# Pancreatic neuroendocrine tumours

Source: https://onco.cc/cancers/pancreatic-net/  
OnCo record `pancreatic-net` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Pancreatic neuroendocrine tumours arise from the hormone-producing islet cells of the pancreas and behave very differently from ordinary pancreatic cancer, often growing for years. Surgery cures localised tumours; advanced disease is treated in sequence with somatostatin analogues, lutetium-177 dotatate, targeted tablets and oral chemotherapy, and a minority secrete insulin or gastrin.

## Summary

Pancreatic neuroendocrine tumours arise from islet cells and are graded by Ki-67 like other neuroendocrine tumours, but their genetics are their own: MEN1 is the most commonly mutated gene in sporadic tumours, with DAXX or ATRX loss and mutations in the mTOR pathway following, while KRAS and TP53, the drivers of ductal adenocarcinoma, are absent. Most are non-functioning and present as a mass or as liver metastases; the functioning minority cause syndromes, insulinoma with fasting hypoglycaemia (usually benign and cured by enucleation), gastrinoma with the ulcer disease of Zollinger-Ellison syndrome (controlled with proton-pump inhibitors, often malignant and often part of MEN1), and rarer glucagonomas and VIPomas. Germline testing is offered because MEN1, VHL, neurofibromatosis type 1 and tuberous sclerosis all predispose, and small non-functioning tumours under about two centimetres are often watched rather than removed.

Surgery is curative for localised disease: enucleation or distal pancreatectomy for small tumours and a Whipple procedure for those in the head. For advanced disease, 2011 brought two tablets at once. RADIANT-3 (New England Journal of Medicine 2011) randomised 410 patients with progressive tumours to everolimus or placebo and lengthened progression-free survival from 4.6 to 11.0 months; the sunitinib phase 3 (New England Journal of Medicine 2011) was stopped early after 171 patients with 11.4 against 5.5 months. CLARINET (2014), in which almost half the patients had pancreatic tumours, established lanreotide as antiproliferative first-line therapy, and the E2211 trial (Journal of Clinical Oncology 2023) showed that adding capecitabine to temozolomide lengthened progression-free survival from 14.4 to 22.7 months with a higher response rate, making CAPTEM the chemotherapy of choice when shrinkage is needed. Streptozocin, approved in 1982, remains a guideline option.

Radioligand therapy and cabozantinib have since reordered the sequence. Lutathera's 2018 approval covered all gastroenteropancreatic tumours on the strength of NETTER-1 in midgut disease, and NETTER-2 (Lancet 2024), in which more than half the patients had pancreatic tumours, showed first-line lutetium-177 dotatate lengthened progression-free survival from 8.5 to 22.8 months in grade 2 and 3 disease. CABINET (New England Journal of Medicine 2024) randomised a separate pancreatic cohort to cabozantinib or placebo after prior therapy and lengthened progression-free survival from 4.4 to 13.8 months, leading to approval in March 2025. Belzutifan was approved in 2021 for VHL-associated pancreatic tumours not needing immediate surgery, and its LITESPARK-015 trial has a sporadic pancreatic NET cohort. COMPETE (Lancet 2025) and COMPOSE test 177Lu-edotreotide against everolimus and against chemotherapy, and hepatic-dominant disease is still treated with embolisation, ablation and resection.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: pNET; Islet cell tumour; Pancreatic NET; Insulinoma; Gastrinoma; Non-functioning pancreatic neuroendocrine tumour
- Tags: subtype-page; endocrine
- Group: endocrine
- Burden: A small minority of pancreatic cancers but the site with the most approved drugs of any neuroendocrine tumour; most are non-functioning and found on imaging, while insulinomas and gastrinomas announce themselves through their hormones.
- Subtypes: Non-functioning pancreatic NET (the majority, found as a mass or liver metastases); Insulinoma (fasting hypoglycaemia, usually benign, cured by enucleation); Gastrinoma and Zollinger-Ellison syndrome (often duodenal or pancreatic head, often MEN1); Glucagonoma, VIPoma and somatostatinoma (rare functioning tumours); MEN1- and VHL-associated pancreatic NET (multiple, young onset); Grade 1 to 2 pancreatic NET (somatostatin analogue, radioligand, everolimus, sunitinib, cabozantinib); Grade 3 well-differentiated pancreatic NET (see the grade 3 record)
- Biomarkers: Ki-67 index and mitotic count (WHO grade); Chromogranin A (monitoring); Somatostatin receptor PET (staging and radioligand eligibility); Fasting glucose, insulin, C-peptide and proinsulin (insulinoma); Fasting gastrin and gastric pH (gastrinoma); Germline MEN1, VHL, NF1 and TSC testing; MEN1, DAXX and ATRX status in the tumour (prognostic, research); MGMT status (CAPTEM response, investigational)

