Extrapulmonary neuroendocrine carcinoma
Extrapulmonary neuroendocrine carcinoma is the fast-growing, poorly differentiated form of neuroendocrine cancer arising outside the lung, most often in the bowel, oesophagus, stomach or pancreas. It behaves like small-cell lung cancer and is treated the same way, with platinum and etoposide chemotherapy, and drugs against the DLL3 protein are now in phase 3 trials.
Overview
Neuroendocrine carcinoma is a different disease from the well-differentiated tumours it shares a name with. The WHO classification defines it by poorly differentiated small-cell or large-cell morphology with a Ki-67 above 20 percent and usually far higher, and its genetics follow small-cell lung cancer, with loss of TP53 and RB1 rather than the MEN1, DAXX and ATRX mutations of neuroendocrine tumours; a subset of colorectal carcinomas carry BRAF V600E and a few are microsatellite unstable. Somatostatin receptor expression is usually weak, so FDG PET stages the disease where somatostatin receptor PET stages tumours, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) combine a carcinoma component with adenocarcinoma or squamous carcinoma. Merkel cell carcinoma of the skin and neuroendocrine prostate cancer are covered on their own pages.
Treatment is borrowed wholesale from small-cell lung cancer. Moertel showed in 1991 that cisplatin with etoposide produced responses in most anaplastic neuroendocrine carcinomas, and platinum-etoposide has been first-line therapy since; the NORDIC NEC series (Annals of Oncology 2013) of 305 patients confirmed that most respond but relapse quickly, and found that carcinomas with a Ki-67 below 55 percent responded less often to platinum yet lived longer, an observation that helped separate grade 3 well-differentiated tumours from true carcinoma. Randomised evidence is scarce: the ECOG-ACRIN EA2142 trial compared capecitabine-temozolomide with platinum-etoposide in high-grade gastroenteropancreatic neoplasms and did not show the oral regimen superior, and the Italian SENECA trial found both CAPTEM and FOLFIRI active in the second line. Localised disease is resected or given chemoradiotherapy with perioperative platinum-etoposide, as in limited-stage small-cell lung cancer.
Immunotherapy and DLL3 are the two openings. The DART basket trial (SWOG S1609) reported responses to nivolumab with ipilimumab in high-grade neuroendocrine carcinoma but not in low-grade tumours, and PD-1 or PD-L1 antibodies are added to first-line chemotherapy by extrapolation from IMpower133 and CASPIAN while dedicated phase 2 trials such as NICE-NEC test the combination directly. DLL3, the surface protein behind tarlatamab's approval in small-cell lung cancer, is expressed by most neuroendocrine carcinomas: the T-cell engagers obrixtamig (DAREON-5, and the phase 3 DAREON-NEC-1 with carboplatin-etoposide in DLL3-positive extrapulmonary carcinoma), peluntamig and ZG006 are in trials that enrol these tumours alongside small-cell lung cancer.
State of the art
- Platinum-etoposide remains the backbone after more than three decades, with immunotherapy added by extrapolation from small-cell lung cancer.
- The 2019 WHO split of grade 3 tumour from carcinoma has stopped many slower tumours receiving platinum they would not respond to.
- DLL3-directed T-cell engagers have reached a phase 3 trial specific to extrapulmonary carcinoma.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowBone pain flare or fracture (radium-223)
Sudden severe bone pain, or back pain with weakness or numbness in the legs (possible spinal cord compression).
- Check before combiningKidneys: Carboplatin
Dose by Calvert formula using GFR (see the calculators).
- Check before combiningKidneys: Cisplatin
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
- Check before combiningKidneys: Etoposide
Reduce to 75% for CrCl 15-50.
