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.

The frontier is alpha-emitting PRRT: 212Pb-DOTAMTATE (AlphaMedix) met all primary endpoints in phase 2 with a 54% response rate in PRRT-naive patients and Breakthrough designation, and 225Ac-DOTATATE (RYZ101) is in the phase 3 ACTION-1 trial after lutetium failure. SSTR antagonist ligands, dosimetry-personalised dosing, and combinations with CAPTEM or immunotherapy are being tested. Open problems include the lack of randomised evidence for sequencing, the absence of effective therapy for SSTR-negative and high-grade disease, a 2-3% risk of therapy-related leukaemia after PRRT, and isotope supply.