Systemic Therapy of Advanced Well-differentiated Small Bowel Neuroendocrine Tumors Progressive on Somatostatin Analogues

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors whose management requires a nuanced and multi-disciplinary approach in order to control symptoms, halt tumor growth, and improve survival outcomes. Of late, the treatment landscape of NENs has advanced considerably as a result of several pivotal clinical trials, which have established somatostatin analogues as first-line therapy for advanced, metastatic, well-differentiated neuroendocrine tumors (NETs). However, an evolving classification system as well as an increased understanding of distinct clinical, molecular, and biologic features contribute to complexity in management. In particular, there remains limited randomized prospective data in the somatostatin analogue (SSA)-refractory setting for patients with primary tumors that originate in the small bowel. For well-differentiated small bowel neuroendocrine tumors (SBNETs), treatment beyond SSAs includes radionuclide therapy, targeted agents, liver-directed therapy, and to a lesser extent, cytotoxic chemotherapy. In the current era, selection of these agents is largely based on expert opinion in the context of patient and tumor characteristics without definitive data on the preferred order of agents to administer. In this review, we aim to describe the treatment landscape of metastatic SBNETs beyond SSAs and provide an overview of novel treatments which are currently under clinical evaluation.