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Ben C Whitelaw Department of Endocrinology, King’s College Hospital NHS Foundation Trust, London, UK

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How and when to use temozolomide to treat aggressive pituitary tumours Temozolomide is an oral chemotherapy which has an established role in treating glioblastoma multiforme (GBM) and has since 2006 been used to treat aggressive and malignant

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J Cros Department of Pathology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France
U1149 – University Paris Diderot, Paris, France

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O Hentic Department of Gastroenterology and Pancreatology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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V Rebours U1149 – University Paris Diderot, Paris, France
Department of Gastroenterology and Pancreatology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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M Zappa Department of Radiology, AP-HP, DHU UNITY, Beaujon Hospital, Clichy, France

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N Gille Department of Pathology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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N Theou-Anton Department of Somatic Genetic, AP-HP, DHU UNITY, Bichat University Hospital, Paris, France

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D Vernerey Methodology and Quality of Life in Oncology Unit (EA 3181), University Hospital of Besançon, Besançon, France

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F Maire Department of Gastroenterology and Pancreatology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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P Lévy U1149 – University Paris Diderot, Paris, France
Department of Gastroenterology and Pancreatology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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P Bedossa Department of Pathology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France
U1149 – University Paris Diderot, Paris, France

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V Paradis Department of Pathology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France
U1149 – University Paris Diderot, Paris, France

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P Hammel U1149 – University Paris Diderot, Paris, France
Department of Digestive Oncology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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P Ruszniewski U1149 – University Paris Diderot, Paris, France
Department of Gastroenterology and Pancreatology, AP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France

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A Couvelard U1149 – University Paris Diderot, Paris, France
Department of Pathology, AP-HP, DHU UNITY, Bichat University Hospital, Paris, France

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Introduction Evidences suggesting the efficacy of temozolomide (TEM), a DNA-alkylating agent, in advanced pancreatic neuroendocrine tumors (PNETs) are accumulating ( Kulke et al. 2006 , Ekeblad et al. 2007 , Strosberg et al. 2011

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Luis V Syro Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia

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Fabio Rotondo Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

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Leon D Ortiz Division of Neuro-Oncology, Instituto de Cancerologia, Clinica Las Americas. Medellin, Colombia

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Kalman Kovacs Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

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many researchers, clinical endocrinologists and neurosurgeons is to find other options of treatment, especially in cases of large, invasive and recurrent tumors and pituitary carcinomas. Temozolomide (TMZ) is an alkylating chemotherapeutic agent used

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Kimberly Perez Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Harvard Medical School, Boston, Massachusetts, USA

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Heather Jacene Harvard Medical School, Boston, Massachusetts, USA
Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Jason L Hornick Harvard Medical School, Boston, Massachusetts, USA
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Chao Ma Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Nuno Vaz Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Lauren K Brais Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Holly Alexander Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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William Baddoo Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Kristina Astone Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

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Edward D Esplin Invitae Corporation, San Francisco, California, USA

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John Garcia Invitae Corporation, San Francisco, California, USA

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Daniel M Halperin Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Matthew H Kulke Section of Hematology and Oncology, Boston University and Boston Medical Center, Boston, Massachusetts, USA

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Jennifer A Chan Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Harvard Medical School, Boston, Massachusetts, USA

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(MTIC). Temozolomide (TMZ) is the oral prodrug which is non-enzymatically converted to MTIC. Direct comparisons of therapeutic efficacy of dacarbazine and TMZ have been conducted in melanoma and found to be similar ( Middleton et al. 2000 , Patel et

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Murali Kesavan Department of Oncology, School of Medicine, The University of Western Australia, Perth, Australia

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Piyush Grover Department of Oncology, Fiona Stanley Hospital, Perth, Australia

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Wei-sen Lam Department of Oncology, Fiona Stanley Hospital, Perth, Australia

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Phillip G Claringbold Department of Oncology, School of Medicine, The University of Western Australia, Perth, Australia

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J Harvey Turner Department of Oncology, School of Medicine, The University of Western Australia, Perth, Australia

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Australian multicenter CONTROL NETs randomized phase II study (NCT02358356) reported a similar 15-month PFS in both arms (90% for 177 Lu-octreotate and 92% for 177 Lu-octreotate, capecitabine and temozolomide (CAPTEM)) ( Pavlakis et al. 2020 ). The long

