What are the management options for Pancreatic Neuroendocrine Tumors (Pan NETs)?

Management Options for Pancreatic Neuroendocrine Tumors (PanNETs)

The management of Pancreatic Neuroendocrine Tumors (PanNETs) requires a multidisciplinary approach with treatment decisions based on tumor characteristics including differentiation, grading, stage, and functional status. 1, 2

Diagnostic Workup

• Histopathological confirmation with immunohistochemical investigation using appropriate antibodies 2
• Biochemical evaluation:
  • Chromogranin A (CgA) and 5-HIAA in 24-hour urine as baseline tests 2
  • Additional tests based on clinical suspicion (thyroid function, PTH, calcium, etc.) 2
• Imaging studies:
  • Somatostatin receptor imaging (preferably Gallium-68 PET/CT) 2
  • CT and MRI for detecting primary tumor and metastases 2
  • Endoscopic ultrasound for pancreatic, duodenal, and gastric tumors 2

Treatment Approaches Based on Disease Stage

Localized Disease

1. Surgical resection is the treatment of choice for localized PanNETs with curative intent 1, 2

   • 5-year survival rates of 80-100% after curative surgery 2
   • For non-functional PanNETs <2 cm, active surveillance may be considered 3
   • For functional PanNETs, surgery is recommended regardless of size for symptom control 3

2. Surgical approach:

   • Formal pancreatectomy with lymph node sampling for most PanNETs 4
   • Enucleation may be considered for insulinomas 4
   • Laparoscopic or open techniques based on tumor location and size 4

Advanced/Metastatic Disease

1. Somatostatin analogs:

   • Lanreotide 120 mg every 4 weeks for unresectable, well- or moderately-differentiated, locally advanced or metastatic GEP-NETs 5
   • Improves progression-free survival and controls hormonal syndromes 5

2. Targeted therapy:

   • Sunitinib (37.5 mg orally once daily) for progressive, well-differentiated pancreatic NETs with unresectable locally advanced or metastatic disease 6
   • Everolimus for advanced, progressive, well-differentiated pancreatic NETs 1, 2

3. Cytoreductive procedures:

   • Surgical debulking for patients with liver metastases and potentially resectable disease 1
   • Radiofrequency ablation, laser therapy, and embolization of liver metastases 1, 2
   • Transarterial chemoembolization (TACE) for liver metastases 4

4. Peptide Receptor Radionuclide Therapy (PRRT):

   • [177Lu]Lu-DOTA-TATE for patients with tumors showing high uptake on somatostatin receptor scintigraphy 2

5. Chemotherapy:

   • Recommended for inoperable or metastatic pancreatic NETs 1
   • Platinum-based chemotherapy (cisplatin or carboplatin) plus etoposide for poorly differentiated NETs 2
   • Alkylating agents like temozolomide and streptozotocin for well-differentiated tumors 1

Management Based on Tumor Grade

Well-differentiated PanNETs (G1/G2)

• G1 (Ki67 <3%): Surgery if resectable; somatostatin analogs for advanced disease 1
• G2 (Ki67 3-20%): Surgery if resectable; somatostatin analogs, targeted therapy, or PRRT for advanced disease 1

Well-differentiated PanNETs (G3) and Poorly-differentiated NECs

• G3 NET (Ki67 >20%, well-differentiated): Consider surgery if resectable; chemotherapy, targeted therapy for advanced disease 1
• NEC (poorly-differentiated): Primarily platinum-based chemotherapy 1, 2

Special Considerations

Perioperative Management for Functional NETs

• Prophylactic administration of somatostatin analogs before procedures:
  • Short-acting octreotide by constant IV infusion (50 μg/hour) starting 12 hours before and continuing 24-48 hours after surgical intervention 1, 2
  • Avoid drugs that release histamine or activate the sympathetic nervous system 1, 2

Carcinoid Heart Disease Screening

• All patients with midgut NETs (with or without hepatic metastasis) and all patients with carcinoid syndrome should be screened for carcinoid heart disease 1, 2
• Screening includes NT-proBNP and echocardiography 1

Follow-up Recommendations

• Every 3 months during active treatment 2
• After curative surgery, follow-up every 3-6 months for more than 5 years 2
• Biochemical markers and imaging (CT or MRI) every 6 months for monitoring during treatment 2

Common Pitfalls and Caveats

1. Delayed diagnosis due to vague symptoms in non-functional PanNETs
2. Underestimation of disease extent without appropriate imaging modalities
3. Inadequate perioperative preparation for functional NETs, which can lead to carcinoid crisis
4. Overlooking hereditary syndromes (MEN1, VHL) that may be associated with PanNETs
5. Failure to consider cytoreductive surgery in metastatic disease, which can provide symptomatic relief and potentially improve survival

The management of PanNETs continues to evolve with advances in molecular diagnostics and targeted therapies. Treatment decisions should be made within a NEN-dedicated multidisciplinary team to optimize outcomes for these complex tumors.