Abstract
Although gastroenteropancreatic neuroendocrine tumors are often perceived as being indolent tumors, more than half of the patients will harbor liver metastases at the time of diagnosis. Gastroenteropancreatic neuroendocrine tumors have the potential to be aggressive and resistant to therapy, making the integration of both locoregional and systemic therapy even more critical in the treatment of patients with locally advanced or metastatic lesions. Over the last several years, significant advancements have been made in the surgical treatment, liver-directed therapy, and medical management of gastroenteropancreatic neuroendocrine tumors. While surgical resection is the cornerstone of therapy, cytoreductive surgery, orthotopic liver transplantation, local ablation, and intra-arterial therapy all improve the prognosis of patients suffering with locally advanced or metastatic disease. In addition, great strides have been made in the medical management of gastroenteropancreatic neuroendocrine tumors, particularly with the evolution of novel molecular targeted therapy, such as everolimus and sunitinib. Hence, gastroenteropancreatic neuroendocrine tumor is becoming a disease process requiring more of a multi-disciplinary approach with the integration of both locoregional and systemic therapies for improved outcomes.
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Fraenkel M, Kim MK, Faggiano A, Valk GD. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol 2012;26:691-703.
Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011;40:1-18, vii.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072.
Scherübl H, Streller B, Stabenow R, Herbst H, Höpfner M, Schwertner C, Steinberg J, Eick J, Ring W, Tiwari K, Zappe SM. Clinically detected gastroenteropancreatic neuroendocrine tumors are on the rise: epidemiological changes in Germany. World J Gastroenterol 2013;19:9012-9019.
Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K, Komoto I, Tanaka M, Imamura M, Jensen RT, Takayanagi R, Shimatsu A. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol 2015;50:58-64.
Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Dig Dis Sci 1991;36:933-942.
Griruelius L, Hultquist G, Stenkvist B. Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. Virchows Arch A Pathol Anat Histol 1975;365:275-288.
Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand A 1976;84:322-330.
Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010;39:707-712.
Bilimoria KY, Talamonti MS, Tomlinson JS, Stewart AK, Winchester DP, Ko CY, Bentrem DJ. Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg 2008;247:490-500.
Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, Di Fonzo M, Tornatore V, Milione M, Angeletti S, Cattaruzza MS, Ziparo V, Bordi C, Pederzoli P, Delle Fave G. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005;12:1083-1092.
Cherif R, Gaujoux S, Couvelard A, Dokmak S, Vuillerme MP, Ruszniewski P, Belghiti J, Sauvanet A. Parenchyma-sparing resections for pancreatic neuroendocrine tumors. J Gastrointest Surg 2012;16:2045-2055.
Watzka FM, Fottner C, Miederer M, Schad A, Weber MM, Otto G, Lang H, Musholt TJ. Surgical therapy of neuroendocrine neoplasm with hepatic metastasis: patient selection and prognosis. Langenbecks Arch Surg 2015;400:349-358.
Mayo SC, de Jong MC, Bloomston M, Pulitano C, Clary BM, Reddy SK, Gamblin TC, Celinksi SA, Kooby DA, Staley CA, Stokes JB, Chu CK, Arrese D, Ferrero A, Schulick RD, Choti MA, Geschwind JF, Strub J, Bauer TW, Adams RB, Aldrighetti L, Mentha G, Capussotti L, Pawlik TM. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010;17:3129-3136.
Touzios JG, Kiely JM, Pitt SC, Rilling WS, Quebbeman EJ, Wilson SD, Pitt HA. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg 2005;241:776-783, discussion 783-785.
Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197:29-37.
Scigliano S, Lebtahi R, Maire F, Stievenart JL, Kianmanesh R, Sauvanet A, Vullierme MP, Couvelard A, Belghiti J, Ruszniewski P, Le Guludec D. Clinical and imaging follow-up after exhaustive liver resection of endocrine metastases: a 15-year monocentric experience. Endocr Relat Cancer 2009;16:977-990.
Steinmüller T, Kianmanesh R, Falconi M, Scarpa A, Taal B, Kwekkeboom DJ, Lopes JM, Perren A, Nikou G, Yao J, Delle Fave GF, O'Toole D. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008;87:47-62.
