In the first installment of the series, the moderator, Matthew H. Kulke, MD, provides an overview and brief description of neuroendocrine tumors (NETs) and introduces the panel, which includes: Pamela L. Kunz, MD, Rodney F. Pommier, MD, and James C. Yao, MD.

Pommier describes the characteristics and types of NETs. Overall, two main distinctions exist, the first group is comprised of patients with pancreatic NETs and the second carcinoids, which includes NETs that arise in the lungs, kidneys, GI tract, and gonads.

There is a difference in both incidences and presentation between the two groups, Pommier notes. Carcinoid tumors appear in roughly 1 in 100,000 while pancreatic NETs occur in 1 in a million, per year. For presentation, approximately 80% with carcinoids have metastatic disease at diagnosis, whereas 60% to 65% of pancreatic NETs are metastatic. In general, Pommier notes, pancreatic NETs can be resected more readily than carcinoids.

Subgroups exist within each of these classifications, Yao notes. For example, colorectal carcinoid tumors are frequently found incidentally during a colonoscopy whereas small bowel carcinoid tumors are not usually diagnosed until symptomatic. Overall, the diagnosis varies depending on the primary location of the tumor.

Neuroendocrine Tumors: Introduction and Overview

Differences exist in the clinical behavior of neuroendocrine tumors (NETs) based on the site of origin and histologic characteristics, Matthew H. Kulke, MD, points out. To compensate for this, Pamela L. Kunz, MD, believes that several standard variables should be part of the pathology report for NETs, including Ki67, mitotic index, grade, and tumor features/size. Using primarily the mitotic index and Ki67, tumors can be differentiated by low, intermediate, and high grades.

Histological features can be used both predictively and prognostically, believes James C. Yao, MD. In terms of prognosis, tumor size is used frequently to determine the aggressiveness of the tumor. In general, Yao believes, the smaller the tumor the lower the grade and generally the more benign. Identifying an intermediate to high-grade tumor has predictive potential, since more aggressive malignant tumors are treated with chemotherapy.

The primary site of the tumor plays a role in its aggressiveness, Rodney F. Pommier, MD, points out. Tumors that are found in the GI tract, particularly the small bowel, are generally thought of as malignant, even when small.

Uncommon forms for NETs, such as goblet cell carcinoids and mixed adenocarcinomas, tend to behave more aggressively, the panel agrees. For tumors with mixed histology, the best approach is to treat the most aggressive component. However, Yao notes, responses to treatment in poorly differentiated NETs are not equivalent to those seen with well-differentiated tumors.

Histological Classification of Neuroendocrine Tumors

Biomarkers can be used in a variety of ways for the management of patients with neuroendocrine tumors (NETs). James C. Yao, MD, notes that biomarkers may be used to aid in screening, diagnosis, prognosis, and predictively to select optimal treatments.

Varying levels of evidence and recommendations exist concerning biomarkers in NETs. Unfortunately, due to the intrinsic nature of the disease, a successful biomarker does not exist for screening patients, Yao regrets. However, to help diagnosis carcinoid tumors, Yao recommends the 5-HIAA test, which measures average serotonin levels over a 24 hour period. This marker is helpful but is not sufficient by itself to make a diagnosis.

Overall, selecting the most appropriate test should be tailored to the individual patient’s needs based on their symptoms. Yao and Rodney F. Pommier, MD, both agree that the markers examined should be selected very specifically on a patient-to-patient basis.

The Role of Biomarkers in Neuroendocrine Tumors

When referred to academic centers, many patients who have been diagnosed with a neuroendocrine tumor (NET) have received a broad assortment of tests and assays. In general, Rodney F. Pommier, MD notes, the first task when seeing these patients is to narrow down the information based on clinical parameters.

To determine diagnosis patterns, Pommier analyzed 150 patients with abdominal carcinoids. Out of these patients, only 3.5% of patients were referred 3 months following their initial presentation. The remaining 96.5% of patients received a diagnosis on average 6.5 years after presentation and even up to 20 years in some cases. In general, these patients receive 35 different initial diagnoses.

This delay, Pommier feels, may be related to the fact that community physicians are not initially thinking about carcinoids as a potential diagnosis. This is due to a combination of the natural characteristics of the disease and a lack of general awareness.

Challenges in the Diagnosis of Neuroendocrine Tumors

The diagnosis of neuroendocrine tumors comes with several inherent challenges, including the identification of type and primary site. To address this, several specialized imaging techniques are available, such as octreotide scans.

In general, Pamela L. Kunz, MD, notes that she generally begins with cross-sectional imaging using a multiphasic contrast-enhanced CT or MRI. She adds that as more data become available on novel therapeutics, the need to conduct an octreotide scan increases. Additionally, if more information is needed regarding the primary site of the tumor an octreotide scan may be required.

