Metastatic Liver Cancer Explained: How to Treat Neuroendocrine Tumor Liver Metastasis

Neuroendocrine tumors (NETs) are rare and often misdiagnosed types of cancer that can develop in various organs throughout the body, with the most common locations being the gastrointestinal tract and pancreas. A well-known case is that of Steve Jobs, the late co-founder of Apple, who was diagnosed with a pancreatic neuroendocrine tumor. Unlike many other cancers, NETs have the unique ability to secrete hormones or peptides such as insulin, gastrin, and glucagon into the bloodstream, which can lead to a variety of symptoms including flushing, unexplained abdominal pain, persistent diarrhea, low potassium levels, recurring peptic ulcers, and hypoglycemia. As the tumor grows, it may also cause symptoms related to physical compression of surrounding organs.

Historically, due to limited awareness and diagnostic tools, many patients with NETs face long delays in diagnosis—often visiting multiple specialists over 5–7 years before receiving a correct diagnosis. By the time the disease is identified, it has often progressed to an advanced stage with local invasion or distant metastasis, most commonly to the liver. This late detection significantly limits the chance for curative surgical intervention.

How Is Liver Metastasis from Neuroendocrine Tumors Treated?

Before initiating any treatment plan, it is essential to confirm the pathological diagnosis and determine the stage of the tumor. Pathologists classify NETs into three grades—G1, G2, and G3—based on the Ki67 index and mitotic count. G1 and G2 tumors are considered neuroendocrine tumors, while G3 is classified as neuroendocrine carcinoma, indicating a more aggressive malignancy. Patients with G1/G2 tumors generally have a better prognosis, even when metastasis occurs, whereas G3 tumors are associated with a poorer outcome.

For patients with G1 or G2 liver metastases, surgical resection or localized treatments may be viable options. Small lesions (less than 3 cm) can be treated with ablation techniques, while solitary metastases may be removed surgically. In selected cases—especially in patients under 45 years old with no extrahepatic disease and a previously resected primary tumor—liver transplantation may be considered, offering a 5-year survival rate of 48% to 60%. For multiple or high tumor burden liver metastases, hepatic artery chemoembolization (TACE) can be highly effective, providing symptom relief in 73% to 100% of cases, with tumor marker reduction in 57% to 91%, and radiological tumor shrinkage in 33% to 50% of patients.

Systemic Treatments for Advanced or G3 Neuroendocrine Liver Metastases

When tumors have spread beyond the liver or are classified as G3 neuroendocrine carcinoma, systemic therapy becomes essential. Treatment strategies may vary depending on the origin of the tumor, especially when comparing pancreatic and non-pancreatic NETs.

Biotherapy (Somatostatin Analogs)
Drugs such as octreotide, octreotide microspheres, and lanreotide are often used for G1/G2 tumors. These medications target somatostatin receptors and can help control symptoms and slow tumor growth. They may also be considered for G3 tumors if the cancer expresses somatostatin receptors, although they are not typically the first-line treatment.

Systemic Chemotherapy
Streptozocin combined with 5-fluorouracil and/or doxorubicin is commonly used for G1/G2 NETs, achieving tumor response rates of 35% to 40%. Temozolomide, either alone or in combination with capecitabine or bevacizumab, is also effective for these tumor types. For G3 neuroendocrine carcinomas, platinum-based regimens (such as etoposide plus cisplatin or carboplatin) are the preferred first-line treatment, particularly for tumors with a Ki67 index above 55%. For those with a lower Ki67 index, temozolomide-based therapy may be used, although there is currently no widely accepted second-line chemotherapy protocol.

Targeted Therapies
Sunitinib, an anti-angiogenic drug targeting VEGFR, PDGFR, c-kit, and RET, is approved for advanced pancreatic NETs. Clinical trials have shown that sunitinib significantly extends progression-free survival compared to placebo. Everolimus, an mTOR inhibitor, is effective for both pancreatic and non-pancreatic NETs and is recommended as a first-line targeted therapy alongside sunitinib for G1/G2 tumors.

Selpercatinib (previously known as sulfatinib) is a novel oral kinase inhibitor developed by Hutchison MediPharma. It targets both angiogenesis and immune evasion pathways. In 2019, the SANET-ep trial demonstrated its efficacy in non-pancreatic NETs, and the SANET-p trial for pancreatic NETs showed promising results. It is expected to receive regulatory approval in China for non-pancreatic NETs in the near future.

Immunotherapy and Radioisotope Treatments
Immunotherapy for NETs remains largely experimental, focusing on checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4. While monotherapy has shown limited efficacy, combination approaches—such as dual immunotherapy or immunotherapy combined with chemotherapy, targeted therapy, or PRRT—are being explored.

Peptide Receptor Radionuclide Therapy (PRRT) uses radiolabeled somatostatin analogs to target SSTR-positive tumors, including those in the stomach, intestines, and pancreas. Real-world data suggest PRRT can be effective, especially when combined with chemotherapy, although it may increase the risk of hematologic toxicity.

Conclusion

With advances in imaging and diagnostic techniques, the detection of neuroendocrine tumors has improved significantly. As a result, a broader range of treatment options is now available, allowing for more personalized and effective care. Even in cases of liver metastasis, a multidisciplinary approach combining systemic therapies and localized treatments can significantly extend survival and improve quality of life for patients with neuroendocrine tumors.