Overview of Neuroendocrine Tumor Treatment

Neuroendocrine tumors (NETs) are classified by grade (G1-G3) and primary site. Well-differentiated NETs are managed with somatostatin analogs (octreotide, lanreotide) for symptom control and antiproliferative effect. Targeted therapies include everolimus (GI/lung NETs) and sunitinib (pancreatic NETs). Lutetium Lu-177 dotatate (Lutathera) provides peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-positive midgut NETs.

Treatment by Site and Grade

Well-Differentiated GI-NETs

  • Somatostatin analogs: octreotide LAR, lanreotide (Somatuline)
  • Lutetium Lu-177 dotatate (Lutathera) — PRRT for SSTR+
  • Everolimus (Afinitor)

Pancreatic NETs

  • Sunitinib (Sutent)
  • Everolimus (Afinitor)
  • Temozolomide + capecitabine (off-label standard)

Epidemiology & Impact

NETs arise from neuroendocrine cells throughout the body (GI 55%, lung 30%, pancreas 5%). Incidence has increased 6-fold over four decades to 7 per 100,000 due to improved detection. NETs range from indolent grade 1-2 tumors to highly aggressive neuroendocrine carcinomas. Carcinoid syndrome from serotonin secretion occurs in approximately 10% of midgut NET patients with liver metastases.

Molecular Biology & Biomarkers

Molecular profiles vary by site and grade. Pancreatic NETs harbor MEN1 (40%), DAXX/ATRX (40%), and mTOR pathway activation. Small bowel NETs have fewer mutations with chromosome 18 loss. Poorly differentiated neuroendocrine carcinomas have TP53 and RB1 loss. Ki-67 index is the most important prognostic marker (G1 under 3%, G2 3-20%, G3 over 20%).

Evolving Treatment Landscape

Treatment is grade and site-dependent. Somatostatin analogs control symptoms and tumor growth in G1-G2 NETs. Everolimus and sunitinib are approved for progressive pancreatic NETs. Lutetium-177 dotatate (Lutathera/PRRT) is standard for somatostatin receptor-positive progressive NETs. Poorly differentiated carcinomas receive platinum-etoposide. Belzutifan is approved for VHL-associated pancreatic NETs.

Approved Neuroendocrine Tumors Therapies

Afinitor
everolimus
FDA Approved 2011 GI/Lung/Pancreatic NETs
Approved Indications (US/FDA)
Treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin; treatment of progressive pancreatic NETs that are unresectable, locally advanced, or metastatic.
Dosing Schedule
10 mg orally once daily
Drug Class
mTOR Inhibitor
Manufacturer
Novartis
Approval Year
2011
Pivotal Trial
NCT01524783 ↗
Key Publication
Yao et al. NEJM 2011 (RADIANT-3) ↗
Sutent
sunitinib
FDA Approved 2011 Pancreatic NETs
Approved Indications (US/FDA)
Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.
Dosing Schedule
37.5 mg orally once daily continuously
Drug Class
Multi-kinase TKI
Manufacturer
Pfizer
Approval Year
2011
Pivotal Trial
NCT00428597 ↗
Key Publication
Raymond et al. NEJM 2011 ↗
Lutathera
lutetium Lu 177 dotatate
FDA Approved 2018 SSTR+ GEP-NETs
Approved Indications (US/FDA)
Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs, in adults.
Dosing Schedule
7.4 GBq (200 mCi) IV every 8 weeks for a total of 4 doses
Drug Class
Peptide Receptor Radionuclide Therapy (PRRT)
Manufacturer
Novartis/AAA
Approval Year
2018
Pivotal Trial
NCT01578239 ↗
Key Publication
Strosberg et al. NEJM 2017 (NETTER-1) ↗
Sandostatin LAR
octreotide LAR
FDA Approved 1998 Functional NETs / Carcinoid
Approved Indications (US/FDA)
Long-term maintenance therapy for patients with acromegaly and symptoms associated with carcinoid tumors. Also demonstrated antiproliferative effect in midgut NETs (PROMID).
Dosing Schedule
20-30 mg IM every 4 weeks
Drug Class
Somatostatin Analog
Manufacturer
Novartis
Approval Year
1998
Key Publication
Xermelo
telotristat ethyl
FDA Approved 2017 2nd Line+
Approved Indications (US/FDA)
Treatment of carcinoid syndrome diarrhea in combination with SSA therapy in adults not adequately controlled by SSA therapy alone.
Dosing Schedule
250 mg orally three times daily with food
Cycle Length
Continuous daily dosing
Combination Therapy
With somatostatin analog (tryptophan hydroxylase inhibitor)
Manufacturer
TerSera Therapeutics
Approval Year
2017
Pivotal Trial
NCT01677910 ↗
Key Publication
Kulke et al. JCO 2017 (TELESTAR) ↗
Rinke et al. JCO 2009 (PROMID) ↗