Dear Colleagues,

On behalf of the NANETS organization, I would like to congratulate everyone involved in the success of our first annual symposium, “New Horizons in NET Management.” This event was held February 8–9, 2008, at the Fairmont Southampton Resort in Bermuda.

The conference offered an exhilarating glimpse at the impact our young society is already having on neuroendocrine tumor (NET) research, education and patient care. Large-scale efforts are underway to maximize collaborative opportunities and to train an upcoming generation of NET-savvy health care providers and researchers. Being the first organization in North America to provide a comprehensive continuing medical education (CME) program on NETs, NANETS plans to enhance our training by developing a complete set of consensus guidelines for NET disease management. These guidelines will be presented at our next conference in Charlotte, North Carolina on October 2–3, 2009, so mark your calendars and join us!

With 166 specialists from around the world participating in the symposium, the message was clear how vital it is to take a multidisciplinary team approach to understand, diagnose and treat NETs. Among the attendees represented were medical and surgical oncologists, endocrinologists, interventional radiologists, nurse practitioners and gastroenterologists, just to name a few.

Our scientific program spanned a wide range of topics with each session briefly reviewed in this report. If you are interested in listening to the actual presentation, click on the “watch the video” button at the end of the appropriate section. In addition, the basic research and clinical research poster sessions were excellent both in the number and quality of submissions. To access those abstracts, click here [www.nanets.net]. Although it would be impossible to describe all the significant research and noteworthy presentations in this overview, the following information summarizes some of the meeting highlights.

We are grateful to our industry sponsors and members of the Corporate Liaison Committee — Molecular Insight Pharmaceuticals, Novartis Oncology, Tercica and The Carcinoid Cancer Foundation — for their support of this event and their partnership in assisting NANETS toward achieving our organizational objectives. And, of course, we offer a special thanks to Executive Director Kari Brendtro for her tireless work in organizing and running the conference.

Larry K. Kvols, MD Chair, NANETS Executive Committee

NANETS/ENETS Alliances: Inspiring the NET Generation

TRANSLATIONAL “CUTTING EDGE” RESEARCH: NOVEL TARGETS AND AGENTS

CHALLENGES FACING ALLIED TEAM MEMBERS: A DIFFERENT PERSPECTIVE

TARGETED RADIOTHERAPEUTICS FOR NETS: THE CLINICAL EXPERIENCE

THE EPIDEMIOLOGY OF NETS: GETTING SPECIFIC

NET PATHOLOGY AND GENETICS: RECOGNIZING DIFFERENCES

ENDOSCOPIC, INTRAVASCULAR AND NON-NUCLEAR IMAGING: SELECTING THE RIGHT PROCEDURES

NUCLEAR IMAGING: WHICH TECHNIQUES ARE MOST EFFICIENT FOR LOCALIZING TUMORS?

BIOCHEMICAL MARKERS: INTERPRETING LABORATORY OBSERVATIONS TO CLINICAL USE

SURGICAL OPTIONS: MAKING THE RIGHT CHOICES

SOMATOSTATIN ANALOGS: OPTIMIZING THEIR USE – OBSTACLES AND SOLUTIONS

SYSTEMIC AND LIVER-DIRECTED TREATMENTS: FROM BASIC SCIENCE TO THERAPIES FOR MANAGING ADVANCED DISEASE

CONCLUSIONS

FACULTY

View list of all Presentation Recordings

This first session introduced several ongoing NANETS initiatives, with focus primarily on the importance of cooperation among groups to enhance NET research and treatments. Wouter W. de Herder, chairman of the European Neuroendocrine Tumor Society (ENETS), introduced a potential alliance between NANETS and ENETS. He called attention to the similarities of the organizations in their aims, approaches and structures. This partnership would benefit both societies and encourage international collaborations, including large clinical trials.

Multicentered Trials and the Role of Oncology Cooperative Groups — Within North America, the National Institute of Health has established NIH Oncology Cooperative Groups, which includes a Neuroendocrine Task Force, to facilitate multicentered trials. Al B. Benson III described the structure and goals of this task force as a means to identify opportunities, optimize collaborations, develop new concepts and enhance visibility for clinical research of NETs.

