{"entity":{"id":"small-intestinal-net","kind":"cancer","name":"Small intestinal neuroendocrine tumours","aka":["Midgut neuroendocrine tumour","Small bowel NET","Ileal carcinoid","Jejunoileal neuroendocrine tumour","SI-NET"],"tldr":"Small intestinal neuroendocrine tumours are slow-growing hormone-producing tumours of the ileum and jejunum, often found only after they have spread to lymph nodes and the liver. Monthly somatostatin analogue injections control symptoms and growth, lutetium-177 dotatate is the main second treatment, and everolimus, cabozantinib and surgery fill in.","summary":"Small intestinal neuroendocrine tumours arise from enterochromaffin cells of the distal jejunum and ileum, are often multiple along the same segment, and stay small while their mesenteric node metastases and the fibrosis around them grow large enough to kink the bowel and its blood supply. Most are well differentiated with a low Ki-67 index, nearly all express somatostatin receptor 2, and about a fifth to a third of patients with liver metastases develop carcinoid syndrome from serotonin that escapes the liver's first-pass clearance; years of exposure can scar the right-sided heart valves. Diagnosis rests on somatostatin receptor PET, chromogranin A and 24-hour urinary 5-HIAA, and the grade is read from Ki-67 and mitotic count on biopsy.\n\nThe treatment sequence was built by a short chain of trials. PROMID (Journal of Clinical Oncology 2009) randomised 85 patients with treatment-naive metastatic midgut tumours to octreotide LAR or placebo and lengthened time to progression from 6.0 to 14.3 months, the first proof that a somatostatin analogue slows growth as well as symptoms; CLARINET (New England Journal of Medicine 2014) did the same for lanreotide across enteropancreatic tumours, with the median progression-free survival not reached against 18.0 months on placebo. NETTER-1 (New England Journal of Medicine 2017) then randomised 231 patients with midgut tumours progressing on octreotide to lutetium-177 dotatate with octreotide or to high-dose octreotide; 65.2 percent against 10.8 percent were progression-free at 20 months, responses rose from 3 to 18 percent, and the final analysis gave median overall survival of 48.0 against 36.3 months, a difference that did not reach statistical significance because of crossover. Lutathera was approved in 2018, and NETTER-2 (Lancet 2024) moved it to first line for grade 2 and 3 tumours with a Ki-67 of 10 percent or more, lengthening progression-free survival from 8.5 to 22.8 months. Everolimus earned its gut indication in RADIANT-4 (Lancet 2016), where progression-free survival was 11.0 against 3.9 months in non-functional lung and gastrointestinal tumours, and cabozantinib was approved in 2025 after the extra-pancreatic cohort of CABINET (New England Journal of Medicine 2024) showed 8.4 against 3.9 months.\n\nSurgery keeps its place even in metastatic disease: resection of the primary with its mesenteric nodes prevents obstruction and ischaemia, and liver metastases are debulked, ablated or embolised when the liver dominates. Carcinoid syndrome is treated by raising the somatostatin analogue dose, adding telotristat ethyl for diarrhoea that persists (TELESTAR, 2017), and giving octreotide by infusion around operations and embolisation to prevent carcinoid crisis. The order of radioligand therapy, everolimus and cabozantinib after somatostatin analogues has never been randomised; COMPETE (Lancet 2025) showed 177Lu-edotreotide beat everolimus on progression-free survival in grade 1 to 2 gastroenteropancreatic tumours, alpha-emitting radioligands are in phase 3 after lutetium failure, and the oral somatostatin agonist paltusotine and a subcutaneous octreotide depot are being tested for carcinoid syndrome.