Neuroendocrine Tumour Symptoms, Stages and Treatment
In this article
What Is a Neuroendocrine Tumour?
Neuroendocrine tumours (NETs) are a rare group of cancers arising from neuroendocrine cells found throughout the body, which combine characteristics of nerve cells and hormone-producing (endocrine) cells. Their incidence has increased markedly over the past twenty years. They most commonly occur in the gastrointestinal system, pancreas and lungs. These tumours are a heterogeneous family of diseases, rather than a single disease: their behaviour ranges from slow-growing to extremely aggressive, and their staging and treatment differ according to the organ of origin. Over the past decade, rapid advances have occurred in diagnosis (Ga-68 DOTATATE PET/CT, new blood tests such as NETest), staging and particularly treatment (peptide receptor radionuclide therapy, new targeted drugs) — successive new FDA approvals in 2025 and 2026 provide the clearest evidence of this. This guide comprehensively covers the entire process, from what neuroendocrine tumours are to current treatment options.
This guide focuses on gastroenteropancreatic (GEP, originating in the stomach, intestines or pancreas) and lung (bronchopulmonary) neuroendocrine tumours — the vast majority of neuroendocrine tumours belong to this group. Merkel cell carcinoma (a rare skin cancer associated with Merkel cell polyomavirus and UV damage, with entirely different biology and treatment — particularly immunotherapies such as avelumab/pembrolizumab) and medullary thyroid cancer (a separate disease arising from calcitonin-secreting C cells, with its own staging and treatment framework) are also technically tumours of neuroendocrine origin. However, because their biology and treatment are fundamentally different from the GEP/lung NETs covered in this guide, they are not discussed in detail here; separate resources are provided below for interested readers.
Terminology: Differences Between NET, NEC, Carcinoid and Carcinoid Syndrome
Several terms in the field of neuroendocrine tumours are frequently confused; these distinctions must first be clarified to read the rest of this guide correctly:
| Term | Meaning |
|---|---|
| Neuroendocrine neoplasm (NEN) | The broadest umbrella term encompassing all neuroendocrine tumours |
| Neuroendocrine tumour (NET) | Well-differentiated neuroendocrine neoplasms; they may range from grade 1 to grade 3 (see the grading section below) |
| Neuroendocrine carcinoma (NEC) | Poorly differentiated neuroendocrine neoplasms, always high-grade and aggressive; treated similarly to small cell lung cancer |
| Carcinoid (tumour) | A historical term generally used for well-differentiated NETs originating in the gastrointestinal system or lungs — "NET" is now preferred, but "carcinoid" is still widely used |
| Carcinoid syndrome | Rather than a tumour type, it is caused by serotonin and other vasoactive substances secreted by certain NETs (particularly those originating in the midgut and metastasising to the liver), and is a cluster of clinical symptoms (flushing, diarrhoea, bronchospasm, heart valve disease) — discussed in a separate section below |
| MiNEN | The current WHO term for mixed tumours in which the neuroendocrine and non-neuroendocrine (for example, adenocarcinoma) components each constitute at least %30 of the mass (formerly "MANEC") |
Embryological Origin: Foregut, Midgut and Hindgut Classification
Gastrointestinal NETs are divided into three groups according to the embryonic gut segment from which they arise — this classification is more than an academic detail, because each group secretes different hormones, has a different somatostatin receptor density and is associated with different clinical syndromes.
| Group | Anatomical Sites | Clinical Features |
|---|---|---|
| Foregut (anterior gut) | Oesophagus, stomach, duodenum, pancreas (bronchopulmonary NETs are also included in this group in a broad sense) | Variable/atypical hormone secretion (for example, gastrin); low serotonin content; direct causation of classic carcinoid syndrome is rare |
| Midgut (middle gut) | Jejunum, ileum, caecum, appendix, ascending colon | Derived from enterochromaffin cells, with serotonin — as the main secretory product; the strongest association with carcinoid syndrome is seen in this group; almost universal high SSTR2 (somatostatin receptor) expression |
| Hindgut (posterior gut) | Distal colon, rectum | Serotonin secretion and carcinoid syndrome are rare; generally clinically silent and detected incidentally |
If a midgut NET has not yet metastasised to the liver, the serotonin it secretes reaches the liver via the portal circulation, where it is largely broken down and inactivated before entering systemic circulation. Therefore, for carcinoid syndrome to occur, the secreted substances must bypass this hepatic "first-pass" clearance and enter systemic circulation directly — in practice, this almost always requires the presence of liver metastases (liver metastases are found in more than %90 of symptomatic cases).