Development of Consensus Guidelines and Centers of Excellence — Dr. de Herder described the process recently used by ENETS to update their Guidelines for the Diagnosis and Treatment of Neuroendocrine Gastroenteropancreatic (GEP) Tumors [www.neuroendocrine.net]. The guidelines focus on distinct primary NETs and optimal interdisciplinary approaches to diagnosis, treatment and disease management. For consensus development, working groups comprised of various specialties discussed specific topics and then presented their recommendations to the ENETS General Assembly. A NANETS working group is currently developing U.S. guidelines using a similar approach. The results will be presented at the 2009 NANETS annual meeting.

Are Clinical Trials Possible Across Borders? — One valuable outcome of an alliance between NANETS and ENETS could be international, multicentered trials. According to Walter I. Kocha, these trials would be better able to recruit sufficient numbers of patients, reduce study time and more readily obtain regulatory approval within involved countries. The biggest challenges these global trials present arise from differences among countries in funding, regulatory approval, treatment standards and access to imaging.

As we gain a better understanding of the molecular factors and pathways underlying NET growth and metastasis, novel drug targets can be identified and pursued. A number of new therapeutic targets were introduced in a session on using translational medicine to combat NETs, chaired by James C. Yao.

MEN1 Gene: A Successful Approach to NETs — The multiple endocrine neoplasia type 1(MEN1) gene is the only gene known to cause common NETs. Stephen J. Marx reviewed the role of MEN1 gene mutations in hereditary and sporadic NETs and the value of MEN1 gene sequencing in the clinical setting. This gene and its molecular pathways are being further explored and could be useful therapeutic targets, as could other genes responsible for hereditary forms of NETs.

GSK3 Beta Inhibitors (Differential Utilization of Signaling Pathways) — NETs have been shown to exploit common cell signaling pathways. Herbert Chen described how innovative, nontraditional thinking about this phenomenon led to identification of GSK3β as a therapeutic target. Lithium chloride, a GSK3β inhibitor used for more than 50 years as a mood stabilizer, is now being tested in a phase II study for efficacy in patients with gastrointestinal NETs.

Related preclinical research by Dr. Chen’s group was presented in four posters by Joel Adler, David Yu Greenblatt, Muthusamy Kunnimalaiyaan and Susan Pitt. [Adler B1, Greenblatt B4, Kunnimalaiyaan B6, Pitt B9] These posters described the identification of molecular pathways manipulated by carcinoid tumors and showed effective inhibition of tumor cell growth with agents known to block these pathways. For example, combination therapy with lithium chloride and valproic acid, another well-known mood stabilizer, appears to inhibit NET cell growth through two different signaling pathways. [Adler B1]

Dendritic Vaccination and Oncolytic Virus — Therapeutic vaccination for metastatic carcinoids can theoretically be accomplished by modifying dendritic cells to express carcinoid-associated antigens, according to Magnus Essand. These modified cells could then activate T lymphocytes to replicate and attack carcinoid cells. Oncolytic viruses can be designed by incorporating carcinoid-specific genes into an adenovirus that selectively replicates in and then destroys NET cells. This approach appears to be feasible. Preparations for clinical trials are underway with Ad[CgA-E1A], which uses the CgA promoter for NET-specific replication.

Two posters presented jointly by researchers at Johns Hopkins University and Neotropix, Inc. described a naturally occurring oncolytic virus that appears to be nonpathogenic and to have selective tropism for NET cells. Initial pharmacokinetic and safety data from a phase I study of Seneca Valley virus (NTX-010) were presented at the symposium. [Hallenbeck C9, Hallenbeck C10]

The multidisciplinary approach necessary for effective NET management requires extensive communication among many different specialists. In this session chaired by William J. Maples, different team members shared their unique perspectives and offered practical advice to symposium attendees.

Team Communication: Nurses’ Impact on Comprehensive Patient Care and Outcomes — Nancy Gardner described the pivotal advocacy role of the nursing staff as a liaison between the patients and other health care providers. She entreated all team members to capitalize on these roles by exchanging sufficient information with the nursing staff and by providing educational resources for nurses and patients.

