Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion
- Jennifer Ang Chan, MD, MPH
Jennifer Ang Chan, MD, MPH
- Dana-Farber Cancer Institute
- Matthew Kulke, MD
Matthew Kulke, MD
- Director of Dana-Farber/Brigham and Women’s Carcinoid and Neuroendocrine Tumor Program
- Associate Professor of Medicine
- Harvard Medical School
- Thomas E Clancy, MD
Thomas E Clancy, MD
- Assistant Professor of Surgery
- Harvard Medical School
Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that are thought to arise from neuroendocrine cells and their precursors located throughout the body. These tumors are characterized by variable but most often indolent biologic behavior. They are also classically characterized by their ability to secrete peptides resulting in distinctive hormonal syndromes.
Classification and nomenclature — NETs can arise at different sites within the body and are classified according to their histologic features. While there are differences in terminology and grading depending on site of origin, all commonly used classification systems reflect a basic separation between more indolent, well-differentiated tumors (which in the digestive system have been traditionally referred to as carcinoid and pancreatic neuroendocrine [islet cell] tumors) and far more aggressive poorly-differentiated types that behave clinically more like small cell carcinoma of the lung. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Classification and nomenclature'.)
This topic review will cover local treatment options for patients with well-differentiated metastatic gastroenteropancreatic NETs. Systemic treatment options to control tumor growth and/or symptoms of hormone hypersecretion from gastroenteropancreatic NETs and treatment of poorly-differentiated neuroendocrine carcinomas are discussed elsewhere, as are the clinical presentation, imaging, and biochemical monitoring for patients with advanced gastroenteropancreatic NETs; pathology and classification of gastroenteropancreatic NETs; clinical features of carcinoid tumors; diagnosis of carcinoid syndrome and tumor localization; treatment of early stage carcinoid tumors; bronchial carcinoid tumors; localization and treatment of pancreatic NETs; evaluation and management of NETs of unknown primary site; management of symptoms of the carcinoid syndrome; carcinoid heart disease; and functioning pancreatic neuroendocrine tumors.
- Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours of the Digestive System, Bosman TF, Hruban RH, Theise ND (Eds), International Agency for Research on Cancer (IARC), Lyon 2010.
- Givi B, Pommier SJ, Thompson AK, et al. Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival. Surgery 2006; 140:891.
- Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003; 197:29.
- Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 2000; 190:432.
- Chen H, Hardacre JM, Uzar A, et al. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg 1998; 187:88.
- Glazer ES, Tseng JF, Al-Refaie W, et al. Long-term survival after surgical management of neuroendocrine hepatic metastases. HPB (Oxford) 2010; 12:427.
- Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010; 17:3129.
- Elias D, Lefevre JH, Duvillard P, et al. Hepatic metastases from neuroendocrine tumors with a "thin slice" pathological examination: they are many more than you think... Ann Surg 2010; 251:307.
- Mayo SC, de Jong MC, Bloomston M, et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol 2011; 18:3657.
- Norlén O, Stålberg P, Zedenius J, Hellman P. Outcome after resection and radiofrequency ablation of liver metastases from small intestinal neuroendocrine tumours. Br J Surg 2013; 100:1505.
- Gillams A, Cassoni A, Conway G, Lees W. Radiofrequency ablation of neuroendocrine liver metastases: the Middlesex experience. Abdom Imaging 2005; 30:435.
- Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory carcinoid hepatic metastases. J Surg Res 2001; 95:8.
- Hellman P, Ladjevardi S, Skogseid B, et al. Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World J Surg 2002; 26:1052.
- Berber E, Flesher N, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases. World J Surg 2002; 26:985.
- Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007; 142:10.
- Mazzaglia PJ, Berber E, Siperstein AE. Radiofrequency thermal ablation of metastatic neuroendocrine tumors in the liver. Curr Treat Options Oncol 2007; 8:322.
- Akyildiz HY, Mitchell J, Milas M, et al. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery 2010; 148:1288.
- Swärd C, Johanson V, Nieveen van Dijkum E, et al. Prolonged survival after hepatic artery embolization in patients with midgut carcinoid syndrome. Br J Surg 2009; 96:517.
- Ruszniewski P, Rougier P, Roche A, et al. Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients. Cancer 1993; 71:2624.
- Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998; 83:2293.
- Christante D, Pommier S, Givi B, Pommier R. Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy. Surgery 2008; 144:885.
- Drougas JG, Anthony LB, Blair TK, et al. Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors. Am J Surg 1998; 175:408.
- Loewe C, Schindl M, Cejna M, et al. Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and lipiodol: assessment of mid- and long-term results. AJR Am J Roentgenol 2003; 180:1379.
- de Baere T, Deschamps F, Teriitheau C, et al. Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results. J Vasc Interv Radiol 2008; 19:855.
- Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol 2008; 31:271.
- Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg 2008; 247:1029.
- King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer 2008; 113:921.
