Pancreatic NETs: Current Challenges and Advances

Interview With Eric Van Cutsem, MD, PhD

Shira Berman; Eric Van Cutsem, MD, PhD

Disclosures

October 06, 2011

Editor's note:

Neuroendocrine tumors (NETs) are rare cancers that can arise in a number of different organs, particularly the gastrointestinal tract, lungs, and pancreas. The clinical course of these tumors can vary widely, making them difficult to diagnose, but research into the pathogenesis of pancreatic NETs (pNETs), in particular, has led to important advances in the diagnosis and management of this challenging tumor type. This cancer, which Steve Jobs was diagnosed as having in 2004 and from which he died on October 5, 2011, is often confused with the more aggressive pancreatic cancer, which took the lives of celebrities Patrick Swayze, Luciano Pavarotti, Michael Landon, and Jack Benny. pNETs grow more slowly than typical pancreatic cancer.

In May 2011, sunitinib and everolimus were approved by the US Food and Drug Association (FDA) for the treatment of progressive, well-differentiated pNETs in patients with unresectable locally advanced or metastatic disease. The approval of these agents represents an important step in the use of targeted therapies for pNETs.

In an interview with Medscape, Eric Van Cutsem, MD, PhD, Head of the Division of Digestive Oncology and Professor of Medicine at the University Hospital Gasthuisberg in Leuven, Belgium, reviewed some of the current challenges in the diagnosis and management of pNETs and how advances in research might affect clinical practice.

Medscape: Why are pNETs often so difficult to diagnose?

Dr. Van Cutsem: pNETs are rare but increasingly common tumors that have a varied clinical course.

In general, NETs can be classified as functional or nonfunctional. Functional tumors actively secrete hormones and produce symptoms related to these excess hormonal secretions. For example, VIPomas, which secrete vasoactive intestinal peptide (VIP), result in profound secretory diarrhea and electrolyte imbalances, while insulinomas result in elevated levels of insulin despite low levels of blood glucose. Functional pNETs are therefore diagnosed through the use of assays measuring, for example, levels of serum insulin, gastrin, or VIP for patients with suspected insulinomas, gastrinomas, or VIPomas, respectively, or urinary 5-HIAA for patients with carcinoid syndrome, which are often localized in the small bowel.[1,2] Although physicians might not initially suspect NET in a patient with these symptoms, their presence makes these tumors somewhat easier to diagnose and assess.

However, only a minority of pNETs are functional. Most are nonfunctional tumors and do not produce hormones that cause symptoms. The lack of these symptoms can make these nonfunctional tumors even more difficult to diagnose. The majority are diagnosed after already metastasizing to the liver and are typically found incidentally on imaging studies or upon presentation with symptoms related to advanced disease, such as abdominal pain, anorexia, or weight loss.[1]

Although nonfunctional pNETs do not secrete active hormones, both functional and nonfunctional pNETs commonly express serum chromogranin A (CgA) and somatostatin. Somatostatin scintigraphy, or octreotide scan, is used to identify pNETs and somatostatin analogues are typically used for symptom control in patients with functional tumors. CgA serves as the best biomarker of disease activity, as its levels often correlate with disease burden.[1,2]

Medscape: Once a diagnosis is made, how should clinicians approach treatment?

Figure.

Approach to the diagnosis and management of pancreatic adenocarcinoma. EUS, endoscopic ultrasound. Courtesy of Tyler Stevens, MD

Dr. Van Cutsem: An important aspect in the treatment of pNETs is predicting the aggressiveness and the likely evolution of the disease. Indolent pNETs are typically distinguished by a lower Ki-67 proliferation index and good differentiation on histology. Rapidly progressing pNETs are typically poorly differentiated and show a higher Ki-67 proliferation index.[3] Tumors that are poorly differentiated and those with a higher Ki-67 proliferation index are at greater risk for disease progression and have a poorer prognosis.[3,4]

Surgery plays an important role in the management of all pNETs, even if it cannot be curative. Debulking surgery, possibly including resection of isolated liver metastases, can improve outcomes.[2] If surgery is not curative, medical therapy is warranted.

Unlike nonpancreatic NETs, pNETs tend to be chemosensitive. The combination of streptozocin plus 5-flurorouracil or doxorubicin shows response rates of 30%-40% and a 2-year overall survival rate greater than 70% in patients with moderately or well-differentiated pNETs.[5] Results from a recent small phase 2 study in a similar population showed promising results of the combination of temozolomide and capecitabine, with an objective response in 70% of patients and a 2-year overall survival rate of 92%.[6]

Patients with functional pNETs often benefit from a somatostatin analogue, such as long-acting octreotide and lanreotide. These drugs can reduce symptoms and slow disease progression in patients with functional pNETs. Their benefit in nonfunctional pNETs is somewhat less clear, but they are frequently used to slow down tumor progression.[2] Patients with functional pNETs and hepatic metastases can undergo localized liver-directed therapies, such as hepatic artery embolization or chemoembolization; the potential benefit of liver transplantation remains unclear.[2]

The mTOR inhibitor everolimus and the tyrosine kinase inhibitor sunitinib are 2 new options for patients with functional or nonfunctional advanced, well-differentiated pNETs. Phase 3 data on both agents published in The New England Journal of Medicine showed a clear benefit with each drug over placebo. Patients treated with sunitinib showed a median progression-free survival of 11.4 months vs 5.5 months for those on placebo, and the median progression-free survival was 11.0 months for those treated with everolimus vs 4.6 months for those on placebo.[7,8]

There are no biomarkers that can identify which patients might benefit from sunitinib vs everolimus. However, the side-effect profile is somewhat different, which might help physicians decide which treatment to select. Specifically, neutropenia, fatigue, and hypertension were more common with sunitinib, while diarrhea, stomatitis, and hyperglycemia were more common with everolimus.

Medscape: What are the next steps in research for pNETs?

Dr. Van Cutsem: Research is moving in a few important directions. Identifying and validating predictive and prognostic biomarkers will play an important role considering how heterogeneous these tumors are.[2] Further research in targeted therapies is also important. For example, pNETs are known to be very vascular; an ongoing phase 2 clinical trial is evaluating the combination of everolimus, octreotide, and the angiogenesis inhibitor bevacizumab in patients with advanced, unresectable pNETs.[9] Ultimately, the question will be how and when to best use each agent and how to use them in combination to improve patient outcomes.

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