What is the best treatment approach for a patient with stage 4 (four) neuroendocrine tumor (NET) of the sigmoid colon with liver metastases (mets)?

Treatment of Stage 4 Neuroendocrine Tumor of Sigmoid with Liver Metastases

For stage 4 sigmoid colon neuroendocrine tumor with liver metastases, resect the primary sigmoid tumor to prevent intestinal complications, initiate somatostatin analog therapy (octreotide LAR or lanreotide 120 mg every 4 weeks) as first-line systemic treatment, and pursue liver-directed therapies (transarterial embolization/chemoembolization) for unresectable liver metastases, reserving peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE for progressive somatostatin receptor-positive disease. 1, 2

Primary Tumor Management

• Resection of the primary sigmoid tumor should be performed even in the presence of extensive liver metastases to prevent bowel obstruction and intestinal ischemia, which are common complications in advanced colorectal neuroendocrine tumors. 1, 2

• The resection should include adequate lymph node clearance, as malignancy is frequent in gastrointestinal neuroendocrine tumors. 2

• This palliative resection is particularly indicated for preventing intestinal complications and may improve survival, though survival benefit remains controversial in stage IV disease. 1

Liver Metastases Assessment and Surgical Approach

• Surgical resection of liver metastases should be considered first when feasible, as it offers the best chance for cytoreduction and symptom control in patients with exclusive or predominant liver disease. 1, 2

• Resection is most appropriate when metastatic disease is localized or when >70% of tumor burden is resectable. 2

• Complete resection is not always necessary; removal of 90% of disease burden can achieve symptom control, though this may be difficult with diffuse disease. 2

• Upfront surgery is contraindicated in the presence of extra-abdominal metastases or high-grade (G3) neuroendocrine neoplasms. 1

First-Line Systemic Therapy

• Somatostatin analogs (octreotide LAR or lanreotide 120 mg every 4 weeks) should be initiated as first-line systemic therapy for both functioning and non-functioning progressive neuroendocrine tumors. 1, 3

• These agents control tumor-associated symptoms and tumor growth, with improvement of flushing and diarrhea achieved in 70-80% of patients with carcinoid syndrome. 1, 3

• Lanreotide 120 mg every 4 weeks is FDA-approved for gastroenteropancreatic NETs and demonstrated improved progression-free survival (median not reached vs 16.6 months for placebo) in well or moderately differentiated metastatic GEP-NETs. 3

Liver-Directed Therapies for Unresectable Disease

• Transarterial therapies (TAE, TACE, DEB-TACE, or TARE) are the primary treatment strategy for multiple, diffuse, or unresectable liver metastases. 1, 2

• All transarterial modalities have shown efficacy for overall survival, tumor growth reduction, and symptom control without clear superiority of one over another. 2

• Vascular and ablative locoregional treatments are valid options for treatment of liver metastases, also in conjunction with systemic therapies or in combination with surgery. 1

• In functional NETs, locoregional therapies should be applied early, following SSA therapy, to further improve control of hormonal symptoms and prevent complications such as carcinoid crisis. 1

• For non-functioning NETs with disease limited to the liver, locoregional therapies can be considered as an alternative to systemic treatment. 1

Peptide Receptor Radionuclide Therapy (PRRT)

• PRRT with 177Lu-DOTATATE should be considered for progressive disease in patients with somatostatin receptor-positive tumors (confirmed by somatostatin receptor imaging). 1, 2

• PRRT is FDA and EMA approved for midgut NETs with Level I evidence and demonstrates disease control rates between 30-80%, PFS 9-23 months, and OS 19-53 months. 1

• Results are significantly better in patients with Ki-67 <55% compared with those with higher Ki-67 values. 1

• PRRT may be considered in patients with NET G3, however patients need to be carefully selected; in patients with Ki-67 >35%, median PFS was only 6.8 months. 1

• Treatment with 177Lu-DOTATATE carries a 3-4% risk of irreversible bone marrow toxicity (leukemia or bone marrow dysplasia) and mild renal toxicity grade 1/2 in 30% of patients long-term. 1

Treatment Sequencing Algorithm

1. Resect the primary sigmoid tumor with adequate lymph node clearance to prevent intestinal complications. 1, 2

2. Assess liver metastases for resectability: If resectable with exclusive or predominant liver disease, proceed with surgical resection. 1, 2

3. Initiate somatostatin analog therapy (lanreotide 120 mg every 4 weeks or octreotide LAR) for disease control and symptom management. 1, 3

4. For unresectable liver metastases, employ transarterial therapies (TAE/TACE preferred to preserve future PRRT candidacy). 1, 2

5. Reserve PRRT with 177Lu-DOTATATE for progressive somatostatin receptor-positive disease after SSA therapy. 1, 2

Critical Pitfalls to Avoid

• Do not withhold primary tumor resection even with extensive liver metastases, as it prevents life-threatening complications (bowel obstruction, intestinal ischemia) and may improve survival. 1, 2

• Chemotherapy should not be used as first-line treatment for well-differentiated gastrointestinal neuroendocrine tumors (G1/G2), as these tumors are largely chemotherapy-insensitive. 1, 2

• Avoid upfront surgery in the presence of extra-abdominal metastases or high-grade (G3) neuroendocrine neoplasms, as this is contraindicated. 1

• Consider preferentially employing TAE or TACE over radioembolization for patients with somatostatin receptor-avid disease who may be future candidates for PRRT, as long-term safety data on Yttrium-90 radioembolization before and after PRRT remain limited. 4

• Monitor for cholelithiasis and complications during somatostatin analog therapy, as gallstones may occur and require periodic monitoring. 3

• Monitor glucose levels closely during somatostatin analog therapy, as both hyperglycemia and hypoglycemia may occur, requiring adjustment of antidiabetic treatment. 3

Liver Transplantation Consideration

• Liver transplantation may be considered in highly selected patients with unresectable liver-confined disease meeting strict criteria: absence of extrahepatic disease, well-differentiated (G1/G2, Ki-67 <10%) NET, previous removal of primary tumor, metastatic diffusion <50% of total liver volume, stable disease for at least 6 months, and age <60 years. 1, 2

• However, recurrence rates are high (31-56%), and this option should be thoroughly discussed within a NET-dedicated multidisciplinary team. 1, 2