The Key to Accurate Results Is Proper Preparation — Robin Sommers provided guidelines and helpful suggestions for collecting specimens and preparing patients for biochemical assays and diagnostic imaging. Adequate patient education is essential for obtaining accurate test results.

Dietary Modifications for Better Digestive Health in NET Patients — The nutritionist’s perspective on dietary management of NETs was presented by Vay Liang W. Go. In addition to the individualized nutritional recommendations specific for NET management, patients need to understand and follow general dietary guidelines for better overall health during their long-term care.

Strategies for Management of Secondary Conditions in Carcinoid/NET Patients — Many secondary conditions can develop in NET patients as a result of the side effects of somatostatin analogs or from the biologically active substances secreted by NETs. Edward M. Wolin described strategies to control these conditions, which include cardiac endomyocardial fibrosis, diabetes mellitus and hypothyroidism.

A striking example of a massive challenge faced by NET team members was depicted on a poster presentation by Pamela Ryan and other health care professionals from Kenner, Louisiana. This success story described how the devastation of Hurricane Katrina necessitated consolidation of four separate facilities into one multidisciplinary clinic. This change was perceived by patients as an improvement in their care. [Ryan C22]

One of the most exciting sessions, chaired by Larry K. Kvols and Thomas M. O’Dorisio, described how four targeted radiotherapeutic agents are being utilized in the treatment of progressive NET diseases. Although each drug combination is distinct in its chemical composition and target, they all deliver lethal radiation doses directly to the tumor with minimal impact on normal tissue. Data generated on both sides of the ocean have been followed closely by North American health care professionals and patients who have limited options at present and who recognize the tremendous hope these agents offer for treating progressive and/or advanced disease.

¹³¹I-MIBG Iobenguane: Clinical Experience — R. Edward Coleman described an ultrapure form of ¹³¹I-MIBG iobenguane (Azedra™, Molecular Insight Pharmaceuticals) that is currently in phase I/II development in the United States. Unlike the standard ¹³¹I-MIBG available in Europe, Azedra eliminates the excess of unlabeled molecules. This allows for higher, more effective radiation doses with better tolerability. Preliminary clinical data from patients with metastatic pheochromocytoma or paraganglioma show good tolerability and meaningful reductions in symptoms, tumor markers and tumor size. These improvements were illustrated in four patient cases. The presented cases also demonstrated the highly targeted uptake of ¹³¹I-MIBG to tumors and the dramatic restoration of patient function following treatment.

¹¹¹In-octreotide Therapy: Safety and Efficacy of High Doses in Somatostatin Expressing Neuroendocrine Neoplasms — Ebrahim S. Delpassand described the safety and efficacy of high-dose (500 mCi) ¹¹¹In-octreotide as treatment of advanced-stage NETs. The study yielded promising response rates, survival benefits and toxicity data. These data suggest that administering multiple doses of 500 mCi ¹¹¹In-octreotide is a valuable approach to stabilizing progressive disease.

U.S. Experience With NET Treatment With ⁹⁰Y-DOTATOC — Another somatostatin analog in clinical development in the United States is ⁹⁰Y-DOTATOC (Onalta™, Molecular Insight Pharmaceuticals). Clinical experience in the United States, presented by David L. Bushnell, indicates that this agent stabilizes patients with advanced-stage progressive disease and improves their symptoms and overall survival rate. Toxicity is limited by co-administering cationic amino acids during infusion to reduce kidney uptake. Dr. Bushnell also described the advantages of combining MIBG with a somatostatin analog to increase the total dose of radiation without exceeding the critical organ dose, since each agent has a different dose-limiting tissue.

A poster presentation by Stacy Michael and Dr. Bushnell’s group described positive results from a phase I trial of ⁹⁰Y-DOTATOC in young patients with neuroblastomas. [Michael C17]

⁹⁰Y-DOTATOC – The European Perspective — Jan Müller-Brand discussed his experience in Switzerland with this agent, beginning in 1996. Analysis of 1290 European patients indicated that ⁹⁰Y-DOTATOC had a stabilizing effect on tumor growth. Posttreatment disease progression occurred in only 15–20% of patients. ⁹⁰Y-DOTATOC also increased patient quality of life, improving symptoms such as diarrhea, asthma and pain in the majority of patients. Although antitumor response is generally better in patients with high octreotide uptake prior to therapy, this is not always the case. Dr. Müller-Brand recommends ⁹⁰Y-DOTATOC for treating patients with progressive NETs and carcinoid syndrome who have somatostatin receptor-positive tumors (determined by histology or scintillation), normal blood counts and normal kidney function.