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor","links":[{"label":"PROMID (JCO 2009)","url":"https://doi.org/10.1200/JCO.2009.22.8510"},{"label":"NETTER-1 (NEJM 2017)","url":"https://doi.org/10.1056/NEJMoa1607427"},{"label":"NETTER-2 (Lancet 2024)","url":"https://doi.org/10.1016/S0140-6736(24)00701-3"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Neuroendocrine_tumor"}],"tags":["subtype-page","endocrine"],"related":["extrapulmonary-nec","grade-3-net","lung-net","pancreatic-net"],"cancers":[],"sections":[],"technologies":["sstr-pet","prrt","radioligand-therapy","tace","radioembolisation-tare","thermal-ablation"],"targets":["sstr2","mtor"],"drugs":["octreotide-lanreotide","lutathera","everolimus","cabozantinib","telotristat-ethyl","ga68-dotatate","itm-11","paltusotine"],"companies":[],"institutions":[],"pathways":[],"terms":["carcinoid-syndrome","chromogranin-a","net-grade-ki67","prrt-term","liver-directed-therapy"],"trials":["promid","clarinet","netter-1","nct03972488","radiant-3-4","cabinet","compete"],"people":[],"bottlenecks":[],"keyPapers":["paper-netter-2-lancet-2024","paper-clarinet-lanreotide-nejm-2014","paper-netter-1-nejm-2017","paper-promid-rinke-jco-2009"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"The commonest neuroendocrine tumour of the gut in Western series and now the commonest cancer of the small intestine; most are grade 1 or 2 and many are found only after they have reached the mesenteric nodes or the liver.","subtypes":["Ileal neuroendocrine tumour (the classic site, often multifocal)","Jejunal neuroendocrine tumour","Duodenal neuroendocrine tumour (gastrinoma, somatostatinoma, ampullary)","Small bowel NET with carcinoid syndrome and liver metastases","Small bowel NET with mesenteric fibrosis and obstruction","Grade 1 (Ki-67 under 3 percent) and grade 2 (3 to 20 percent) small intestinal NET"],"biomarkers":["Ki-67 index and mitotic count (WHO grade, nearly always grade 1 or 2)","Chromogranin A (monitoring, raised by proton-pump inhibitors and kidney disease)","24-hour urinary 5-HIAA (carcinoid syndrome)","Somatostatin receptor PET with gallium-68 or copper-64 DOTATATE (staging and radioligand eligibility)","Echocardiography for carcinoid heart disease","Germline CDKN1B in familial small intestinal NET (rare)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with Ki-67 grading, somatostatin receptor PET, cross-sectional imaging of the liver, chromogranin A and urinary 5-HIAA, echocardiography if carcinoid syndrome is present.","refs":["sstr-pet","ga68-dotatate","net-grade-ki67","chromogranin-a","carcinoid-syndrome"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Localised or resectable disease","approach":"Segmental small bowel resection with mesenteric lymphadenectomy, inspecting the whole small bowel for further primaries; the primary is often removed even when liver metastases are present.","refs":["robotic-surgery","hepatectomy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Advanced, first line","approach":"Octreotide LAR or lanreotide (PROMID, CLARINET); lutetium-177 dotatate first line for grade 2 to 3 tumours with a Ki-67 of 10 percent or more (NETTER-2).","refs":["octreotide-lanreotide","promid","clarinet","lutathera","nct03972488","prrt"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Progression on a somatostatin analogue","approach":"Lutetium-177 dotatate (NETTER-1); everolimus (RADIANT-4); cabozantinib (CABINET); liver-directed therapy for hepatic-dominant disease.","refs":["lutathera","netter-1","everolimus","radiant-3-4","cabozantinib","cabinet","tace","radioembolisation-tare","thermal-ablation","liver-directed-therapy"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"Carcinoid syndrome","approach":"Somatostatin analogue dose escalation, telotristat ethyl for refractory diarrhoea, octreotide infusion around procedures to prevent carcinoid crisis, valve surgery for carcinoid heart disease.","refs":["octreotide-lanreotide","telotristat-ethyl","carcinoid-syndrome"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}},{"setting":"After radioligand therapy","approach":"Everolimus or cabozantinib; 177Lu-edotreotide if approved; alpha-emitting radioligands and retreatment in trials.","refs":["everolimus","cabozantinib","itm-11","compete","ryz101","action-1","alphamedix"],"guideline":{"version":"NCCN Guidelines: Neuroendocrine and Adrenal Tumors","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448"}}],"stateOfArt":["NETTER-1 made this the first cancer treated by a modern radioligand and NETTER-2 has moved that treatment to first line for the faster-growing tumours.","Somatostatin analogues remain the first drug for almost every patient, controlling both hormone symptoms and growth.","Cabozantinib gives a fourth approved systemic option, and COMPETE was the first head-to-head win for a radioligand over a targeted tablet."],"history":[{"year":1907,"title":"Oberndorfer names the small