Treatment Landscape and Ongoing Clinical Trials in Neuroendocrine Tumors

Abstract

Therapy in neuroendocrine tumors (NET) is guided by the presence of hormone-related syndromes, somatostatin receptor status, histology (ki67), aggressiveness and extrahepatic spread. Therapy aims at syndrome and tumor control. Surgery is the only option toward a cure. Loco-regional therapies (e.g. embolisation, radiofrequency ablation) may reduce tumor load and improve clinical syndromes. Somatostatin analogs (SSA) and interferon-alpha are established therapies for carcinoid syndrome (CS). An oral serotonin synthesis inhibitor is evaluated in refractory CS (TELESTAR). Other medical therapies (PPI; diazoxide) are used for syndrome control depending on the tumor type. Antiproliferative therapy options include SSA, novel targeted drugs and systemic chemotherapy. Large placebo-controlled trials provide evidence of the antiproliferative efficacy of SSA (octreotide and lanreotide) in midgut NET and enteropancreatic NET, respectively. Similarly, the novel molecular-targeted therapies, the multiple tyrosine kinase inhibitor (TKI) sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus have been evaluated in placebo-controlled trials, and approved in progressive pancreatic NET. Novel TKIs and combinations of everolimus with SSA or bevacizumab are currently explored in clinical trials to improve response rates or overcome drug resistance. Everolimus and sunitinib (RADIANT-4; Sunland study) are under evaluation in non-pancreatic NET, as well as high dose octreotide vs. Lu-DOTATATE in midgut NET (NETTER-1). Systemic chemotherapy has very limited if any value in slowly growing advanced NET ("carcinoids of different sites"), but is established therapy (streptozotocin/ 5-FU) in pancreatic NET. Future studies will have to establish in which line targeted drugs will be used, especially in pancreatic NET (SEQTOR trial). Molecular markers to preselect patients for specific therapies still need to be identified. Systemic chemotherapy is standard therapy in neuroendocrine carcinoma (NEC G3; first line cisplatin or carboplatin/ etoposide; second-line options include FOLFOX, FOLFIRI or temozolomide +/- capecitabine), however response rates are overall short-lasting (median 4-6 months). References: Pavel et al, ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012;95(2):157-76. Caplin M et al, CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. NEJM 2014 Rinke A et al, 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 Oct 1;27(28):4656-63 Yao JC et al, RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. Raymond E et al., Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. Pavel M, et al. Everolimus plus octreotide for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT 2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378(9808):2005-12. Disclosure: Honoraria for presentations and advisory board meetings from Novartis, Pfizer, IPSEN, Lexicon.Copyright © 2014 European Society for Medical Oncology