Somatostatin Receptor Radionuclide Therapy in Patients with GEP-NETs with LuTate (¹⁷⁷Lu [DOTA0, Tyr3] Octreotate) — Eric P. Krenning described the European experience with another radiolabeled somatostatin analog called ¹⁷⁷Lu [DOTA0, Tyr3] octreotate, or LuTate. Of 562 patients, 321 evaluable patients with gastroenteropancreatic (GEP) NETs were treated according to protocol. Among these patients, LuTate stabilized tumor growth in a sizeable proportion of patients. Only 18% of treated patients experienced progressive disease. Interestingly, imaging studies showed that LuTate had antitumor effects in all patients, even those with progressive disease. This agent also improved quality of life in the majority of patients and had promising survival benefits in patients with stable disease or response. Predictors of survival included: (1) treatment-responsive, nonprogressive disease, (2) the absence of weight loss, (3) high Karnofsky Performance Scores, (4) moderate liver involvement and (5) the absence of bone metastases. Pretreatment OctreoScan uptake and limited tumor mass were not significant predictors of survival. Rates of serious side effects were lower than those of the typical chemotherapeutic agent.

More information on Dr. Krenning’s experience with LuTate is available at http://www.prrt.nl/index.php?lang=en

The epidemiology of NETs was examined in a session chaired by M. Sue O’Dorisio and in several poster presentations. The incidence of NETs and the factors that impact NET development and survival were explored using statistical data from large treatment centers or patient registries.

NETs: Incidence and Prevalence in the United States — M. Sue O’Dorisio reviewed the medical literature on the incidence and prevalence of NETs and on patient survival. It was disturbingly clear from her presentation that the incidences of all types of NETs have increased sharply, while overall survival has not improved over the past 30 years. Dr. O’Dorisio encouraged collaboration among NANETS, ENETS and other groups to generate more accurate information on NETs. More comprehensive epidemiological studies and databases are essential.

The growing incidence and prevalence of NETs were also demonstrated in an epidemiological study presented by Jeannette Mares, winner of the Clinical Abstract Award. [Mares C16] An analysis of over 35,000 NET patients in Surveillance, Epidemiology and End Results (SEER) registries showed an increased incidence of NETs between 1973 and 2004.

Genetic and Environmental Concerns of NETs — Manal M. Hassan discussed the genetic–environmental interactions that contribute to cancer risk as a whole and then focused on how these relate specifically to NETs. A large, hospital-based, case-controlled study identified numerous risk factors related to demographic and medical characteristics of the patients. These included an intriguing association between gastric NETs and a history of diabetes prior to NET diagnosis. Dr. Hassan reminded attendees of the importance of including racial minorities and of analyzing genders separately when determining NET risk factors.

A number of poster presentations explored the epidemiology, natural history and prognostic factors of specific NET types, which include islet cell carcinoma (Cecile Dagohoy [Dagohoy C7]), pancreatic endocrine carcinomas and midgut carcinoids (Jonathan Strosberg [Strosberg C26]). A chart review of patients with metastatic gastroenteropancreatic (GEP) NETs found a high degree of correlation between tumor histologic grade and patient survival. [Strosberg C24] Jonathan Strosberg and his co-authors suggest that “moderately differentiated” be used as a separate prognostic category.

Understanding the histological and genetic changes associated with NETs is important for both classifying and monitoring tumors. This information could also be useful for identifying new therapeutic targets. Presenters in a session chaired by Cesar A. Moran delved into these topics.