See all on the product pages:AtezolizumabCapecitabine + temozolomide (CAPTEM)CarboplatinCisplatinDurvalumabEtoposideFOLFIRI (5-FU, leucovorin, irinotecan)FOLFOX (5-FU, leucovorin, oxaliplatin)IpilimumabLutetium-177 dotatateNivolumabPlatinum + etoposide (EP / CE)Topotecan·Printable cards in the navigator
Anatomy and lymph node drainage
- Pancreatic head (most PDAC)
- Body and tail
- Ampulla
- Islets (pancreatic NET)
- Intrahepatic ducts
- Perihilar (Klatskin)
- Distal bile duct
- Gallbladder
- Nodes: peripancreatic
- Nodes: hepatic hilar
- Nodes: coeliac and superior mesenteric
Most pancreatic cancers arise in the head next to the bile duct, which is why jaundice is the presenting sign; bile duct cancers are named by where along the tree they sit.
- Pancreatic head (most PDAC)
- Body and tail
- Ampulla
- Islets (pancreatic NET)Small-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract · Large-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract · Colorectal NEC (the commonest gut site, BRAF V600E in a subset) · Oesophageal and gastric NEC · Pancreatic NEC (distinguish from grade 3 well-differentiated pancreatic NET) · Neuroendocrine carcinoma of unknown primary · Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
- Intrahepatic ducts
- Perihilar (Klatskin)
- Distal bile duct
- Gallbladder
- peripancreatic
- hepatic hilar
- coeliac and superior mesenteric
Same organ: Pancreatic ductal adenocarcinoma, Biliary tract cancer (cholangiocarcinoma), Intrahepatic cholangiocarcinoma, Extrahepatic cholangiocarcinoma (perihilar and distal), Biliary tract cancer (all types), Neuroendocrine tumours, Pancreatic neuroendocrine tumours, Grade 3 well-differentiated neuroendocrine tumour, Gallbladder cancer, Ampullary cancer (ampulla of Vater)
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- A minority of neuroendocrine neoplasms but the deadliest; the gastrointestinal tract (colon and rectum, oesophagus, stomach, pancreas) and unknown primary are the commonest sites, most patients present with metastases, and survival is measured in months rather than years.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Biopsy with Ki-67, morphology and p53 or Rb immunohistochemistry to separate carcinoma from grade 3 tumour; FDG PET and CT; somatostatin receptor PET only if radioligand therapy is contemplated.
Resection or definitive chemoradiotherapy with perioperative platinum-etoposide, following the limited-stage small-cell lung cancer model.
Platinum with etoposide (cisplatin or carboplatin), with a PD-1 or PD-L1 antibody added by extrapolation from small-cell lung cancer or within a trial.
FOLFIRI, FOLFOX, capecitabine-temozolomide or topotecan; nivolumab with ipilimumab in selected patients (DART); DLL3-directed T-cell engagers in trials.
Reclassify as grade 3 neuroendocrine tumour and treat accordingly.
Subtypes & biomarkers
top- Small-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract
- Large-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract
- Colorectal NEC (the commonest gut site, BRAF V600E in a subset)
- Oesophageal and gastric NEC
- Pancreatic NEC (distinguish from grade 3 well-differentiated pancreatic NET)
- Neuroendocrine carcinoma of unknown primary
- Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
- Small-cell carcinoma of the cervix, bladder and other extrapulmonary sites
- Ki-67 above 20 percent, usually far higher, with poorly differentiated morphology
- Synaptophysin, chromogranin and INSM1 by immunohistochemistry (chromogranin may be weak)
- p53 and Rb by immunohistochemistry (abnormal in carcinoma, retained in grade 3 tumour)
- FDG PET (somatostatin receptor PET usually negative)
- DLL3 expression (trial eligibility)
- BRAF V600E and microsatellite instability in colorectal NEC
- Ki-67 above or below 55 percent (platinum sensitivity, NORDIC NEC)
How often this target appears
- 1991Moertel: cisplatin with etoposide produces responses in anaplastic neuroendocrine carcinoma
- 2010WHO classification separates poorly differentiated neuroendocrine carcinoma from neuroendocrine tumours
- 2013NORDIC NEC: Ki-67 below 55 percent predicts less platinum response but longer survival
- 2019WHO digestive system classification: grade 3 tumour and carcinoma become distinct entities
- 2020DART (SWOG S1609): nivolumab with ipilimumab active in high-grade neuroendocrine carcinoma
- 2024Tarlatamab approved for small-cell lung cancer, opening DLL3 as a target for extrapulmonary carcinoma
- 2026DAREON-NEC-1 phase 3 of obrixtamig with carboplatin-etoposide opens in DLL3-positive extrapulmonary carcinoma
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 9 changes by month →- 2026-09-17This recordExtrapulmonary neuroendocrine carcinomaFacts on this page last checked
When this page itself was last checked or edited.
