Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors that form a distinct entity. Approximately 75–80% of patients present with liver metastases at the time of their diagnosis, and 20%–25% will develop these lesions in the course of their disease. The presence of secondary deposits in the liver significantly increases the morbidity and mortality in these patients. The only potentially curative treatment is the surgical resection of the primary tumor and hepatic lesions. However, only 10% of patients presents under ideal conditions for that approach. Several techniques aimed at localized liver lesions have been applied also with interesting results in terms of survival and symptom control. The same has been demonstrated with new systemic therapies (target therapies). However, these are still under study, in order to define their true role in the management of these patients. This paper intends to address, in a general way, the various treatment options in patients with liver metastases from neuroendocrine tumors.
The neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that share some biological characteristics, that have been addressed as a common entity [
The latest figures from the UK, Sweden, and Switzerland suggested that their incidence is 2-3/100000 with a higher prevalence in females [
NETs are classically characterized by their ability to secrete hormones and/or vasoactive peptides, which results in many of their clinical manifestations, ganging up on specific hormonal syndromes. The most frequent syndrome is the carcinoid syndrome, which results from the secretion of serotonin and includes symptoms such as skin flushing, severe diarrhea, abdominal cramping, and electrolyte abnormalities [
The liver is the most important place of metastatic disease [
Patients with liver metastases have a worsening of their morbidity and mortality, as compared to patients without these lesions. According to Touzios et al. [
Patients with NETs often develop liver metastases (NLMs) affecting significantly their morbidity and mortality. About 75%–80% of patients present with hepatic metastasis at the time of diagnosis (synchronous), while 20%–25% develop secondary lesions in the course of their illness (metachronous) [
The presence of liver metastases is closely related to the appearance/aggravation of symptoms. Many peptides and hormones are metabolized in liver. The presence of hepatic metastases leads to less metabolization of these peptides leading to an increase of their circulating levels. Sometimes, only then, the complete disease phenotype is present. Consequently, the symptomatic control is an essential aspect of the treatment of NLMs [
Hepatic involvement is an important prognostic factor, despite the primary site of tumor. Its distribution, in the way it modifies therapeutic management, reflects the aggressiveness of the tumor. Liver metastases are divided into 3 types according to the localization. Type I metastases are lesions only confined to one hepatic lobe or limited to two adjacent segments, corresponding to about 20%–25% of cases. Type II metastases include the presence of dominant injury with small satellites contralateral (10%–15% of cases). Type III metastases correspond to diffuse multifocal, being the most prevalent being (60%–70% cases). Because of the possibility of surgical resection, type I is associated with a favorable outcome. Type III metastases have a worse prognosis regarding the greater liver involvement and the lack of surgical approach. In this group of patients, liver transplantation can be considered a form of treatment [
Surgery consistently proved its superiority in relation to nonsurgical therapies. However, the complete excision of secondary lesions is only an option for a small number of patients (10%–20%) [
Therapeutic options for patients without surgical indication have been improved in the latest years [
The surgical resection is the only potentially curative treatment in NETs. Curative intention depends on the stage and presentation of the disease [
Regarding the criteria for selecting patients with NLMs, there is no consensus, since the several studies developed included a small number of patients and different surgical procedures. However, when the complete excision of a significant number of liver metastasis is possible, surgery must always be considered. In a recent retrospective study, 74 cases were analyzed and the 5-year survival rate was more than 60% in all patients who underwent surgical resection of liver metastases. In 65% of these patients, excision was incomplete, and there was no worsening of the prognosis [
Translating these results into clinical practice, in 2008, the European Neuroendocrine Tumor Society (ENETS) issued general guidelines for surgical resection based on the three types of liver involvement. For patients with hepatic involvement of type I surgical resection is the first therapeutic option, while in patients with the involvement of type III it is totally excluded [
The presence of abdominal lymph node involvement, including local recurrence, is not an absolute contraindication for surgery, if the excision of lymph nodes and liver metastases and/or recurrent lesions could be done simultaneously or in planned staggered phases [
Recurrence after resection is common with the 5-year recurrence rate being greater than 97%. Therefore, surgical resection should be as radical as possible. Extensive lymphadenectomy and a careful exploration of the entire abdominal cavity should be carried out during surgical procedure [
Cytoreductive surgery may be useful for a small and restricted group of patients. It is usually recommended in cases where more than 90% of the tumor can be excised or in young patients [
Liver transplantation is a therapeutic approach with an intention to cure, to prolong survival or control of carcinoid symptoms. Liver transplantation is only indicated in cases of metastatic disease if the primary tumor is an NET [
Regarding biomarkers analyses and their correlation with transplant outcome, the authors found that patients with a low Ki-67 and normal expression of E-cadherin had a more favorable prognosis. On the other hand, p53 status had no influence on prognosis [
In patients with diffuse and unresectable liver disease, with uncontrolled symptoms (resistant to medical therapy support), liver transplantation should be considered and may be an option in carefully selected patients [
Patients with NET tumors can be selected to treatment with different types of ablative techniques such as cryoablation, alcohol ablation (these two are less used), and radiofrequency ablation (RFA).