Pathology and Tumor Profiling — Cesar A. Moran gave an overview of classification systems and markers used for tumor profiling. He emphasized the need for a unified classification scheme that, unlike the current World Health Organization (WHO) system, encompasses all neuroendocrine neoplasms and uses consistent nomenclature and criteria. Proposed systems are based on tumor grade and differentiation, but meaningful histological stratification will require additional prognostic markers and molecular signatures.

Molecular Genetics of NETs — Ricardo V. Lloyd described analysis of the distinct molecular genetic profiles of different NETs, using techniques such as microRNA expression analysis. These studies give new insight into the pathogenesis and molecular biology of NETs and suggest the need to tailor treatment according to specific tumor type.

Two abstract presentations also showed the value of using molecular genetics to study NETs. Puja Gaur described the molecular profiling of newly established NET cell lines to identify potential therapeutic targets. [Gaur B2] Valeria Giandomenico used bioinformatics to analyze and compare gene expression microarrays from primary carcinoid tumors and liver metastases. Genes shown to be preferentially expressed in carcinoid cells are potential markers or drug targets. [Giandomenico B3]

Epigenetics: Methylation of LINE-1 and Alu Elements — Since the MEN1 gene product influences CpG DNA methylation, Asif Rashid studied methylation of LINE-1 and Alu, two types of repetitive DNA elements found throughout the human genome. His data showed global hypomethylation in NETs that correlates with tumor site, metastatic state and other features. Although the meaning of this is still unclear, one hypothesis is that hypomethylation in NETs contributes to genomic instability.

A poster presentation by Chris Harris provided another potential clue: a LINE-1 gene product had altered expression and cellular localization in NETs and other cancers. [Harris B5]

Pancreatic Endocrine Tumors in MEN1 Patients — Robert T. Jensen discussed the characteristics and treatment of pancreatic endocrine tumors caused by MEN1. Since MEN1 patients typically live for many years, he emphasized that treatment of this tumor type is difficult and must be carefully considered, because some of the treatment decisions have long-term implications. Two other important challenges are localizing small tumors (diameter <2 centimeters) and knowing when and how to treat gastrinomas and nonfunctional, nonmetastatic pancreatic endocrine tumors. Treatment controversies include: (1) the value of performing the Whipple procedure in these patients and (2) whether or not distal pancreatectomy should be routinely performed at the time of surgery.

Imaging is a critical part of managing NETs. A tremendous variety of imaging modalities are available for diagnosing, staging and monitoring NETs. Since each technique has a unique set of advantages, understanding the contributions of each is essential for selecting the appropriate imaging strategy. A session chaired by Richard R. P. Warner provided thorough overviews of endoscopic, intravascular and radiological imaging techniques.

Endoscopy in Diagnosis of NETs — Michelle Kang Kim discussed the value of endoscopy for diagnosing NETs of gastrointestinal origin. Several experimental endoscopic modalities were described. For example, balloon enteroscopy allows access to the entire small bowel for imaging, sampling and intervention. Endoscopic mucosal resection (EMR) is a less invasive way to resection luminal carcinoid tumors. Endoscopic ultrasound is being used to guide fine needle injection (FNI) or radiofrequency ablation (RFA) for safe and effective delivery of targeted therapy to carcinoid tumors.

Intravascular Techniques and Imaging — Joshua L. Weintraub reviewed the intravascular techniques available for detecting NETs and explained how to determine the appropriate procedure. Selective arterial stimulation and hepatic venous sampling (ASVS) is the new standard for localizing occult insulinomas and islet cell adenomas. Although angiography can accurately identify pheochromocytomas, noninvasive tests have a high level of sensitivity and accuracy and are preferred to avoid the risk of hypertensive crisis.

Radiological Imaging — JunSung Choi reviewed the appropriate uses of computed tomography and magnetic resonance imaging modalities. Radiological imaging strategies should be tailored to tumor type, tumor site and patient condition but will always be limited by lesion size. Dr. Choi recommended a combination of cross-sectional and functional imaging when evaluating NET patients.

Nuclear medicine imaging exploits receptors and mechanisms unique to NET cells by using them as targets for specific tracers. Since early diagnosis and treatment are critical for optimal NET management, researchers continue to search for more sensitive imaging techniques. Several promising agents and procedures have been identified in recent years. R. Edward Coleman chaired a session on available and experimental nuclear imaging compounds to highlight this evolving field.

