{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:36:49Z","timestamp":1791988609086,"version":"4.4.0"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,30]],"date-time":"2023-07-30T00:00:00Z","timestamp":1690675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials\/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.<\/jats:p>","DOI":"10.3390\/biology12081069","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:26:40Z","timestamp":1690766800000},"page":"1069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7765-3745","authenticated-orcid":false,"given":"Leonidas N.","family":"Diamantopoulos","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5688-8702","authenticated-orcid":false,"given":"Markos","family":"Kalligeros","sequence":"additional","affiliation":[{"name":"Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-1257","authenticated-orcid":false,"given":"Thorvardur R.","family":"Halfdanarson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Diamantis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Toumpanakis","sequence":"additional","affiliation":[{"name":"Neuroendocrine Tumor Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1159\/000334612","article-title":"Diffuse endocrine system, neuroendocrine tumors and immunity: What\u2019s new?","volume":"95","author":"Ameri","year":"2012","journal-title":"Neuroendocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1001\/jamaoncol.2017.0589","article-title":"Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States","volume":"3","author":"Dasari","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3322\/caac.21493","article-title":"Gastroenteropancreatic Neuroendocrine Tumors","volume":"68","author":"Cives","year":"2018","journal-title":"CA Cancer J. 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