How Common Is It? (Current Statistics)
According to a recent study based on the SEER database (Yu Q, et al., "Dethroning of Neuroendocrine Tumor as an Orphan Disease," Cancers, published 15 October 2025, DOI: 10.3390/cancers17203323; n=231.659 patients, 2000-2021 data), US NET incidence rose from 4,6 per 100.000 in 2000 to, in 2021, a rate per 100.000 of 8,2 (average annual increase +2,90/100.000; p<0,05) — in the authors' words, "NETs can no longer be characterised as rare/orphan diseases based on current US incidence and prevalence trends." According to 2021 data, prevalence reached %0,064 of the US population. Five-year overall survival by stage: localised %82,3, regional %66,9, distant metastasis %26,1; by grade: G1 %80,0, G2 %66,5, G3-G4 %16,6; by primary site: appendix %75,9, small intestine %74,4, colorectal %72,1, lung %49,1, liver %28,2.
Note: Because GLOBOCAN classifies cancers by organ rather than histology (stomach, pancreas, lung, etc.), a single, separate global incidence figure for neuroendocrine tumours is not available — NET cases are reported within the statistics for their respective organs. Similarly, Türkiye's Ministry of Health national cancer statistics do not report neuroendocrine tumours as a separate histological category; a reliable NET incidence/prevalence figure specific to Türkiye could not be found during this research. Consequently, this guide presents only US/SEER-based data and does not generate figures specific to Türkiye — a much more accurate approach than providing false/fabricated statistics.
According to another historically frequently cited SEER analysis (Dasari A, et al., JAMA Oncology, online 27 April 2017, DOI: 10.1001/jamaoncol.2017.0589), age-standardised incidence increased between 1973-2012 from 1,09 to 6,98 per 100.000 (approximately 6,4-fold); most of this increase reflects rising early/incidental diagnosis rates due to greater use of imaging and endoscopy. In the same study, median overall survival in distant metastatic disease differed strikingly by primary site: 5,83 years in small-intestinal NETs, but only 6 months in lung NETs and 4 months in colon NETs — illustrating how differently diseases grouped under "NET" can behave.
Hereditary Syndromes and Risk Factors
The vast majority of NETs occur sporadically (nonhereditarily); however, in a small number of patients an underlying hereditary syndrome markedly increases the risk of tumour development. Identifying these patients is critical to follow-up/screening plans for both patients and their families.
| Syndrome | Gene | Associated NETs | Risk/Penetrance |
|---|---|---|---|
| MEN1 (Multiple Endocrine Neoplasia type 1) | MEN1 (menin) | Pancreatic/duodenal NET (mainly gastrinomas and nonfunctional tumours), parathyroid and pituitary adenoma | Lifetime duodenopancreatic NET risk >%80; hyperparathyroidism >%95; pituitary adenoma %49-58 |
| MEN2A/2B | RET (proto-oncogene) | Medullary thyroid cancer, pheochromocytoma | Medullary thyroid cancer risk ~%100 (hence early prophylactic thyroidectomy is considered in children diagnosed with MEN2); pheochromocytoma risk up to %50 |
| Von Hippel-Lindau (VHL) disease | VHL | Pancreatic NET, pheochromocytoma/paraganglioma, also renal cell cancer and CNS haemangioblastoma | Pancreatic NET %5-17; overall penetrance nearly complete by age 65 |
| Neurofibromatosis type 1 (NF1) | NF1 | Duodenal/periampullary somatostatinoma, GI NET, pheochromocytoma | Somatostatinoma is relatively rare but markedly more frequent in NF1 patients than in sporadic cases; NF1-associated duodenal somatostatinomas tend to metastasise less than sporadic tumours |
| Tuberous Sclerosis Complex | TSC1/TSC2 | Nonfunctional pancreatic NET | Although markedly increased compared with the general population, the absolute risk is low (~%0,65); generally detected incidentally on surveillance MRI |
An important development has occurred in recent years for tumours associated with VHL disease: the HIF-2α inhibitor belzutifan (Welireg)received FDA approval on 13 August 2021 for VHL-associated renal cell cancer, pancreatic NET and CNS haemangioblastoma; on 14 May 2025, it was also approved, independently of VHL, for locally advanced/metastatic pheochromocytoma or paraganglioma , becoming the first approved oral treatment for this tumour group (LITESPARK-015 study, ORR %26, median response duration 20,4 months). This topic is discussed in detail in our website articles on pheochromocytoma/paraganglioma treatment and belzutifan approval .
