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Advances in the management and treatment of gastroenteropancreatic neuroendocrine tumors

EC Feliber, RR Perry,AI Vinik

Gastroenteropancreatic tumors or pancreatic neuroendocrine tumors (PNETs) are relatively rare tumors, but are being recognized with increasing frequency. They comprise of secretory and nonsecretory tumors. Secretory tumors are recognized by distinct clinical syndromes, such as insulinoma and gastrinoma and nonsecretory tumors present clinically as mass effect and metastases. PNETs occur sporadically or as part of the multiple endocrine neoplasia type and von Hippel–Lindau and von Recklinghausen syndromes. Biomarkers for these tumors include peptides that are known to be secreted, and in addition chromogranins useful for detection, pancreastatin and Neurokinin A. New techniques are being developed for tumor localization, including PET scanning and peptide receptor scanning. Neuroendocrine tumors tend to be more sensitive to containment using somatostatin analogs and the currently available analog that binds the somatostatin receptors 2 and 5 will soon include agonists that also target the 1, 3 and 4 receptors. This at least has the theoretical advantage of greater efficacy, if not specificity, and a wider range of tumor targets. Two new agents have been approved for treating PNETs; a tyrosine kinase inhibitor and an mTOR inhibitor, which have interesting actions on increasing progression-free survival. Perhaps of great interest is the prediction of response to these agents based upon mutations involving the tyrosine kinase or mTOR pathway, the MEN1 gene and the ret proto-oncogene and the recent recognition of DAXX and ATRX genes associated with chromatin remodeling. There is emerging concurrence on the pathology and staging of these tumors. Of additional benefit is the use of bone alkaline phosphatase and telopeptide as markers of osteoblasts and osteoclast activation. Surgical excision remains the mainstay of treatment of the primary tumor and somatostatin analogs control symptoms and may have some antitumor activity. Recently there has been interest in healthrelated quality of life. Of particular interest is the relationship of quality of life to progression-free survival and to the pathophysiology of these tumors. A flurry of interest in the use of combination therapies and interventions based upon known pathophysiology is likely to be rewarded with new and emerging treatment for PNETs in the not too distant future.