Cusati D, Zhang L, Harmsen WS, Hu A, Farnell MB, Nagorney DM, Donohue JH, Que FG, Reid-Lombardo KM, Kendrick ML. Metastatic nonfunctioning pancreatic neuroendocrine carcinoma to liver: surgical treatment and outcomes. J Am Coll Surg 2012;215:117-124,discussion 124-125.
Capurso G, Rinzivillo M, Bettini R, Boninsegna L, Delle Fave G, Falconi M. Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg 2012;99:1480-1486.
Bertani E, Fazio N, Botteri E, Chiappa A, Falconi M, Grana C, Bodei L, Papis D, Spada F, Bazolli B, Andreoni B. Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach. Surgery 2014;155:607-614.
Nguyen SQ, Angel LP, Divino CM, Schluender S, Warner RRP. Surgery in malignant pancreatic neuroendocrine tumors. J Surg Oncol 2007;96:397-403.
Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave G, Falconi M. Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. Neuroendocrinology 2011;93:223-229.
Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation 1998;66:1307-1312.
Le Treut YP, Delpero JR, Dousset B, Cherqui D, Segol P, Mantion G, Hannoun L, Benhamou G, Launois B, Boillot O, Domergue J, Bismuth H. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report. Ann Surg 1997;225:355-364.
Florman S, Toure B, Kim L, Gondolesi G, Roayaie S, Krieger N, Fishbein T, Emre S, Miller C, Schwartz M. Liver transplantation for neuroendocrine tumors. J Gastrointest Surg 2004;8:208-212.
Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol 2007;47:460-466.
de Herder WW, Mazzaferro V, Tavecchio L, Wiedenmann B. Multidisciplinary approach for the treatment of neuroendocrine tumors. Tumori 2010;96:833-846.
Grąt M, Remiszewski P, Smoter P, Wronka K, Grąt K, Lewandowski Z, Koperski L, Górnicka B, Pacho R, Zborowska H, Patkowski W, Krawczyk M. Outcomes following liver transplantation for metastatic neuroendocrine tumors. Transplant Proc 2014;46:2766-2769.
Olausson M, Friman S, Herlenius G, Cahlin C, Nilsson O, Jansson S, Wängberg B, Ahlman H. Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors. Liver Transpl 2007;13:327-333.
Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery 2010;148:1288-1293, discussion 1293.
Norlen 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;100:1505-1514.
Rossi S, Viera FT, Ghittoni G, Cobianchi L, Rosa LL, Siciliani L, Bortolotto C, Veronese L, Vercelli A, Gallotti A, Ravetta V. Radiofrequency ablation of pancreatic neuroendocrine tumors: a pilot study of feasibility, efficacy, and safety. Pancreas 2014;43:938-945.
de Baere T, Deschamps F, Tselikas L, Ducreux M, Planchard D, Pearson E, Berdelou A, Leboulleux S, Elias D, Baudin E. GEP-NETS update: Interventional radiology: role in the treatment of liver metastases from GEP-NETs. Eur J Endocrinol 2015;172:R151-166.
Mohan H, Nicholson P, Winter DC, O'Shea D, O'Toole D, Geoghegan J, Maguire D, Hoti E, Traynor O, Cantwell CP. Radiofrequency Ablation for Neuroendocrine Liver Metastases: A Systematic Review. J Vasc Interv Radiol 2015;26:935-942.
Devcic Z, Rosenberg J, Braat AJ, Techasith T, Banerjee A, Sze DY, Lam MG. The efficacy of hepatic 90Y resin radioembolization for metastatic neuroendocrine tumors: a meta-analysis. J Nucl Med 2014;55:1404-1410.
Sadaria MR, Hruban RH, Edil BH. Advancements in pancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol 2013;7:477-490.
Donati M, Basile F. New trends in the multidisciplinary treatment of liver tumors. Future Oncol 2013;9:1093-1096.
Alagusundaramoorthy SS, Gedaly R. Role of surgery and transplantation in the treatment of hepatic metastases from neuroendocrine tumor. World J Gastroenterol 2014;20:14348-14358.