Symptoms: Functional and Nonfunctional NETs
NET symptoms may arise through two separate mechanisms: mass effect (due to tumour size/location, such as bowel obstruction, pain or jaundice) and hormonal hypersecretion (specific to the hormone produced by the tumour, seen in "functional" NETs). Most NETs are actually nonfunctional— they do not cause a distinct hormonal syndrome and are generally detected only through mass effect or incidentally on imaging; this often delays diagnosis.
| Syndrome | Secreted Hormone | Typical Symptoms |
|---|---|---|
| Insulinoma | Insulin | Fasting hypoglycaemia: sweating, palpitations, confusion, loss of consciousness (Whipple's triad: hypoglycaemia symptoms + low glucose + resolution with glucose) |
| Gastrinoma (Zollinger-Ellison syndrome) | Gastrin | Recurrent/treatment-resistant peptic ulcers, severe reflux, chronic diarrhoea |
| Glucagonoma | Glucagon | Necrolytic migratory erythema (characteristic skin rash), hyperglycaemia, weight loss, tendency towards venous thrombosis |
| VIPoma (Verner-Morrison syndrome) | Vasoactive intestinal peptide (VIP) | Severe watery diarrhoea, hypokalaemia, achlorhydria ("WDHA syndrome") |
| Somatostatinoma | Somatostatin | Diabetes, gallstones, steatorrhoea (fatty stools) — generally recognised late, often associated with NF1 (in the duodenal form) |
| Carcinoid syndrome | Serotonin and other vasoactive substances | Sudden flushing, watery diarrhoea, bronchospasm, carcinoid heart disease — discussed in detail below |
- Abdominal pain, bloating or changes in bowel habits
- Unexplained weight loss
- Signs of bowel obstruction (advanced stage, due to mass effect)
- Right upper quadrant pain or jaundice due to liver metastases
- Cough, recurrent pneumonia (in lung NETs, due to airway obstruction)
- Liver or pancreatic mass found incidentally on imaging (the most common presentation of nonfunctional NETs)
Carcinoid Syndrome
Carcinoid syndrome is a cluster of symptoms mainly seen in midgut NETs with liver metastases, resulting from serotonin and other vasoactive substances reaching systemic circulation. It occurs in only a subset of patients diagnosed with NETs (mostly midgut NETs with liver metastases).
- Sudden, hot-flush-like redness of the face/neck (flushing) — the most characteristic symptom
- Frequent watery diarrhoea
- Abdominal cramps
- Bronchospasm/wheezing
- Carcinoid heart disease (fibrosis of the right-sided heart valves — particularly the tricuspid and pulmonary valves)
Anaesthesia induction, tumour manipulation (during surgery or biopsy) or certain drugs may trigger sudden, severe hormone release ("carcinoid crisis") in patients with carcinoid syndrome, causing severe hypotension, arrhythmia or bronchospasm. Consequently, prophylactic octreotide before surgical/interventional procedures is a standard precaution in patients with known or suspected carcinoid syndrome.
How Is It Diagnosed?
Biochemical Tests and Biomarkers
| Test | Use | Limitations |
|---|---|---|
| Chromogranin A (CgA) | The most commonly used general NET biomarker; associated with tumour burden | Substantial false-positive rate — in one study, %23 of patients with elevated CgA proved to be false positives (Butler OL, et al., Frontiers in Endocrinology, 2020); proton pump inhibitor (PPI) use, renal/hepatic failure, chronic atrophic gastritis and inflammatory bowel disease may cause falsely elevated levels |
| 24-hour urinary 5-HIAA | Particularly in midgut NETs/NETs with carcinoid syndrome; sensitivity %73, specificity %100 (for midgut carcinoid) | Because serotonin secretion is rare in foregut and hindgut NETs, benefit is limited in this group; foods high in serotonin (bananas, pineapple, tomatoes, walnuts) should be avoided for 48 hours before testing; acetaminophen and risperidone may artificially lower the level |
| NETest (multigene expression test) | A next-generation blood biomarker based on a 51-gene transcript signature; in a comparison at an ENETS centre of excellence (Malczewska A, et al., Endocrine Connections, 2021), sensitivity was %99 and specificity %65 — in the same cohort, CgA sensitivity was only %18-32 | Currently used mainly at ENETS centres of excellence, and not yet included as a mandatory test in current NCCN/ENETS guidelines; routine clinical use in Türkiye is limited |
Imaging: Ga-68 DOTATATE PET/CT
Developed to image NET cells bearing somatostatin receptors (SSTR), Ga-68 DOTATATE PET/CT is now the gold standard in NET imaging. According to a prospective comparison (Sadowski SM, et al., Journal of Clinical Oncology, 2016), the patient-level detection rate was %95,1 for Ga-68 DOTATATE PET/CT, %45,3 for conventional CT/MRI, and only %30,9 for older-generation In-111-pentetreotide scintigraphy (p<0,001). This superiority makes Ga-68 DOTATATE PET/CT indispensable both in diagnosis/staging and in determining eligibility for peptide receptor radionuclide therapy (PRRT).
