Emerging Approaches in the Management of Patients with Neuroendocrine Liver Metastasis: Role of Liver-Directed and Systemic Therapies

Abstract

Neuroendocrine tumors (NETs) are rare neoplasms arising from cells of the neuroendocrine system in a multitude of anatomic locations, and representing a wide range of histologies. Compared with other malignancies from the same organ (eg, pancreatic NET vs pancreatic ductal adenocarcinoma), NETs are often indolent in both biology and disease progression. However, metastasis will develop in almost 40% of patients with NETs during the course of their disease, most commonly to the liver. ¹ Modlin I.M. Lye K.D. Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003; 97 : 934-959 Crossref PubMed Scopus (1839) Google Scholar In contrast to other malignancies, in a proportion of patients with neuroendocrine liver metastasis (NELM) disabling clinical symptoms can develop secondary to the production of specific biogenic amines and polypeptide hormones. Therefore, treatment of patients with NELM is focused on optimizing quality of life through reduction of such hormone-related symptoms, and improving survival in patients with disease amenable to liver-directed therapy, including hepatic resection, thermal ablation, and intra-arterial therapy (IAT). ² Chamberlain R.S. Canes D. Brown K.T. et al. Hepatic neuroendocrine metastases: does intervention alter outcomes?. J Am Coll Surg. 2000; 190 : 432-445 Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar ^{,  3} Chen H. Hardacre J.M. Uzar A. et al. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival?. J Am Coll Surg. 1998; 187 ( discussion 92–93) : 88-92 Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar ^{,  4} Knox C.D. Anderson C.D. Lamps L.W. et al. Long-term survival after resection for primary hepatic carcinoid tumor. Ann Surg Oncol. 2003; 10 : 1171-1175 Crossref PubMed Scopus (84) Google Scholar ^{,  5} Nave H. Mossinger E. Feist H. et al. Surgery as primary treatment in patients with liver metastases from carcinoid tumors: a retrospective, unicentric study over 13 years. Surgery. 2001; 129 : 170-175 Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar ^{,  6} Sarmiento J.M. 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 : 29-37 Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar ^{,  7} Mayo S.C. de Jong M.C. Pulitano C. et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010; 17 : 3129-3136 Crossref PubMed Scopus (246) Google Scholar ^{,  8} Mayo S.C. de Jong M.C. Bloomston M. et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol. 2011; 18 : 3657-3665 Crossref PubMed Scopus (104) Google Scholar To date, hepatic resection remains the only potentially curative option for patients with NELM, with 5-year survival after hepatectomy ranging from 60% to 80% in recent series. ⁶ Sarmiento J.M. 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 : 29-37 Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar ^{,  7} Mayo S.C. de Jong M.C. Pulitano C. et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol. 2010; 17 : 3129-3136 Crossref PubMed Scopus (246) Google Scholar ^{,  8} Mayo S.C. de Jong M.C. Bloomston M. et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol. 2011; 18 : 3657-3665 Crossref PubMed Scopus (104) Google Scholar ^{,  9} Norton J.A. Warren R.S. Kelly M.G. et al. Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery. 2003; 134 ( discussion 1063–1065) : 1057-1063 Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar ^{,  10} Frilling A. Li J. Malamutmann E. et al. Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease. Br J Surg. 2009; 96 : 175-184 Crossref PubMed Scopus (131) Google Scholar ^{,  11} Scigliano S. Lebtahi R. Maire F. et al. Clinical and imaging follow-up after exhaustive liver resection of endocrine metastases: a 15-year monocentric experience. Endocr Relat Cancer. 2009; 16 : 977-990 Crossref PubMed Scopus (59) Google Scholar Until recent reports of the use of somatostatin analogues in neuroendocrine tumors of mid-gut origin, and sunitinib and everolimus in patients with advanced pancreatic NETs (PNETs), there has been little success in the use of systemic therapy to treat patients with advanced NELM, with historic responses ranging from 15% to 20%. ¹² Raymond E. Dahan L. Raoul J.L. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364 : 501-513 Crossref PubMed Scopus (1613) Google Scholar ^{,  13} Engstrom P.F. Lavin P.T. Moertel C.G. et al. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol. 1984; 2 : 1255-1259 Crossref PubMed Scopus (211) Google Scholar ^{,  14} Yao J.C. Shah M.H. Ito T. et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364 : 514-523 Crossref PubMed Scopus (1895) Google Scholar ^{,  15} O'Toole D. Hentic O. Corcos O. et al. Chemotherapy for gastro-enteropancreatic endocrine tumours. Neuroendocrinology. 2004; 80 : 79-84 Crossref PubMed Scopus (78) Google Scholar As these systemic agents are not curative, there is still considerable interest in the use of liver-directed therapy to increase patient survival and address hormonally related symptoms. In addition to surgery, IAT has emerged as an alternative liver-directed approach to treat patients with NELM. We review the management of patients with NELM with an emphasis on clarifying the relative roles of surgery, IAT, as well as emerging systemic therapeutic agents. To accomplish this, we performed an extensive literature search in PubMed using medical subject headings (ie, neuroendocrine, carcinoid, liver metastasis, hepatic metastases, hepatectomy, liver resection, transplantation, intra-arterial therapy, radiation therapy, chemotherapy) to identify relevant articles for inclusion.