Treatment of Metastatic Neuroendocrine Tumors 

Patients with metastases from a neuroendocrine cancer may become symptomatic from hormone hypersecretion, rather than from tumor bulk. Approximately 10 to 30 percent of pancreatic neuroendocrine tumors secrete hormones that can result in clinical syndromes.  In particular, patients with small bowel or appendiceal carcinoid tumors may develop carcinoid syndrome, typically after development of hepatic metastases that allow entry of vasoactive substances such as serotonin into the systemic circulation.

Patient’s symptomatology from hormonal excess may be well controlled with the use of somatostatin analogs such as octreotide.  Cytotoxic chemotherapy and molecularly targeted therapies can be used to inhibit tumor growth.  In patients with GI and pancreatic neuroendocrine tumors, there is emerging evidence for use of VEGF inhibitors such as bevacizumab, tyrosine kinase inhibitors including sunitinib, and the mTOR inhibitor everolimus. In patients with limited metastases, local options may be considered.

Options for treatment of neuroendocrine tumors metastatic to the liver

Surgical resection

Neuroendocrine cancers are one of a small number of tumors for which surgical debulking confers some survival advantage. Cytoreductive surgery, a mainstay in the management of widely metastatic disease, aims to control symptoms and improve survival by removing or destroying disseminated tumor metastases. In addition, the often-crippling symptoms associated with many of these tumors may be eased by decreasing tumor load. In a series of patients with unresectable disease who underwent surgical debulking, 50% of patients reported an improvement in symptoms for a mean duration of 39 months. Several reports have demonstrated for both pancreatic neuroendocrine and carcinoid tumors that palliative surgery elicited a hormonal response in virtually all patients, with decreased pain in 90% of patients. This symptomatic improvement is especially important for patients with no medical options for managing their disease, such as the necrolytic migratory erythema of glucagonoma. Aggressive resection of hepatic metastatic disease seems to be associated with improved overall survival although this conclusion is not based on any randomized trials. Several centers report that the 5-year survival for patients treated with hepatic resection is around 70-80%. Most recommend considering hepatic resection if more than 90% of the tumor can be excised and less than 75% of the liver is involved.

Hepatic artery embolization

The therapy of hepatic artery embolization (HAE) is predicated on the anatomical observation that most tumors within the hepatic parenchyma receive the bulk of their blood supply from the hepatic artery, whereas the portal vein supplies most of the normal hepatic parenchyma. Chemoembolization involves infusion of vaso-occlusive material into the hepatic artery to reduce blood supply to the tumor along with an infusion of high dose chemotherapy. Coils, gelfoam, polyvinyl alcohol, and iodinated oil have been used to embolize arteries with the addition of doxorubicin, cisplatin, mitomycin C, streptozocin, and 5-fluorouracil. None of these combinations has produced significantly superior results. Contraindications to this procedure include tumor composing more than 50% of the hepatic volume, bilirubin greater than 2.0, AST greater than 100, or portal vein thrombosis. Multiple studies have shown reductions in hormonal levels in greater than 90% of patients. Unfortunately, these responses have lasted for little more than a year. Complication rates can approach 20%.

Radiofrequency ablation

RFA provides a novel approach for those with limited hepatic involvement by utilizing selective thermal coagulation of tumor to destroy isolated metastases. In a retrospective study of patients with metastatic carcinoid and neuroendocrine pancreatic tumors, the investigators reported clearance of tumor in 17%-46% of patients. Likewise, symptom improvement was noted in 71% patients with carcinoid syndrome, and 75% also reduced their 5-HIAA and CgA by at least 50%. Similarly, though data in hepatic neuroendocrine metastases are limited to small series, several studies have demonstrated the effectiveness of RFA in the treatment of unresectable hepatocellular carcinomas and hepatic metastases of colon carcinoma.

Liver transplantation

Hepatic metastases from malignant neuroendocrine tumors have been evaluated as an indication for liver transplantation. In one of the largest series of neuroendocrine tumors, 103 patients received liver transplants. Two and five-year survival was 60% and 47% respectively. Disease-free survival was 60% at one year and 23% at three years. Favorable prognostic factors included age less than 50 years old, lung or bowel primary tumor, and pre-transplant treatment with somatostatin analogues.