Low-grade (G1/G2), well-differentiated NETs express somatostatin receptors densely and are best imaged with Ga-68 DOTATATE PET, whereas dedifferentiated/high-grade tumours may lose somatostatin receptors and instead show more pronounced uptake on FDG-PET because of their increased glucose metabolism. Consequently, both imaging methods may be used together to assess the full heterogeneity of disease, particularly in NETs with mixed/aggressive behaviour or an uncertain treatment response.
Definitive diagnosis is established through a biopsy of suspicious tissue, rather than imaging or biochemical tests; pathological examination determines both histological type and the grade described below (Ki-67/mitotic count).
Histological Classification and Grading (WHO)
Under the World Health Organization's (WHO) 2019 (5th edition) classification of digestive system tumours and its 2022 update extending this to all organ systems (Rindi G, et al., Endocrine Pathology, 2022, DOI: 10.1007/s12022-022-09708-2), gastroenteropancreatic neuroendocrine neoplasms are classified by jointly assessing morphology (degree of differentiation) and proliferation rate (Ki-67 index/mitotic count):
| Category | Differentiation | Ki-67 Index | Mitotic Count |
|---|---|---|---|
| NET G1 | Well differentiated | <%3 | <2/2 mm² |
| NET G2 | Well differentiated | %3-20 | 2-20/2 mm² |
| NET G3 | Well differentiated | >%20 | >20/2 mm² |
| NEC (neuroendocrine carcinoma) | Poorly differentiated | >%20 (usually >%70) | >20/2 mm² |
Because the Ki-67 index can exceed %20 in both groups, these entities are often confused — yet their distinction is morphology rather than grade: if tumour cells appear well differentiated (gland-like, retaining organoid architecture), regardless of how high Ki-67 is, they are classified as NET G3 and may respond relatively well to somatostatin analogues/targeted therapies; if cells appear poorly differentiated (with small-cell or large-cell carcinoma morphology), they are classified as NEC and treated with platinum-based chemotherapy similarly to small cell lung cancer. Making this distinction correctly is crucial in the pathology report because it directly changes treatment selection.
Mixed tumours previously called "MANEC" (mixed adenoneuroendocrine carcinoma) were renamed under the 2019 WHO classification as MiNEN (mixed neuroendocrine–non-neuroendocrine neoplasm). This change was made because the old term was misleading: the non-neuroendocrine component is not always adenocarcinoma (it may also be squamous cell carcinoma), and both components need not always be malignant (carcinoma). Diagnosis requires each component to constitute at least %30 of the mass (La Rosa S, et al., Endocrine Pathology, 2016).
Staging: TNM Systems Varying by Organ
Unlike most cancers, neuroendocrine tumours are staged using different T/N/M criteria according to their organ of origin — pancreatic NET, small-intestinal NET, gastric NET and lung carcinoid each have their own staging table. The current system is AJCC edition 8 (2017), and the "Version 9" update published in 2024 (Chauhan A, et al., CA: A Cancer Journal for Clinicians, 2024, DOI: 10.3322/caac.21840) did not change T/N/M categories, instead reviewing molecular prognostic factors such as ALT (alternative lengthening of telomeres) and ATRX/DAXX gene loss — therefore, the following tables remain current.
Pancreatic NET (pNET) Staging
In AJCC edition 7, pancreatic NETs were staged using the same system as exocrine pancreatic adenocarcinoma (based on major vascular invasion). This approach was found not to reflect NET biology, and in AJCC edition 8 it was aligned with the European Neuroendocrine Tumor Society's (ENETS) tumour-size-based system.