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Louis de Mestier Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), and Université de Paris, Clichy, France
Centre of Research on Inflammation, INSERM U1149, Paris, France

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Anne Couvelard Centre of Research on Inflammation, INSERM U1149, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospitals (APHP), and Université de Paris, Clichy/Paris, France

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Anela Blazevic Division Endocrinology, Department of Internal Medicine, ENETS Centre of Excellence, Erasmus Medical Center, Rotterdam, The Netherlands

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Olivia Hentic Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), and Université de Paris, Clichy, France

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Wouter W de Herder Division Endocrinology, Department of Internal Medicine, ENETS Centre of Excellence, Erasmus Medical Center, Rotterdam, The Netherlands

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Vinciane Rebours Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), and Université de Paris, Clichy, France
Centre of Research on Inflammation, INSERM U1149, Paris, France

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Valérie Paradis Centre of Research on Inflammation, INSERM U1149, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospitals (APHP), and Université de Paris, Clichy/Paris, France

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Philippe Ruszniewski Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), and Université de Paris, Clichy, France
Centre of Research on Inflammation, INSERM U1149, Paris, France

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Leo J Hofland Division Endocrinology, Department of Internal Medicine, ENETS Centre of Excellence, Erasmus Medical Center, Rotterdam, The Netherlands

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Jérôme Cros Centre of Research on Inflammation, INSERM U1149, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospitals (APHP), and Université de Paris, Clichy/Paris, France

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)), dacarbazine (DTIC) (alone or combined with 5FU ( Walter et al. 2015 , de Mestier et al. 2019 )) and its oral prodrug temozolomide (TMZ) (alone or combined with capecitabine (CAP) ( Koumarianou et al. 2015 , de Mestier et al. 2020 b ). However

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Philipp Melhorn Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Peter Mazal Department of Pathology, Medical University of Vienna, Vienna, Austria

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Ladislaia Wolff Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Petar Popov Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Elisabeth Kretschmer-Chott Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Alexander Haug Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria

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Marius E Mayerhoefer Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill Cornell Medical College, Cornell University, New York, New York, USA

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Markus Raderer Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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Barbara Kiesewetter Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

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alkylating agent temozolomide plus the antimetabolite capecitabine (CAPTEM) has increasingly been evaluated and is now endorsed as an option for patients with advanced pancreatic and pulmonary NET who are candidates for chemotherapy ( Pavel et al. 2020

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M Cives Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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M Ghayouri Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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B Morse Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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M Brelsford Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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M Black Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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A Rizzo Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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A Meeker Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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J Strosberg Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute

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Introduction Chemotherapy regimens containing the oral alkylating agent temozolomide are active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70% ( Kulke et al . 2006

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Ophélie De Rycke Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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Thomas Walter Department of Gastro-enterology and oncology, Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France

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

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Olivia Hentic Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France

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Catherine Lombard-Bohas Department of Gastro-enterology and oncology, Hospices Civils de Lyon, Edouard Herriot University Hospital, Lyon, France

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Romain Coriat Department of Gastroenterology, Cochin University Hospital, Paris, France

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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, Centre de Recherche sur l’Inflammation, INSERM, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospital, Paris/Clichy, France

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Philippe Ruszniewski Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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Jérôme Cros Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France
Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon University Hospital, Paris/Clichy, France

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Louis de Mestier Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France
Université de Paris, Centre de Recherche sur l’Inflammation, INSERM, Paris, France

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). Combinations of alkylating agents (dacarbazine (DTIC) or temozolomide (TEM)) and fluoropyrimidines (5-fluorouracil (5FU) or capecitabine (CAP)) have been found to be effective in this setting, with an objective response rate of between 40 and 50% and median

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Dorota Dworakowska Department of Hypertension and Diabetes, Medical University of Gdańsk, Gdańsk, Poland
Guys Richard Dimbleby Department of Cancer Research, Kings College London, London, UK
Endocard LTD, London, UK

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Ashley B Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
Centre for Endocrinology, William Harvey Institute, Barts and the London School of Medicine, London, UK

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adenoma demonstrated in their series a high Ki-67 index, rapid growth, frequent recurrence and resistance to conventional treatments and/or temozolomide ( Dai et al. 2016 ). The specific criteria include proposed tumour infiltration of the adjacent

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