Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and heterogenous malignancies. Recent advances in histopathological classification according to the anatomical site of origin, proliferation rate, and extend of the disease have created a valid and powerful tool for the prognostic stratification of GEP-NETs. Chromogranin A is still the best available marker used for the biochemical confirmation of these tumors, but new more sensitive markers are urgently required. Although scintigraphy with In-111-octreotide has widely been applied for the localization and staging of GEP-NETs, newer imaging modalities based on the functional characteristics of these tumors are evolving aiming not only to facilitate the diagnosis but also prognosis and evaluation of treatment. Somatostatin receptors are the primary therapeutic targets through somatostatin analogs and peptide receptor radionuclide therapy (PRRT) producing symptomatic, biochemical and to a lesser extent antiproliferative effects. Due to the relatively limited and erratic response to chemotherapy, new molecular targeted therapies exploiting some of the biological properties of GEP-NETs such as increased vascularity and inhibition of pathways involved in downstream signal transduction have evolved. Some of these therapies, the mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have been recently validated in phase III studies producing practice changing outcomes. In addition, two oral chemotherapeutic agents temozolomide and capecitabine, show promising effects and may replace streptozotocin-based regimens whereas combination therapies with the angiogenesis inhibitor bevacizumab are being investigated. Although progression free survival is used as a feasible primary end point due to the long survival of patients even in the presence of extensive disease prolongation of overall survival following the introduction of new therapies needs to be established.