Key points

Introduction

Well-differentiated neuroendocrine tumors (NETs) are an uncommon and heterogeneous group of neoplasms that arise throughout the body, most commonly in the lung and gastrointestinal tract. These tumors are subdivided into carcinoid tumors and pancreatic NETs (panNETs). Carcinoid tumors develop from the neuroendocrine tissues of the aerodigestive tract, and panNETs develop from the endocrine tissues of the pancreas (ie, islets of Langerhans). This group of well-differentiated NETs is both morphologically and clinically distinct from high-grade neuroendocrine carcinomas, tumors that are characterized by an extremely aggressive behavior and are treated along small cell lung cancer paradigms with platinum-based chemotherapy. Epidemiologic data from the last 30 years have demonstrated that the incidence of NETs continues to increase, although there have been no significant changes in survival from this disease.

panNETs are the second most common tumor of the pancreas and represent 1% to 2% of all pancreatic neoplasms. Although most panNETs are slow growing, after the development of metastatic disease (most commonly in the liver), median survival ranges from 2 to 5 years; most patients with liver metastases will die of the disease. About one-third of panNETs are functional tumors and produce clinical syndromes due to excessive hormone secretion; these functional panNETs are classified by the hormones they hypersecrete and include insulinoma (secrete insulin and cause hypoglycemia), gastrinoma (secrete gastrin and cause Zollinger-Ellison syndrome, which is characterized by severe peptic ulcer disease), glucagonoma (secrete glucagon and cause hyperglycemia), and vasoactive intestinal polypeptide (VIP) (VIPoma, secrete VIP and cause severe secretory diarrhea). Nonfunctional panNETs are tumors that do not secrete hormones or the products they secrete do not cause a clinical syndrome, such as pancreatic polypeptide, chromogranin A, ghrelin, neurotensin, subunits of chorionic gonadotropin, and neuron-specific enolase. Metastatic disease is a common presentation for most patients with panNETs, especially those with nonfunctioning tumors given the absence of clinical symptoms that would warrant earlier clinical evaluation.

Asymptomatic patients diagnosed with advanced, metastatic panNETs are often monitored initially; however, with time, often their disease will progress and require treatment. The typical indications for therapy are pain and symptoms due to tumor bulk, symptoms from hormone secretion for functional tumors, high tumor burden, or progression of disease under observation. Given the heterogeneous clinical presentations and complex spectrum of aggressiveness of panNETs, their treatment is challenging and requires multimodality management with surgeons, interventional radiologists, medical oncologists, endocrinologists, and gastroenterologists. This article focuses on the data and rationale supporting the use of systemic treatments for advanced, metastatic, well-differentiated panNETs.

Introduction

Well-differentiated neuroendocrine tumors (NETs) are an uncommon and heterogeneous group of neoplasms that arise throughout the body, most commonly in the lung and gastrointestinal tract. These tumors are subdivided into carcinoid tumors and pancreatic NETs (panNETs). Carcinoid tumors develop from the neuroendocrine tissues of the aerodigestive tract, and panNETs develop from the endocrine tissues of the pancreas (ie, islets of Langerhans). This group of well-differentiated NETs is both morphologically and clinically distinct from high-grade neuroendocrine carcinomas, tumors that are characterized by an extremely aggressive behavior and are treated along small cell lung cancer paradigms with platinum-based chemotherapy. Epidemiologic data from the last 30 years have demonstrated that the incidence of NETs continues to increase, although there have been no significant changes in survival from this disease.

panNETs are the second most common tumor of the pancreas and represent 1% to 2% of all pancreatic neoplasms. Although most panNETs are slow growing, after the development of metastatic disease (most commonly in the liver), median survival ranges from 2 to 5 years; most patients with liver metastases will die of the disease. About one-third of panNETs are functional tumors and produce clinical syndromes due to excessive hormone secretion; these functional panNETs are classified by the hormones they hypersecrete and include insulinoma (secrete insulin and cause hypoglycemia), gastrinoma (secrete gastrin and cause Zollinger-Ellison syndrome, which is characterized by severe peptic ulcer disease), glucagonoma (secrete glucagon and cause hyperglycemia), and vasoactive intestinal polypeptide (VIP) (VIPoma, secrete VIP and cause severe secretory diarrhea). Nonfunctional panNETs are tumors that do not secrete hormones or the products they secrete do not cause a clinical syndrome, such as pancreatic polypeptide, chromogranin A, ghrelin, neurotensin, subunits of chorionic gonadotropin, and neuron-specific enolase. Metastatic disease is a common presentation for most patients with panNETs, especially those with nonfunctioning tumors given the absence of clinical symptoms that would warrant earlier clinical evaluation.

