Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy

Abstract

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 (111)In-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.

Appendiceal neuroendocrine neoplasms: diagnosis and management

“…However, aNENs may be under-reported in several series or may not even be registered in any cancer database as they are considered to be indolent (Van Eeden et al 2002, Hauso et al 2008, Alexandraki & Kaltsas 2012. Indeed, in the Surveillance, Epidemiology and End Results (SEER) series, only neoplasms considered as malignant are included, with aNENs displaying a very low prevalence (McCusker et al 2002).…”

“…Moreover, there are currently a number of systemic therapies available for patients with disseminated disease (Alexandraki & Kaltsas 2012, Pape et al 2012. Recent findings of patients with advanced aNENs (Grozinsky-Glasberg et al 2013) have shown that treatment with somatostatin analogues (SSAs) is associated with more prolonged progression-free survival compared to placebo (Pape et al 2012).…”

“…Regarding the small number of functional aNENs reported, treatment with SSAs should be administered (Kaltsas et al 2004, Alexandraki & Kaltsas 2012. However, because of the rarity of these cases, precise indications and the duration of such treatment have not been defined (Pape et al 2012).…”

“…These tumours are thought to arise from neuroendocrine (NE) cells (Kulke & Mayer 1999), predominantly enterochromaffin or Kulschitsky cells, which exhibit different histopathological features and hormone-secreting capacity according to the primary site of origin (Creutzfeldt 1996, Alexandraki & Kaltsas 2012.…”

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

“…Recently, two targeted therapies, the tyrosine-kinase inhibitor sunitinib and the mTOR inhibitor everolimus, have been shown to be effective in prolonging progressionfree survival in both pNETs and intestinal NETs, and have been approved for treatment of pNETs (Pavel et al 2011, Raymond et al 2011, Yao et al 2011b. Both drugs act at least in part via inhibition of tumor angiogenesis, promoting interest in the vascular features of NETs (Alexandraki & Kaltsas 2012). Well-established angiogenic growth factors, such as VEGF-A (Terris et al 1998) or angiopoietins (Srirajaskanthan et al 2009, Detjen et al 2010, are present in NETs.…”