New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors

Abstract

Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogues is established in symptom relief, but the efficacy of interferon and radiopeptide targeted therapy is not clear. The utility of a variety of tyrosine kinase and antiangiogenic agents is variable and under investigation, whereas the role of cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, whereas the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation is under examination. This article describes the current options for systemic therapy for GEP-NETs within the framework of the current World Health Organization classification system.

Figure 1

Schema of Gastroenteropancreatic neuroendocrine tumors and treatment options

Figure 2. Overview of the novel therapeutic targets for GEP-NETs

Neuroendocrine tumors are highly angiogenic and dependent on EGF/EGFR and VEGF/VEGFR activation to initiate and maintain, proliferation, survival and invasion. Intracellular targeting of the mTor pathway (Everolimus, Temsirolimus), AKT/STAT (Atiprimod) or growth factor receptors (e.g. Gefitinib or Sorafenib) have “some” therapeutic efficacy in individual tumors. Targeting VEGF with Bevacizumab inhibits”cross-talk” between tumor cells and endothelial cells in the tumor microenvironment. This is a critical relationship in metastatic development.