- 2026MilestoneDAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard ChemotherapyDAREON-NEC-1 phase 3 of obrixtamig with carboplatin-etoposide opens in DLL3-positive extrapulmonary carcinoma
A milestone in how this cancer is treated.
- 2024MilestoneTarlatamabTarlatamab approved for small-cell lung cancer, opening DLL3 as a target for extrapulmonary carcinoma
A milestone in how this cancer is treated.
- 2020Trial resultDART (SWOG S1609): nivolumab plus ipilimumab in rare tumoursDART (SWOG S1609): nivolumab plus ipilimumab in rare tumours reported
Neuroendocrine cohort: about one in four responded, concentrated in high-grade disease; angiosarcoma cohort about one in four, mostly cutaneous scalp and face tumours; many other cohorts inactive.
- 2020MilestoneDART (SWOG S1609): nivolumab plus ipilimumab in rare tumoursDART (SWOG S1609): nivolumab with ipilimumab active in high-grade neuroendocrine carcinoma
A milestone in how this cancer is treated.
- 2019MilestoneNeuroendocrine tumour grade (Ki-67) and WHO classificationWHO digestive system classification: grade 3 tumour and carcinoma become distinct entities
A milestone in how this cancer is treated.
What is in development for Extrapulmonary neuroendocrine carcinoma, drawn from the whole corpus: 7 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 · 1
Drugs in phase 2 · 1
Trials under way · 4
- DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy · phase 3 · Boehringer Ingelheim
- DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers · phase 2 · Boehringer Ingelheim
- A Study of Peluntamig (PT217) in Patients With Neuroendocrine Carcinomas Expressing DLL3 (the SKYBRIDGE Study) · phase 1/2 · Phanes Therapeutics
- DART (SWOG S1609): nivolumab plus ipilimumab in rare tumours · phase 2 · National Cancer Institute and SWOG Cancer Research Network
Targets under investigation · 1
Open problems and what is being done
No randomised trial has improved on platinum-etoposide in first line.
and how the field plans to fix it →What is being done about thisRare cancers and small trialsAvailable nowNothing recorded yet.
In trialsIdeas and roadmapsNothing recorded yet.
Also on OnCo: Find a trial · Expert centres.
Whether adding a PD-1 or PD-L1 antibody helps, as it does in small-cell lung cancer, is untested in a phase 3.
Second-line therapy has no standard.
The disease is too rare and too heterogeneous by site for site-specific trials, so basket designs dominate.
and how the field plans to fix it →What is being done about thisRare cancers and small trialsAvailable nowNothing recorded yet.
In trialsIdeas and roadmapsNothing recorded yet.