Cryoablation is the most studied thermoablation technique [
Alcohol ablation also known as percutaneous alcohol injection (PAI) has already been studied in different series [
RFA consists in intense heat production from radiofrequency waves through alternating electric current and can be performed by percutaneous or laparoscopic approach [
The largest clinical study until involving patients with hepatic lesions treated with RFA was reported by the Cleveland Clinic. Eighty-nine patients were followed and submitted to a total of 119 laparoscopic RFAs. Results showed that about 90% of the patients experienced immediate relief of symptoms after the procedure, with a mean progression-free survival of 1.3 years. From these 89 patients, 22% had recurrence, and from these 22% recurrences, 63% corresponded to new liver lesions and 59% to extrahepatic disease [
An important limitation of the effectiveness of this technique is the size of the tumor. It seems to be difficult to totally eradicate lesions greater than 3 cm, and lesions greater than 5 cm are unsuitable for RFA, as demonstrated by Mazzagalia et al. [
RFA is a procedure with low morbidity (5%–12%) and low 30-day mortality (0%-1%) [
Hepatic artery embolization (HAE) and hepatic artery chemoembolization (HACE) are two different technics that can also be used in the treatment of liver metastasis. Hepatic arterial embolization is frequently applied as a palliative technique in patients with hepatic-predominant metastatic NET who are not candidates for surgical resection. It is based on the principle that tumors in the liver derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive most of their blood supply from the portal vein.
Using this technic, we can block blood supply with nutrients and oxygen to the tumor with consequent ischemia/necrosis [
Both HAE and HACE are palliative techniques used in patients with unresectable lesions, with diffuse and progressive liver disease, with symptoms not controlled with medical treatment and without impaired liver function [
These therapies have proved to be a valuable option, particularly in patients with more than 75% of hepatic involvement, carefully selected, without additional risk factors [
Just as in other therapeutic procedures might exist associated complications, sometimes severe. Sepsis, liver and renal failure, carcinoid crisis, necrotizing cholecystitis, and peptic ulcer bleeding have been reported in about 7.5 to 23.8% of patients. The most frequent is the postembolization syndrome (i.e., fever, abdominal pain, leukocytosis, increased transaminases, and bilirubin), which occurs in 90% of patients, in most cases self-limited (24–72 hours of duration) [
External radiation therapy has limited value in NETs, being only indicated in the presence of symptomatic brain and bone metastases [
Saxena et al. [
Complications such as postembolization syndrome are common, with a small risk of radiation gastritis and ulceration [
More studies are needed to realize the best use of this treatment.
Since NETs are a rare pathology, large randomized studies in patients with NLMs are difficult to perform. This limitation leads to an overall assessment of restricted systemic therapies that cannot be translated in to a consensual treatment algorithm. However, the data obtained from a single center study showed that the aggressive medical treatment of NLMs instead of surgical therapy increases the 3-year survival rate to 76.4% and the 5-year survival rate to 63.9%. Therefore, conservative treatment, that is, “wait and watch,” is no longer accepted [
The majority of NETs is expressed on the surface of their cells somatostatin receptors (SSTR 1–5). Their activation inhibits the secretion of peptides and amines by tumor cells and also the effect of tumor growth factors inducing apoptosis [
The main use of SSA is in symptomatic control. In an initial study, the subcutaneous administration of octreotide at the dose of 150 mg TID improved symptoms, especially carcinoid syndrome, in 88% of patients [
In more recent years, there has been evidence that SSA can have antitumor activity and also be able to reduce tumor growth by direct action on somatostatin receptors. It is even possible that specific receptors can induce apoptosis [
Severe adverse events with SSA therapy are infrequent. However, nausea, vomiting, diarrhea, steatorrhea, cardiac abnormalities, arrhythmias, hypothyroidism, and hypoglycemia were reported in different percentages [
Interferon is an immunomodulator that inhibits the production of several growth factors and also has antiangiogenic properties. When used in NET’s treatment these agents seem to have an additional activity which is the hyperregulation of somatostatin receptors [
In some clinical studies, treatment with INF-
PRRT is a therapeutic option with particular advantages in patients with a symptomatic disease and tumors with positive somatostatin receptors, not candidates for surgery. This technique uses a radioactive peptide bound to SSA, which after the interaction with the receptor is internalized, releasing specific and localized radioactivity, allowing a precise destruction of tumor cells [
Scintigraphy with somatostatin can predict the efficacy of PRRT as with the SSA. Low uptake indicates 20% of the possibility of the effect on liver metastasis, and high uptake indicates the possibility of 60% effectiveness [
NETs sensitivity to cytotoxic therapy appears to have correlation with the primary location of the tumor and tumor grade [
