Bevacizumab-based combination therapy for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a systematic review of the literature

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) consist of a large heterogeneous group of epithelial tumors with neuroendocrine differentiation that arises in gastrointestinal tract and pancreatic tissues. Advanced GEP-NENs are considered distinct disease entity with limited approved treatment options and poor prognosis. So, we will explore in this systematic review the value of using bevacizumab-based combination in this subset of NENs. PubMed, Medline, the Cochrane Library, trip database and Google Scholar were searched using the terms GEP-NENs OR Gastroenteropancreatic neuroendocrine tumors AND systemic anticancer therapy AND Bevacizumab and selecting only the English literature. Outcomes of interest included progression-free survival and overall survival (PFS and OS), tumor response and toxicities. A total of 17 potentially relevant trials were identified, of which eight studies were excluded. Hence, nine trials involving 320 patients were included. Median PFS was reported in eight out of the nine studies ranging from 8.2 to 16.5 months. Median OS was reported in one study, and it was 33.3 months for the whole group. The disease control rate was reported in the seven studies, and it ranged from 80 to 96 %. The overall response rate was reported in eight studies, and it ranged from 0 to 64 %. Frequently reported grade 3/4 toxicities were gastrointestinal toxicities, mucocutaneous toxicities and hematologic toxicities (particularly leucopenia). The current evidence from the available clinical trials suggests that bevacizumab in combination with some other anticancer agents (especially mTOR inhibitors and interferons) could be a more effective and tolerable treatment for advanced GEP-NENs in the future. However, such bevacizumab-based combination cannot be recommended outside the setting of clinical trials.