Download PDF
Der Nuklearmediziner 2021; 44(04): 326-333
DOI: 10.1055/a-1556-8264
Quo vadis NET?

Medikamentöse Systemtherapie bei Neuroendokrinen Neoplasien des GastroEnteropankreatischen Systems

Systemic treatment options for neuroendocrine neoplasias of the gastroenteropancreatic system
Christoph Josef Auernhammer
1   Medizinische Klinik 4, LMU Klinikum, Ludwig-Maximilians-Universität, München
4   ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Ludwig-Maximilians-Universität, München
,
Stefan Böck
2   Medizinische Klinik 3, LMU Klinikum, Ludwig-Maximilians-Universität, München
4   ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Ludwig-Maximilians-Universität, München
,
Christoph Benedikt Westphalen
2   Medizinische Klinik 3, LMU Klinikum, Ludwig-Maximilians-Universität, München
4   ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Ludwig-Maximilians-Universität, München
,
Leonie Beyer
3   Klinik und Poliklinik für Nuklearmedizin, LMU Klinikum, Ludwig-Maximilians-Universität, München
4   ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Ludwig-Maximilians-Universität, München
,
Christine Spitzweg
1   Medizinische Klinik 4, LMU Klinikum, Ludwig-Maximilians-Universität, München
4   ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), LMU Klinikum, Ludwig-Maximilians-Universität, München
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Neuroendokrine Neoplasien (NEN) des GastroEnteroPankreatischens Systems (GEP-Systems) im inoperablen fortgeschrittenen Stadium erfordern eine differenzierte Systemtherapie abhängig von Klassifikation und Grading, Primärtumorlokalisation, Somatostatinrezeptorexpression, Tumordynamik, Tumorlast und Funktionalität. Somatostatinanaloga, Peptid Rezeptor Radionuklid Therapie (PRRT), Streptozotocin- oder Temozolomid-basierte Chemotherapieprotokolle und molekular zielgerichtete Therapien mit Everolimus oder Sunitinib sind jeweils etablierte Therapieoptionen bei verschiedenen neuroendokrinen Tumoren (NET). Neue vielversprechende Therapieansätze sind Multityrosinkinaseinhibitoren (TKIs) wie Surufatinib, Cabozantinib, Lenvatinib oder Pazopanib. Cisplatin/Etoposid ist die Standard 1st-line Chemotherapie bei neuroendokrinen Karzinomen (NEC). Bisher zeigten die meisten klinischen Studien zur Immuntherapie bei NET G1/G2 enttäuschende Studienergebnisse, aber die mögliche Effektivität der kombinierten Checkpoint-Inhibition sollte bei höherproliferativen NEN G3 weiter untersucht werden. Molekularpathologie mit Next Generation Sequencing (NGS) und personalisierte Therapie spielen auch bei den NEN eine zunehmende Rolle.

Abstract

Inoperable advanced neuroendocrine neoplasias (NEN) of the GastroEnteroPancreatic Systems (GEP-System) need differentiated systemic treatment strategies depending on classification and grading, primary tumor location, somatostatin receptor expression, tumor dynamics, tumor load, and functionality. Somatostatin analogs, peptide receptor radionuclide therapy (PRRT), streptozotocin- or temozolomide-based chemotherapy protocols and molecularly targeted therapies with everolimus or sunitinib are established therapeutic options in the various neuroendocrine tumors (NET). New promising therapeutic options are multi tyrosine kinase inhibitors (TKIs), such as surufatinib, cabozantinib, lenvatinib, or pazopanib. Cisplatin/Etoposid is standard 1st-line chemotherapy in neuroendocrine carcinomas (NEC). So far, most clinical trials with immunotherapy in NET G1/G2 have shown disappointing results, however the efficacy of combined checkpoint inhibitor therapy should be further investigated in higher proliferative NEN G3. Molecular pathology using next generation sequencing (NGS) and personalized therapy approaches play an increasing role in NENs.

