This paper is part of a special collection highlighting the work of emerging leaders in the endocrine cancer field
The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.
Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.
The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.
More information is on the Reasons to publish page.
Sept 2018 onwards | Past Year | Past 30 Days | |
---|---|---|---|
Full Text Views | 39 | 39 | 23 |
PDF Downloads | 56 | 56 | 35 |
Ahn HK, Choi JY, Kim KM, Kim H, Choi SH, Park SH, Park JO, Lim HY, Kang WK, Lee J, et al.2013 Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. British Journal of Cancer 109 1414–1419. (https://doi.org/10.1038/bjc.2013.470)
Algarin-Perneth S, Suleiman R, Abeykoon JP, Halfdanarson T, Fuentes-Bayne HE, Yi JE, Peikert T & & Mcgarrah PW 2023 Deep and repeated response to trastuzumab deruxtecan in a patient with human epidermal growth factor receptor 2-amplified large-cell neuroendocrine carcinoma with brain metastases: a case report. JCO Precision Oncology 7 e2300242. (https://doi.org/10.1200/PO.23.00242)
Al-Toubah T, Pelle E, Valone T, Haider M & & Strosberg JR 2021 Efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms. Journal of the National Comprehensive Cancer Network 20 29–36. (https://doi.org/10.6004/jnccn.2021.7017)
Al-Toubah T, Morse B & & Strosberg J 2022 Efficacy of capecitabine and temozolomide in small bowel (midgut) neuroendocrine tumors. Current Oncology 29 510–515. (https://doi.org/10.3390/curroncol29020046)
Andreatos N, Mcgarrah PW, Sonbol MB, Starr JS, Capdevila J, Sorbye H & & Halfdanarson TR 2023 Managing metastatic extrapulmonary neuroendocrine carcinoma after first-line treatment. Current Oncology Reports 25 1127–1139. (https://doi.org/10.1007/s11912-023-01438-w)
Apostolidis L, Bergmann F, Jager D & & Winkler EC 2016 Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma. Cancer Medicine 5 2261–2267. (https://doi.org/10.1002/cam4.807)
Apostolidis L, Dal Buono A, Merola E, Jann H, Jager D, Wiedenmann B, Winkler EC & & Pavel M 2021 Multicenter analysis of treatment outcomes for systemic therapy in well differentiated Grade 3 neuroendocrine tumors (NET G3). Cancers (Basel) 13. (https://doi.org/10.3390/cancers13081936)
Arora A, Zaemes J, Ozdemirli M & & Kim C 2023 Response to selpercatinib in a patient with RET fusion-positive pulmonary large-cell neuroendocrine carcinoma: a case report. Frontiers in Oncology 13 1134151. (https://doi.org/10.3389/fonc.2023.1134151)
Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, Mccall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, et al.2015 The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. American Journal of Surgical Pathology 39 683–690. (https://doi.org/10.1097/PAS.0000000000000408)
Borghesani M, Reni A, Lauricella E, Rossi A, Moscarda V, Trevisani E, Torresan I, Al-Toubah T, Filoni E, Luchini C, et al.2024 Efficacy and toxicity analysis of mFOLFIRINOX in high-grade gastroenteropancreatic neuroendocrine neoplasms. Journal of the National Comprehensive Cancer Network 22 1–8. (https://doi.org/10.6004/jnccn.2024.7005)
Boutin M, Mathews A, Badesha J, Paul A, Safro M, Gill S, Stuart HC, Schaeffer D, Farnell D & & Loree JM 2022 Well-differentiated Grade 3 neuroendocrine tumors: characteristics, treatments, and outcomes from a population-based study. Pancreas 51 756–762. (https://doi.org/10.1097/MPA.0000000000002100)
Brautigam K, Rodriguez-Calero A, Kim-Fuchs C, Kollar A, Trepp R, Marinoni I & & Perren A 2021 Update on histological reporting changes in neuroendocrine neoplasms. Current Oncology Reports 23 65. (https://doi.org/10.1007/s11912-021-01062-6)
Brenner B, Tang LH, Shia J, Klimstra DS & & Kelsen DP 2007 Small cell carcinomas of the gastrointestinal tract: clinicopathological features and treatment approach. Seminars in Oncology 34 43–50. (https://doi.org/10.1053/j.seminoncol.2006.10.022)
Burkart J, Owen D, Shah MH, Abdel-Misih SRZ, Roychowdhury S, Wesolowski R, Haraldsdottir S, Reeser JW, Samorodnitsky E, Smith A, et al.2018 Targeting BRAF mutations in high-grade neuroendocrine carcinoma of the colon. Journal of the National Comprehensive Cancer Network 16 1035–1040. (https://doi.org/10.6004/jnccn.2018.7043)
Butt BP, Stokmo HL, Ladekarl M, Mitkina Tabaksblat E, Sorbye H, Revheim ME & & Hjortland GO 2021 1108P Folfirinox in the treatment of advanced gastroenteropancreatic neuroendocrine carsinomas. Annals of Oncology 32 S915. (https://doi.org/10.1016/j.annonc.2021.08.190)
Capdevila J, Arques O, Hernandez Mora JR, Matito J, Caratu G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P & Lopez Lopez C, et al.2020 Epigenetic EGFR gene repression confers sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas. Clinical Cancer Research 26 902–909.