In many cases, several diagnostic tests are performed in an attempt to identify the primary site of the tumor, moderator Matthew H. Kulke, MD, points out. Rodney F. Pommier, MD, believes these efforts are completely necessary, as different treatments become available based on the type of tumor. In general, identifying the tumor type and primary site becomes more crucial, as new trials form and agents are approved.

Techniques for Diagnosing Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are associated with several inherited genetic syndromes. In general, James C. Yao, MD notes, most of these syndromes are associated with pancreatic NETs, including MEN1 (multiple endocrine neoplasia type 1), tuberous sclerosis, and neurofibromatosis. Finally, Yao notes, although Von Hippel—Lindau disease is generally associated with clear cell renal carcinomas this condition also predisposes patients to develop pancreatic NETs.

Matthew H. Kulke, MD, stresses the importance of genetic counseling for patients and family members diagnosed with these genetic syndromes since this counseling may guide screening and tumor detection.

The utilization of genetic mutations to guide treatment selection is still evolving as a strategy in NETs. At this point, Yao notes, in pancreatic NETs, the most common mutations found were in 

, and genes in the mTOR pathway. These mutations may have implications for therapeutic selection, Yao notes; however, validation is still needed to confirm their utility.

The Genetics Behind Familial Neuroendocrine Tumors

In this segment the panelists describe surgical approaches available for patients with neuroendocrine tumors (NETs), which vary based on the primary site of the tumor. To start, Rodney F. Pommier, MD, provides an overview of current strategies in lung carcinoids, pancreatic NETs, and small bowel tumors.

The same standard oncologic operations used for non-small cell lung cancer can be applied to patients with lung carcinoids, Pommier notes. Moreover, these patients generally respond more favorably to surgery, since their cancer is less likely to be related to smoking. Additionally, the tumor may cause unusual syndromes, such as Cushing's syndrome, which are alleviated by resection.

Pommier categorizes pancreatic NETs into two categories based on tumor sizes. Small tumors are generally very small and not localized at the time of the surgery. Once they are found, they can generally be enucleated without major pancreatic resection. However, in larger tumors the feasibility of resection relies heavily on location.

In small bowel tumors, the size of the tumor is less important than the degree of nodal involvement, Pommier notes. In these patients, a wide lymph node resection is advised.

Pommier states that strict criteria exist regarding surgical resection in patients with metastatic disease; however, many of these guidelines may not apply for NETs. He adds that studies have shown that patients with multiple hepatic metastases with 70% to 90% of their disease debulked will have the same outcomes as patients who have a 100% resection. As a result, Pommier believes, achieving a complete resection with negative margins is not entirely necessary.

Panelists, James C. Yao, MD, and Pamela L. Kunz, MD, believe the treatment decision should be individualized and based on a multidisciplinary context. Yao notes that generally patients with a more indolent treatment course benefit from surgery for a longer duration. Kunz notes that other means, such as therapeutic intervention, are being examined to reduce the risk of recurrence following resection.

Surgical Treatment of Neuroendocrine Tumors

The surgical resection of neuroendocrine tumors (NETs) often alleviates many of the symptoms caused by NET-related hormone hypersecretion. However, in addition to surgery, somatostatin analogs can be administered to alleviate these symptoms.

In his research, Rodney F. Pommier, MD, notes that the rate of carcinoid crisis was much higher than initially believed, at nearly 30%. Due to this increased risk of crisis during surgery, Pommier recommends administering somatostatin analogs followed by a period of observation prior to surgery. In the adjuvant setting, data does not support continued treatment.

James C. Yao, MD, describes the PROMID trial that examined octreotide LAR in patients with small bowel carcinoids. This trial showed that treatment with octreotide LAR significantly delayed time to progression. In general, Yao believes the benefits of treatment with somatostatin analogs outweighs the risks and warrants its administration in most cases. Despite this, Yao notes, an analysis of the linked SEER-Medicare database found that treatment with somatostatin analogs is widely under utilized.

Due to side effects, Pamela L. Kunz, MD, believes that only patients who will benefit the most should receive treatment with somatostatin analogs. She discourages the empirical use of these agents before surgery and feels they do not have a role in the adjuvant setting.

A common side effect of somatostatin analog therapy is cholelithiasis, warranting an assessment of a need for long-term therapy. Pommier notes that if long-term therapy is required and an abdominal surgery is planned it may be wise to perform a cholecystectomy. However, Pommier notes, this procedure should be individualized based on the primary site and risks associated with each tumor.

Role of Somatostatin Analogs in Neuroendocrine Tumors

Several treatment options are now available for patients with neuroendocrine tumors (NETs), including two new targeted therapies that have been approved for pancreatic NETs. These agents, everolimus and sunitinib, were approved based on an improvement in progression-free survival (PFS), James C. Yao, MD, explains.