Schlüsselwörter

Neuroendokriner Tumor - Neuroendokrines Karzinom - Somatostatinanaloga - PRRT - Chemotherapie - molekular zielgerichtete Therapie - Immuntherapie - Next Generation Sequencing

Keywords

Neuroendocrine tumor - neuroendocrine carcinoma - somatostatin analoga - PRRT - chemotherapy - molecularly targeted therapy - immune therapy - next generation sequencing


Publication History

Article published online:
29 November 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 WHO. Classification of Tumours. Digestive System Tumours. 5th ed. Edited by The WHO Classfifcation of Tumours Editorial Board. Lyon: IARC Press; 2019
    Search in Google Scholar
  • 2 Lloyd RV, Osamura RY, Klöppel G. et al. WHO Classification of Tumours of Endocrine Organs. 4 ed. Lyon: IARC Press; 2017
    Search in Google Scholar
  • 3 Rinke A, Wiedenmann B, Auernhammer C. et al. [Practiceguideline neuroendocrine tumors - AWMF-Reg. 021-27]. Z Gastroenterol 2018; 56: 583-681
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Pavel M, Öberg K, Falconi M. et al. ESMO Guidelines Committee: Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31: 844-860
    CrossrefPubMedSearch in Google Scholar
  • 5 Janson ET, Knigge U, Dam G. et al. Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol 2021 Jul 60: 931-941
    CrossrefPubMed
  • 6 The WHO Classfifcation of Tumours Editorial Board. WHO Classification of Tumours. Thoracic Tumours. 5th ed. Lyon: IARC Press; 2021
    Search in Google Scholar
  • 7 Rindi G, Klimstra DS, Abedi-Ardekani B. et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; 31: 1770-1786
    CrossrefPubMedSearch in Google Scholar
  • 8 Caplin ME, Baudin E, Ferolla P. et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 2015; 26: 1604-1620
    CrossrefPubMedSearch in Google Scholar
  • 9 Baudin E, Caplin M, Garcia-Carbonero R. et al. ESMO Guidelines Committee: Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;
    CrossrefPubMedSearch in Google Scholar
  • 10 Singh S, Bergsland EK, Card CM. et al. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines. J Thorac Oncol 2020; 15: 1577-1598
    CrossrefPubMedSearch in Google Scholar
  • 11 Auernhammer CJ, Spitzweg C, Angele MK. et al. Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. Lancet Diabetes Endocrinol 2018; 404-415
    CrossrefPubMedSearch in Google Scholar
  • 12 Rinke A, Auernhammer CJ, Bodei L. et al. Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?. Gut 2021;
    CrossrefPubMedSearch in Google Scholar
  • 13 Jin XF, Spampatti MP, Spitzweg C. et al. Supportive therapy in gastroenteropancreatic neuroendocrine tumors: Often forgotten but important. Rev Endocr Metab Disord 2018;
    CrossrefPubMedSearch in Google Scholar
  • 14 Hofland J, Herrera-Martínez AD, Zandee WT. et al. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer 2019; 26: R145-R156
    CrossrefPubMedSearch in Google Scholar
  • 15 Strosberg J, El-Haddad G, Wolin E. et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376: 125-135
    CrossrefPubMedSearch in Google Scholar
  • 16 Pavel M, Cwikla JB, Lombard-Bohas C. et al. 1162MO Efficacy and safety of lanreotide autogel (LAN) 120 mg every 14 days in progressive pancreatic or midgut neuroendocrine tumours (NETs): CLARINET FORTE study results. Ann Oncol 2020; 31 (Suppl. 04)
    CrossrefPubMedSearch in Google Scholar
  • 17 Lamberti G, Faggiano A, Brighi N. et al. Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. J Clin Endocrinol Metab 2020;
    CrossrefPubMedSearch in Google Scholar
  • 18 Yordanova A, Wicharz MM, Mayer K. et al. The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy. Clin Cancer Res 2018; 24: 4672-4679
    CrossrefPubMedSearch in Google Scholar
  • 19 Lepage C, Phelip JM, Lievre A. et al. 1163P - Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours (NETs): An international double-blind, placebo-controlled randomized phase II trial. Annals of Oncology 2020; 31 (Suppl. 04) S711-S724