| Category | Definition |
|---|---|
| T1 | Confined to the pancreas, <2 cm |
| T2 | Confined to the pancreas, 2-4 cm |
| T3 | Confined to the pancreas, >4 cm, or invades the duodenum/bile duct |
| T4 | Invades adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of major vessels (coeliac trunk or superior mesenteric artery) |
| N0 / N1 | No / present regional lymph node involvement |
| N2 (new in edition 8) | ≥4 regional lymph nodes involved |
| M0 / M1 | No / present distant metastasis |
Small-Intestinal (Midgut) NET Staging
| Category | Definition |
|---|---|
| T1 | Invades lamina propria/submucosa, ≤1 cm |
| T2 | Invades muscularis propria, or >1 cm |
| T3 | Extends through muscularis propria into subserosal tissue without penetrating the serosa |
| T4 | Invades visceral peritoneum (serosa) or other organs/adjacent structures |
| N0 | No regional node involvement |
| N1 | Regional metastases in <12 nodes |
| N2 | Large mesenteric masses (>2 cm) or extensive nodal involvement (≥12 nodes) |
| M1a/b/c | Liver only / extrahepatic only / both |
Gastric NET: Type I/II/III Classification
The behaviour of gastric NETs (gastric carcinoids) differs greatly according to their mechanism of development; they are therefore first classified as Type I/II/III, then staged using standard TNM:
| Feature | Type I | Type II | Type III |
|---|---|---|---|
| Associated condition | Chronic atrophic gastritis (autoimmune) → achlorhydria/hypergastrinaemia | Zollinger-Ellison syndrome + MEN1 (gastrinoma-related) | Sporadic, gastrin-independent |
| Frequency | %70-80 | %5-6 | %15-25 |
| Size/number | Multiple, small (<1 cm) | Similar, thickened gastric folds | Single, large (>2 cm), often ulcerated, high Ki-67 |
| Malignant potential | Low — metastasis <%5 | Variable — metastasis %10-30 | High — 5-year survival only %30-50 |
Lung (Bronchopulmonary) Carcinoid: Typical and Atypical
Lung carcinoids are classified by their own histological distinction rather than the G1/G2/G3 grading system used for other NETs, and are staged using the standard AJCC edition 8 lung cancer (NSCLC) TNM system — there is no separate NET-specific staging system:
| Type | Histological Criterion | 5-Year Survival |
|---|---|---|
| Typical carcinoid | <2 mitoses/2 mm², no necrosis | ~%94 |
| Atypical carcinoid | 2-10 mitoses/2 mm² and/or presence of necrosis | ~%67 |
The role of the Ki-67 index in distinguishing typical from atypical lung carcinoids is debated, and it is not routinely recommended for this distinction.
Treatment Approach: Overview
NET treatment is based on a personalised plan jointly assessing the following five factors, rather than a single standard algorithm:
- Organ of tumour origin (pancreas, small intestine, stomach, lung, etc.)
- Degree of differentiation (G1/G2/G3 or NEC)
- Stage and tumour burden (localised/resectable or metastatic)
- Whether it is functional (presence of a hormonal syndrome)
- The patient's general condition and comorbidities
NET treatment should therefore be planned by multiple specialists — medical oncologists, nuclear medicine specialists, endocrinologists, gastroenterologists, surgeons and radiologists — working together within a multidisciplinary tumour board setting.
Surgery and Local/Regional Treatments
Surgery remains the most definitive treatment option in early-stage and selected metastatic patients:
- Endoscopic resection: for small tumours on the inner gastrointestinal lining, performed by reaching the stomach/duodenum with an endoscope
- Local excision/resection: removal of the tumour and surrounding organ tissue (with regional lymph nodes if necessary)
- Liver metastasectomy: may be performed in selected patients with a limited number of liver metastases
- Hepatic artery embolisation/chemoembolisation: selective interruption of blood flow to the tumour in unresectable tumours spread to the liver, taking advantage of the liver's dual blood supply (portal vein + hepatic artery)
- Radiofrequency ablation (RFA): a minimally invasive method using heat to destroy small liver metastases
- Liver transplantation: rarely considered in young patients with extensive liver-dominant disease who meet highly selective criteria
Somatostatin Analogues (SSA)
Somatostatin analogues — octreotide LAR (Sandostatin LAR) and lanreotide (Somatuline Autogel/Depot) — are used as first-line systemic treatment in somatostatin receptor-positive, well-differentiated NETs both to control hormonal symptoms and to slow tumour growth.
In a placebo-controlled phase 3 study (Rinke A, et al., Journal of Clinical Oncology, 2009), median time to tumour progression in metastatic midgut NET was 14,3 months with octreotide LAR versus 6 months with placebo (HR 0,34 — approximately %66 risk reduction); HR was 0,25 in the nonfunctional tumour subgroup and 0,23 in the functional tumour subgroup.
According to the study by Caplin ME et al. (New England Journal of Medicine, published 17 July 2014), median progression-free survival was not reached with lanreotide, versus 18 months in the placebo arm (HR 0,47 — approximately %53 risk reduction). This study led to FDA approval of lanreotide specifically for progression-free survival, rather than symptom control alone (16 December 2014).
Current FDA-approved dosing: Octreotide LAR is given as a 20-30 mg IM injection every 4 weeks (titrated according to clinical response); lanreotide is given as a 120 mg deep subcutaneous injection every 4 weeks.
Peptide Receptor Radionuclide Therapy (PRRT)
PRRT is a "theranostic" treatment approach (usable for both imaging and treatment) that targets tumour cells with radiation from within by attaching a radioactive isotope (Lutetium-177) to a carrier molecule (DOTATATE) that binds to somatostatin receptors.