## Standard of care

- Diagnosis and staging: Contrast CT or MRI, somatostatin receptor PET, biopsy with Ki-67 grading, chromogranin A, hormone assays where a syndrome is suspected, and germline testing. ([Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [Gallium-68 DOTATATE (and Cu-64 DOTATATE)](https://onco.cc/drugs/ga68-dotatate/), [Neuroendocrine tumour grade (Ki-67) and WHO classification](https://onco.cc/terms/net-grade-ki67/), [Chromogranin A](https://onco.cc/terms/chromogranin-a/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/))
- Localised, resectable: Enucleation or distal pancreatectomy for small tumours, Whipple procedure for tumours in the head, lymphadenectomy for tumours over two centimetres; surveillance for small non-functioning tumours. ([Whipple procedure (pancreaticoduodenectomy)](https://onco.cc/terms/whipple/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/))
- Functioning syndromes: Surgery for insulinoma with diazoxide or everolimus to control hypoglycaemia beforehand; high-dose proton-pump inhibitors and resection for gastrinoma; somatostatin analogues for glucagonoma and VIPoma. ([Somatostatin analogues (octreotide, lanreotide)](https://onco.cc/drugs/octreotide-lanreotide/), [Everolimus](https://onco.cc/drugs/everolimus/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/))
- Advanced, first line: Lanreotide or octreotide (CLARINET); lutetium-177 dotatate first line for grade 2 to 3 tumours with a Ki-67 of 10 percent or more (NETTER-2); CAPTEM when shrinkage is needed. ([Somatostatin analogues (octreotide, lanreotide)](https://onco.cc/drugs/octreotide-lanreotide/), [CLARINET](https://onco.cc/trials/clarinet/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET](https://onco.cc/trials/nct03972488/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/))
- Progression on a somatostatin analogue: Lutetium-177 dotatate; everolimus (RADIANT-3); sunitinib; cabozantinib (CABINET); CAPTEM or streptozocin-based chemotherapy. ([Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Everolimus](https://onco.cc/drugs/everolimus/), [RADIANT-3 and RADIANT-4](https://onco.cc/trials/radiant-3-4/), [Sunitinib](https://onco.cc/drugs/sunitinib/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [CABINET (Alliance A021602)](https://onco.cc/trials/cabinet/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/), [Streptozocin](https://onco.cc/drugs/streptozocin/))
- Liver-dominant disease: Resection, thermal ablation, chemoembolisation or radioembolisation, alongside systemic therapy. ([Hepatectomy (liver resection)](https://onco.cc/terms/hepatectomy/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [Transarterial chemoembolisation (TACE)](https://onco.cc/technologies/tace/), [Radioembolisation (TARE / SIRT, yttrium-90)](https://onco.cc/technologies/radioembolisation-tare/), [Liver-directed therapy (TACE, TARE, HAI, ablation)](https://onco.cc/terms/liver-directed-therapy/))
- VHL-associated pancreatic NET: Belzutifan for tumours not requiring immediate surgery (approved 2021). ([Belzutifan](https://onco.cc/drugs/belzutifan/), [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/))

## State of the art

- Five approved systemic drug classes (somatostatin analogues, radioligand therapy, mTOR inhibition, anti-angiogenic kinase inhibitors and oral chemotherapy) give years of sequential control.
- NETTER-2 put lutetium-177 dotatate in first line for grade 2 to 3 disease and CABINET added cabozantinib after prior therapy.
- Belzutifan was the first drug approved for a hereditary neuroendocrine syndrome, in VHL disease.

## Open problems

- The best order of radioligand therapy, everolimus, sunitinib, cabozantinib and CAPTEM is unknown.
- Which small non-functioning tumours can safely be watched rather than resected.
- MGMT and other predictors of CAPTEM response are not validated for decisions.
- Grade 3 well-differentiated tumours sit between the tumour and carcinoma paradigms and need their own trials.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor
- RADIANT-3 (NEJM 2011): https://doi.org/10.1056/NEJMoa1009290
- Sunitinib in pancreatic NET (NEJM 2011): https://doi.org/10.1056/NEJMoa1003825
- CABINET (NEJM 2024): https://doi.org/10.1056/NEJMoa2403991
- Wikipedia: https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor

## Connected records

- cancers: [Extrapulmonary neuroendocrine carcinoma](https://onco.cc/cancers/extrapulmonary-nec/), [Grade 3 well-differentiated neuroendocrine tumour](https://onco.cc/cancers/grade-3-net/), [Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors](https://onco.cc/cancers/ipmn-cystic-precursors/), [Lung neuroendocrine tumours (typical and atypical carcinoid)](https://onco.cc/cancers/lung-net/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Pancreatic acinar cell carcinoma](https://onco.cc/cancers/pancreatic-acinar-cell-carcinoma/), [Pancreatoblastoma](https://onco.cc/cancers/pancreatoblastoma/), [Small intestinal neuroendocrine tumours](https://onco.cc/cancers/small-intestinal-net/)
- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Radioembolisation (TARE / SIRT, yttrium-90)](https://onco.cc/technologies/radioembolisation-tare/), [Radioligand therapy (beta emitters)](https://onco.cc/technologies/radioligand-therapy/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [Transarterial chemoembolisation (TACE)](https://onco.cc/technologies/tace/)
- targets: [HIF-2α](https://onco.cc/targets/hif2a/), [Menin](https://onco.cc/targets/menin/), [mTOR](https://onco.cc/targets/mtor/), [Somatostatin receptor 2](https://onco.cc/targets/sstr2/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [177Lu-edotreotide](https://onco.cc/drugs/itm-11/), [212Pb-DOTAMTATE](https://onco.cc/drugs/alphamedix/), [Actinium-225 DOTATATE](https://onco.cc/drugs/ryz101/), [Belzutifan](https://onco.cc/drugs/belzutifan/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/), [Diazoxide](https://onco.cc/drugs/diazoxide/), [Everolimus](https://onco.cc/drugs/everolimus/), [Gallium-68 DOTATATE (and Cu-64 DOTATATE)](https://onco.cc/drugs/ga68-dotatate/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Somatostatin analogues (octreotide, lanreotide)](https://onco.cc/drugs/octreotide-lanreotide/), [Streptozocin](https://onco.cc/drugs/streptozocin/), [Sunitinib](https://onco.cc/drugs/sunitinib/)
- terms: [Chromogranin A](https://onco.cc/terms/chromogranin-a/), [Hepatectomy (liver resection)](https://onco.cc/terms/hepatectomy/), [Liver-directed therapy (TACE, TARE, HAI, ablation)](https://onco.cc/terms/liver-directed-therapy/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/), [Neuroendocrine tumour grade (Ki-67) and WHO classification](https://onco.cc/terms/net-grade-ki67/), [PRRT (peptide receptor radionuclide therapy)](https://onco.cc/terms/prrt-term/), [Whipple procedure (pancreaticoduodenectomy)](https://onco.cc/terms/whipple/)
- trials: [A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs](https://onco.cc/trials/nct05459844/), [A Trial to Assess Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With GEP-NET](https://onco.cc/trials/nct05050942/), [ACTION-1](https://onco.cc/trials/action-1/), [An Open-label Phase 3 Study of Lutetium (177Lu) Oxodotreotide Injection in Subjects With Advanced Gastrointestinal Pancreatic Neuroendocrine Tumors.](https://onco.cc/trials/nct05884255/), [Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL](https://onco.cc/trials/nct04924075/), [CABINET (Alliance A021602)](https://onco.cc/trials/cabinet/), [CLARINET](https://onco.cc/trials/clarinet/), [COMPETE](https://onco.cc/trials/compete/), [Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE](https://onco.cc/trials/nct04919226/), [NETTER-1](https://onco.cc/trials/netter-1/), [RADIANT-3 and RADIANT-4](https://onco.cc/trials/radiant-3-4/), [Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET](https://onco.cc/trials/nct03972488/), [Zanzalintinib Versus Everolimus in Participants With Locally Advanced or Metastatic Neuroendocrine Tumors](https://onco.cc/trials/nct06943755/)
- key papers: [CABINET (Alliance A021602): cabozantinib for advanced neuroendocrine tumours](https://onco.cc/key-papers/paper-cabinet-cabozantinib-nejm-2024/), [CLARINET: lanreotide in metastatic enteropancreatic neuroendocrine tumours](https://onco.cc/key-papers/paper-clarinet-lanreotide-nejm-2014/), [NETTER-2: lutetium-177 dotatate as first treatment for higher-grade gastroenteropancreatic neuroendocrine tumours](https://onco.cc/key-papers/paper-netter-2-lancet-2024/), [RADIANT-3: everolimus for advanced pancreatic neuroendocrine tumours](https://onco.cc/key-papers/paper-radiant-3-everolimus-pnet-yao-nejm-2011/), [Sunitinib malate for the treatment of pancreatic neuroendocrine tumours](https://onco.cc/key-papers/paper-raymond-sunitinib-pnet-nejm-2011/)
- ideas: [Dosimetry-personalised PRRT instead of four fixed cycles](https://onco.cc/ideas/idea-net-dosimetry-prrt/)
- people: [Jennifer A. Chan](https://onco.cc/people/jennifer-chan/)

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