Neuroendocrine tumors (NETs) encompass a heterogeneous group of neoplasms arising nearly anywhere in the body. Importantly, the nomenclature and staging of NETs have evolved considerably, with progressively more attention paid to grade and site of origin. According to the 2010 WHO classification scheme, NETs are divided into well-differentiated (low- and intermediategrade) NETs and poorly differentiated (high-grade) neuroendocrine carcinomas.1–3 The distinction between poorly differentiated and well-differentiated tumors is based on tumor grade (high vs. low/intermediate), mitotic count (> 20 per 10 high-powered field), and Ki-67 proliferation index (> 20%). Given their high predilection for metastases, high-grade tumors are typically treated with platinum-based systemic chemotherapy.4
Among well-differentiated tumors, distinguishing between carcinoid and pancreatic NETs (pancNETs) has become increasingly important, given accumulating evidence suggesting a differential response to therapy.1,2 Although histologically similar, pancNETs are thought to be more responsive to chemotherapy.5 In addition, sunitinib and everolimus were both recently approved specifically for pancNETs; neither agent has received FDA approval for carcinoid.6–9 In contrast, the antitumor activity of octreotide has only been definitively shown in carcinoid.5,10 Although somewhat archaic, the term carcinoid will be used throughout this article to encompass well-differentiated NETs arising from the foregut (lungs, thymus, stomach, duodenum), midgut (small bowel, cecum, appendix), or hindgut (descending colon, rectum).
Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a serious challenge.11,12 Surgical resection of both primary and metastatic lesions remains the mainstay of treatment, but patients frequently present with advanced, unresectable disease. In these patients, management of hormone-mediated symptoms and/or tumor bulk eventually becomes necessary. Importantly, the potentially indolent nature of carcinoids is a serious consideration. Although tumor grade, stage, and primary site influence overall survival, most patients can expect to experience slow progression over many years. For example, patients with metastatic tumors arising in the small bowel (jejunum and ileum) have a median overall survival longer than 5 years (65 months), a 5-year overall survival of 54%, and a 10-year overall survival of 30%.13 As a result, the type and timing of therapy must be carefully considered in the context of the expected disease course (weighing risks and benefits). In the absence of syndrome-associated symptoms or resectable disease, many advocate for waiting until evidence for radiographic progression or progressive symptoms before initiating antitumor therapy.11,14 For liver-dominant disease, liver-directed treatment such as resection, ablation, and embolization are often used.15 Octreotide is routinely used to control hormone-mediated symptoms, but also has proven antitumor activity in tumors arising in the small bowel.10 Beyond octreotide, no standard therapy exists. Additional systemic treatment options are desperately needed. Recent data suggest that vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) may be valid therapeutic targets, but definitive proof is lacking.
Dr. Paulson has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors. Dr. Bergsland had disclosed that she is an advisory board member for Pfizer, Inc., and receives clinical research support from Novartis, Genentech, Inc., Roche, and sanofi-aventis U.S.
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