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. 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).^- 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.^- 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%.^- 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.

Figure 1

Overall survival from time of first liver-directed operation for patients with hepatic neuroendocrine metastasis. Median overall survival was 125.1 months, with 5- and 10-year survival of 74 and 51%, respectively. (With kind permission from Springer Science+Business Media: Annals of Surgical Oncology, Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis, vol 17, 2010, pages 3129–3136, Mayo SC, de Jong MC, Pulitano C, et al, Figure 1 [7].)

Figure 2

(A) Overall survival of propensity-matched patients stratified by receipt of surgery vs intra-arterial therapy (IAT) (p = 0.04). (B) Kaplan-Meier survival for propensity-matched patients with >25% hepatic tumor burden undergoing either IAT or hepatic resection of neuroendocrine liver metastasis (NELM). Patients with high-volume symptomatic disease benefited the most from surgical management (median survival: surgery, 87 months vs IAT, 51 months; p = 0.04). With kind permission from Springer Science+Business Media: Annals of Surgical Oncology, Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis, vol 18, 2011, pages 3657–3665, Mayo SC, de Jong MC, Bloomston M, et al, Figures 3C and 2 [8].

Figure 3

(A) Time to progression (TTP) in the Placebo-Controlled Prospective Randomized Study on the Antiproliferative Efficacy of Octreotide LAR in Patients with Metastatic Neuroendocrine Midgut Tumors trial for patients treated with octreotide LAR; the TTP in the octreotide LAR group was 14.3 months vs 6 months in the placebo group (p = 0.000072). Log-rank test stratified by functional activity: p = 0.000072; hazard ratio = 0.34 (95% CI, 0.20–0.59). (Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved. Rinke A, Müller HH, Schade-Brittinger C, et al; PROMID Study Group: 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 vol 27[28], 2009:4656–4663 [64].) (B) Progression-free survival (PFS) in the phase 3 RAD001 in Advanced Neuroendocrine Tumors (RADIANT-3) trial; patients in the everolimus group had a median PFS of 11.0 months compared with 4.6 months in the placebo group (p < 0.001). (From New England Journal of Medicine, Yao JC, Shah MH, Ito T; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group, Everolimus for advanced pancreatic neuroendocrine tumors, vol 364, pages 514–523. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)