Also on OnCo: Find a trial · Expert centres.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Bethesda, MD · government | United States | none recorded | 1 | 2,905 | 47,715 | - | |
Portland, OR · consortium | United States | none recorded | 1 | 42 | 1,880 | none recorded | - |
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Rotterdam · cancer center | Netherlands | none recorded | 0 | 852 | 12,180 | - | |
Madrid · hospital | Spain | none recorded | 0 | 764 | 13,767 | - | |
Taipei · hospital | Taiwan | none recorded | 0 | 746 | 8,966 | - | |
Goyang · cancer center | South Korea | none recorded | 0 | 573 | 9,401 | - | |
| Switzerland | none recorded | 0 | 470 | 4,598 | - | ||
Shanghai · hospital | China | none recorded | 0 | 464 | 6,795 | - | |
Munich · university | Germany | none recorded | 0 | 438 | 4,021 | - | |
Chandigarh · hospital | India | none recorded | 0 | 398 | 3,509 | - | |
São Paulo · cancer center | Brazil | none recorded | 0 | 352 | 2,396 | - | |
Kyoto · hospital | Japan | none recorded | 0 | 251 | 1,942 | - | |
Uppsala · hospital | Sweden | none recorded | 0 | 211 | 1,236 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Extrapulmonary neuroendocrine carcinoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Extrapulmonary neuroendocrine carcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Ki-67 above 20 percent, usually far higher, with poorly differentiated morphology, Synaptophysin, chromogranin and INSM1 by immunohistochemistry, p53 and Rb by immunohistochemistry, FDG PET, DLL3 expression), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Small-cell neuroendocrine carcinomaof the gastrointestinal tract, Large-cell neuroendocrine carcinomaof the gastrointestinal tract, Colorectal NEC.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Diagnosis and staging
- For my situation (diagnosis and staging), which of the standard options do you recommend and why?Why: Guideline options include: Biopsy with Ki-67, morphology and p53 or Rb immunohistochemistry to separate carcinoma from grade 3 tumour; FDG PET and CT; somatostatin receptor PET only if radioligand therapy is contemplated.
Localised disease
- For my situation (localised disease), which of the standard options do you recommend and why?Why: Guideline options include: Resection or definitive chemoradiotherapy with perioperative platinum-etoposide, following the limited-stage small-cell lung cancer model.
- Am I a candidate for Platinum + etoposide (EP / CE), Etoposide, Cisplatin or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Metastatic, first line
- For my situation (metastatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: Platinum with etoposide (cisplatin or carboplatin), with a PD-1 or PD-L1 antibody added by extrapolation from small-cell lung cancer or within a trial.
- Am I a candidate for Platinum + etoposide (EP / CE), Etoposide, Carboplatin or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Second line
- For my situation (second line), which of the standard options do you recommend and why?Why: Guideline options include: FOLFIRI, FOLFOX, capecitabine-temozolomide or topotecan; nivolumab with ipilimumab in selected patients (DART); DLL3-directed T-cell engagers in trials.
- Am I a candidate for FOLFIRI (5-FU, leucovorin, irinotecan), FOLFOX (5-FU, leucovorin, oxaliplatin), Capecitabine + temozolomide (CAPTEM) or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of DART (SWOG S1609): nivolumab plus ipilimumab in rare tumours and DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Ki-67 near 20 to 55 percent with well-differentiated features
- For my situation (ki-67 near 20 to 55 percent with well-differentiated features), which of the standard options do you recommend and why?Why: Guideline options include: Reclassify as grade 3 neuroendocrine tumour and treat accordingly.
- Am I a candidate for Capecitabine + temozolomide (CAPTEM), Lutetium-177 dotatate, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy, DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers, A Study of Peluntamig (PT217) in Patients With Neuroendocrine Carcinomas Expressing DLL3 (the SKYBRIDGE Study), Peluntamig?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No randomised trial has improved on platinum-etoposide in first line”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Whether adding a PD-1 or PD-L1 antibody helps, as it does in small-cell lung cancer, is untested in a phase 3”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Extrapulmonary neuroendocrine carcinoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
11targets
9drugs
16companies
7pathways
1terms
4trials
4Latest papers
topQuery for this cancer: (TITLE:"Extrapulmonary neuroendocrine carcinoma" OR ABSTRACT:"Extrapulmonary neuroendocrine carcinoma" OR TITLE:"Extrapulmonary NEC" OR ABSTRACT:"Extrapulmonary NEC" OR TITLE:"Gastroenteropancreatic neuroendocrine carcinoma" OR ABSTRACT:"Gastroenteropancreatic neuroendocrine carcinoma" OR TITLE:"GEP-NEC" OR ABSTRACT:"GEP-NEC" OR TITLE:"Extrapulmonary small-cell carcinoma" OR ABSTRACT:"Extrapulmonary small-cell carcinoma" OR TITLE:"Large-cell neuroendocrine carcinoma of the gut" OR ABSTRACT:"Large-cell neuroendocrine carcinoma of the gut") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Extrapulmonary neuroendocrine carcinoma, not a curated reading list.
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