Capdevila J, Hernando J, Teule A, Lopez C, Garcia-Carbonero R, Benavent M, Custodio A, Garcia-Alvarez A, Cubillo A, Alonso V, et al.2023 Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin. Nature Communications 14 2973. (https://doi.org/10.1038/s41467-023-38611-5)
Caplin M, Sundin A, Nillson O, Baum RP, Klose KJ, Kelestimur F, Plockinger U, Papotti M, Salazar R, Pascher A, et al.2012 Enets Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroendocrinology 95 88–97. (https://doi.org/10.1159/000335594)
Carlsen EA, Fazio N, Granberg D, Grozinsky-Glasberg S, Ahmadzadehfar H, Grana CM, Zandee WT, Cwikla J, Walter MA, Oturai PS, et al.2019 Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocrine-Related Cancer 26 227–239. (https://doi.org/10.1530/ERC-18-0424)
Chan DL, Bergsland EK, Chan JA, Gadgil R, Halfdanarson TR, Hornbacker K, Kelly V, Kunz PL, McGarrah PW, Raj NP, et al.2021a Temozolomide in grade 3 gastroenteropancreatic neuroendocrine neoplasms: a multicenter retrospective review. Oncologist 26 950–955. (https://doi.org/10.1002/onco.13923)
Chan DL, Ulaner GA, Pattison D, Wyld D, Ladwa R, Kirchner J, Li BT, Lai WV, Pavlakis N, Roach PJ, et al.2021b Dual PET imaging in bronchial neuroendocrine neoplasms: the NETPET score as a prognostic biomarker. Journal of Nuclear Medicine 62 1278–1284. (https://doi.org/10.2967/jnumed.120.257659)
Chan DL, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W, Hallet J, Myrehaug S, Law C, Thawer A, et al.2022 Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): combined results from NET-001 and NET-002 trials. European Journal of Cancer 169 74–81. (https://doi.org/10.1016/j.ejca.2022.03.029)
Chan DL, Hayes AR, Karfis I, Conner A, Furtado O'Mahony L, Mileva M, Bernard E, Roach P, Marin G, Pavlakis N, et al.2023 Dual [(68)Ga]DOTATATE and [(18)F]FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms: a multicentre validation of the NETPET score. British Journal of Cancer 128 549–555. (https://doi.org/10.1038/s41416-022-02061-5)
Chantrill L, Ransom D, Chan D, Nagrial A, Pavlakis N, Markman B, Karapetis C, Sjoquist K, Simes J & Gebski V et al.2024 NABNEC: a randomised phase II study of nab -paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas (GI-NECs). Journal of Clinical Oncology 42.(https://doi.org/10.1093/annonc/mdx368.042)
Choe J, Kim KW, Kim HJ, Kim DW, Kim KP, Hong SM, Ryu JS, Tirumani SH, Krajewski K & & Ramaiya N 2019 What is new in the 2017 World Health Organization classification and 8th American Joint Committee on Cancer Staging System for pancreatic neuroendocrine neoplasms? Korean Journal of Radiology 20 5–17. (https://doi.org/10.3348/kjr.2018.0040)
Dahdaleh FS, Calva-Cerqueira D, Carr JC, Liao J, Mezhir JJ, O'dorisio TM & & Howe JR 2012 Comparison of clinicopathologic factors in 122 patients with resected pancreatic and ileal neuroendocrine tumors from a single institution. Annals of Surgical Oncology 19 966–972. (https://doi.org/10.1245/s10434-011-1997-4)
Das S & & Dasari A 2021 Epidemiology, incidence, and prevalence of neuroendocrine neoplasms: are there global differences? Current Oncology Reports 23 43. (https://doi.org/10.1007/s11912-021-01029-7)
Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T & & Yao JC 2017 Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology 3 1335–1342. (https://doi.org/10.1001/jamaoncol.2017.0589)
Daskalakis K, Tsoli M, Angelousi A, Kassi E, Alexandraki KI, Kolomodi D, Kaltsas G & & Koumarianou A 2019 Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms. Endocrine Connections 8 641–653. (https://doi.org/10.1530/EC-19-0134)
De Mestier L, Lamarca A, Hernando J, Zandee W, Alonso-Gordoa T, Perrier M, Walenkamp AM, Chakrabarty B, Landolfi S, Van Velthuysen MF, et al.2021 Treatment outcomes of advanced digestive well-differentiated grade 3 NETs. Endocrine-Related Cancer 28 549–561. (https://doi.org/10.1530/ERC-21-0109)
