 1, 15, 29 of CRT) followed by surgery. Patients with cT4 tumors, cT3 within 5 cm from the anal verge, or high cT3 within 2 mm of the mesorectal fascia (MRF) were included. Safety was presented in terms of number of toxicity failures, according to protocolized criteria based on expected toxicity of CRT and bevacizumab, and severe adverse events. Histopathological response was described in terms of extent (according to Mandard’s Tumor Regression Grade) and pattern (shrinkage vs. fragmentation). Efficacy outcomes were histopathological response, incidence of locoregional recurrences (LRR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). Results: We included 35 patients; 66% were male with a median age of 61 years (range, 25-77). About 71% of tumors involved the MRF at baseline, 56% were cT4, and 71% were cN+. Eight patients developed toxicity failures (3 bowel perforations, 2 pulmonary embolisms, 2 bleedings, and 1 anal mucositis requiring surgery). These toxicity failures exceeded the predefined stopping rules and led to study termination after 35 patients. Pathological complete response was observed in 4 patients, and 1 was ypT0N1 (total 15%), and 5 more achieved a major response (TRG1). Ten-year incidences of LRR and DM were 6% (95% confidence interval [CI], 0%-13%) and 31% (95% CI, 16%-47%), respectively; both DFS and OS were 60% (95% CI, 44%-76%). Conclusion: Neoadjuvant CRT with concomitant bevacizumab results in high DFS and OS after long follow-up, but with concerning numbers of early toxicity failures. Incorporating bevacizumab into neoadjuvant treatment of LARC, possibly in combination with novel therapeutic strategies, may result in promising long-term oncological outcomes and deserves further investigation.