REVIS Somatostatin Receptor and MIBG Neuroendocrine Tumor Imaging — Gregory Wiseman compared the imaging agents used for OctreoScan and MIBG, including their mechanisms of uptake, sensitivity and specificity. He also described OctreoScan and MIBG practical methodology and made recommendations on which technology was best able to image the different tumor types. In addition to scintigraphic imaging for functional status, Dr. Wiseman recommended obtaining a SPECT/CT (single photon emission computed tomography/computed tomography hybrid) for every patient to most accurately localize the tumor anatomically.

Positron Emission Tomography of Neuroendocrine Tumors — Stanley J. Goldsmith gave an overview of nuclear imaging techniques, focusing on positron emission tomography (PET). PET is able to image tumors as small as 3 millimeters in diameter but requires sophisticated equipment and training that are unavailable at many institutions. Clinical data support the use of PET techniques with a variety of radiotracers, such as ¹⁸F-FDG, ¹⁸F-FDOPA, ⁶⁸Ga-DOTA-TOC and ¹¹C-5HTP.

A poster presentation by Italo Zanzi described a small pilot study using PET with ¹⁸F-FDOPA to successfully image small NETs that were not detected with more conventional modalities. [Zanzi C28]

Novel Imaging Compounds — Kjell E. Öberg reviewed the development of new radiotracers for the early diagnosis and treatment of NETs. The experimental compounds ⁶⁸Ga-DOTA-TOC and ¹¹C-5HTP were described and compared to available imaging compounds. Of the many imaging procedures available, PET with ¹¹C-5HTP appears to be the most sensitive. Many additional compounds are also in development, including tracers that could explore tumor biology in live human subjects, such as markers for epidermal growth factor (EGF), apoptosis and proliferation.

NET diagnosis is complicated by the diverse clinical manifestations of NETs and symptom overlap with other medical conditions. For this reason, biochemical evaluation using various biomarkers is critical for early diagnosis and equally important for monitoring disease progression and therapeutic response. A session chaired by Eugene A. Woltering covered the proper selection, use and validation of predictive and prognostic biomarkers.

Biochemical Evaluation of NETs — Aaron I. Vinik reviewed common misdiagnoses of NETs patients and the biomarkers that help differentiate NETs from other medical conditions. Available biochemical markers include 5-HIAA, chromogranin A (CgA), neurokinin A and Ki67. Selection of the appropriate biomarker depends on tumor type and the information needed (eg, prognosis, extent or site of metastases, treatment response).

Clinical Significance of Biomarkers — Thomas M. O’Dorisio compared the clinical significance and assay reliability of CgA and pancreastatin serum levels. The standard, CgA, is foregut-specific and is an accurate marker for metastasis. However, CgA levels may be elevated due to other conditions and are subject to variation among the different commercial laboratory assays. The newly-developed marker pancreastatin, a derivative of the CgA molecule, appears to have advantages over CgA. It has good specificity and sensitivity and its levels reflect liver tumor burden, which is useful for monitoring therapeutic intervention and disease progression.

Several poster presentations also assessed potential bioassays:

Biochemical Markers in the Diagnosis and Management of Neuroendocrine Tumors — The NANETS consensus guidelines in development will contain a risk-based algorithm to help practicing physicians diagnose and monitor NETs. According to Lowell Anthony, the algorithm will include recommended laboratory tests, biomarker assays, imaging techniques and procedures. Biomarker choice will be based on the presence or absence of symptoms and the tumor location, type, grade and size. Biomarker-related issues that still need to be resolved are: (1) selection of the appropriate biomarker(s) for each NET disease, (2) whether or not more than one biomarker should be followed in a patient and how to prioritize among multiple biomarkers and (3) criteria for resolving conflicting data from different biomarkers.

A session chaired by Rodney F. Pommier highlighted the prominent role of surgery in NET treatment. Surgical operations can enhance symptom control, quality of life and survival. Surgery remains the only treatment option capable of completely curing patients.