    CrossrefPubMedSearch in Google Scholar
  • 20 Sullivan I, Le Teuff G, Guigay J. et al. Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. Eur J Cancer 2017; 75: 259-267
    CrossrefPubMedSearch in Google Scholar
  • 21 Lenotti E, Alberti A, Spada F. et al. Outcome of Patients With Metastatic Lung Neuroendocrine Tumors Submitted to First Line Monotherapy With Somatostatin Analogs. Front Endocrinol (Lausanne) 2021;
    CrossrefPubMedSearch in Google Scholar
  • 22 Ferolla P, Brizzi MP, Meyer T. et al. Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol 2017; 18: 1652-1664
    CrossrefPubMedSearch in Google Scholar
  • 23 Lamarca A, Barriuso J, McNamara MG. et al. Temozolomide-Capecitabine Chemotherapy for Neuroendocrine Neoplasms: The Dilemma of Treatment Duration. Neuroendocrinology 2020; 110: 155-157
    CrossrefPubMedSearch in Google Scholar
  • 24 Chatzellis E, Angelousi A, Daskalakis K. et al. Activity and Safety of Standard and Prolonged Capecitabine/TemozolomideAdministration in Patients with Advanced Neuroendocrine Neoplasms. Neuroendocrinology 2019; 109: 333-345
    CrossrefPubMedSearch in Google Scholar
  • 25 De Rycke O, Walter T, Perrier M. et al. Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer 2021; 28: 457-466
    CrossrefPubMedSearch in Google Scholar
  • 26 Al-Toubah T, Morse B, Pelle E. et al. Efficacy of FOLFOX in Patients with Aggressive Pancreatic NeuroendocrineTumors After Prior Capecitabine/Temozolomide. Oncologist 2021; 26: 115-119
    CrossrefPubMedSearch in Google Scholar
  • 27 Adant S, Shah GM, Beauregard JM. Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2020; 47: 907-921
    CrossrefPubMedSearch in Google Scholar
  • 28 Klomp MJ, Dalm SU, de Jong M. et al. Epigenetic regulation of somatostatin and somatostatin receptors in neuroendocrine tumors and other types of cancer. Rev Endocr Metab Disord 2020;
    CrossrefPubMedSearch in Google Scholar
  • 29 Ballal S, Yadav MP, Damle NA. et al. Concomitant 177Lu-DOTATATE and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors: A Long-term-Outcome, Toxicity, Survival, and Quality-of-Life Study. Clin Nucl Med 2017; 42: e457-e466
    CrossrefPubMedSearch in Google Scholar
  • 30 Pavlakis N, Ransom DT, Wyld D. et al. Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: Phase II study evaluating the activity of 177Lu-Octreotate peptide receptor radionuclide therapy (LuTate PRRT) and capecitabine, temozolomide CAPTEM)-First results for pancreas and updated midgut neuroendocrine tumors (pNETS, mNETS). Journal of Clinical Oncology 2020; 38 (Suppl. 15) 4608-4608
    CrossrefPubMedSearch in Google Scholar
  • 31 Chantadisai M, Kulkarni HR, Baum RP. Therapy-related myeloid neoplasm after peptide receptor radionuclide therapy (PRRT) in 1631 patients from our 20 years of experiences: prognostic parameters and overall survival. Eur J Nucl Med Mol Imaging 2021; 48: 1390-1398
    CrossrefPubMedSearch in Google Scholar
  • 32 Strosberg JR, Caplin ME, Kunz PL. et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors. Journal of Clinical Oncology 2021; 39 (Suppl. 15) 4112-4112
    CrossrefPubMedSearch in Google Scholar
  • 33 Bodei L, Modlin IM, Luster M. et al. Myeloid neoplasms after chemotherapy and PRRT: myth and reality. Endocr Relat Cancer 2016; 23: C1-7
    CrossrefPubMedSearch in Google Scholar
  • 34 Strosberg J, Leeuwenkamp O, Siddiqui MK. Peptide receptor radiotherapy re-treatment in patients with progressive neuroendocrine tumors: A systematic review and meta-analysis. Cancer Treat Rev 2021;
    CrossrefPubMedSearch in Google Scholar
  • 35 Raymond LM, Korzun T, Kardosh A. et al. The state of PRRT and its sequencing amongst current therapeutic options for gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 2021;
