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Neuroendocrine tumors
Neuroendocrine tumors (NETs) arise from specialized hormone-producing neuroendocrine cells found throughout the body. Once considered exceptionally rare, their incidence has more than sextupled over the past four decades — driven largely by advances in imaging, pathology, and clinical awareness. NETs range from slow-growing tumors with favorable long-term outcomes to aggressive malignancies that spread rapidly. Understanding this spectrum is essential to timely diagnosis and appropriate management
Prevalence
2.5–6.7 / 100,000
8,275–22,177
US Estimated
12,825–34,371
EUROPE ESTIMATED
Age of Onset
Typically 40–65 years; median age at diagnosis ~63 years
ICD-10
C7A – Malignant carcinoid
D3A — Benign carcinoid
C25.4 — Malignant islet cell/PNET
Inheritance Pattern
Autosomal dominant
Most neuroendocrine tumors are sporadic, though some are associated with autosomal dominant hereditary syndromes including MEN1 and MEN2
Autosomal recessive
Mitochondrial/Multigenic
X-linked dominant
Autosomal dominant
5 Facts you should know
FACT
NETs are far more common than once believed
Incidence has increased more than sixfold over the past 40 years — from 1.09 to 6.98 per 100,000 — making NETs one of the fastest-growing cancer diagnoses in the U.S. This rise reflects improved imaging, better pathological recognition, and more widespread endoscopic surveillance, not a true increase in disease burden alone
FACT
Most NETs are non-functioning — and silent
Approximately 60–70% of NETs do not produce a clinically recognizable hormonal syndrome. These tumors are frequently discovered incidentally on imaging performed for unrelated reasons, often when already locally advanced or metastatic. The absence of symptoms does not indicate biological indolence
FACT
Ki-67 index is the cornerstone of diagnosis and treatment planning
The WHO 2022 grading system classifies NETs based on Ki-67 proliferation index: G1 (<3%), G2 (3–20%), G3 (>20%), with poorly differentiated NECs forming a separate category. Grade determines prognosis, imaging approach, and systemic therapy selection — making Ki-67 the single most important pathological result in NET management
FACT
Somatostatin receptor status is both a diagnostic and therapeutic key
Most well-differentiated NETs overexpress somatostatin receptors (especially SSTR2), enabling highly sensitive 68Ga-DOTATATE PET-CT imaging and eligibility for peptide receptor radionuclide therapy (PRRT) with Lutetium-177 DOTATATE (Lutathera). Receptor status is therefore a critical biomarker that directly opens — or closes — a treatment pathway
FACT
5
Up to 10% of NETs occur in the context of a hereditary syndrome
NETs associated with MEN1, MEN2, VHL syndrome, NF1, or Tuberous Sclerosis Complex often present at a younger age, are multifocal, and require germline testing and coordinated surveillance across multiple organ systems. Genetic counseling should be considered in all patients with young onset, family history, or multifocal disease
Interest over time
Google searches
Common signs & symptoms
Carcinoid syndrome
Episodic skin flushing, secretory diarrhea, wheezing/bronchoconstriction, telangiectasias — caused by serotonin and vasoactive peptides; typically in metastatic midgut NETs
Insulinoma
Whipple's triad — hypoglycemia symptoms with fasting, blood glucose <55 mg/dL, relief with glucose; most common functional pancreatic NET
Gastrinoma (Zollinger-Ellison Syndrome)
Severe/recurrent peptic ulcers, GERD, diarrhea, elevated fasting serum gastrin
VIPoma
Profuse watery diarrhea, hypokalemia, achlorhydria (WDHA/Verner-Morrison syndrome)
Glucagonoma
Necrolytic migratory erythema (pathognomonic rash), new-onset diabetes, weight loss, anemia
Current treatments
Treatment depends on disease severity and organ involvement.