Delle Fave G, Kwekkeboom DJ, Van Cutsem E, Rindi G, Kos-Kudla B, Knigge U, Sasano H, Tomassetti P, Salazar R, Ruszniewski P, et al.2012 Enets Consensus Guidelines for the management of patients with gastroduodenal neoplasms. Neuroendocrinology 95 74–87. (https://doi.org/10.1159/000335595)
Dillon JS 2020 Workup of gastroenteropancreatic neuroendocrine tumors. Surgical Oncology Clinics of North America 29 165–183. (https://doi.org/10.1016/j.soc.2019.10.002)
Eads JR, Catalano PJ, Fisher GA, Rubin D, Iagaru A, Klimstra DS, Konda B, Kwong MS, Chan JA, De Jesus-Acosta A, et al.2022 Randomized phase II study of platinum and etoposide (EP) versus temozolomide and capecitabine (CAPTEM) in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): ECOG-ACRIN EA2142. Journal of Clinical Oncology 40 4020–4020. (https://doi.org/10.1200/JCO.2022.40.16_suppl.4020)
Eads JR, Halfdanarson TR, Asmis T, Bellizzi AM, Bergsland EK, Dasari A, El-Haddad G, Frumovitz M, Meyer J, Mittra E, et al.2023 Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocrine-Related Cancer 30 e220206. (https://doi.org/10.1530/ERC-22-0206)
Elvebakken H, Perren A, Scoazec JY, Tang LH, Federspiel B, Klimstra DS, Vestermark LW, Ali AS, Zlobec I, Myklebust TÅ, et al.2021 A consensus-developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations. Neuroendocrinology 111 883–894. (https://doi.org/10.1159/000511905)
Elvebakken H, Hjortland GO, Garresori H, Andresen PA, Janssen EAM, Vintermyr OK, Lothe IMB & & Sorbye H 2023 Impact of KRAS and BRAF mutations on treatment efficacy and survival in high-grade gastroenteropancreatic neuroendocrine neoplasms. Journal of Neuroendocrinology 35 e13256. (https://doi.org/10.1111/jne.13256)
Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, Vinik A, Van Cutsem E, Bang YJ, Lee SH, et al.2017 Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Annals of Oncology 28 339–343. (https://doi.org/10.1093/annonc/mdw561)
Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, Mowatt KB, Dinnen RD, Mao Y, Stevens PD, et al.2013 Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the Pancreas Center at Columbia University experience. Cancer Chemotherapy and Pharmacology 71 663–670. (https://doi.org/10.1007/s00280-012-2055-z)
Fonseca PJ, Uriol E, Galvan JA, Alvarez C, Perez Q, Villanueva N, Berros JP, Izquierdo M & & Vieitez JM 2013 Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. Case Reports in Oncology 6 441–449. (https://doi.org/10.1159/000354754)
Fottner C, Apostolidis L, Ferrata M, Krug S, Michl P, Schad A, Roth W, Jaeger D, Galle PR & & Weber MM 2019 A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC). Journal of Clinical Oncology 37 4103–4103. (https://doi.org/10.1200/JCO.2019.37.15_suppl.4103)
Fraenkel M, Kim M, Faggiano A, De Herder WW, Valk GD & Knowledge NETwork 2014 Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocrine-Related Cancer 21 R153–R163. (https://doi.org/10.1530/ERC-13-0125)
Genus TSE, Bouvier C, Wong KF, Srirajaskanthan R, Rous BA, Talbot DC, Valle JW, Khan M, Pearce N, Elshafie M, et al.2019 Impact of neuroendocrine morphology on cancer outcomes and stage at diagnosis: a UK nationwide cohort study 2013–2015. British Journal of Cancer 121 966–972. (https://doi.org/10.1038/s41416-019-0606-3)
Gile JJ, Mcgarrah PW, Leventakos K, Sonbol MB, Starr JS, Eiring RA, Hobday TJ & & Halfdanarson TR 2023 Efficacy of first-line checkpoint inhibitors in combination with chemotherapy in high-grade extrapulmonary metastatic neuroendocrine carcinomas. Journal of Neuroendocrinology 35 e13283. (https://doi.org/10.1111/jne.13283)
Girard N, Mazieres J, Otto J, Lena H, Lepage C, Egenod T, Smith D, Madelaine J, Gérinière L, El Hajbi F, et al.2021 LBA41 - nivolumab (nivo) ± ipilimumab (ipi) in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine tumors (NECs) (GCO-001 NIPINEC). Annals of Oncology 32 S1283–S1346. (https://doi.org/10.1016/j.annonc.2021.08.2119)