Carcinoid syndrome and carcinoid heart disease

The term “carcinoid syndrome” refers to a constellation of symptoms mediated by various humoral factors, namely serotonin and the tachykinins, which are elaborated by carcinoid tumors. In the presence of localized disease, carcinoid neoplasms produce 5-hydroxytryptamine, which is taken up and stored in the platelets while the excesses are inactivated from the liver and lung and transformed into 5-hydroxyindoleacetic acid (5-HIAA). In the presence of liver metastases, however, patients may develop the malignant carcinoid syndrome, which results when vasoactive substances produced by the carcinoid tumor escape hepatic degradation and gain access into the systemic circulation. It is also due to high level of 5-HT degradation by the liver.  It is relatively uncommon for disease localized to the gut to display symptoms of serotonin secretion. Clinical findings of the carcinoid syndrome include skin flushing, excessive diarrhea, right-sided heart disease, and bronchoconstriction.

Nearly 40% of patients exhibiting carcinoid syndrome will develop carcinoid heart disease (CHD) with fibrotic endocardial plaques and associated heart valve dysfunction that classically involves the tricuspid valve. Advanced changes of tricuspid valvular disease have been associated with poor long-term survival, and carcinoid valvular disease, rather than tumor dissemination, is the cause of death in approximately one-third of these patients. Serotonin is presumed to be the catalyst for the cardiac fibrotic process. Nearly 95% of patients present with right-sided heart valve disease, characterized by tricuspid insufficiency and pulmonary stenosis and the subsequent development of pulmonary hypertension. Left-sided cardiac disease may be seen in up to 10% of patients, as is commonly associated with angina and coronary vasospasm.

Treatment of metastatic disease elsewhere in the body

Chemotherapy

Besides somatostatin analogues, common chemotherapeutic options for metastatic neuroendocrine cancers include interferon alpha and cytotoxic agents. Interferon alpha has been shown to inhibit protein and hormone synthesis in tumor cells, inhibit angiogenesis, and stimulate the immune system. Additionally, interferon alpha upregulates the expression of somatostatin receptors and may therefore act synergistically with somatostatin analogues in the treatment of classic carcinoid syndrome.

Cytotoxic agents are typically employed as first-line treatments for malignant neuroendocrine tumors with elevated proliferation indices (Ki-67 antibody >5-10%). Traditionally, single-agent cytotoxic treatments have produced limited benefit in patients with neuroendocrine cancers, with response rates of less than 30%. Therefore, combination therapies, such as streptozocin, 5-FU, and doxorubicin, are commonly utilized in the treatment algorithms of highly proliferating neuroendocrine tumors.  This combination has been found to elicit a response rate in excess of 50% in malignant pancreatic tumors.

Radiolabeled Somatostatin Analogues

In recent years, several research groups in nuclear medicine and radiopharmacy have sought to develop radiolabelled receptor-binding somatostatin analogues which act as vehicles to guide radioactivity to somatostatin receptor (SSTR)-expressing tissues, such as carcinoid metastases. The first promising dodecanetetraacetic acid-chelated somatostatin analogue is 90Y-1,4,7,10-tetraazacyclododecane-N,N’,N”,N'”-tetraacetic acid (DOTA)0, Tyr3, octreotide (90Y-DOTATOC). This molecule couples a radiolabelled somatostatin analogue with 90Y, a pure ß-emitter. In a phase II study to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 90Y-DOTATOC, the study authors demonstrated an objective response rate of 38% and a significant reduction in clinical symptoms. More recently, treatment with 177Lu-DOTA0, Tyr3octreotate (177Lu-DOTATATE), a compound with greater SSTR-2 affinity, has been shown to effect complete or partial tumor responses in nearly 30% of patients with neuroendocrine disease. Importantly, 90Y-DOTATOC seems to more effective in larger tumors while 177Lu-DOTATATE effects improved tumor response in smaller lesions; as such, combination therapies utilizing both 90Y-DOTATOC and 177Lu-DOTATATE are currently being explored.

Future therapeutic options including molecular targeting

The growth, differentiation, phenotype, and hormonal expression of carcinoid tumors depend upon a network of cellular signaling cascades. Several pathways and individual molecules have been implicated in the tumorigenesis of carcinoids and are currently under evaluation. Novel agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have demonstrated promising activity in patients with advanced neuroendocrine tumors. Inhibition of angiogenesis by targeting VEGF is especially promising, given the highly vascular nature of neuroendocrine tumors. Recent data suggest the importance of alternative pathways, which include alterations in raf-1/MEK/ERK, Notch, and glycogen synthase kinase-3ß.