What are the recommended treatment options for neuroendocrine tumors considering tumor grade, stage, functional status, and overall patient health?

Neuroendocrine Tumor Treatment

Surgery is the only curative treatment and should be offered to all patients with resectable disease who are fit for operation, regardless of tumor grade or functional status. 1

Treatment Algorithm Based on Disease Stage and Resectability

Localized/Resectable Disease (Limited to Primary and Regional Lymph Nodes)

• Perform complete surgical resection with curative intent for all fit patients with disease confined to the primary site and regional lymph nodes. 1, 2
• Remove the primary tumor with negative margins and perform regional lymph node dissection. 2, 3
• For pancreatic NETs, formal pancreatectomy with lymph node sampling is recommended for most cases; enucleation is reserved only for small insulinomas. 4
• For type III gastric NETs, perform radical gastrectomy with lymph node dissection. 4
• Consider cholecystectomy during abdominal surgery if long-term somatostatin analogue therapy is anticipated, as these agents increase gallstone formation risk. 1, 2, 5

Potentially Resectable Liver Metastases

• Surgical resection should be considered when complete removal of all disease is feasible, even in the presence of liver metastases. 1, 2
• Combined approaches using resection plus ablative techniques (radiofrequency ablation, microwave ablation) may be employed for paucilesional disease or small-volume tumors. 1
• Ablation provides symptom relief and is most useful in combination with resection. 1

Unresectable/Metastatic Disease: Treatment Selection by Grade and Functional Status

The choice of systemic therapy depends on tumor grade (Ki-67 index), primary site, functional status, and somatostatin receptor expression. 1

Well-Differentiated NETs (G1/G2, Ki-67 ≤20%)

First-line options:

• Somatostatin analogues (octreotide or lanreotide 120 mg every 4 weeks) for disease stabilization in well-differentiated gastroenteropancreatic NETs, particularly those with somatostatin receptor expression. 1, 5, 6, 7
• For functioning tumors with carcinoid syndrome, somatostatin analogues are first-line to control hormonal symptoms; lanreotide reduces the need for short-acting rescue therapy. 5
• Administer prophylactic octreotide 12 hours before and 48 hours after surgery in functioning tumors to prevent carcinoid crisis. 2

Second-line options for progressive disease:

• Peptide receptor radionuclide therapy (PRRT) with Lu-177 DOTATATE (7.4 GBq every 8 weeks for 4 doses) for somatostatin receptor-positive midgut NETs and other well-differentiated NETs with documented progression. 8, 9, 7
• Everolimus for progressive, well-differentiated pancreatic NETs (advanced, inoperable, or metastatic disease with radiological progression within 12 months). 1, 6, 7
• Sunitinib as an alternative targeted therapy for progressive, well-differentiated pancreatic NETs. 1, 6

Well-Differentiated High-Grade NETs (G3, Ki-67 >20% but well-differentiated morphology)

• Capecitabine plus temozolomide (CAPTEM) is the preferred first-line systemic therapy, showing 35% objective response rate and median progression-free survival of 9.4 months. 9
• FOLFOX is an alternative option with 28.6% response rate and median progression-free survival of 13 months. 9
• PRRT may be considered if somatostatin receptor expression is maintained, with 20% response rate and 9.1 months median progression-free survival. 9
• Platinum-etoposide has activity but responses are short-lived (median PFS 2.9 months) and should be reserved for highly proliferative cases approaching neuroendocrine carcinoma behavior. 9

Poorly Differentiated Neuroendocrine Carcinomas (G3, poorly differentiated)

• Platinum-based chemotherapy (cisplatin or carboplatin plus etoposide) is first-line treatment for poorly differentiated, high-grade neuroendocrine carcinomas. 1
• Chemotherapy may also be used for inoperable or metastatic pancreatic and bronchial NETs with aggressive clinical course. 1

Locoregional Therapies for Liver-Dominant Disease

• Hepatic artery embolization or chemoembolization for symptom control and tumor debulking in patients with liver-predominant disease. 1, 6
• External beam radiotherapy specifically for palliation of painful bone metastases. 1

Multidisciplinary Management Requirements

All NET patients must be discussed at a multidisciplinary tumor board before initiating definitive treatment, with representation from gastroenterologists/endocrinologists, medical oncologists, surgeons, radiologists, nuclear medicine specialists, histopathologists, and clinical nurse specialists. 1, 4

Surveillance Strategy Post-Treatment

• Measure chromogranin A and perform CT or MRI every 3-6 months for G1/G2 tumors. 3, 4
• Increase surveillance frequency to every 2-3 months for G3 tumors. 2, 4
• Somatostatin receptor imaging (Ga-68 PET/CT or SSRS) should be performed 18-24 months post-resection if receptor expression was confirmed. 2, 3
• 24-hour urinary 5-HIAA for monitoring functional midgut NETs with carcinoid syndrome. 3, 4

Critical Treatment Principles

The primary aim is to keep patients disease-free and symptom-free for as long as possible while maintaining optimal quality of life. 1

• Determine tumor extent, metastases, histological grade (Ki-67 index), and secretory profile before planning treatment. 1
• For patients unfit for surgery, focus treatment on symptom improvement and quality of life maintenance. 1
• Enroll patients in clinical trials of novel therapies whenever possible. 1

Common Pitfalls to Avoid

• Do not use somatostatin analogues within 4 weeks (long-acting) or 24 hours (short-acting) before PRRT administration, as they competitively block somatostatin receptors and reduce treatment efficacy. 8
• Avoid repeated high-dose glucocorticoids during PRRT, as they down-regulate SSTR2 receptors. 8
• Monitor for cholelithiasis during somatostatin analogue therapy; gallstones occur frequently and may require intervention. 5
• Adjust antidiabetic medications carefully, as somatostatin analogues cause both hyperglycemia and hypoglycemia. 5
• Screen all NET patients for MEN-1 syndrome with clinical examination and family history; suspect hereditary syndromes when second endocrine tumors are present or family history is positive. 1, 2, 4