Gupta A, Duque M & & Saif MW 2013 Treatment of poorly differentiated neuroendocrine carcinoma of the pancreas. Journal of the Pancreas 14 381–383. (https://doi.org/10.6092/1590-8577/1661)
Hadoux J, Malka D, Planchard D, Scoazec JY, Caramella C, Guigay J, Boige V, Leboulleux S, Burtin P, Berdelou A, et al.2015 Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocrine-Related Cancer 22 289–298. (https://doi.org/10.1530/ERC-15-0075)
Halfdanarson TR, Reidy DL, Vijayvergia N, Halperin DM, Goldstein G, Kong G, Michael M, Leyden S, Grozinsky-Glasberg S, Sorbye H, et al.2022 Pivotal phase III COMPOSE trial will compare 177Lu-edotreotide with best standard of care for well-differentiated aggressive grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors. Journal of Clinical Oncology 40 TPS514–TPS514. (https://doi.org/10.1200/JCO.2022.40.4_suppl.TPS514)
Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, Barriuso J, Pavel M, O'toole D, Walter T, et al.2015 Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocrine-Related Cancer 22 657–664. (https://doi.org/10.1530/ERC-15-0119)
Hentic O, Hammel P, Couvelard A, Rebours V, Zappa M, Palazzo M, Maire F, Goujon G, Gillet A, Levy P, et al.2012 FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocrine-Related Cancer 19 751–757. (https://doi.org/10.1530/ERC-12-0002)
Hijioka S, Hosoda W, Matsuo K, Ueno M, Furukawa M, Yoshitomi H, Kobayashi N, Ikeda M, Ito T, Nakamori S, et al.2017 Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: a Japanese multicenter pancreatic NEN-G3 study. Clinical Cancer Research 23 4625–4632. (https://doi.org/10.1158/1078-0432.CCR-16-3135)
Hindie E 2017 The NETPET score: combining FDG and somatostatin receptor imaging for optimal management of patients with metastatic well-differentiated neuroendocrine tumors. Theranostics 7 1159–1163. (https://doi.org/10.7150/thno.19588)
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, et al.2018 First-line Atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. New England Journal of Medicine 379 2220–2229. (https://doi.org/10.1056/NEJMoa1809064)
Howe JR 2015 The supporting role of (18)FDG-PET in patients with neuroendocrine tumors. Annals of Surgical Oncology 22 2107–2109. (https://doi.org/10.1245/s10434-015-4484-5)
Janson ET, Sorbye H, Welin S, Federspiel B, Gronbaek H, Hellman P, Ladekarl M, Langer SW, Mortensen J, Schalin-Jantti C, et al.2014 Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncologica 53 1284–1297. (https://doi.org/10.3109/0284186X.2014.941999)
Jeong H, Shin J, Jeong JH, Kim KP, Hong SM, Kim YI, Ryu JS, Ryoo BY & & Yoo C 2021 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 6 100119. (https://doi.org/10.1016/j.esmoop.2021.100119)
Jia R, Li Y, Xu N, Jiang HP, Zhao CH, Liu RR, Shi Y, Zhang YY, Wang SY, Zhou H, et al.2022 Sintilimab in patients with previously treated metastatic neuroendocrine neoplasms. Oncologist 27 e625–e632. (https://doi.org/10.1093/oncolo/oyac097)
Jiao Y, Shi C, Edil BH, De Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, et al.2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331 1199–1203. (https://doi.org/10.1126/science.1200609)
Keane F, Bajwa R, Selenica P, Park W, Roehrl MH, Reis-Filho JS, Mandelker D & & O'reilly EM 2023 Dramatic, durable response to therapy in gBRCA2-mutated pancreas neuroendocrine carcinoma: opportunity and challenge. npj Precision Oncology 7 40. (https://doi.org/10.1038/s41698-023-00376-x)
Keck KJ, Choi A, Maxwell JE, Li G, O'Dorisio TM, Breheny P, Bellizzi AM & & Howe JR 2017 Increased grade in neuroendocrine tumor metastases negatively impacts survival. Annals of Surgical Oncology 24 2206–2212. (https://doi.org/10.1245/s10434-017-5899-y)
Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C, Nagrial A, et al.2020 Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clinical Cancer Research 26 4454–4459. (https://doi.org/10.1158/1078-0432.CCR-20-0621)
Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, Schrock AB, Morosini D, Ross JS, Miller VA, et al.2016 BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discovery 6 594–600. (https://doi.org/10.1158/2159-8290.CD-15-1192)
Knappskog S, Grob T, Venizelos A, Amstutz U, Hjortland GO, Lothe IM, Kersten C, Hofsli E, Sundlov A, Elvebakken H, et al.2023 Mutation spectrum in liquid versus solid biopsies from patients with advanced gastroenteropancreatic neuroendocrine carcinoma. JCO Precision Oncology 7 e2200336. (https://doi.org/10.1200/PO.22.00336)
Konukiewitz B, Schlitter AM, Jesinghaus M, Pfister D, Steiger K, Segler A, Agaimy A, Sipos B, Zamboni G, Weichert W, et al.2017 Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. Modern Pathology 30 587–598. (https://doi.org/10.1038/modpathol.2016.217)
Korse CM, Taal BG, Van Velthuysen MLF & & Visser O 2013 Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. European Journal of Cancer 49 1975–1983. (https://doi.org/10.1016/j.ejca.2012.12.022)
Kulke MH, Anthony LB, Bushnell DL, De Herder WW, Goldsmith SJ, Klimstra DS, Marx SJ, Pasieka JL, Pommier RF, Yao JC, et al.2010 NANETS treatment guidelines: Well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 39 735–752. (https://doi.org/10.1097/MPA.0b013e3181ebb168)
Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, et al.2008 Activity of sunitinib in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology 26 3403–3410. (https://doi.org/10.1200/JCO.2007.15.9020)
Kunz PL, Graham NT, Catalano PJ, Nimeiri HS, Fisher GA, Longacre TA, Suarez CJ, Martin BA, Yao JC, Kulke MH, et al.2023 Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). Journal of Clinical Oncology 41 1359–1369. (https://doi.org/10.1200/JCO.22.01013)
Lee H, Nakamoto R, Moore SE, Pantel AR, Eads JR, Aparici CM & & Pryma DA 2022 Combined quantification of (18)F-FDG and (68)Ga. Academic Radiology 29 1308–1316. (https://doi.org/10.1016/j.acra.2021.10.004)
Lithgow K, Venkataraman H, Hughes S, Shah H, Kemp-Blake J, Vickrage S, Smith S, Humphries S, Elshafie M, Taniere P, et al.2021 Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort. Scientific Reports 11 17947. (https://doi.org/10.1038/s41598-021-97247-x)
Liu AJ, Ueberroth BE, Mcgarrah PW, Buckner Petty SA, Kendi AT, Starr J, Hobday TJ, Halfdanarson TR & & Sonbol MB 2021 Treatment outcomes of well-differentiated high-grade neuroendocrine tumors. Oncologist 26 383–388. (https://doi.org/10.1002/onco.13686)
Lu M, Zhang P, Zhang Y, Li Z, Gong J, Li J, Li J, Li Y, Zhang X, Lu Z, et al.2020 Efficacy, safety, and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ib trial. Clinical Cancer Research 26 2337–2345. (https://doi.org/10.1158/1078-0432.CCR-19-4000)
Luecke S, Fottner C, Lahner H, Jann H, Zolnowski D, Quietzsch D, Grabowski P, Cremer B, Maasberg S, Pape UF, et al.2022 Treatment approaches and outcome of patients with neuroendocrine neoplasia grade 3 in German Real-World clinical practice. Cancers (Basel) 14. (https://doi.org/10.3390/cancers14112718)
McGarrah PW, Hobday TJ, Starr JS, Kendi AT, Graham RP, Sonbol MB & & Halfdanarson TR 2020 Efficacy of somatostatin analog (SSA) monotherapy for well-differentiated grade 3 (G3) gastroenteropancreatic neuroendocrine tumors (NETs). Journal of Clinical Oncology 38 617–617. (https://doi.org/10.1200/JCO.2020.38.4_suppl.617)
Merola E, Alonso Gordoa T, Zhang P, Al-Toubah T, Pelle E, Kolasinska-Cwikla A, Zandee W, Laskaratos F, De Mestier L, Lamarca A, et al.2021 Somatostatin analogs for pancreatic neuroendocrine tumors: any benefit when Ki-67 is >/=10%? Oncologist 26 294–301. (https://doi.org/10.1002/onco.13633)
