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Jaume Capdevila
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Lara Iglesias Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Irene Halperin Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Ángel Segura Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Javier Martínez-Trufero Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Maria Ángeles Vaz Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Jesús Corral Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Gabriel Obiols Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Enrique Grande Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Juan Jose Grau Medical Oncology Department, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medical Oncology Department, Endocrinology Department, Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain

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Josep Tabernero
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Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.

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Martyn E Caplin Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Marianne Pavel Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Jarosław B Ćwikła Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Alexandria T Phan Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Markus Raderer Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Eva Sedláčková Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Guillaume Cadiot Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Edward M Wolin Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Jaume Capdevila Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Lucy Wall Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Guido Rindi Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Alison Langley Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Séverine Martinez Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Edda Gomez-Panzani Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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Philippe Ruszniewski Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK
Royal Free Hospital, Charité University Medicine Berlin, University of Warmia and Mazury, University of Texas MD Anderson Cancer Center, University Hospital, Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Robert‐Debré Hospital, Markey Cancer Center, Vall d'Hebron University Hospital, Western General Hospital, Università Cattolica del Sacro Cuore, Ipsen, Ipsen, Beaujon Hospital, Paris Diderot University, London, UK

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on behalf of the CLARINET Investigators
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In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

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James Yao University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Abhishek Garg Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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David Chen Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Jaume Capdevila Vall d’Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Autonomous University of Barcelona, Barcelona, Spain

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Paul Engstrom Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

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Rodney Pommier Oregon Health and Science University, Portland, Oregon, USA

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Eric Van Cutsem University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium

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Simron Singh Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada

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Nicola Fazio European Institute of Oncology, Milan, Italy

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Wei He Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Markus Riester Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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Parul Patel Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Maurizio Voi Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

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Michael Morrissey Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

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Marianne Pavel University of Erlangen-Nuremberg, Erlangen, Germany

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Matthew Helmut Kulke Dana Farber Cancer Institute, Boston, Massachusetts, USA

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Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

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Louis de Mestier Université de Paris, Department of Gastroenterology-Pancreatology, Beaujon University Hospital (APHP), Clichy, France

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Angela Lamarca Division of Cancer Sciences, Department of Medical Oncology, The Christie NHS Foundation, University of Manchester, Manchester, United Kingdom

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Jorge Hernando Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Wouter Zandee Department of Internal Medicine, Sector Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands
Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Teresa Alonso-Gordoa Department of Medical Oncology, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain

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Marine Perrier Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France

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Annemiek ME Walenkamp Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

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Bipasha Chakrabarty Department of Pathology, The Christie, Manchester, United Kingdom

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Stefania Landolfi Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain

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Marie-Louise F Van Velthuysen Department of Pathology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

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Gursah Kats-Ugurlu Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Alejandra Caminoa Department of Pathology, University Hospital Ramon y Cajal, Madrid, Spain

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Maxime Ronot Université de Paris, Department of Radiology, Beaujon University Hospital (APHP), Clichy, France

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Prakash Manoharan Department of Radiology and Nuclear Medicine, The Christie, Manchester, United Kingdom

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Alejandro Garcia-Alvarez Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Tessa Brabander Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

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María Isabel García Gómez-Muriel Department of Radiology, University Hospital Ramon y Cajal, Madrid, Spain

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Guillaume Cadiot Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France

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Anne Couvelard Université de Paris, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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Jaume Capdevila Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Marianne E Pavel Department of Endocrinology, Erlangen University Hospital, Erlangen, Germany

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Jérôme Cros Université de Paris, Department of Pathology, Beaujon/Bichat University Hospital (APHP), Clichy/Paris, France

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There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5–12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0–24.0)) and targeted therapies (12.0 months (8.2–15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8–8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2–9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61–8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01–3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

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Marcia S Brose Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania, USA

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Jaume Capdevila Gastrointestinal and Endocrine Tumor Unit, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Rossella Elisei Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Lars Bastholt Department of Clinical Oncology, Odense University Hospital, Odense, Denmark

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Dagmar Führer-Sakel Department of Endocrinology, Diabetes and Metabolism and Clinical Chemistry, University Hospital Essen, Essen, Germany

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Sophie Leboulleux Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France
Department of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Hôpitaux Universitaires de Genève, Geneve, Switzerland

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Iwao Sugitani Department of Endocrine Surgery, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

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Matthew H Taylor Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA

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Zhuoying Wang Department of Head Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
Department of Head Neck Surgery, Renji Hospital Affiliated to Jiaotong University School of Medicine, Shanghai, China

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Lori J Wirth Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Francis P Worden Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

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John Bernard Sanofi, Cambridge, Massachusetts, USA

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Paolo Caferra Sanofi, Amsterdam, The Netherlands
Department of Pharmacy, University of Pisa, Pisa, Italy

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Raffaella M Colzani Sanofi, Cambridge, Massachusetts, USA

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Shiguang Liu Sanofi, Cambridge, Massachusetts, USA

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Martin Schlumberger Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France

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The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55–1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

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