Treatment of Neuroendocrine Tumours: Approach of GEP-NETS

Authors

  • Nathalie Baudoux, MD Department of Hematology-oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC
  • Mustapha Tehfe, MD, MSC Department of Hematology-oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC Division of Hematology-Oncology, CHUM, Centre de Recherche CHUM, University of Montreal, Montreal, Quebec

DOI:

https://doi.org/10.58931/cot.2025.2237

Abstract

Neuroendocrine tumours (NETs) represent a rare entity, with various anatomic primary tumour sites, three different grades, a functional or non-functional status, and differences in somatostatin receptor expression, making NETs a heterogeneous disease. The management of these tumours is challenging and varies from a simple watch-and-wait strategy to more complex multi-modality treatment combinations. The choice of treatments depends on the previously mentioned factors. NETs most frequently arise from the gastro-entero-pancreatic (GEP) tract. The article reviews the classification, diagnosis, and staging of well-differentiated GEP-NETs, and discusses different therapeutic options.

Author Biographies

Nathalie Baudoux, MD , Department of Hematology-oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC

Dr. Baudoux is currently a fellow and clinical instructor in digestive oncology at the Montreal University Hospital. She obtained her medical degree from the University of Tours (France) and then completed a residency in internal medicine and medical oncology in Switzerland.

Mustapha Tehfe, MD, MSC, Department of Hematology-oncology, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC Division of Hematology-Oncology, CHUM, Centre de Recherche CHUM, University of Montreal, Montreal, Quebec

Dr. Mustapha Tehfe is a Clinical Professor at the University of Montreal and a hematologist-oncologist at Centre Hospitalier de l’Université de Montréal (CHUM). His clinical practice focusses on GI oncology and thoracic oncology. He is the “Renouveau” Program Pre-Clerkship Director at the Faculty of Medicine, University of Montreal.

References

Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology. 2017;3(10):1335–1342. doi:10.1001/jamaoncol.2017.0589.

WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol.10). https://publications.iarc.fr.

Fottner C, Ferrata M and Weber M.M, Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NENS): when to consider, how to diagnose? Rev. Endocr. Metab. Disord. 2017;18:393-410.

Halperin DM, Shen C, Dasari A, Xu Y, Chu Y, Zhou S, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18(4):525-534. doi: 10.1016/S1470-2045(17)30110-9.

Onaitis MW, Kirshbom PM, Hayward TZ, Quayle FJ, Feldman JM, Seigler HF, et al. Gastrointestinal carcinoids: characterization by site of origin and hormone production. Ann Surg. 2000;232(4):549-56. doi: 10.1097/00000658-200010000-00010.

Bourdeleau P, Couvelard A, Ronot M, Lebtahi R, Hentic O, Ruszniewski P, et al. Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms. Ther Adv Med Oncol. 2023;15:17588359231179310. doi: 10.1177/17588359231179310.

O’Toole D, Grossman A, Gross D, Delle Fave G, Barkmanova J, O’Connor J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: biochemical markers. Neuroendocrinology. 2009;90(2):194-202. doi: 10.1159/000225948.

Vezzosi D, Walter T, Laplanche A, Raoul JL, Dromain C, Ruszniewski P, et al. Chromogranin A measurement in metastatic well-differentiated gastroenteropancreatic neuroendocrine carcinoma: screening for false positives and a prospective follow-up study. Int J Biol Markers. 2011;26(2):94-101. doi: 10.5301/JBM.2011.8327.

Sundin A, Arnold R, Baudin E, Cwikla JB, Eriksson B, Fanti S, et al. ENETS Consensus guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine & hybrid imaging. Neuroendocrinology. 2017;105(3):212-244. doi: 10.1159/000471879.

Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16(3):978-85. doi: 10.1158/1078-0432.CCR-09-1759.

Eto K, Yoshida N, Iwagami S, Iwatsuki M, Baba H. Surgical treatment for gastrointestinal neuroendocrine tumors. Ann Gastroenterol Surg. 2020;4(6):652-659. doi: 10.1002/ags3.12396.

Aziz H, Howe JR, Pawlik TM. Surgery vs observation for patients with small pancreatic neuroendocrine tumors. JAMA Surg. 2021;156(5):412-413. doi: 10.1001/jamasurg.2020.5640.

Xu A, Suz P, Reljic T, Are AC, Kumar A, Powers B, et al. Perioperative carcinoid crisis: a systematic review and meta-analysis. Cancers (Basel). 2022;14(12):2966. doi: 10.3390/cancers14122966.

Singh S, Moody L, Chan DL, Metz DC, Strosberg J, Asmis T, et al. Follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. JAMA Oncol. 2018;4(11):1597-1604. doi: 10.1001/jamaoncol.2018.2428.

Tierney JF, Chivukula SV, Wang X, Pappas SG, Schadde E, Hertl M, et al. Resection of primary tumor may prolong survival in metastatic gastroenteropancreatic neuroendocrine tumors. Surgery. 2019;165(3):644-651. doi: 10.1016/j.surg.2018.09.006.