    CrossrefPubMedSearch in Google Scholar
  • 36 Mitry E, Walter T, Baudin E. et al. Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) – a phase II non-randomised trial. Eur J Cancer 2014; 50: 3107-3115
    CrossrefPubMedSearch in Google Scholar
  • 37 Merola E, Dal Buono A, Denecke T. et al. Efficacy and Toxicity of 5-Fluorouracil-Oxaliplatin in Gastroenteropancreatic Neuroendocrine Neoplasms. Pancreas 2020; 49: 912-917
    CrossrefPubMedSearch in Google Scholar
  • 38 Apostolidis L, Dal Buono A, Merola E. et al. Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3). Cancers (Basel) 2021; 13: 1936
    CrossrefPubMedSearch in Google Scholar
  • 39 La Salvia A, Espinosa-Olarte P, Riesco-Martinez MDC. et al. Targeted Cancer Therapy: What's New in the Field of NeuroendocrineNeoplasms?. Cancers (Basel) 2021; 13: 1701
    CrossrefPubMedSearch in Google Scholar
  • 40 Das S, Dasari A. Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors. Ther Adv Med Oncol 2021;
    CrossrefPubMedSearch in Google Scholar
  • 41 Xu J, Shen L, Zhou Z. et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21: 1500-1512
    CrossrefPubMedSearch in Google Scholar
  • 42 Xu J, Shen L, Bai C. et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21: 1489-1499
    CrossrefPubMedSearch in Google Scholar
  • 43 Capdevila J, Fazio N, Lopez C. et al. Lenvatinib in Patients With Advanced Grade 1/2 Pancreatic and Gastrointestinal Neuroendocrine Tumors: Results of the Phase II TALENT Trial (GETNE1509). J Clin Oncol 2021; 39: 2304-2312
    CrossrefPubMedSearch in Google Scholar
  • 44 Stadler ZK, Maio A, Chakravarty D. et al. Therapeutic Implications of Germline Testing in Patients With Advanced Cancers. J Clin Oncol 2021;
    CrossrefPubMedSearch in Google Scholar
  • 45 Hasanov E, Jonasch E. MK-6482 as a potential treatment for von Hippel-Lindau disease-associated clear cell renal cell carcinoma. Expert Opin Investig Drugs 2021; 30: 495-504
    CrossrefPubMedSearch in Google Scholar
  • 46 Srinivasan R, Donskov F, Iliopoulos O. et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2? (HIF-2?) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). Journal of Clinical Oncology 2021; 39 (Suppl. 15) 4555-4555
    CrossrefPubMedSearch in Google Scholar
  • 47 Brandi ML, Agarwal SK, Perrier ND. et al. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42: 133-170
    CrossrefPubMedSearch in Google Scholar
  • 48 Grozinsky-Glasberg S, Lines KE, Avniel-Polak S. et al. Preclinical drug studies in MEN1-related neuroendocrine neoplasms (MEN1-NENs). Endocr Relat Cancer 2020; 27: R345-R355
    CrossrefPubMedSearch in Google Scholar
  • 49 Puccini A, Poorman K, Salem ME. et al. Comprehensive Genomic Profiling of Gastroenteropancreatic NeuroendocrineNeoplasms (GEP-NENs). Clin Cancer Res 2020; 26: 5943-5951
    CrossrefPubMedSearch in Google Scholar
  • 50 Zakka K, Nagy R, Drusbosky L. et al. Blood-based next-generation sequencing analysis of neuroendocrineneoplasms. Oncotarget 2020; 11: 1749-1757
    CrossrefPubMedSearch in Google Scholar
  • 51 Sigal DS, Bhangoo MS, Hermel JA. et al. Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors. Oncotarget 2018; 9: 35809-35812
    CrossrefPubMedSearch in Google Scholar
  • 52 Mosele F, Remon J, Mateo J. et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2020; 31: 1491-1505
    CrossrefPubMedSearch in Google Scholar
  • 53 Sorbye H, Welin S, Langer SW. et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDICNEC study. Ann Oncol 2013; 24: 152-160
    CrossrefPubMedSearch in Google Scholar
  • 54 Elvebakken H, Perren A, Scoazec JY. et al. A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations. Neuroendocrinology 2020;
    CrossrefPubMedSearch in Google Scholar
  • 55 Apostolidis L, Dal Buono A, Merola E. et al. Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3). Cancers (Basel) 2021; 13: 1936