- Gaur SK, Friese JL, Sadow CA, et al. Hepatic arterial chemoembolization using drug-eluting beads in gastrointestinal neuroendocrine tumor metastatic to the liver. Cardiovasc Intervent Radiol 2011; 34:566.
- Arrese D, McNally ME, Chokshi R, et al. Extrahepatic disease should not preclude transarterial chemoembolization for metastatic neuroendocrine carcinoma. Ann Surg Oncol 2013; 20:1114.
- Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005; 104:1590.
- Cao CQ, Yan TD, Bester L, et al. Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. Br J Surg 2010; 97:537.
- Memon K, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes. Int J Radiat Oncol Biol Phys 2012; 83:887.
- Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003; 9:261.
- Kitano M, Davidson GW, Shirley LA, et al. Transarterial Chemoembolization for Metastatic Neuroendocrine Tumors With Massive Hepatic Tumor Burden: Is the Benefit Worth the Risk? Ann Surg Oncol 2016; 23:4008.
- Vogl TJ, Gruber T, Naguib NN, et al. Liver metastases of neuroendocrine tumors: treatment with hepatic transarterial chemotherapy using two therapeutic protocols. AJR Am J Roentgenol 2009; 193:941.
- Dong XD, Carr BI. Hepatic artery chemoembolization for the treatment of liver metastases from neuroendocrine tumors: a long-term follow-up in 123 patients. Med Oncol 2011; 28 Suppl 1:S286.
- Pitt SC, Knuth J, Keily JM, et al. Hepatic neuroendocrine metastases: chemo- or bland embolization? J Gastrointest Surg 2008; 12:1951.
- Ruutiainen AT, Soulen MC, Tuite CM, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol 2007; 18:847.
- Schell SR, Camp ER, Caridi JG, Hawkins IF Jr. Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg 2002; 6:664.
- Kennedy A, Bester L, Salem R, et al. Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference. HPB (Oxford) 2015; 17:29.
- Benson AB 3rd, Geschwind JF, Mulcahy MF, et al. Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study. Eur J Cancer 2013; 49:3122.
- Chandra P, Yarandi SS, Khazai N, et al. Management of intractable hypoglycemia with Yttirum-90 radioembolization in a patient with malignant insulinoma. Am J Med Sci 2010; 340:414.
- Bhagat N, Reyes DK, Lin M, et al. Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. Cardiovasc Intervent Radiol 2013; 36:449.
- Lewis MA, Jaramillo S, Roberts L, et al. Hepatic artery embolization for neuroendocrine tumors: postprocedural management and complications. Oncologist 2012; 17:725.
- Gates J, Hartnell GG, Stuart KE, Clouse ME. Chemoembolization of hepatic neoplasms: safety, complications, and when to worry. Radiographics 1999; 19:399.
- Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg 1997; 225:355.
- Lang H, Oldhafer KJ, Weimann A, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg 1997; 225:347.
- van Vilsteren FG, Baskin-Bey ES, Nagorney DM, et al. Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival. Liver Transpl 2006; 12:448.
- Marín C, Robles R, Fernández JA, et al. Role of liver transplantation in the management of unresectable neuroendocrine liver metastases. Transplant Proc 2007; 39:2302.
- Olausson M, Friman S, Herlenius G, et al. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007; 13:327.
- Gedaly R, Daily MF, Davenport D, et al. Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database. Arch Surg 2011; 146:953.
- Le Treut YP, Grégoire E, Klempnauer J, et al. Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study. Ann Surg 2013; 257:807.
- Mester J, Eng C. Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome. J Surg Oncol 2015; 111:125.
- Florman S, Toure B, Kim L, et al. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg 2004; 8:208.
- Gaujoux S, Gonen M, Tang L, et al. Synchronous resection of primary and liver metastases for neuroendocrine tumors. Ann Surg Oncol 2012; 19:4270.
- Cho CS, Labow DM, Tang L, et al. Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer 2008; 113:126.
- Daskalakis K, Karakatsanis A, Stålberg P, et al. Clinical signs of fibrosis in small intestinal neuroendocrine tumours. Br J Surg 2017; 104:69.
- Gulec SA, Mountcastle TS, Frey D, et al. Cytoreductive surgery in patients with advanced-stage carcinoid tumors. Am Surg 2002; 68:667.
- Capurso G, Rinzivillo M, Bettini R, et al. Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg 2012; 99:1480.
- Classification and nomenclature
- NATURAL HISTORY AND TREATMENT OPTIONS
- OVERVIEW OF THE APPROACH TO LOCAL TREATMENT
- HEPATIC PREDOMINANT METASTATIC DISEASE
- Surgical resection
- Nonsurgical liver-directed therapy
- - Ablation
- - Hepatic artery embolization
- Technique and outcomes
- Liver transplantation
- MANAGEMENT OF THE PRIMARY TUMOR IN PATIENTS WITH METASTATIC DISEASE
- PREVENTION AND MANAGEMENT OF CARCINOID CRISIS
- SUMMARY AND RECOMMENDATIONS