A New Era for the Systemic Therapy of Neuroendocrine Tumors

Abstract

After completing this course, the reader will be able to:1. Describe the underlying biology of neuroendocrine tumors including pancreatic neuroendocrine tumors (PNETs) and carcinoids and the importance of these biologic features in the evolution of new drugs for these diseases.2. Cite the historical data regarding the use of cytotoxic agents in the treatment of pancreatic neuroendocrine tumors and carcinoids.3. Explain the significance of recent clinical trials utilizing biologic agents, in particular octreotide, the small molecule tyrosine kinase inhibitor, sunitinib and the mammalian target of rapamycin (mTOR) inhibitor, everolimus, and how these medications have altered the natural history of both pancreatic neuroendocrine tumors and carcinoids.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTCarcinoids and pancreatic neuroendocrine tumors are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease. An improved understanding of the molecular mechanisms involved in these tumors has implicated several pathways that have led to new therapeutic approaches. In this manuscript, we describe the biology of neuroendocrine tumors and approaches to systemic therapy. We review early data regarding the use of cytotoxics and several recent studies employing more targeted approaches that promise to change the standard of care. Specifically, phase III studies indicate that pharmacologic inhibition of the vascular endothelial growth factor pathway with sunitinib, and of the mammalian target of rapamycin pathway with everolimus, appears to have altered the natural history of these diseases. These successes set the stage for further advances in the management of patients with neuroendocrine tumors. The Oncologist 2012; 17:326 -338Correspondence: Neal J. Meropol, M.D.,

Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) – A phase II non-randomised trial

“…No new agent has been approved for this disease over the last three decades and very few studies assessing chemotherapy or targeted treatments have been conducted in GI-NETs only [3,22]. Most other studies were performed in heterogeneous populations including foregut NET and PNET with limited or inaccurate NET grade or stage definition.…”

“…The management of metastatic NETs is difficult when they are not accessible to surgery and there is currently no standard treatment for GI-NETs [3]. Interferon alpha has been used as a treatment of carcinoid tumours of the midgut for almost 20 years, although often with potentially high toxicity [4].…”

Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) – A phase II non-randomised trial

“…Two new targeted therapies with a different mechanism of action (sunitinib and everolimus) have been approved in the treatment of well-differentiated unresectable or metastatic progressive P-NETs [1]. The results obtained with sunitinib confirm that inhibition of vascular endothelial growth factor (VEGF) receptor has the potential for blocking the growth of neuroendocrine tumours (NETs) which are highly vascular neoplasms known to overexpress VEGF and its receptor [11,12].…”

“…Their low incidence is gradually increasing and may be underestimated, as most P-NETs (90%) are non-functional and therefore challenging to diagnose [1][2][3][4][5]. The median survival time for patients with distant metastatic disease is approximately 33-39 months [1,6], and the 5-year survival rate is approximately 40% [7].…”

Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary

“…Functional NET are associated with clinical symptoms due to hormonal secretion by the tumors; both nonfunctional and functional NET can present with symptoms related to the primary tumor, particularly obstruction, or symptoms from metastatic disease [1][2][3][4]. More than 60% of NET originate in the gastrointestinal (GI) tract, the majority of which are nonfunctional [1,[5][6][7].…”