Dacarbazine is another cytostatic agent with proof of effectiveness in pancreatic NETs, with a response rate of 34% in phase II study [
Platinum based chemotherapy may be useful in patients with high grade undifferentiated tumors and with liver metastases. In these patients, chemotherapy is the first line treatment. Response rate was 42%–80% using cisplatin and etoposide and 78% with combination of oxaliplatin [
Although chemotherapy could be used as rescue treatment, it is not considered the first line of the nonsurgical treatment. Furthermore, the presence of liver metastases is associated with a poor response compared to NETs without liver metastasis [
Conventional chemotherapeutic agents have limited efficacy in metastasized NETs. Despite positive results in some way to the little differentiated carcinomas and primary for the pancreas in relation to other locations, overall response rates are low and the impact on survival is small [
NETs are highly vascular tumors that express on their cell surface vascular endothelial growth factor (VEGF) receptors. Tumor progression seems to be associated with high levels of circulating VEGF, making this possible therapeutic target, such as in other neoplasms [
Bevacizumab (a monoclonal antibody), sunitinib, sorafenib, and pazopanib (tyrosine kinase inhibitors) have been the most studied drugs in pancreatic NETs [
Bevacizumab was introduced in a randomized clinical study with patients being treated with SSA and bevacizumab compared to the combined therapy with Peg INF-
Sunitinib has been the most studied agent. Based on positive results from phase II studies, sunitinib was tested in a double-blind phase III study in patients with well-differentiated and progressive pancreatic NET compared with placebo. The primary endpoint (progression-free survival) was statistically higher among patients with sunitinib (11.4 months compared with 5.5 months in the placebo group). Also positive was the objective response rate of 9.3%, with stabilization of the disease in 63% of patients [
Algorithm treatment in patients with neuroendocrine tumors and hepatic metastases (adapted from [
The mTOR pathway is of great importance since it interferes with the control of cell growth, apoptosis, and protein synthesis. The presence of mTOR pathway abnormalities is acknowledged in NETs, and these abnormalities are also believed to be in part responsible for the development of these tumors. Two mTOR inhibitors have been studied in pancreatic NETs, Temsirolimus, and Everolimus [
In a phase II clinical study with Everolimus has demonstrated a response rate of 9.6% and stabilization of the disease in 67.8% of patients [
The NETs frequently metastasize to the liver, and the presence of liver metastases worsens the prognosis of patients, increasing morbidity and mortality. Different therapeutic options have been developed for the management of patients with NLMs. Surgery resection remains the gold standard, especially in well-differentiated resectable lesions and also improves symptomatic control in selected cases.
Other liver-directed methods are also advantageous, especially in the presence of predominantly liver disease. In addition, they can be combined with each other and with surgery and systemic therapeutic, allowing a greater range of treatment and increased overall survival and progression-free survival. Those modalities include the RFA, in situations of localized liver damage up to 3 cm of diameter, and HACE, in the case of diffuse liver disease
Systemic therapy is important in controlling symptoms, particularly in carcinoid tumors, with the SSA. For those patients who are not candidates to surgery, SSA can also offer control of disease progression in low grade NET. These agents remain the core of medical therapy for metastatic carcinoid tumors.
In pNETs and particularly in high grade NETs with liver metastases, chemotherapy has a substantial role.
More recently, the inhibitors of the mTOR pathway and VEGF pathway has been shown very promising in controlling disease progression in pNETs. It is not known their role in high grade tumors and whenever necessary they can be used together with SSA.
There are still some questions that need to be addressed in future studies. For instance, the prevention of tumor progression is one of the main investigating areas. In this area, the role of LAR octreotide (in advanced tumors other than small intestine), lanreotide (investigation is already ongoing in nonfunctioning NET), and pasireotide (SOM230 in NETs from all sites of origin) is being evaluated. The use of everolimus and sunitinib in early stage tumors is another interesting issue, and its role in tumor progression prevention is still to be defined.
Physicians and NET patients are also waiting for guidelines that acknowledge the best treatment approach for patients with grade 3 tumors from any origin and site. The combination of small molecule inhibitors and chemotherapy could be an option.
The combination of molecular target therapy and chemotherapy, namely, SSA plus chemotherapy, temozolamide and everolimus or temozolamide, and sunitinib in pNET patients should also be addressed in clinical trials.
T. Amaral works as a Medical Consultant for INFARMED-Autoridade Nacional do Medicamento e produtos de Saúde., IP, National Authority of Medicines and Health Products, I.P. L. Costa has received honoraria and research Grants from Novartis and Amgen and has received speaker fees from Novartis and Amgen. The other authors have no disclosures to report.