Teaching pack: Neuroendocrine tumours

Neuroendocrine neoplasms range from indolent grade 1 tumours that patients live with for decades to poorly differentiated neuroendocrine carcinomas that behave like small-cell lung cancer. Most arise in the small bowel, pancreas, rectum or lung; many secrete hormones (serotonin, insulin, gastrin) that cause syndromes, and most well-differentiated tumours express somatostatin receptor 2 (SSTR2), which is the hinge of both diagnosis and therapy. Incidence has risen six-fold over 40 years, largely from incidental detection on imaging and endoscopy.

Therapy is sequenced by grade, receptor status and tempo. Somatostatin analogues (octreotide, lanreotide) control symptoms and slow growth (PROMID, CLARINET). For progression, peptide receptor radionuclide therapy with 177Lu-DOTATATE (NETTER-1; NETTER-2 first line for grade 2-3) is standard, and 177Lu-edotreotide beat everolimus head-to-head in COMPETE (PFS 23.9 vs 14.1 months) with an FDA decision due August 2026. Targeted pills (everolimus, sunitinib, and since March 2025 cabozantinib after CABINET) and chemotherapy (CAPTEM for pancreatic NETs; platinum-etoposide for neuroendocrine carcinoma) fill in. Surgery and liver-directed therapy (resection, embolisation, ablation, transplant in rare cases) remain central because disease is often liver-dominant.

• Theranostic paradigm; first-line PRRT in higher-grade disease.
• Theranostic paradigm is routine: SSTR PET selects, 177Lu-DOTATATE treats, including first line for grade 2-3 disease.
• First head-to-head radioligand-versus-drug trial (COMPETE) won on PFS; FDA decision on 177Lu-edotreotide due 28 August 2026.
• Cabozantinib approved (2025) across pancreatic and extra-pancreatic NETs after prior therapy, with an 81% reduction in progression risk in lung/thymic NETs.
• Alpha PRRT (212Pb-DOTAMTATE) met all phase 2 endpoints with Breakthrough designation; 225Ac-DOTATATE in phase 3.
• Germline testing and syndrome-directed care (belzutifan for VHL) are standard for pancreatic NETs.

1. 1907Oberndorfer coins 'Karzinoid' for small-bowel tumours
2. 1954Carcinoid syndrome described (Thorson)
3. 1987Octreotide approved
4. 1988Octreotide approved for carcinoid syndrome
5. 1994111In-octreotide scintigraphy (OctreoScan) approved
6. 2000First 90Y- and 177Lu-DOTATOC/DOTATATE PRRT series (Rotterdam, Basel)
7. 2009PROMID: octreotide slows tumour growth
8. 2011Everolimus (RADIANT-3) and sunitinib approved for pancreatic NETs
9. 2014CLARINET: lanreotide antiproliferative approval
10. 201668Ga-DOTATATE PET (Netspot) approved; RADIANT-4 extends everolimus to lung/GI NETs

• Actinium-225 DOTATATE (product)
• 177Lu-edotreotide (product)
• COMPETE (trial)
• 212Pb-DOTAMTATE (product)
• ALPHAMEDIX-02 (trial)
• ACTION-1 (trial)
• Peptide receptor radionuclide therapy (PRRT) (technology)
• Somatostatin receptor PET (68Ga/64Cu-DOTATATE) (technology)
• Cabozantinib (product)
• Dosimetry-personalised PRRT instead of four fixed cycles (idea)
• SSTR antagonist radioligands to increase tumour dose (idea)
• Beta PRRT → alpha PRRT (pairing)

• PROMID (phase 3, n=85): Time to tumour progression: 14.3 months vs 6 months, HR 0.34
• RADIANT-3 and RADIANT-4 (phase 3, n=712): Progression-free survival (RADIANT-3): 11 months vs 4.6 months, HR 0.35
• CABINET (Alliance A021602) (phase 3, n=298): Progression-free survival (pancreatic NET): 13.8 months vs 4.4 months, HR 0.23
• CLARINET (phase 3, n=204): Progression-free survival: 18 months, HR 0.47
• COMPETE (phase 3, n=309): Progression-free survival: 23.9 months vs 14.1 months, HR 0.67
• SANET-ep and SANET-p (phase 3, n=369): Progression-free survival (SANET-ep): 9.2 months vs 3.8 months, HR 0.33

• Neuroendocrine carcinoma (high grade) behaves like SCLC.
• Sequencing of PRRT vs targeted therapy.
• Sequencing is unproven: no randomised trial orders SSA, PRRT, everolimus, cabozantinib and chemotherapy.
• SSTR-negative, FDG-avid and high-grade disease has few options; neuroendocrine carcinoma outcomes remain poor.
• Therapy-related MDS/AML (~2-3%) and renal toxicity after PRRT; long-term data on retreatment are thin.
• Overall survival benefits are hard to demonstrate because patients live for years and cross over.

1. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
2. What is the first T-cell engager to improve survival in a common solid tumour?
   Answer

   Tarlatamab (Imdelltra), DLL3×CD3, in second-line small-cell lung cancer: OS 13.6 vs 8.3 months in DeLLphi-304.
3. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
4. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.

• Wikipedia: https://en.wikipedia.org/wiki/Neuroendocrine_tumor
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1448