Asymptomatic patients diagnosed with advanced, metastatic panNETs are often monitored initially; however, with time, often their disease will progress and require treatment. The typical indications for therapy are pain and symptoms due to tumor bulk, symptoms from hormone secretion for functional tumors, high tumor burden, or progression of disease under observation. Given the heterogeneous clinical presentations and complex spectrum of aggressiveness of panNETs, their treatment is challenging and requires multimodality management with surgeons, interventional radiologists, medical oncologists, endocrinologists, and gastroenterologists. This article focuses on the data and rationale supporting the use of systemic treatments for advanced, metastatic, well-differentiated panNETs.

Pathology

Since 2010, the classification of panNETs has been based on the revised criteria from the World Health Organization, which is defined by the cytologic grade and the proliferative index (as assessed by the Ki-67 and/or mitotic count). In these revised criteria, tumors are broken down by differentiation status (well and poorly differentiated) and grade (grade 1, low; grade 2, intermediate; and grade 3, high). Although the family of well-differentiated tumors are classically of the grade 1 or grade 2 type and generally have a more indolent, less aggressive course, grade 3 or high-grade neuroendocrine carcinomas are typically poorly differentiated and classified as large or small cell carcinomas; these grade 3 neuroendocrine carcinomas are highly aggressive, akin to small cell lung cancers, and are associated with a poor prognosis.

To support this belief, many studies have looked at the relationship between tumor grade and survival; not surprisingly, tumor grade seems to be correlated with survival; in one retrospective analysis of 425 patients with panNETs, the 5-year survival rates for grade 1, grade 2, and grade 3 tumors were 75%, 62%, and 7%, respectively. Unfortunately, this grading system is not universally incorporated into most of the clinical trials investigating panNETs and makes the interpretation of the published data somewhat challenging.

However, recent data also suggest that it may not be correct to consider all grade 3 gastroenteropancreatic (GEP)-NETs as a single entity. Specifically, it has been suggested that some well-differentiated grade 3 NETs may behave differently than poorly differentiated grade 3 NETs. Furthermore, data on treatment outcomes suggest that NETs with a Ki-67 proliferation index in the lower end of the G3 range respond less robustly to chemotherapy agents, such as platinum drugs. In one study, it was shown that grade 3 GEP-NETs with a Ki-67 proliferation index less than 55% were less responsive to first-line platinum-based chemotherapy, though this subgroup achieved longer survival in comparison with grade 3 GEP-NETs with a Ki-67 proliferation index of 55% or greater (14 months vs 10 months). Further corroborating these data, in an investigation of 45 patients specifically with grade 3 panNETs, studying survival and treatment response based on poorly or well-differentiated status, differences were appreciated both in survival and response by therapy type. Specifically, the well-differentiated subgroup demonstrated improved overall survival (OS) in comparison with the poorly differentiated subgroup (52.0 months vs 10.1 months). Looking at responses to therapy, although both poorly and well-differentiated grade 3 panNETs responded to alkylating chemotherapy agents, poorly differentiated tumors had a higher response to platinum agents. Based on the findings of these studies, current research efforts are directed toward a better understanding of grade 3 NETs, both pancreatic and extrapancreatic, as they seem to be a more heterogeneous group than originally thought.

Genetics

Systemic treatment of advanced pancreatic neuroendocrine tumors

The treatment of patients with advanced, metastatic panNETs, whether inherited or sporadic, is approached in a multidisciplinary manner and may include surgical resection, liver-directed therapies, and/or systemic treatments. In unresectable patients, the goals of these therapies are to palliate tumor-related symptoms and prolong the life span.

There are multiple systemic therapy options available for the treatment of metastatic panNETs. These systemic options include somatostatin analogue therapy, targeted agents, and cytotoxic chemotherapy.

Targeted therapies

In recent years, targeted agents have been evaluated as therapy options for panNETs. All NETs are known to be highly vascular; for this reason, targeted angiogenic inhibitors have been heavily investigated as a treatment option in the spectrum of NETs. Specific biological agents that have been studied include those directed against vascular endothelial growth factor (VEGF) as well as those targeting mTOR. Sunitinib and everolimus are the only targeted therapies approved for progressive panNETs. Both single and combination therapies have been tested in clinical trials.