According to the NETTER-1 study (Strosberg J, et al., New England Journal of Medicine, published 12 January 2017), Lu-177-DOTATATE produced approximately %79 risk reduction in progression-free survival in advanced somatostatin receptor-positive midgut NETs (HR 0,21; 20-month PFS rate %65,2 versus %10,8). Based on these results, Lu-177-DOTATATE (Lutathera), on 26 January 2018 , became the first radioactive drug to receive FDA approval for GEP-NETs; the current label covers all adult and (since 23 April 2024) paediatric patients aged 12 and over with somatostatin receptor-positive GEP-NETs, without requiring a previous line of treatment.
The NETTER-2 study (Strosberg J, et al., Lancet, 2024) investigated Lu-177-DOTATATE in higher-grade (G2/G3) GEP-NETs as first-line treatment and found median progression-free survival of 22,8 months versus 8,5 months (HR 0,276; p<0,0001). However, as of the date of this research (August 2026), this study has not led to a new FDA approval or label change in the US — the manufacturer stated that the existing 2018 approval already has no prior treatment requirement and therefore already covers first-line use, and announced that it would not make a separate application. In Europe, the application for a first-line-specific label extension was, following an unfavourable EMA signal due to the absence of proven overall survival benefit and concerns about haematological/renal toxicity, withdrawn on 9 May 2025. Accordingly, NETTER-2 data are used as supportive/educational evidence in clinical practice, but should not be presented as an official "first-line approval".
No record was found of the branded Lutathera product being reimbursed in Türkiye as a TİTCK-licensed/SGK-covered packaged drug. However, Türkiye has a strong domestic radiopharmaceutical production infrastructure (including Lu-177 produced by Eczacıbaşı-Monrol/Curium), and many nuclear medicine centres reportedly label DOTATATE in-house using domestically produced Lu-177 and administer PRRT. The exact legal/reimbursement framework for this practice (hospital pharmacy radiopharmaceutical preparation exemption or a separate regulation, and how much SGK covers for the patient) could not be clearly verified in this research — therefore, patients are advised to contact the nuclear medicine centre performing the procedure directly for cost and reimbursement details.
mTOR Inhibitor, Tyrosine Kinase Inhibitors and Other Targeted Therapies
In the RADIANT-3 study (Yao JC, et al., NEJM, 2011), median progression-free survival in pancreatic NET was 11,0 months versus 4,6 months (approximately %65 risk reduction), and everolimus received FDA approval on 5 May 2011 for pancreatic NET. In the RADIANT-4 study (nonfunctional GI/lung NET), median PFS was 11,0 months versus 3,9 months (HR 0,48), and this indication was approved on 26 February 2016 . (The RADIANT-2 study, conducted in patients with carcinoid syndrome, did not reach statistical significance on independent assessment and did not secure approval for this indication.)
In the SUN 1111 phase 3 study (Raymond E, et al., NEJM, 2011), median PFS in advanced pancreatic NET was 10,2 months versus 5,4 months, and sunitinib received FDA approval on 20 May 2011 (only two weeks after everolimus).
Based on the CABINET study (Alliance A021602), cabozantinib received FDA approval on 26 March 2025 for previously treated advanced pancreatic NETs and GI/lung (extrapancreatic) NETs. In the pancreatic NET arm (n=99), median PFS was 13,8 months versus 3,3 months (HR 0,22; p<0,0001); in the extrapancreatic NET arm (n=199), median PFS was 8,5 months versus 4,2 months (HR 0,40; p<0,0001). This approval is the latest targeted agent added to the NET treatment arsenal.
This combination has not received a separate FDA approval as a combination for NET — both drugs are individually approved for other cancer types, and their use in NET is an evidence-based/off-label approach included in NCCN guidelines (category 2A), based on retrospective and phase 2 data. It is frequently preferred, particularly in higher-grade (G2/G3) pancreatic NETs.
Surufatinib received approval in China (NMPA) for extrapancreatic NET on 30 December 2020 and pancreatic NET on 18 June 2021 (brand name Sulanda). In the US, the FDA rejected the application through a Complete Response Letter announced on 2 May 2022, requesting a multiregional study better representing the US population rather than citing safety concerns; this remained unchanged as of August 2026, and the drug is also unlicensed in Türkiye.
Treatment of Carcinoid Syndrome
Somatostatin analogues (octreotide/lanreotide) are first-line treatment for carcinoid syndrome. Additional treatment options are used for patients whose diarrhoea persists despite this treatment:
Based on the TELESTAR study, the tryptophan hydroxylase inhibitor telotristat ethyl received FDA approval on 28 February 2017 — its indication is use in carcinoid syndrome diarrhoea inadequately controlled by somatostatin analogue therapy, as an addition to SSA therapy (rather than monotherapy). It is a symptom management drug rather than an antitumour agent.
Patients with carcinoid syndrome are advised to avoid foods such as alcohol, hard cheeses and chilli peppers (capsaicin), and stressful situations that may trigger flushing/shortness of breath. Some patients who develop carcinoid heart disease may require heart valve replacement.
