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 efficacy and safety of neoadjuvant chemoradiotherapy (CRT, 25 × 2Gy with twice daily 825mg/m 2 capecitabine) combined with bevacizumab (5mg/kg, day -14, 1, 15, 29 of CRT) followed by surgery. Patients with cT4 tumours, cT3 within 5cm from the anal verge or high cT3 within 2mm of the mesorectal fascia (MRF) were included. Safety was presented in terms of number of toxicity failures, according to protocolised 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 Tumour 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). 71% of tumours involved the MRF at baseline, 56% were cT4 and 71% were cN+. Eight patients developed toxicity failures (three bowel perforations, two pulmonary embolisms, two bleedings and one 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 one was ypT0N1 (total 15%), and 5 more achieved a major response (TRG1). 10-year incidences of LRR and DM were 6% (95%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. Micro Abstract Targeted agents may improve neoadjuvant treatment for locally advanced rectal cancer. We investigated safety and efficacy of neoadjuvant chemoradiotherapy with bevacizumab. 35 patients participated: we observed promising 10-year disease free and overall survival (both 60%) and several serious adverse events including perforations and bleedings. Investigating the combination of bevacizumab with novel neoadjuvant treatments might lead to promising long term results.