What is the initial treatment approach for patients diagnosed with neuroendocrine tumors?

Initial Treatment Approach for Neuroendocrine Tumors

Surgery with curative intent should always be performed whenever feasible as the optimal initial management, as early surgical removal prior to the development of regional or distant metastases provides the best outcomes for mortality and quality of life. 1

Treatment Algorithm Based on Disease Extent

Localized Disease (No Metastases)

• Complete surgical resection with curative intent is the standard of care for patients presenting with localized NETs, achieving 86% three-year overall survival and 81% disease-free survival 1, 2, 3
• Surgical approach must include complete removal of the primary tumor with negative margins and regional lymph node dissection 3
• Even when the primary tumor is resected, removal is indicated to prevent complications such as bleeding or small-bowel obstruction 1

Metastatic Disease Confined to Liver

• Surgical and locoregional approaches should be considered primarily when disease is restricted to the liver 1
• For solitary or isolated liver metastases: surgical resection with or without radiofrequency ablation (RFA) 1
• For multifocal or diffuse liver disease: transarterial chemoembolization (TACE) or transarterial embolization (TAE) are preferred, achieving symptomatic response rates of 60-95% and radiological response of 33-80% 1
• Removal of the primary tumor even in the presence of liver metastases has a positive prognostic impact on survival 1

Advanced Metastatic Disease

• For unresectable, well or moderately differentiated gastroenteropancreatic NETs: somatostatin analog therapy (lanreotide 120 mg every 4 weeks) is first-line treatment after disease progression on initial therapy, demonstrating statistically significant improvement in progression-free survival (HR 0.47, p<0.001) 2, 4
• Combined approaches using resection and ablative techniques may be considered if complete removal is feasible 3
• Chemotherapy is appropriate specifically for highly proliferating NETs and pancreatic NETs, though the vast majority of NETs are rather insensitive to this treatment 1

Essential Pre-Treatment Evaluation

Before initiating any treatment, the following must be determined through multidisciplinary tumor board review 1:

• Anatomical location and local invasion of adjacent structures using CT and MRI 1, 2
• Tumor functionality status through baseline chromogranin A and 5-HIAA testing 1, 5, 2
• Somatostatin receptor (SSTR) status via somatostatin receptor scintigraphy or 68Ga-PET imaging 1, 2
• Histological grading with Ki-67 proliferation index: NET G1 (Ki-67 ≤2%), NET G2 (Ki-67 3-20%), NEC G3 (Ki-67 >20%) 5, 2
• TNM staging according to site of origin 5

Special Considerations for Functioning Tumors

• For functionally active tumors causing carcinoid syndrome: prophylactic octreotide administration 12 hours before and 48 hours after surgery is mandatory to prevent carcinoid crisis 3
• Cytoreductive strategies (TACE, TAE, RFA) should always be considered with the intention of ameliorating clinical symptoms in functioning tumors 1
• Avoid medications that release histamine or activate the sympathetic nervous system during surgery 3

Critical Pitfalls to Avoid

• Never rely solely on conventional imaging without somatostatin receptor imaging, as this may miss NETs that are SSTR-positive and amenable to targeted therapies 2
• Failure to obtain Ki-67 index leads to improper grading and inappropriate treatment selection, which directly impacts survival outcomes 2
• For patients undergoing abdominal surgery with liver metastases who will likely receive long-term somatostatin analog therapy, cholecystectomy should be considered to prevent gallstone complications 1, 3, 4

Treatment Sequencing Principles

The treatment options are not mutually exclusive and are largely interchangeable, but should be chosen and implemented in correct sequence by an experienced multidisciplinary team to provide the highest benefit while minimizing risks and ensuring the best quality of life 1. In selected cases, peptide receptor radionuclide therapy (PRRNT) may be beneficial as neoadjuvant therapy to render a patient accessible to surgery 1.