Treatment of High-Grade Neuroendocrine Carcinoma (NEC)
Unlike well-differentiated NETs, poorly differentiated neuroendocrine carcinoma (NEC) shows biological aggressiveness similar to small cell lung cancer and is treated accordingly:
Cisplatin (or carboplatin) combined with etoposide is considered standard first-line treatment for NEC; studies such as TOPIC-NEC compared etoposide-cisplatin with irinotecan-cisplatin without demonstrating clear superiority — both regimens remain valid options. As of the date of this research (August 2026), there is no approved NEC-specific immunotherapy — combinations such as atezolizumab+platinum/etoposide are investigational in extrapulmonary NEC; immunotherapy use based on tumour-agnostic biomarkers such as MSI-high/TMB-high is a general oncology approach rather than NEC-specific.
Side Effects
- Somatostatin analogues: injection-site reactions, gallstone risk, mild hyperglycaemia/steatorrhoea (fat malabsorption)
- PRRT (Lu-177-DOTATATE): nausea/vomiting (due to amino acid infusion), transient bone marrow suppression, rarely renal toxicity or risk of secondary myelodysplastic syndrome/leukaemia years later
- Everolimus: stomatitis (mouth sores), pneumonitis (lung inflammation), hyperglycaemia, increased infection risk
- Sunitinib/cabozantinib: hypertension, hand-foot syndrome, fatigue, thyroid dysfunction
- Chemotherapy (CAPTEM, platinum-etoposide): bone marrow suppression, nausea, fatigue, hair loss (varies by regimen)
Global Approval and Evidence Timeline
The following is a chronological list of milestone FDA approvals and evidence in neuroendocrine tumour treatment:
FDA approval based on the RADIANT-3 study; the first new treatment approved in pNET in approximately 30 years.
FDA approval based on the SUN 1111 study, only two weeks after everolimus.
Based on the CLARINET study; the first somatostatin analogue approved specifically for progression-free survival, rather than symptom control alone.
Based on the RADIANT-4 study, everolimus's indication was expanded to extrapancreatic NETs.
Approved for SSA-resistant carcinoid syndrome diarrhoea based on the TELESTAR study.
Based on the NETTER-1 study; the first peptide receptor radionuclide therapy (PRRT) approved for GEP-NETs, marking the beginning of a new era in NET treatment.
The first HIF-2α inhibitor; approved for renal cell cancer, pancreatic NET and CNS haemangioblastoma associated with VHL disease.
Approval expanded to somatostatin receptor-positive GEP-NET in paediatric patients aged 12 and over.
Based on the CABINET study; the latest targeted agent approved in previously treated advanced NETs.
Based on the LITESPARK-015 study; the first oral treatment approved for PPGL, also usable in patients without VHL.
Situation in Türkiye: TİTCK Licensing and SGK Reimbursement
Octreotide LAR (Sandostatin LAR) and lanreotide (Somatuline Autogel)are licensed in Türkiye and reimbursed by SGK (under SUT article 4.2.14.C, subject to a medical board report issued by a medical oncology specialist). Everolimus (Afinitor) is licensed/reimbursed for pancreatic NET; SUT was found to require indication-specific Ki-67 ≤%20, RECIST-documented progression within 12 months and previous somatostatin analogue/chemotherapy use, and to prohibit combination with sunitinib (note: another brand of the same active ingredient — Certican — is used for post-transplant immunosuppression and should not be confused with it). Sunitinib (Sutent) is similarly licensed/reimbursed for pancreatic NET, and SUT was found to require Ki-67 ≤%5. Capecitabine and temozolomide are general oncology drugs licensed and reimbursed in Türkiye.
According to the SUT text found in this research, temozolomide's reimbursement restriction appears specific to glioblastoma/malignant glioma; its combined use with capecitabine (CAPTEM) in NET treatment relies on general oncology prescribing practice rather than a separate SUT article for a NET indication. Accordingly, the extent to which CAPTEM is actually reimbursed without difficulty in NET could not be confirmed directly from the current SUT text; checking the current SUT before prescribing is recommended.
As stated above, no record was found of the branded Lutathera product being reimbursed in Türkiye as a TİTCK-licensed/SGK-covered packaged drug; however, PRRT using domestically produced Lu-177 is reportedly administered at many nuclear medicine centres. It should be remembered that costs and reimbursement coverage may vary by the centre performing the procedure.
Telotristat ethyl (Xermelo) and belzutifan (Welireg) had no licensed product record found in Türkiye (confirmation through TİTCK's current licensed product list is recommended). Surufatinib is also unlicensed in Türkiye, as it is not approved in the US either. Cabozantinib (Cabometyx)may be licensed in Türkiye for other indications such as kidney/liver cancer; however, it should be stated that the scope of TİTCK licensing and SGK reimbursement for this very new NET indication (March 2025) could not be verified in this research.