    CrossrefPubMedSearch in Google Scholar
  • 56 Jeong H, Shin J, Jeong JH. et al. Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study. ESMO Open 2021;
    CrossrefPubMedSearch in Google Scholar
  • 57 Pellat A, Cottereau AS, Palmieri LJ. et al. Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions. Cancers (Basel) 2021; 13: 2448
    CrossrefPubMedSearch in Google Scholar
  • 58 McNamara MG, Scoazec JY, Walter T. Extrapulmonary poorly differentiated NECs, including molecular and immune aspects. Endocr Relat Cancer 2020; 27: R219-R238
    CrossrefPubMedSearch in Google Scholar
  • 59 Sorbye H, Kong G, Grozinsky-Glasberg S. PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocr Relat Cancer 2020; 27: R67-R77
    CrossrefPubMedSearch in Google Scholar
  • 60 Albertelli M, Dotto A, Nista F. et al. Present and future of immunotherapy in Neuroendocrine Tumors. Rev Endocr Metab Disord 2021;
    CrossrefPubMedSearch in Google Scholar
  • 61 La Salvia A, Espinosa-Olarte P, Riesco-Martinez MDC. et al. Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms?. Cancers (Basel) 2021; 13: 1701
    CrossrefPubMedSearch in Google Scholar
  • 62 Bongiovanni A, Maiorano BA, Azzali I. et al. Activity and Safety of Immune Checkpoint Inhibitors in NeuroendocrineNeoplasms: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2021; 14: 476
    CrossrefPubMedSearch in Google Scholar
  • 63 Patel SP, Othus M, Chae YK. et al. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic NeuroendocrineTumors. Clin Cancer Res 2020; 26: 2290-2296
    CrossrefPubMedSearch in Google Scholar
  • 64 Klein O, Kee D, Markman B. et al. Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers. Clin Cancer Res 2020; 26: 4454-4459
    CrossrefPubMedSearch in Google Scholar
  • 65 Patel SP, Mayerson E, Chae YK. et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-Grade Neuroendocrine Neoplasm Cohort. Cancer 2021;
    CrossrefPubMedSearch in Google Scholar
  • 66 Koffas A, Toumpanakis C. Comparative safety review of the current therapies for gastroenteropancreatic neuroendocrine tumors. Expert Opin Drug Saf 2021; 20: 321-334
    CrossrefPubMedSearch in Google Scholar
  • 67 Ricci C, Lamberti G, Ingaldi C. et al. Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials. Cancers (Basel) 2021; 13: 358
    CrossrefPubMedSearch in Google Scholar
  • 68 Leyden S, Kolarova T, Bouvier C. et al. Unmet needs in the international neuroendocrine tumor (NET) community: Assessment of major gaps from the perspective of patients, patient advocates and NET health care professionals. Int J Cancer 2020; 146: 1316-1323
    CrossrefPubMedSearch in Google Scholar
  • 69 Magi L, Mazzuca F, Rinzivillo M. et al. Multidisciplinary Management of Neuroendocrine Neoplasia: A Real-World Experience from a Referral Center. J Clin Med 2019; 8: 910
    CrossrefPubMedSearch in Google Scholar
  • 70 Merola E, Zandee W, de Mestier L. et al. Histopathological Revision for Gastroenteropancreatic NeuroendocrineNeoplasms in Expert Centers: Does It Make the Difference?. Neuroendocrinology 2021; 111: 170-177
    CrossrefPubMedSearch in Google Scholar
  • 71 Barrio M, Czernin J, Fanti S. et al. The Impact of Somatostatin Receptor-Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis. J Nucl Med 2017; 58: 756-761
    CrossrefPubMedSearch in Google Scholar
  • 72 Munker S, Vogelhuber M, Bornschein J. et al. EpiCO (epirubicin, cyclophosphamide and vincristine) as treatment for extrapulmonary high-grade neuroendocrine neoplasms. Z Gastroenterol 2020; 58: 133-136
    Thieme ConnectPubMedSearch in Google Scholar
  • 73 Craig Z, Swain J, Batman E. et al. NET-02 trial protocol: a multicentre, randomised, parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extrapulmonary neuroendocrinecarcinoma (NEC). BMJ Open 2020;
    CrossrefPubMedSearch in Google Scholar