Mizuno Y, Kudo A, Akashi T, Akahoshi K, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Tanaka S, et al.2018 Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms. Journal of Cancer Research and Clinical Oncology 144 1155–1163. (https://doi.org/10.1007/s00432-018-2636-2)
Morizane C, Machida N, Honma Y, Okusaka T, Boku N, Kato K, Nomura S, Hiraoka N, Sekine S, Taniguchi H, et al.2022 Effectiveness of etoposide and cisplatin vs irinotecan and cisplatin therapy for patients with advanced neuroendocrine carcinoma of the digestive system: the TOPIC-NEC phase 3 randomized clinical trial. JAMA Oncology 8 1447–1455. (https://doi.org/10.1001/jamaoncol.2022.3395)
Morken S, Langer SW, Sundlov A, Vestermark LW, Ladekarl M, Hjortland GO, Svensson JB, Tabaksblat EM, Haslerud TM, Assmus J, et al.2023 Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms. British Journal of Cancer 129 1930–1939. (https://doi.org/10.1038/s41416-023-02462-0)
Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA & WHO Classification of Tumours Editorial Board 2020 The 2019 WHO classification of tumours of the digestive system. Histopathology 76 182–188. (https://doi.org/10.1111/his.13975)
Nakano M, Shimada Y, Matsumoto Y, Saiki T, Zhou Q, Sasaki K, Moriyama M, Yoshihara K, Natsumeda M, Kuriyama Y, et al.2022 Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma. Clinical Journal of Gastroenterology 15 413–418. (https://doi.org/10.1007/s12328-022-01599-4)
NCCN Guidelines 2023 Neuroendocrine and Adrenal Tumors. Plymouth Meeting, PA, USA: National Comprehensive Cancer Network. (available at: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448)
Nicolini S, Severi S, Ianniello A, Sansovini M, Ambrosetti A, Bongiovanni A, Scarpi E, Di Mauro F, Rossi A, Matteucci F, et al.2018 Investigation of receptor radionuclide therapy with (177)Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. European Journal of Nuclear Medicine and Molecular Imaging 45 923–930. (https://doi.org/10.1007/s00259-017-3925-8)
Okuyama H, Ikeda M, Okusaka T, Furukawa M, Ohkawa S, Hosokawa A, Kojima Y, Hara H, Murohisa G, Shioji K, et al.2020 A phase II trial of everolimus in patients with advanced pancreatic neuroendocrine carcinoma refractory or intolerant to platinum-containing chemotherapy (NECTOR trial). Neuroendocrinology 110 988–993. (https://doi.org/10.1159/000505550)
Olsen IH, Knigge U, Federspiel B, Hansen CP, Skov A, Kjaer A & & Langer SW 2014 Topotecan monotherapy in heavily pretreated patients with progressive advanced stage neuroendocrine carcinomas. Journal of Cancer 5 628–632. (https://doi.org/10.7150/jca.9409)
Panzuto F, Rinzivillo M, Spada F, Antonuzzo L, Ibrahim T, Campana D, Fazio N & & Delle Fave G 2017 Everolimus in pancreatic neuroendocrine carcinomas G3. Pancreas 46 302–305. (https://doi.org/10.1097/MPA.0000000000000762)
Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, Fontaine A, Shah MH, Kasi A, Baghdadi TA, et al.2020 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 neuroendocrine tumors. Clinical Cancer Research 26 2290–2296. (https://doi.org/10.1158/1078-0432.CCR-19-3356)
Patel SP, Mayerson E, Chae YK, Strosberg J, Wang J, Konda B, Hayward J, Mcleod CM, Chen HX, Sharon E, et al.2021 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 127 3194–3201. (https://doi.org/10.1002/cncr.33591)
Pavel ME, Hainsworth JD, Baudin E, Peeters M, Horsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, et al.2011 Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378 2005–2012. (https://doi.org/10.1016/S0140-6736(1161742-X)
Pavel ME, Baudin E, Öberg KE, Hainsworth JD, Voi M, Rouyrre N, Peeters M, Gross DJ & & Yao JC 2017 Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Annals of Oncology 28 1569–1575. (https://doi.org/10.1093/annonc/mdx193)
Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, Hochmair MJ, Ozguroglu M, Ji JH, et al.2019 Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (Caspian): a randomised, controlled, open-label, phase 3 trial. Lancet 394 1929–1939. (https://doi.org/10.1016/S0140-6736(1932222-6)
Pellat A, Dreyer C, Couffignal C, Walter T, Lombard-Bohas C, Niccoli P, Seitz JF, Hentic O, Andre T, Coriat R, et al.2018 Clinical and biomarker evaluations of sunitinib in patients with grade 3 digestive neuroendocrine neoplasms. Neuroendocrinology 107 24–31. (https://doi.org/10.1159/000487237)
Perren A, Couvelard A, Scoazec JY, Costa F, Borbath I, Delle Fave G, Gorbounova V, Gross D, Grossma A, Jense RT, et al.2017 Enets consensus guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification. Neuroendocrinology 105 196–200. (https://doi.org/10.1159/000457956)
Raj N, Coffman K, Le T, Do RKG, Rafailov J, Choi Y, Chou JF, Capanu M, Dunphy M, Fox JJ, et al.2022 Treatment response and clinical outcomes of well-differentiated high-grade neuroendocrine tumors to lutetium-177-DOTATATE. Neuroendocrinology 112 1177–1186. (https://doi.org/10.1159/000525216)
Riesco Martinez M, Capdevila Castillon J, Alonso P, Jimenez-Fonseca P, Teule A, Grande E, Sevilla A, Benavent M, Alonso-Gordoa T, Custodio B, et al.2022 496MO Final overall survival results from the NICE-NEC trial (GETNE-T1913): a phase II study of nivolumab and platinum-doublet chemotherapy (CT) in untreated advanced G3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or unknown (UK) origin. Annals of Oncology 33 S225–S226.
Ricco G, Seminerio R, Andrini E, Malvi D, Gruppioni E, Altimari A, Zagnoni S, Campana D & & Lamberti G 2023 BRAF V600E-mutated large cell neuroendocrine carcinoma responding to targeted therapy: a case report and review of the literature. Anti-Cancer Drugs 34 1076–1084. (https://doi.org/10.1097/CAD.0000000000001508)
Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, De Krijger RR, Dietel M, El-Naggar AK, et al.2018 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Modern Pathology 31 1770–1786. (https://doi.org/10.1038/s41379-018-0110-y)
Rossi RE, Rausa E, Cavalcoli F, Conte D & & Massironi S 2018 Duodenal neuroendocrine neoplasms: a still poorly recognized clinical entity. Scandinavian Journal of Gastroenterology 53 835–842. (https://doi.org/10.1080/00365521.2018.1468479)
Rust E, Hubele F, Marzano E, Goichot B, Pessaux P, Kurtz JE & & Imperiale A 2012 Nuclear medicine imaging of gastro-entero-pancreatic neuroendocrine tumors. The key role of cellular differentiation and tumor grade: from theory to clinical practice. Cancer Imaging 12 173–184. (https://doi.org/10.1102/1470-7330.2012.0026)
Sahu A, Jefford M, Lai-Kwon J, Thai A, Hicks RJ & & Michael M 2019 CAPTEM in metastatic well-differentiated intermediate to high grade neuroendocrine tumors: a single centre experience. Journal of Oncology 2019 9032753. (https://doi.org/10.1155/2019/9032753)
Schnell RR, Eiring RA, Miller MC, Mcgarrah PW & & Halfdanarson TR 2023 Cabozantinib as salvage therapy for well differentiated grade 3 neuroendocrine tumors (G3 NETs). NANETS 2023 Symposium Abstracts. Endocrine Abstracts 98 C14. (https://doi.org/10.1530/endoabs.98.C14)
Shen L, Yu X, Lu M, Zhang X, Cheng Y, Zhang Y, Li Z, Xu J, Weng D & Wu C, et al.2021 Surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma: results from a multicenter, open-label, single-arm, phase II trial. Journal of Clinical Oncology 39 e16199. (https://doi.org/10.1200/JCO.2021.39.15_suppl.e16199)
Shi C & & Klimstra DS 2014 Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Seminars in Diagnostic Pathology 31 498–511. (https://doi.org/10.1053/j.semdp.2014.08.008)
Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz K, Chasen B, Capdevila J, Tafuto S, Oh D, et al.2024 [177LU]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study. Journal of Clinical Oncology 42.
