Metastatic disease

Patients with malignat pancreatic neuroendocrine neoplasms ofter present with liver metastases. Unlike liver metastases from other tumors that rapidly lead to liver failure, liver metastases from neuroendocrine neoplasms are generally slow growing. The management of liver metastases is multimodal, and involves a combination of more than one method of treatment.

All liver metastases from pancreatic neuroendocrine neoplasms should be evaluated for possible complete surgical removal (R0/R1resection, without macroscopic tumor residual). The minimal requirements for resection with curative intent are the presence of well-differentiated (G1/G2) resectable liver disease, the absence of severe comorbidities, absence of unresectable lymph node and peritoneal carcinomatosis, and the absence of extra-abdominal metastases. Resection of metastases of G3 neoplasms is in general not recommended. The type of surgical resection is related to the patient’s general condition, the number and location of liver metastases, the complexity of the liver resection, and the estimation of the future remnant liver parenchyma volume. One- and two-step procedures may be undertaken, depending upon whether the liver disease is unilobar or complex. Extended liver resections can safely remove 65–70% of the whole liver volume. Because of these limitations, only 20% of patients with liver metastases will undergo curative resection.

Debulking resections (R2 resections, with macrosopic tumor residual) can be justified in palliative situations to reduce the disease burden. Removal of approximately 90% of the tumor volume is recommended, but lower percentage may be considered in refractory functioning NET ). Debulking resections should be carried out as part of a multimodal strategy that includes loco-regional ablation techniques.

Resection of the pancreatic tumor in patients with synchronous unresectable liver metastases has been proposed in selected cases to relieve symptoms caused by the primary tumor (e.g. jaundice). The few studies available showed a potential survival benefit.

Liver transplantation may be a therapy options in a very small subset of patients (1%). This option may be proposed to patients suffering from severe hormonal syndromes refractory to medical therapy, or to patients with non-functional tumors with diffuse unresectable liver metastases refractory to all other available treatments. Minimal requirements for consideration of liver transplantation are the following criteria: well-differentiated neoplasm (G1/G2), absence of extrahepatic disease, pancreatic tumor removed prior to transplantation, stable disease for at least one year. The efficacy of this procedure remains controversial, and a long-term disease-free survival by transplantation will be an exceptional event even in this highly selected subgroup.

Locoregional ablation therapies are interventional palliative procedures that take advantage of different energies to treat large, multiple unresectable liver metastases. These procedures can be combined or can be used in association with debulking surgery. Here is a list of the ablation techniques used for liver metastases from pancreatic neuroendocrine neoplasms: 

Trans-arterial embolization (TAE or “bland embolization”): In this procedure, selective occlusion of hepatic artery branches is carried out using Lipiodol and microspheres. Hepatic artery branches are reached via an angiography-guided catheter.

Trans-arterial chemoembolization (TACE): TACE combines embolization with chemotherapy. This is done by giving chemotherapy (dacarbazin, doxorubicin, mytomicin C) through an angiography-guided catheter directly into the hepatic artery branches, then plugging up the artery with Lipiodol and microspheres. 

Radiofrequency ablation (RFA): This procedure uses high-energy radio waves for treatment. A thin, needle-like probe is inserted percutaneously and into the tumor, guiding it into place with ultrasound. A high-frequency current is then passed through the tip of the probe, which heats the tumor and destroys the cancer cells by coagulative necrosis.

Locoregional ablation therapies can achieve local control of liver metastases, but it is uncleat whether they are associated with a time-to-progression or survival benefit. The choice of the ablative locoregional procedure depends on the local expertise, extension and location of liver involvement.
 
Peptide receptor radionuclide therapy (PRRT): PPRT combines somatostatin analogues (octreotide) with a radionuclide to form molecules called radiolabeled somatostatin analogues. These radiopeptides are injected and bind to neuroendocrine neoplastic cells, that have receptors for them. Once bound, radiopeptides emit radiation and kill the tumor cells they are bound to. The two radionuclides that are attached to octreotide to create radiopeptides are yttrium-90 (90Y-DOTA-TOC) and lutetium-177 (177Lu-DOTA-TATE). This type of therapy can be applied only to individuals whose tumors express somatostatin receptors (as shown by OCTREOSCAN™ or 68-Ga-DOTA-TATE PET-CT) to induce tumor remission.
 
Somatostatin analogues (octreotide and lanreotide): These have been the most widely used medications to treat well differentiated metastatic disease (G1) expressing somatostatin receptors on OCTREOSCAN™ or 68-Ga-DOTA-TATE PET-CT. Somatostatin analogues can be also used to relieve hormonal syndrome in funtional neoplasms other than insulinoma. These drugs can be injected once a month (long-acting repeatable or LAR).
 
Chemotherapy: It is mostly used in aggressive liver metastases (G2/G3), or when tumor progression occurs after somatostatin analogues administration. Different chemotherapy agents have been tested (in monotherapy or combined therapy), including capecitabine, temozolomide, doxorubicin, streptozotocin, 5-fluorouracil, dacarbazin, etoposide, cisplatin, oxaliplatin, and carboplatin.
 
Targeted therapy: Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to normal cells. Everolimus targets mTOR protein, that regulates angiogenesis, proliferation, and tumor cell metabolism. Sunitinib malate blocks tyrosine-kinase receptors and inhibits angiogenesis and cell proliferation. Everolimus and Sunitinib can be used in progressive disease, in combination with somatostatin analogues. Recent randomized clinical trials demonstrated that targeted therapy significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors. Side effects, however, may be frequent.
 
Given the wide array of palliative therapy available, and the limited evidence in favor of one or another strategy, optimization of diverse management strategies is best achieved by multidisciplinary assessment and consensus-based therapy.