Small intestinal neuroendocrine tumours
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.
Overview
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.
The 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.
Surgery 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.
State of the art
- 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.
Anatomy and lymph node drainage
- Right colon (MSI-high, BRAF commoner)
- Left colon and sigmoid
- Rectum
- Anal canal (HPV squamous)
- Appendix
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- Nodes: pericolic
- Nodes: mesenteric root
- Nodes: para-aortic
- Nodes: mesorectal
- Nodes: lateral pelvic and inguinal (anal)
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
- Right colon (MSI-high, BRAF commoner)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
- Left colon and sigmoid
- Rectum
- Anal canal (HPV squamous)
- AppendixSmall bowel NET with carcinoid syndrome and liver metastases
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- pericolic
- mesenteric root
- para-aortic
- mesorectal
- lateral pelvic and inguinal (anal)
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.
- Somatostatin receptor PET (68Ga/64Cu-DOTATATE)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on Nuclide: Roadmaps.
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.
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.
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).
Lutetium-177 dotatate (NETTER-1); everolimus (RADIANT-4); cabozantinib (CABINET); liver-directed therapy for hepatic-dominant disease.
Somatostatin analogue dose escalation, telotristat ethyl for refractory diarrhoea, octreotide infusion around procedures to prevent carcinoid crisis, valve surgery for carcinoid heart disease.
Everolimus or cabozantinib; 177Lu-edotreotide if approved; alpha-emitting radioligands and retreatment in trials.
Subtypes & biomarkers
top- 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
- 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)
How often this target appears
- 1907Oberndorfer names the small bowel tumours 'Karzinoid'
- 1954Carcinoid syndrome described
- 1988Octreotide approved for carcinoid syndrome symptoms
- 2009PROMID: octreotide LAR slows midgut tumour growth
- 2014CLARINET: lanreotide halves the risk of progression in enteropancreatic tumours
- 2016RADIANT-4 extends everolimus to gut and lung tumours; gallium-68 DOTATATE PET approved
- 2017NETTER-1 published; telotristat ethyl approved for carcinoid syndrome diarrhoea
- 2018Lutathera approved in the United States and Europe
- 2024NETTER-2: lutetium-177 dotatate first line for grade 2 to 3 tumours; CABINET published
- 2025Cabozantinib approved for previously treated neuroendocrine tumours; COMPETE published
Dated changes read from the records linked to this indication: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 15 changes by month →- 2026-09-17This recordSmall intestinal neuroendocrine tumoursFacts on this page last checked
When this page itself was last checked or edited.
- 2025Trial resultCOMPETECOMPETE reported
PFS 23.
- 2025MilestoneCabozantinibCabozantinib approved for previously treated neuroendocrine tumours; COMPETE published
A milestone in how this cancer is treated.
- 2024Trial resultCABINET (Alliance A021602)CABINET (Alliance A021602) reported
PFS HR 0.
- 2024MilestoneStudy to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NETNETTER-2: lutetium-177 dotatate first line for grade 2 to 3 tumours; CABINET published
A milestone in how this cancer is treated.
- 2018MilestoneLutetium-177 dotatateLutathera approved in the United States and Europe
A milestone in how this cancer is treated.
What is in development for Small intestinal neuroendocrine tumours, drawn from the whole corpus: 14 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 2
Drugs in phase 2 · 1
Technologies being tested · 1
Trials under way · 4
- ACTION-1 · phase 3 · BMS (RayzeBio)
- A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs · phase 3 · Sinotau Pharmaceutical Group
- Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE · phase 3 · ITM Solucin GmbH
- Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET · phase 3 · Advanced Accelerator Applications
Trials reported · 4
- COMPETE · phase 3 · 2025 · positive
- CABINET (Alliance A021602) · phase 3 · 2024 · positive
- NETTER-1 · phase 3 · 2017 · positive
- RADIANT-3 and RADIANT-4 · phase 3 · 2011 · positive
Ideas not yet in a trial · 2
Open problems and what is being done
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.
What is being done about thisAdvanced and metastatic diseaseAvailable nowIn trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on Nuclide: Indications.
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.
Trials
topTrials recruiting now
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Landmark trials
Direct links plus the targets, companies, and technologies of this cancer's products.
isotopes
1fronts
1technologies
8targets
1drugs
11companies
8terms
2trials
8roadmaps
1ideas
2key papers
5Cabozantinib is approved for previously treated neuroendocrine tumours of any origin and is a standard later-line choice, including for lung carcinoids.
Patients newly diagnosed with an advanced grade 2 or 3 neuroendocrine tumour of the gut or pancreas that shows somatostatin receptors on imaging can now receive lutetium dotatate as their first treatment, gaining more than a year of additional disease control and a much higher chance of tumour shrinkage. It does not settle whether radioligand therapy is better than other first-line options such as capecitabine-temozolomide or everolimus, and long-term marrow safety with earlier use needs surveillance.
People treated with the radioactive drug lutetium-177 dotatate kept feeling well for much longer - years rather than months, in several measures - than people on the standard high-dose hormone injection, on top of the tumour-control benefit already shown.
Lutetium-177 dotatate is a standard treatment for progressive small bowel neuroendocrine tumours after somatostatin analogues, and NETTER-2 has since moved it into first-line use for higher-grade tumours.
Somatostatin analogues are the standard first-line antiproliferative treatment for grade 1 to 2 gastroenteropancreatic neuroendocrine tumours whether or not they cause a hormone syndrome.
Latest papers
topQuery for this indication: (TITLE:"Small intestinal neuroendocrine tumours" OR ABSTRACT:"Small intestinal neuroendocrine tumours" OR TITLE:"Midgut neuroendocrine tumour" OR ABSTRACT:"Midgut neuroendocrine tumour" OR TITLE:"Small bowel NET" OR ABSTRACT:"Small bowel NET" OR TITLE:"Ileal carcinoid" OR ABSTRACT:"Ileal carcinoid" OR TITLE:"Jejunoileal neuroendocrine tumour" OR ABSTRACT:"Jejunoileal neuroendocrine tumour" OR TITLE:"SI-NET" OR ABSTRACT:"SI-NET") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Small intestinal neuroendocrine tumours, not a curated reading list.
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