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European Endocrinology Highlights New Developments in the Treatment of Neuroendocrine Tumours – RADIANT-4, NETTER-1 and Telotristat Etiprate Emilia Sbardella and Ashley Grossman Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK Abstract Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose incidence has increased significantly in recent years, and whose optimal management remains controversial. We report the latest innovations in their management, in particular the results of three trials concerning the use of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in non-functional NETs of lung/gastrointestinal (GI) origin, the first randomised trial of radiolabelled 177 Lu-DOTATATE in patients with mid-gut NETs, and the use of the 5-HT synthesis inhibitor, telotristat etiprate, in patients with the carcinoid syndrome. Keywords Neuroendocrine tumours, treatment, everolimus, 177 Lu-DOTATATE, 5-HT synthesis inhibitor, telotristat etiprate Disclosure: Emilia Sbardella has nothing to disclose in relation to this article. Ashley Grossman has received consulting and lecture fees from Novartis, and was part of the NETTER-1 research trial. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 7 January 2016 Published Online: 29 February 2016 Citation: European Endocrinology, 2016;12(1):44–6 Correspondence: Ashley Grossman, OCDEM, University of Oxford, Churchill Hospital, Headington, OX3 7LE, UK. E: Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms that originate from different types of neuroendocrine cells throughout the body. 1 While previously considered to be relatively uncommon, their overall incidence has been reported as increasing for reasons which are unclear. 2–4 Surgery is the only truly curative therapy, but there are now a variety of other treatment options although their specific use and sequencing remains controversial. 3 However, somatostatin analogues (SSAs), particularly the long-acting formulations of octreotide and lanreotide, are highly effective for symptomatic patients with secretory syndromes, and recent studies have also shown their ability to retard tumour progression in the PROMID, CLARINET and RADIANT-2 trials. 5–8 The multi-ligand SSA pasireotide was also shown to control the symptoms of carcinoid syndrome in patients with advanced NETs refractory/resistant to octreotide long-acting release (LAR) therapy. 9 Recently, at the European Cancer Congress (ECC) of the European Society for Medical Oncology (ESMO) in Vienna, in September 2015, three trials were presented which provide novel data on therapeutic options. Previous studies have demonstrated the efficacy of everolimus, an inhibitor of mammalian target of rapamycin (mTOR) (a serine–threonine kinase that stimulates cell growth, proliferation and angiogenesis) 10–12 to slow tumour progression of pancreatic NETs (RADIANT-3) 13 and symptomatic mid-gut tumours (RADIANT-2). 7 RADIANT-4 was a placebo- controlled, double-blind, phase III study carried out in 13 European centres on the efficacy and safety of everolimus in patients with 60 advanced, progressive, non-functional NETs of the lung and gut. 14 Non-functional NETs are often diagnosed later when the cancer has become advanced, and at present there are limited treatment options available. This is particularly important for patients with lung carcinoids, as there is currently no approved treatment for such patients.The trial included 302 patients in which the patients were randomised (2:1) to everolimus (10 mg/d) or placebo and were stratified by tumour origin, World Health Organization performance status and prior SSA treatment. There was a statistically significant 52% reduction in the relative risk of progression or death in favour of everolimus, with a clinically relevant 7.1-month prolongation of progression-free survival (PFS) compared with those who had taken placebo. In addition, everolimus was well tolerated and its established safety profile confirmed. Over many years, peptide receptor radionuclide therapy (PRRT) using radiolabelled octreotide has been extensively used for the treatment of progressive NETs, and while individual results have been encouraging, there has been no formal assessment of such therapy. For most NETs, molecular-targeted radiation therapy involves the systemic administration of a radiolabelled peptide designed to target somatostatin receptors on tumour cells with high affinity and specificity. 15 Over the past 15 years, PRRT with the radiolabelled somatostatin receptor agonists, such as 90 Y-DOTATOC, 177 Lu-DOTATATE and 177 Lu-DOTATOC, have been successfully used to target metastatic and inoperable NETs. 15-16 Now, Strosberg and colleagues have presented data from the NETTER-1 trial, 17 a phase III multicentre, stratified, TOUCH ME D ICA L ME D IA