Frequently Asked Questions
- Is a neuroendocrine tumour cancer?
- Yes, neuroendocrine tumours are cancers; however, their behaviour varies greatly — some (particularly grade G1) may progress slowly for years, while others (NEC) can be highly aggressive.
- Are neuroendocrine tumour and carcinoid tumour the same thing?
- "Carcinoid" is an older/traditional term generally used for well-differentiated NETs originating in the gastrointestinal system or lungs; "NET" is preferred in current medical terminology, but the two largely overlap.
- Does every neuroendocrine tumour cause carcinoid syndrome?
- No. Carcinoid syndrome mainly occurs in midgut (middle gut) NETs with liver metastases; many NETs, particularly pancreatic and nonfunctional tumours, do not cause this syndrome.
- What is the difference between Ga-68 DOTATATE PET/CT and regular PET/CT?
- Standard FDG-PET images cells' glucose use, whereas Ga-68 DOTATATE PET specifically targets cells bearing somatostatin receptors; it is therefore markedly more sensitive than FDG-PET for detecting well-differentiated NETs.
- Can PRRT (Lu-177-DOTATATE) be given to all NET patients?
- No, PRRT is effective only in tumours showing somatostatin receptor positivity on Ga-68 DOTATATE PET/CT; this treatment does not work in receptor-negative tumours.
- Yu Q, et al. "Dethroning of Neuroendocrine Tumor as an Orphan Disease: US Incidence, Prevalence, and Survival in the 21st Century." Cancers. 2025;17(20):3323.
- Dasari A, 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.
- Hofland J, de Herder WW. "Gastrointestinal Neuroendocrine Tumors and the Carcinoid Syndrome." Endotext. Updated: 25 August 2023.
- Rindi G, et al. "Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms." Endocrine Pathology. 2022;33(1):115-154.
- La Rosa S, Sessa F, Uccella S. "Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs)." Endocrine Pathology. 2016;27(4):284-311.
- Butler OL, et al. "Frequency and Causes of False-Positive Elevated Plasma Concentrations of Fasting Gut Hormones." Frontiers in Endocrinology. 2020;11:606264.
- Malczewska A, Oberg K, Kos-Kudla B. "NETest is superior to chromogranin A in neuroendocrine neoplasia." Endocrine Connections. 2021;10(1):110-123.
- Sadowski SM, et al. "Prospective Study of 68Ga-DOTATATE PET/CT for Detecting GEP-NETs." Journal of Clinical Oncology. 2016;34(6):588-596.
- Valk GD, et al. "Multiple Endocrine Neoplasia Type I." Endotext. Updated: 28 March 2026.
- Lath D, Anastasopoulou C, Kasi A. "Multiple Endocrine Neoplasias Type 2." StatPearls. Updated: 12 April 2026.
- Giles RH, et al. "Von Hippel-Lindau Syndrome." GeneReviews. Updated: 1 May 2025.
- Mowrey K, et al. "Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex." Frontiers in Neurology. 2021;12:627672.
- Chauhan A, et al. "Critical Updates in Neuroendocrine Tumors: Version 9 AJCC Staging System." CA: A Cancer Journal for Clinicians. 2024;74(4):359-367.
- Menon G, Cho MS, Gupta A, Kasi A. "Gastric Neuroendocrine Tumors." StatPearls. Updated: 6 July 2025.
- Ramirez RA, et al. "A Multidisciplinary Approach to Pulmonary Carcinoid Tumors and DIPNECH." Translational Lung Cancer Research. 2022;11(12).
- Rinke A, et al. (PROMID Study Group). Journal of Clinical Oncology. 2009;27(28):4656-4663.
- Caplin ME, et al. "Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors." New England Journal of Medicine. 17 July 2014.
- Strosberg J, et al. (NETTER-1). New England Journal of Medicine. 2017;376(2):125-135.
- Strosberg J, et al. (NETTER-2). Lancet. 2024.
- Yao JC, et al. (RADIANT-3). New England Journal of Medicine. 2011.
- Raymond E, et al. (SUN 1111). New England Journal of Medicine. 2011.
- FDA. "FDA Approves Belzutifan for Cancers Associated with Von Hippel-Lindau Disease." August 2021.
- FDA. "FDA Approves Belzutifan for Pheochromocytoma or Paraganglioma." May 2025.
- Alliance for Clinical Trials in Oncology. CABINET (A021602) study results, ASCO Post summary, 2025.
- HUTCHMED. "NMPA Approval of Surufatinib (Sulanda) in China for Advanced Pancreatic Neuroendocrine Tumors." June 2021.
Was this article helpful?
Your feedback helps us improve our content.