Sorbye H, Grande E, Pavel M, Tesselaar M, Fazio N, Reed NS, Knigge U, Christ E, Ambrosini V, Couvelard A, et al.2023 European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. Journal of Neuroendocrinology 35 e13249. (https://doi.org/10.1111/jne.13249)
Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG, Ohrling K, et al.2013 Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the Nordic NEC study. Annals of Oncology 24 152–160. (https://doi.org/10.1093/annonc/mds276)
Spada F, Antonuzzo L, Marconcini R, Radice D, Antonuzzo A, Ricci S, Di Costanzo F, Fontana A, Gelsomino F, Luppi G, et al.2016 Oxaliplatin-based chemotherapy in advanced neuroendocrine tumors: clinical outcomes and preliminary correlation with biological factors. Neuroendocrinology 103 806–814. (https://doi.org/10.1159/000444087)
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, et al.2011 Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 376 125–135.
Tanaka H, Matsusaki S, Baba Y, Isono Y, Kumazawa H, Sase T, Okano H, Saito T, Mukai K & & Kaneko H 2015 Neuroendocrine tumor G3: a pancreatic well-differentiated neuroendocrine tumor with a high proliferative rate. Clinical Journal of Gastroenterology 8 414–420. (https://doi.org/10.1007/s12328-015-0609-4)
Thang SP, Lung MS, Kong G, Hofman MS, Callahan J, Michael M & & Hicks RJ 2018 Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. European Journal of Nuclear Medicine and Molecular Imaging 45 262–277. (https://doi.org/10.1007/s00259-017-3821-2)
Thiis-Evensen E & & Boyar Cetinkaya R 2023 Incidence and prevalence of neuroendocrine neoplasms in Norway 1993–2021. Journal of Neuroendocrinology 35 e13264. (https://doi.org/10.1111/jne.13264)
Velayoudom-Cephise FL, Duvillard P, Foucan L, Hadoux J, Chougnet CN, Leboulleux S, Malka D, Guigay J, Goere D, Debaere T, et al.2013 Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocrine-Related Cancer 20 649–657. (https://doi.org/10.1530/ERC-13-0027)
Venizelos A, Elvebakken H, Perren A, Nikolaienko O, Deng W, Lothe IMB, Couvelard A, Hjortland GO, Sundlov A, Svensson J, et al.2021 The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocrine-Related Cancer 29 1–14. (https://doi.org/10.1530/ERC-21-0152)
Vijayvergia N, Dasari A, Deng M, Litwin S, Al-Toubah T, Alpaugh RK, Dotan E, Hall MJ, Ross NM, Runyen MM, et al.2020 Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. British Journal of Cancer 122 1309–1314. (https://doi.org/10.1038/s41416-020-0775-0)
Walter T, Tougeron D, Baudin E, Le Malicot K, Lecomte T, Malka D, Hentic O, Manfredi S, Bonnet I, Guimbaud R, et al.2017 Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: are they really heterogeneous? Insights from the FFCD-GTE national cohort. European Journal of Cancer 79 158–165. (https://doi.org/10.1016/j.ejca.2017.04.009)
Walter T, Lievre A, Coriat R, Malka D, Elhajbi F, Di Fiore F, Hentic O, Smith D, Hautefeuille V, Roquin G, et al.2023 Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet. Oncology 24 297–306. (https://doi.org/10.1016/S1470-2045(2300001-3)
Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C & & Oberg K 2011 Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 117 4617–4622. (https://doi.org/10.1002/cncr.26124)
White BE, Rous B, Chandrakumaran K, Wong K, Bouvier C, Van Hemelrijck M, George G, Russell B, Srirajaskanthan R & & Ramage JK 2022 Incidence and survival of neuroendocrine neoplasia in England 1995–2018: a retrospective, population-based study. Lancet Regional Health. Europe 23 100510. (https://doi.org/10.1016/j.lanepe.2022.100510)
WHO 2017 WHO Classification of tumours of endocrine organs. Eds, Lloyd RV, Osamura RY, Klöppel G & & Rosai J Lyon, France: International Agency for Research on Cancer.
WHO 2022 Endocrine and Neuroendocrine tumours. 5 th ed. Lyon, France: International Agency for Research on Cancer.
Xu J, Shen L, Bai C, Wang W, Li J, Yu X, Li Z, Li E, Yuan X, Chi Y, et al.2020a Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. Oncology 21 1489–1499. (https://doi.org/10.1016/S1470-2045(2030493-9)
Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, Li Z, Xu N, Li E, Liu T, et al.2020b Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. Oncology 21 1500–1512. (https://doi.org/10.1016/S1470-2045(2030496-4)
Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, De Wilde RF, Maitra A, Hicks J, Demarzo AM, et al.2012 Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. American Journal of Surgical Pathology 36 173–184. (https://doi.org/10.1097/PAS.0b013e3182417d36)