What is the recommended treatment for patients with midgut neuroendocrine tumors based on the PROMID (Prolonged Release of Octreotide (somatostatin analog) in Neuroendocrine Tumors) study?

Treatment of Midgut Neuroendocrine Tumors Based on the PROMID Study

Based on the PROMID study, octreotide LAR 30 mg intramuscularly every 4 weeks is the recommended first-line treatment for patients with metastatic midgut neuroendocrine tumors to control tumor growth. 1

Evidence from the PROMID Study

• The PROMID study was a placebo-controlled phase III trial of 85 patients with metastatic midgut NETs that demonstrated octreotide LAR significantly prolonged time to tumor progression (TTP) compared to placebo (14.3 vs 6.0 months, p=0.000072) 1, 2
• After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group versus 37.2% in the placebo group 1, 2
• The antiproliferative effect was observed in both functionally active and inactive tumors 2
• The most favorable effect was observed in patients with low hepatic tumor burden and resected primary tumor 2

Current Treatment Algorithm for Midgut NETs

First-Line Therapy

• For patients with advanced/metastatic midgut NETs with clinically significant tumor burden or progressive disease, initiate somatostatin analog (SSA) therapy: 1
  • Octreotide LAR 30 mg IM every 4 weeks [ESMO-MCBS v1.1 score: 2] 1
  • Lanreotide 120 mg deep SC every 4 weeks is an alternative option based on the CLARINET study [ESMO-MCBS v1.1 score: 3] 1

Management of Carcinoid Syndrome

• For patients with carcinoid syndrome, standard doses of octreotide LAR are 20-30 mg IM every 4 weeks 1
• Short-acting octreotide (150-250 mcg SC TID) can be added for rapid relief or breakthrough symptoms 1
• Consider telotristat for persistent diarrhea despite SSA therapy 1

Disease Progression After SSA Therapy

For patients with disease progression on first-line SSA therapy, options include:

1. Peptide Receptor Radionuclide Therapy (PRRT):

   • 177Lu-DOTATATE has shown significant improvement in progression-free survival compared to high-dose octreotide LAR in the NETTER-1 trial (not reached vs 8.4 months) 1, 3
   • Objective tumor response rate: 18% with 177Lu-DOTATATE vs 3% with high-dose octreotide 3

2. Hepatic-directed therapies for hepatic-predominant disease: 1

   • Arterial embolization
   • Hepatic chemoembolization
   • Hepatic radioembolization (category 2B)
   • Cytoreductive surgery/ablative therapy if near-complete resection possible (category 2B) 1

3. Everolimus can be considered for progressive disease (category 3) 1

4. Interferon alpha can be considered if other treatment options have been exhausted (category 3) 1

Factors Affecting Treatment Response

• Favorable prognostic factors for response to SSA therapy: 4

  • Male sex
  • Low hepatic tumor burden
  • Resected primary tumor
  • Well-differentiated tumors (G1)
  • Stable disease at treatment initiation

• Unfavorable prognostic factors: 4

  • Pancreatic primary location
  • Extensive liver metastases
  • Intermediate grade tumors (G2)
  • Extremely elevated chromogranin A levels (>10x ULN)

Important Clinical Considerations

• A watch-and-wait approach may be appropriate in selected patients with NET G1 and/or low tumor burden (<10% liver involvement and no extra-abdominal disease) with stable disease 1
• Consider cardiology consultation and echocardiogram to assess for carcinoid heart disease in patients with carcinoid syndrome, especially before major surgery 1
• Long-acting SSAs should be interrupted at least 4 weeks before PRRT and should be continued no earlier than 1 hour after PRRT cycle(s) 1
• For patients with refractory symptoms, consider shortening the injection interval of long-acting SSAs to every 3 or 2 weeks (off-label) 1
• The median duration of antiproliferative effect of octreotide LAR may be longer than initially reported (up to 37 months in some studies) 4