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Louis de Mestier Department of Gastroenterology and Pancreatology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France

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Jean-Baptiste Danset Department of Hepato-Gastroenterology, European Georges-Pompidou Hospital, APHP, Paris, France

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Cindy Neuzillet Department of Digestive Oncology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France

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Vinciane Rebours Department of Gastroenterology and Pancreatology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France

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Jérôme Cros Department of Pathology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France

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Nadem Soufir Department of Genetics, Bichat Hospital, Paris 7 University, APHP, Clichy, France

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Pascal Hammel Department of Digestive Oncology, Beaujon Hospital, Paris 7 University, APHP, Clichy, France

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Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

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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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A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8–27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1–11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18–105) before ALK to 100 (IQR 56–180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

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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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The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.

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Louis de Mestier
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Clarisse Dromain Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Gaspard d'Assignies Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Jean-Yves Scoazec Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Nathalie Lassau Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Rachida Lebtahi Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Hedia Brixi
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Emmanuel Mitry Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Rosine Guimbaud Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Frédéric Courbon Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Michèle d'Herbomez Department of Hepato-Gastroenterology and Digestive Oncology, Department of Radiology, Department of Radiology, Department of Pathology, Integrated Research Cancer Institute in Villejuif, Department of Nuclear Medicine, Department of Medical Oncology, Department of Digestive Oncology, Department of Nuclear Medicine, Department of Biology and Pathology, Robert-Debré University Hospital, Avenue du Général Koenig, 51092 Reims Cedex, France

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Guillaume Cadiot
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Well-differentiated neuroendocrine tumors (NETs) are a group of heterogeneous rare tumors. They are often slow-growing and patients can have very long survival, even at the metastatic stage. The evaluation of tumor progression and therapeutic responses is currently based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria. As for other malignancies, RECIST criteria are being reexamined for NETs in the era of targeted therapies because tumor response to targeted therapies is rarely associated with shrinkage, as opposed to prolonged progression-free survival. Therefore, size-based criteria no longer seem to be suitable to the assessment of NET progression and therapeutic responses, especially considering targeted therapies. New imaging criteria, combining morphological and functional techniques, have proven relevant for other malignancies treated with targeted therapies. To date, such studies have rarely been conducted on NETs. Moreover, optimizing the management of NET patients also requires considering clinical, biological, and pathological aspects of tumor evolution. Our objectives herein were to comprehensively review current knowledge on the assessment of tumor progression and early prediction of therapeutic responses and to broaden the outlook on well-differentiated NETs, in the era of targeted therapies.

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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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