bowel tumours 'Karzinoid'","refs":[]},{"year":1954,"title":"Carcinoid syndrome described","refs":["carcinoid-syndrome"]},{"year":1988,"title":"Octreotide approved for carcinoid syndrome symptoms","refs":["octreotide-lanreotide"]},{"year":2009,"title":"PROMID: octreotide LAR slows midgut tumour growth","refs":["promid","octreotide-lanreotide"]},{"year":2014,"title":"CLARINET: lanreotide halves the risk of progression in enteropancreatic tumours","refs":["clarinet"]},{"year":2016,"title":"RADIANT-4 extends everolimus to gut and lung tumours; gallium-68 DOTATATE PET approved","refs":["radiant-3-4","everolimus","sstr-pet","ga68-dotatate"]},{"year":2017,"title":"NETTER-1 published; telotristat ethyl approved for carcinoid syndrome diarrhoea","refs":["netter-1","telotristat-ethyl"]},{"year":2018,"title":"Lutathera approved in the United States and Europe","refs":["lutathera","prrt"]},{"year":2024,"title":"NETTER-2: lutetium-177 dotatate first line for grade 2 to 3 tumours; CABINET published","refs":["nct03972488","lutathera","cabinet"]},{"year":2025,"title":"Cabozantinib approved for previously treated neuroendocrine tumours; COMPETE published","refs":["cabozantinib","compete"]}],"pipeline":["itm-11","compete","ryz101","action-1","alphamedix","nct06943755","nct07087054","cam2029","idea-net-antagonist-ligands","idea-net-dosimetry-prrt"],"openProblems":["No randomised trial orders radioligand therapy, everolimus and cabozantinib after somatostatin analogues.","Whether removing the primary improves survival in patients with liver metastases has never been tested prospectively.","Chromogranin A is unreliable and no blood test yet replaces imaging for follow-up.","Overall survival gains are hard to show because patients live for years and cross over."],"parent":"neuroendocrine"},"route":"/cancers/small-intestinal-net/","neighbours":{"cancer":[{"id":"extrapulmonary-nec","kind":"cancer","name":"Extrapulmonary neuroendocrine carcinoma","route":"/cancers/extrapulmonary-nec/"},{"id":"goblet-cell-adenocarcinoma","kind":"cancer","name":"Goblet cell adenocarcinoma of the appendix","route":"/cancers/goblet-cell-adenocarcinoma/"},{"id":"grade-3-net","kind":"cancer","name":"Grade 3 well-differentiated neuroendocrine tumour","route":"/cancers/grade-3-net/"},{"id":"localised-small-bowel-adenocarcinoma","kind":"cancer","name":"Localised small bowel adenocarcinoma (stage I to III, resected)","route":"/cancers/localised-small-bowel-adenocarcinoma/"},{"id":"lung-net","kind":"cancer","name":"Lung neuroendocrine tumours (typical and atypical carcinoid)","route":"/cancers/lung-net/"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","route":"/cancers/metastatic-ppgl/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"pancreatic-net","kind":"cancer","name":"Pancreatic neuroendocrine tumours","route":"/cancers/pancreatic-net/"}],"technology":[{"id":"prrt","kind":"technology","name":"Peptide receptor radionuclide therapy (PRRT)","route":"/technologies/prrt/"},{"id":"radioembolisation-tare","kind":"technology","name":"Radioembolisation (TARE / SIRT, yttrium-90)","route":"/technologies/radioembolisation-tare/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"},{"id":"robotic-surgery","kind":"technology","name":"Robotic & minimally invasive surgery","route":"/technologies/robotic-surgery/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"},{"id":"thermal-ablation","kind":"technology","name":"Thermal ablation (RFA, microwave, cryo)","route":"/technologies/thermal-ablation/"},{"id":"tace","kind":"technology","name":"Transarterial chemoembolisation (TACE)","route":"/technologies/tace/"}],"target":[{"id":"mtor","kind":"target","name":"mTOR","route":"/targets/mtor/"},{"id":"sstr2","kind":"target","name":"Somatostatin receptor 2","route":"/targets/sstr2/"}],"drug":[{"id":"itm-11","kind":"drug","name":"177Lu-edotreotide","route":"/drugs/itm-11/"},{"id":"alphamedix","kind":"drug","name":"212Pb-DOTAMTATE","route":"/drugs/alphamedix/"},{"id":"ryz101","kind":"drug","name":"Actinium-225 DOTATATE","route":"/drugs/ryz101/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"cam2029","kind":"drug","name":"CAM2029 (octreotide subcutaneous depot)","route":"/drugs/cam2029/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"ga68-dotatate","kind":"drug","name":"Gallium-68 DOTATATE (and Cu-64 