Mayo SC, de Jong MC, Bloomston M, Pulitano C, Clary BM, Reddy SK, Clark Gamblin T, Celinski SA, Kooby DA, Staley CA, Stokes JB, Chu CK, Arrese D, Ferrero A, Schulick RD, Choti MA, Geschwind JF, Strub J, Bauer TW, Adams RB, Aldrighetti L, Mentha G, Capussotti L, Pawlik TM. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol 2011;18:3657-3665.
Maire F, Lombard-Bohas C, O'Toole D, Vullierme MP, Rebours V, Couvelard A, Pelletier AL, Zappa M, Pilleul F, Hentic O, Hammel P, Ruszniewski P. Hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from well-differentiated midgut endocrine tumors: a prospective randomized study. Neuroendocrinology 2012;96:294-300.
Fiore F, Del Prete M, Franco R, Marotta V, Ramundo V, Marciello F, Di Sarno A, Carratù AC, de Luca di Roseto C, Colao A, Faggiano A. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocrine 2014;47:177-182.
Pitt SC, Knuth J, Keily JM, McDermott JC, Weber SM, Chen H, Rilling WS, Quebbeman EJ, Agarwal DM, Pitt HA. Hepatic neuroendocrine metastases: chemo- or bland embolization? J Gastrointest Surg 2008;12:1951-1960.
Bhagat N, Reyes DK, Lin M, Kamel I, Pawlik TM, Frangakis C, Geschwind JF. Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. Cardiovasc Intervent Radiol 2013;36:449-459.
Guiu B, Deschamps F, Aho S, Munck F, Dromain C, Boige V, Malka D, Leboulleux S, Ducreux M, Schlumberger M, Baudin E, de Baere T. Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs. drug-eluting beads. J Hepatol 2012;56:609-617.
Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-4663.
Reidy-Lagunes D, Thornton R. Pancreatic neuroendocrine and carcinoid tumors: what's new, what's old, and what's different? Curr Oncol Rep 2012;14:249-256.
Caplin ME, Pavel M, Ćwikla JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-233.
Cives M, Kunz P, Morse B, Coppola D, Schell M, Campos T, Nguyen P, Nandoskar P, Khandelwal V, Strosberg J. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer 2015;22:1-9.
Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2011;38:302-311.
Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003;21:2689-2696.
Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61-72.
Burns WR, Edil BH. Neuroendocrine pancreatic tumors: guidelines for management and update. Curr Treat Options Oncol 2012;13:24-34.
Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin–doxorubicin, streptozocin–fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519-523.
Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004;22:4762-4771.
Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268-275.
Abdel-Rahman O, Fouad M. Temozolomide-based combination for advanced neuroendocrine neoplasms: a systematic review of the literature. Future Oncol 2015;11:1275-1290.
Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA, Jr., Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011;331:1199-1203.
de Wilde RF, Edil BH, Hruban RH, Maitra A. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nat Rev Gastroenterol Hepatol 2012;9:199-208.
Milan SA, Yeo CJ. Neuroendocrine tumors of the pancreas. Curr Opin Oncol 2012;24:46-55.
Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol 2012;47:941-960.
Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26:4311-4318.
Eriksson B. New drugs in neuroendocrine tumors: rising of new therapeutic philosophies? Curr Opin Oncol 2010;22:381-386.
Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res 2013;73:1449-1453.
Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, Li JZ, Baum CM, Fuchs CS. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-3410.
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Custem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-513.
De Jong MC, Farnell MB, Sclabas G, Cunningham SC, Cameron JL, Geschwind JF, Wolfgang CL, Herman JM, Edil BH, Choti MA, Schulick RD, Nagorney DM, Pawlik TM. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 2010;252:142-148.
Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, Kwekkeboom D, Lau WY, Klersy C, Vilgrain V, Davidson B, Siegler M, Caplin M, Solcia E, Schilsky R. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 2014;15:e8-21.
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Grandhi, M.S., Lafaro, K.J. & Pawlik, T.M. Role of Locoregional and Systemic Approaches for the Treatment of Patients with Metastatic Neuroendocrine Tumors. J Gastrointest Surg 19, 2273–2282 (2015). https://doi.org/10.1007/s11605-015-2931-z
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DOI: https://doi.org/10.1007/s11605-015-2931-z