Resectability of Pancreatic Neuroendocrine vs Exocrine Tumors with Liver Metastasis
Yes, this statement is fundamentally true: pancreatic neuroendocrine tumors (PNETs) with liver metastases can be resectable with curative intent and excellent long-term survival, whereas pancreatic exocrine adenocarcinomas with liver metastases are considered stage IV disease and are not candidates for curative resection. 1, 2
Key Distinction in Treatment Philosophy
Pancreatic Neuroendocrine Tumors with Liver Metastases
The National Comprehensive Cancer Network explicitly recommends surgical resection of both the primary tumor and liver metastases for patients with pancreatic neuroendocrine tumors and liver metastases, achieving a 10-year overall survival rate of 50.4% and 5-year survival ranging from 41% to 100%. 1
Curative resection (R0, R1) of gastroenteropancreatic neuroendocrine tumors with liver metastases is associated with a 5-year overall survival rate of around 85%. 3
For resectable disease, surgical excision of both primary and liver metastases should be performed either in staged or synchronous fashion with curative intent. 1, 4
When performing staged procedures, hepatectomy should be done before pancreatic resection to reduce risk of perihepatic sepsis from the contaminated biliary tree. 1
Pancreatic Exocrine Adenocarcinoma with Liver Metastases
Pancreatic adenocarcinoma with liver metastases is universally considered metastatic stage IV disease and is not a candidate for surgical resection with curative intent. 2
The American Society of Clinical Oncology emphasizes the critical importance of distinguishing tumor histology, as pancreatic NETs have dramatically better outcomes than adenocarcinoma and warrant aggressive surgical approaches. 2
High-grade (G3) pancreatic neuroendocrine carcinomas are also generally not operated on, as these tumors are widely metastasized at the time of diagnosis and behave more like adenocarcinomas. 3
Evidence Supporting Aggressive Surgery for PNETs with Liver Metastases
Survival Benefits
Meta-analysis of 2,849 patients demonstrated that palliative resection of the primary tumor in patients with PNETs and unresectable liver metastases significantly increased survival (pooled hazard ratio 0.36,95% CI: 0.30-0.45, P<0.001). 5
In a single-center series, patients with PNETs and unresectable liver metastases who underwent primary tumor resection had 5-year disease-specific survival of 82% compared to 50% in nonoperated patients (P=0.027). 6
At multivariate analysis, patients with primary tumor removed had improved survival (hazard ratio 0.18; 95% CI 0.05-0.66; P=0.010). 6
Indications for Cytoreductive Surgery
Cytoreductive surgery should be considered when metastatic disease is localized or if >70% of tumor load is thought resectable, which may decrease endocrine and local symptoms and might help to improve systemic treatment. 3
Debulking surgery is recommended for alleviating symptoms of carcinoid syndrome in patients affected by metastatic functioning small intestinal NETs. 3
Patients with high tumor burden of functioning pancreatic NETs may benefit from debulking surgery (e.g., insulinoma, VIPoma), and surgery is generally recommended for this indication. 3
Important Caveats and Selection Bias
A critical caveat is that preselection biases due to better performance status or less advanced disease are likely to influence these favorable survival results. 3
Patients who underwent aggressive surgical approaches appeared to have better baseline characteristics, including less advanced disease and better performance status. 5
GEP-NET liver metastases are frequently more extensive than those which are identified, even intraoperatively, and a real curative resection is difficult to achieve. 3
The potential advantage of palliative surgery, either primary tumor resection or debulking surgery in advanced GEP-NETs, is controversial in terms of survival and underlies the bias of preselection of better prognosis patients for surgery. 3
Prognostic Factors Affecting Surgical Candidacy
Favorable Prognostic Factors for Surgery
Well-differentiated low-grade (G1) tumors with mitotic count <2/10 HPF and Ki-67 <3% are associated with favorable prognosis. 1
Lower hepatic tumor burden (<25% liver involvement) is associated with better outcomes. 1, 6
Younger age and better performance status predict improved survival. 6
Contraindications to Aggressive Surgery
High-grade (G3) tumors with mitotic count >20/10 HPF and Ki-67 >20% are associated with poor prognosis and are generally not candidates for aggressive surgical resection. 3, 1
The need for palliative resection of nonfunctioning pancreatic NETs is debated in patients with Ki-67 >10%. 3
Declining performance status and cachexia are associated with poor prognosis and may preclude surgery. 1
Alternative Treatment Options for Unresectable Disease
Locoregional Therapies
In patients with liver metastases who are ineligible for complete surgical resection, vascular and ablative locoregional modalities can be considered as an alternative to surgery. 3
Radiofrequency ablation in tumors <5 cm in size has shown 70%-80% symptomatic responses with control of symptoms up to 1 year. 3
Selective hepatic transcatheter arterial embolization or chemoembolization can be applied in the treatment of liver metastases from all types of neuroendocrine G1/G2 tumors, with complete or partial response for symptoms occurring in 70%-100% of patients. 3
Liver Transplantation
Liver transplantation may be a valid option in very selected patients with unresectable liver metastases when the following criteria are met: absence of extrahepatic disease, histological confirmation of well-differentiated (G1/G2, Ki-67 <10%) NET, previous removal of primary tumor, metastatic diffusion <50% of total liver volume, stable disease in response to therapy for at least 6 months before transplant consideration, and age <60 years. 3
In these highly selected patients with good baseline prognostic factors, a 5-year overall survival of 69%-97.2% has been reported. 3
Systemic Therapy
Lanreotide or octreotide are recommended as first-line systemic therapy options for patients with hormone-related symptoms, with lanreotide demonstrating improved progression-free survival in the CLARINET study. 1
Everolimus is recommended as a biologically targeted agent, administered at 10 mg orally once daily, with a median progression-free survival of 11.0 months. 1
Sunitinib is also recommended as a biologically targeted agent, administered at 37.5 mg orally once daily, with a median progression-free survival of 11.4 months. 1