Norton JA, Warren RS, Kelly MG, Zuraek MB, Jensen RT. Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery. 2003;134(6):1057-63. doi: 10.1016/j.surg.2003.07.025. PMID: 14668741.

Kennedy A, Bester L, Salem R, Sharma RA, Parks RW, Ruszniewski P; NET-Liver-Metastases Consensus Conference. Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference. HPB (Oxford). 2015;17(1):29-37. doi: 10.1111/hpb.12326.

Moris D, Tsilimigras DI, Ntanasis-Stathopoulos I, Beal EW, Felekouras E, Vernadakis S, et al. Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review. Surgery. 2017;162(3):525-536. doi: 10.1016/j.surg.2017.05.006.

Dillon JS, Kulke MH, Hörsch D, Anthony LB, Warner RRP, Bergsland E, et al. Time to sustained improvement in bowel movement frequency with telotristat ethyl: analyses of phase III studies in carcinoid syndrome. J Gastrointest Cancer. 2021;52(1):212-221. doi: 10.1007/s12029-020-00375-2.

Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide lar in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): results of long-term survival. Neuroendocrinology. 2017;104(1):26-32. doi: 10.1159/000443612.

Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-33. doi: 10.1056/NEJMoa1316158.

Pavel M, Ćwikła JB, Lombard-Bohas C, Borbath I, Shah T, Pape UF, et al. Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results. Eur J Cancer. 2021;157:403-414. doi: 10.1016/j.ejca.2021.06.056.

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.

Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus highdose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024;403(10446):2807-2817. doi: 10.1016/S0140-6736(24)00701-3.

Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-13. doi: 10.1056/NEJMoa1003825. Erratum in: N Engl J Med. 2011;364(11):1082.

Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, et al. Phase 3 Trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. 2024. doi: 10.1056/NEJMoa2403991. Epub ahead of print.

Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. 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. 2011;378(9808):2005-2012. doi: 10.1016/S0140-6736(11)61742-X.

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-23. doi: 10.1056/NEJMoa1009290.

Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977. doi: 10.1016/S0140-6736(15)00817-X.

Hijoka S, Honma Y, Machida N, Mizuno N, Hamaguchi T, Boku N, et al. A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET). J Clin Oncol. 2025;43(4_suppl). Doi:10.1200/JCO.2025.43.4_suppl.6.

Kulke MH, Ou FS, Niedzwiecki D, Huebner L, Kunz P, Kennecke HF, et al. Everolimus with or without bevacizumab in advanced pNET: CALGB 80701 (Alliance). Endocr Relat Cancer. 2022;29(6):335-344. doi: 10.1530/ERC-21-0239.

Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22(23):4762-71. doi: 10.1200/JCO.2004.04.024. Erratum in: J Clin Oncol. 2005;23(1):248.

Kunz PL, Graham NT, Catalano PJ, Nimeiri HS, Fisher GA, Longacre TA, et al. Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2023;41(7):1359-1369. doi: 10.1200/JCO.22.01013.

Arrivi G, Verrico M, Roberto M, Barchiesi G, Faggiano A, Marchetti P, et al. Capecitabine and temozolomide (CAPTEM) in advanced neuroendocrine neoplasms (NENs): a systematic review and pooled analysis. Cancer Manag Res. 2022;14:3507-3523. doi: 10.2147/CMAR.S372776.

Apostolidis L, Dal Buono A, Merola E, Jann H, Jäger D, Wiedenmann B, et al. Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3). Cancers (Basel). 2021;13(8):1936. doi: 10.3390/cancers13081936.

Al-Toubah T, Morse B, Pelle E, Strosberg J. Efficacy of FOLFOX in patients with aggressive pancreatic neuroendocrine tumors after prior capecitabine/temozolomide. Oncologist. 2021;26(2):115-119. doi: 10.1002/onco.13611.

Donadio MD, Brito ÂB, Riechelmann RP. A systematic review of therapeutic strategies in gastroenteropancreatic grade 3 neuroendocrine tumors. Ther Adv Med Oncol. 2023;15:17588359231156218. doi: 10.1177/17588359231156218.

Albertelli M, Dotto A, Nista F, Veresani A, Patti L, Gay S, et al. Present and future of immunotherapy in neuroendocrine tumors. Rev Endocr Metab Disord. 2021;22(3):615-636. doi: 10.1007/s11154-021-09647

Halperin DM, Liu S, Dasari A, Fogelman D, Bhosale P, Mahvash A, et al. Assessment of clinical response following atezolizumab and bevacizumab treatment in patients with neuroendocrine tumors: a nonrandomized clinical trial. JAMA Oncol. 2022;8(6):904-909. doi: 10.1001/jamaoncol.2022.0212.

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Published

2025-08-14

How to Cite

Baudoux, N., & Tehfe, M. (2025). Treatment of Neuroendocrine Tumours: Approach of GEP-NETS. Canadian Oncology Today, 2(2), 27–36. https://doi.org/10.58931/cot.2025.2237

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Volume 2, Issue 2, Summer 2025

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