Determining the optimal therapy to administer remains a question that should be individualized. Yao recommends administering the targeted agents before chemotherapy for patients with moderate disease volume. However, Yao notes, for patients with heavy tumor volume, it may be necessary to administer chemotherapy upfront.

The optimal targeted agent to administer can be personalized based on comorbidities, Yao describes. Patients with lung disease, COPD, or uncontrolled diabetes should not receive everolimus. Additionally, Yao notes, someone with cardiovascular disease or hypertension should not receive the VEGF inhibitor sunitinib. Outside of this approach for determining treatment, the optimal sequence for these agents has yet to be discovered, Pamela L. Kunz, MD, notes.

In general, the targeted agents approved for pancreatic NETs have led to real benefits for patients. As an example, Yao and Rodney F. Pommier, MD, describe the level of response experienced with everolimus in the RADIANT trials. In both examples, patients receiving everolimus remained on treatment for five or more years with stable disease.

Emerging Treatment Options in Neuroendocrine Tumors

The clinical benefits of targeted therapies in neuroendocrine tumors (NETs) have primarily been restricted to the pancreatic type. However, clinical trials are currently under way examining the mTOR inhibitor everolimus in a broader patient population.

The RADIANT-2 trial examined everolimus plus octreotide compared to octreotide and placebo as a treatment for patients with carcinoid tumors, James C. Yao, MD, explains. The hazard ratio for progression-free survival in this trial was 0.77 in favor of treatment with everolimus; however, this benefit was not statistically significant. To further cull out the benefits of everolimus in this population, the RADIANT-4 trial will examine everolimus plus best supportive care compared to supportive care and placebo.

Overall, the efficacy of targeted agents in NETs varies by location with a clear divide appearing between pancreatic NETs and carcinoids. Furthermore, Yao notes, as research continues, a subclassification within carcinoid types may become more apparent. The further subdivision of NETs will be shaped by ongoing trials, Yao believes.

Two important phase III trials in this space, Yao notes, have finished accrual and will help shape further understanding of subclasses. The CLARINET study, Yao notes, is examining lanreotide versus placebo in non-functioning enteropancraetic NETs. Additionally, the SWOG 0518 study is looking at octreotide with interferon alfa-2b compared to octreotide and bevacizumab for advanced, high-risk, NETs.

Targeted Therapies in Neuroendocrine Tumors

Chemotherapeutic treatment approaches may be beneficial in some cases of neuroendocrine tumors (NETs). As an example, Pamela L. Kunz, MD, notes that patients with bulky, hepatic or rapidly progressive disease may benefit from treatment with cytotoxic agents. These agents are most beneficial in patients with symptoms caused by hormone secretion who will benefit from tumor shrinkage beyond prolonged stabilization of disease achieved by targeted therapies.

Overall, the only approved chemotherapy in this space is streptozocin, which was approved at a time when clinical trial standards weren't as rigorous, Kunz states. To date, many of the results reported in the study that led to the approval of streptozocin have not been replicated. At this time, Kunz notes, the agent temozolomide represents the most exciting cytotoxic in this space.

Kunz describes that a small study of 30 patients with pancreatic NETs demonstrated a 70% response rate to the cytotoxic agent temozolomide, which is an alkylating agent like streptozocin. To cull this data out further, a phase II study will examine temozolomide with or without capecitabine as a treatment for patients with pancreatic NETs. However, despite promising early data in pancreatic NETs, patients with carcinoid tumors remained unresponsive to chemotherapeutic approaches.

Treating Neuroendocrine Tumors With Chemotherapy

The number of patients with neuroendocrine tumors (NETs) receiving treatment in the community setting is beginning to increase, with the approval of new therapies and the development of effective guidelines. In many cases, Rodney F. Pommier, MD, explains, patients are receiving treatment recommendations from a multidisciplinary team at a cancer center prior to receiving treatment in a community practice.

Given the inherent difficulties in the management of NETs, a unique multidisciplinary team is required to guide treatment decisions. In addition to surgical and medical oncologists, Pommier believes the team should include interventional radiologists, endocrinologists, nuclear medicine experts, cardiologists, and medical geneticists. Another important member, Pamela L. Kunz, MD adds, are pathologists, particularly given the importance of histology.

The panel recommends continued communication between local oncologists and larger centers. This approach aligns with the scarce data available on treatment sequences, Pommier believes. In general, he feels, it is best for a multidisciplinary team to see the patient first, since it is possible to provide an upfront treatment that may lower the chances of a successful surgical resection.

The initial treatment should be tailored on an individual patient basis, James C. Yao, MD, stresses. With the availability of new agents it is possible for patients to receive treatment closer to home, which most patients prefer, Yao notes. However, despite the influx of new agents, there is still a large unmet need in this space calling for more clinical trials, Yao notes.

Management of Neuroendocrine Tumors