Initial Treatment Approach for Neuroendocrine Tumors
Surgery with curative intent should always be performed whenever feasible as the primary treatment for neuroendocrine tumors, as this represents the only potentially curative option and improves survival even in the presence of metastases. 1
Immediate Diagnostic Requirements Before Treatment
Before initiating any therapy, obtain the following essential information through a multidisciplinary tumor board 1:
- Histopathological confirmation with chromogranin A, synaptophysin, and Ki-67 proliferation index to establish WHO grading (G1: Ki-67 ≤2%, G2: Ki-67 3-20%, G3: Ki-67 >20%) 2, 3
- Anatomical location and local invasion status via CT/MRI 1
- Somatostatin receptor (SSTR) status using 68Ga-PET or 111In-pentetreotide scintigraphy 1
- Tumor functionality (hormone secretion causing clinical syndromes) 1
- Baseline biochemical markers: chromogranin A and 24-hour urinary 5-HIAA 1, 2
Treatment Algorithm Based on Disease Extent
Localized Disease (No Metastases)
Perform complete surgical resection with negative margins and regional lymph node dissection 1, 4. This applies to:
- Primary tumor removal to prevent complications (bleeding, bowel obstruction) 1
- Tumors of any size, though those <2 cm have lower metastatic risk 4
- Even when long-term cure is the goal 1
Liver-Restricted Metastatic Disease
Prioritize surgical and locoregional approaches first 1:
- Few liver lesions: Surgical resection with or without radiofrequency ablation (RFA) 1
- Multifocal/diffuse liver disease: Transarterial chemoembolization (TACE) or transarterial embolization (TAE) as preferred choices, achieving 60-95% symptomatic response rates and 18-24 month response duration 1
- Removal of primary tumor even with liver metastases present, as this has positive prognostic impact on survival 1
Functionally Active Tumors
Always consider cytoreductive strategies (TACE, TAE, RFA, SIRT) with the specific intention of ameliorating clinical symptoms 1:
- Prophylactic octreotide administration 12 hours before and 48 hours after surgery to prevent carcinoid crisis 4
- Avoid histamine-releasing medications and sympathetic nervous system activators perioperatively 4
- Consider cholecystectomy during abdominal surgery if long-term somatostatin analog therapy is anticipated 1, 4
Metastatic Disease Beyond Liver
Implement treatment sequence based on tumor characteristics 1:
- Highly proliferating NETs and pancreatic NETs: Chemotherapy is appropriate (temozolomide alone or with capecitabine showing 70% response rate for pancreatic NETs; cisplatin-etoposide for poorly differentiated G3 NECs with 42-67% response rate) 3
- Well-differentiated metastatic NETs: Somatostatin analogs (octreotide LAR or lanreotide 120 mg every 4 weeks) as first-line therapy, particularly for small intestinal NET G1/G2 3, 5, 6
- Pancreatic NETs: FDA-approved targeted therapies (everolimus, sunitinib) based on phase III trials 3, 6
- SSTR-positive tumors: Peptide receptor radionuclide therapy (PRRNT) may be beneficial, including as neoadjuvant therapy to render patients accessible to surgery 1
Critical Pitfalls to Avoid
Do not rely solely on conventional imaging without somatostatin receptor imaging, as this will miss NETs expressing somatostatin receptors 3. The vast majority of NETs are insensitive to chemotherapy, so reserve chemotherapy specifically for highly proliferating tumors, pancreatic NETs, or poorly differentiated G3 tumors 1.
Failure to obtain Ki-67 index leads to improper grading and inappropriate treatment selection 3. All treatment decisions must be made within an experienced multidisciplinary team to provide highest benefit while minimizing risks and ensuring best quality of life 1.
Follow-Up Protocol
Monitor with biochemical markers and imaging 3, 4:
- Conventional imaging (CT/MRI) every 3-6 months for NET G1/G2
- Every 2-3 months for NEC G3
- Somatostatin receptor imaging after 18-24 months if SSTR expression confirmed