Surgery
Resection remains the only potentially curative approach for localized or regional disease. Liver-directed therapies (hepatic artery embolization, ablation, surgical cytoreduction) are considered for liver-dominant metastatic disease in selected patients
Somatostatin Analogs (SSAs)
Octreotide LAR (Sandostatin LAR, Novartis) and lanreotide (Somatuline Depot, Ipsen) are FDA-approved for symptomatic control of carcinoid syndrome and have demonstrated antiproliferative activity. The PROMID and CLARINET trials established benefit in midgut and non-functional NETs respectively
Peptide Receptor Radionuclide Therapy (PRRT)
Lutetium-177 DOTATATE (Lutathera, Advanced Accelerator Applications/Novartis) was FDA-approved in 2018 for somatostatin receptor-positive GEP-NETs progressing on SSAs. The NETTER-1 trial demonstrated a 79% reduction in risk of progression or death vs. high-dose octreotide (HR 0.18)
mTOR Inhibition
Everolimus (Afinitor, Novartis) is FDA-approved for advanced progressive non-functional GI and lung NETs (RADIANT-4 trial) and for pancreatic NETs (RADIANT-3 trial)
Tyrosine Kinase Inhibition
Sunitinib (Sutent, Pfizer) is FDA-approved for progressive, well-differentiated, malignant pancreatic NETs based on significant PFS improvement in its pivotal Phase III trial
Antisecretory Therapy
Telotristat ethyl (Xermelo, Lexicon) is a tryptophan hydroxylase inhibitor FDA-approved for carcinoid syndrome diarrhea inadequately controlled on SSAs (TELESTAR trial)
Chemotherapy
Temozolomide ± capecitabine (TEMCAP) is widely used for higher-grade NETs, PRRT-refractory disease, and pancreatic NETs. Streptozocin-based regimens retain historical use for PNETs. Platinum/etoposide ± immunotherapy is used for poorly differentiated NECs, including SCLC-type
Clinical trials
| Title | Description | Phases | Status | Interventions | More Information |
|---|---|---|---|---|---|
| DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy | This study is open to adults with advanced extrapulmonary neuroendocrine cancer. The purpose of this study is to find out if a study medicine called obrixtamig plus standard chemotherapy (carboplatin and etoposide) improves survival when compared to standard chemotherapy (carboplatin and etoposide)... | Phase 3 | Not yet recruiting | Drug: Obrixtamig Drug: Carboplatin Drug: Etoposide Device: Ventana DLL3 RxDx assay | More Info |
| DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers | This study is open to adults with small cell lung cancer and other neuroendocrine tumours. The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this study is to find a suitable dose of BI 764532 (also called obrix... | Phase 2 | Recruiting | Drug: BI 764532, dose 1 Drug: BI 764532, dose 2 | More Info |
| DAREON™-7: A Study to Test How Well Different Doses of BI 764532 in Addition to Chemotherapy Are Tolerated by People With Advanced Neuroendocrine Cancers | This study is open to adults aged 18 and older or above legal age who have a specific type of advanced neuroendocrine cancer (NEC). Their tumours must be positive for a marker called DLL3. The purpose of this study is to test a medicine called BI 764532 in addition to chemotherapy. The study has Pa... | Phase 1 | Recruiting | Drug: BI 764532 Drug: Carboplatin Drug: Etoposide Drug: Cisplatin | More Info |
| A Study to Test Different Doses of Obrixtamig in Patients With Small Cell Lung Cancer and Other Neuroendocrine Tumours That Are Positive for DLL3 | This study is open to adults with small cell lung cancer and other neuroendocrine cancers that are positive for the tumour marker delta-like 3 (DLL3). The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this stud... | Phase 1 | Recruiting | Drug: Obrixtamig - parenteral 1 Drug: Obrixtamig - parenteral 2 | More Info |
| A Study to Test How Well Different Doses of Obrixtamig (BI 764532) in Combination With Ezabenlimab Are Tolerated by People With Small Cell Lung Cancer and Other Neuroendocrine Tumours That Are Positive for DLL3 | This study is open to adults with small cell lung cancer and other neuroendocrine tumours that are positive for the tumour marker Delta-like 3 (DLL3). The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this stud... | Phase 1 | Active | Drug: Obrixtamig Drug: Ezabenlimab | More Info |
| A Study to Test How BI 764532 is Taken up by Tumours in People With Small-cell Lung Cancer or Neuroendocrine Cancer | This study is open to adults with small cell lung cancer and other neuroendocrine cancers. The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this study is to find out how a medicine called BI 764532 gets distrib... | Phase 1 | Recruiting | Drug: BI 764532 Drug: [89Zr]Zr-BI 764532 | More Info |
| Efficacy and Safety of 177Lu-edotreotide PRRT in GEP-NET Patients | The purpose of the study is to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastro... | Phase 3 | Active | Drug: 177Lu-edotreotide PRRT Drug: Everolimus Other: Amino-Acid Solution | More Info |
| Study of Cabozantinib With Lu-177 in Patients With Somatostatin Receptor 2 Positive Neuroendocrine Tumors | The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib. | Phase 1 | Active | Drug: Cabozantinib Drug: Lu-177 | More Info |
| A First-in-Human Phase I Trial With Antibody Drug Conjugate ADCT-701 in Neuroendocrine Tumors, Carcinomas and Malignant Peripheral Nerve Sheath Tumors | Background: Neuroendocrine neoplasms (NENs) are rare cancers in the gastrointestinal tract, pancreas, lungs, adrenal glands, and other areas of the body. Many of these cancers have a high risk of relapse and a low chance of survival. Better treatments are needed. Objective: To test a new drug, AD... | Phase 1 | Recruiting | Drug: ADCT-701 | More Info |
| SVV-001 With Nivolumab and Ipilimumab in Patients With Poorly Differentiated Neuroendocrine Carcinomas (NEC) or Well-Differentiated High-Grade Neuroendocrine Tumors (NET) | The purpose of this study is to determine: 1. The highest dose of the trial intervention that targets neuroendocrine tumors and is tolerated by patients. 2. The highest frequency of dosing of the trial intervention that targets neuroendocrine tumors and is tolerated by patients. 3. The highest dose... | Phase 1 | Recruiting | Biological: Seneca Valley Virus-001 (SVV-001) Drug: Nivolumab Drug: Ipilimumab | More Info |