DOTATATE)","route":"/drugs/ga68-dotatate/"},{"id":"lutathera","kind":"drug","name":"Lutetium-177 dotatate","route":"/drugs/lutathera/"},{"id":"paltusotine","kind":"drug","name":"Paltusotine","route":"/drugs/paltusotine/"},{"id":"octreotide-lanreotide","kind":"drug","name":"Somatostatin analogues (octreotide, lanreotide)","route":"/drugs/octreotide-lanreotide/"},{"id":"telotristat-ethyl","kind":"drug","name":"Telotristat ethyl","route":"/drugs/telotristat-ethyl/"}],"term":[{"id":"carcinoid-syndrome","kind":"term","name":"Carcinoid syndrome and carcinoid heart disease","route":"/terms/carcinoid-syndrome/"},{"id":"chromogranin-a","kind":"term","name":"Chromogranin A","route":"/terms/chromogranin-a/"},{"id":"hepatectomy","kind":"term","name":"Hepatectomy (liver resection)","route":"/terms/hepatectomy/"},{"id":"liver-directed-therapy","kind":"term","name":"Liver-directed therapy (TACE, TARE, HAI, ablation)","route":"/terms/liver-directed-therapy/"},{"id":"net-grade-ki67","kind":"term","name":"Neuroendocrine tumour grade (Ki-67) and WHO classification","route":"/terms/net-grade-ki67/"},{"id":"prrt-term","kind":"term","name":"PRRT (peptide receptor radionuclide therapy)","route":"/terms/prrt-term/"}],"trial":[{"id":"nct05459844","kind":"trial","name":"A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs","route":"/trials/nct05459844/"},{"id":"nct05050942","kind":"trial","name":"A Trial to Assess Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With GEP-NET","route":"/trials/nct05050942/"},{"id":"action-1","kind":"trial","name":"ACTION-1","route":"/trials/action-1/"},{"id":"cabinet","kind":"trial","name":"CABINET (Alliance A021602)","route":"/trials/cabinet/"},{"id":"nct07087054","kind":"trial","name":"Carcinoid Syndrome Efficacy Study Featuring an Oral Daily Paltusotine Regimen","route":"/trials/nct07087054/"},{"id":"clarinet","kind":"trial","name":"CLARINET","route":"/trials/clarinet/"},{"id":"compete","kind":"trial","name":"COMPETE","route":"/trials/compete/"},{"id":"nct04919226","kind":"trial","name":"Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE","route":"/trials/nct04919226/"},{"id":"netter-1","kind":"trial","name":"NETTER-1","route":"/trials/netter-1/"},{"id":"promid","kind":"trial","name":"PROMID","route":"/trials/promid/"},{"id":"radiant-3-4","kind":"trial","name":"RADIANT-3 and RADIANT-4","route":"/trials/radiant-3-4/"},{"id":"nct03972488","kind":"trial","name":"Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET","route":"/trials/nct03972488/"},{"id":"nct06943755","kind":"trial","name":"Zanzalintinib Versus Everolimus in Participants With Locally Advanced or Metastatic Neuroendocrine Tumors","route":"/trials/nct06943755/"}],"paper":[{"id":"paper-cabinet-cabozantinib-nejm-2024","kind":"paper","name":"CABINET (Alliance A021602): cabozantinib for advanced neuroendocrine tumours","route":"/key-papers/paper-cabinet-cabozantinib-nejm-2024/"},{"id":"paper-clarinet-lanreotide-nejm-2014","kind":"paper","name":"CLARINET: lanreotide in metastatic enteropancreatic neuroendocrine tumours","route":"/key-papers/paper-clarinet-lanreotide-nejm-2014/"},{"id":"paper-netter-1-nejm-2017","kind":"paper","name":"NETTER-1: 177Lu-Dotatate for midgut neuroendocrine tumours progressing on octreotide","route":"/key-papers/paper-netter-1-nejm-2017/"},{"id":"paper-netter-2-lancet-2024","kind":"paper","name":"NETTER-2: lutetium-177 dotatate as first treatment for higher-grade gastroenteropancreatic neuroendocrine tumours","route":"/key-papers/paper-netter-2-lancet-2024/"},{"id":"paper-promid-rinke-jco-2009","kind":"paper","name":"PROMID: octreotide LAR in the control of tumour growth in metastatic midgut neuroendocrine tumours","route":"/key-papers/paper-promid-rinke-jco-2009/"},{"id":"paper-radiant-4-everolimus-lancet-2016","kind":"paper","name":"RADIANT-4: everolimus for advanced non-functional neuroendocrine tumours of the lung or gastrointestinal tract","route":"/key-papers/paper-radiant-4-everolimus-lancet-2016/"}],"idea":[{"id":"idea-net-dosimetry-prrt","kind":"idea","name":"Dosimetry-personalised PRRT instead of four fixed cycles","route":"/ideas/idea-net-dosimetry-prrt/"},{"id":"idea-net-antagonist-ligands","kind":"idea","name":"SSTR antagonist radioligands to increase tumour dose","route":"/ideas/idea-net-antagonist-ligands/"}],"person":[{"id":"jennifer-chan","kind":"person","name":"Jennifer A. Chan","route":"/people/jennifer-chan/"}]}}