Foregut and Pancreatic Endocrine Tumors — Janice L. Pasieka reviewed surgical options for foregut and pancreatic tumors, such as enucleation, distal pancreatectomy/splenectomy and Whipple resection. Selection of the appropriate technique varies by tumor type, size, grade and functional state. However, cytoreduction efforts should always be considered for patients with metastatic disease. Dr. Pasieka also discussed several surgical controversies and challenged NANETS members to address these issues: (1) the role of surgery in the MEN1 patient, (2) the role of cytoreduction in asymptomatic GEP NETs (early intervention versus waiting until the lesion is at least 2 centimeters in diameter) and (3) the use of laparoscopic versus open surgery.

Midgut, Appendiceal and Hindgut NETs — J. Philip Boudreaux described characteristics of midgut, appendiceal and hindgut NETs and recommended criteria for determining the appropriate surgical strategy. According to Dr. Boudreaux, even removing only the primary tumor has measurable survival benefits. However, surgical options should still be approached cautiously. Clinicians should: (1) focus on the primary complaint, (2) gather information from imaging and biomarkers to best plan the procedure, (3) preserve as much tissue as possible and (4) follow up with appropriate postoperative surveillance.

Bronchial Carcinoids — Surgical intervention for bronchial carcinoids is a very important topic in NET treatment. Among the difficult decisions that must be made are when and where to resect. Lynn H. Harrison Jr. gave practical advice about diagnosing bronchial carcinoids, selecting surgical treatment and adjunctive therapy, and performing postoperative surveillance.

The Role of Transplantation for Metastatic NETs Involving the Liver — The role of liver transplantation in patients with metastatic NETs is among the most controversial topics in NET management. NET patients who undergo a liver transplantation procedure have a lower survival rate than other transplant patients and a high rate of recurrence. Christopher B. Hughes reviewed other treatment options and the success rate of liver transplantation in NET patients. Dr. Hughes also discussed criteria for determining when transplantation may be indicated, such as the risks to the patient and the risk of recurrence. The details of obtaining a donor liver and choosing appropriate transplantation and follow-up procedures were also considered.

Somatostatin analogs have made many important contributions to the treatment of NETs. They can effectively relieve hormonal symptoms in many patients and have few side effects. Despite vast experience with these agents, their optimal use is still widely debated. A session chaired by Walter Kocha provided an overview of somatostatin analogs, including the difficulties associated with them and suggestions for optimizing their use.

Symptomatic Control — Eugene A. Woltering discussed the role of somatostatin analogs in attaining symptomatic control. Selection of the optimal octreotide dose is difficult and controversial. Dr. Woltering suggested that many patients are treated with inadequate doses and that patient weight should be taken into consideration to determine proper dosing. Loss of symptom control over time could be minimized by objectively measuring octreotide plasma levels and adjusting doses to compensate. Switching patients who fail on the long-acting release (LAR) formulation to continuous pump infusion has also proven beneficial.

Somatostatin Analogs: Is the Available Novel Agent Any Different From Octreotide and Lanreotide? — Larry K. Kvols did not give this presentation on SOM230 (pasireotide) due to time constraints, but participants showed their interest in this agent by asking questions. Pasireotide is a second-generation somatostatin analog in development by Novartis Oncology. Data from a phase II study suggests that this agent holds much promise. Since only patients refractory to LAR octreotide have been treated, it is difficult to compare the antitumor effects of pasireotide and octreotide.

Somatostatin Analogs: Do They Control Proliferation and Improve Survival? — It is unclear whether or not somatostatin analogs have antitumor effects or survival advantages. A comprehensive overview of the literature, presented by Martyn E. Caplin, showed that octreotide and lanreotide are rarely able to reduce tumor size. However, they are associated with high rates of dose-dependent tumor stabilization. The value of somatostatin analogs in patients with nonfunctioning NETs is unknown. Placebo-controlled, sufficiently powered studies will be necessary to definitively prove antitumor effects.

A poster presentation by members of ENETS, including Dr. Caplin, described an ongoing study that will address the antitumor potential of lanreotide. [Lasage C13] The randomized, controlled, double-blind, 96-week study was designed to evaluate progression-free survival in 200 patients with nonfunctioning NETs treated with high-dose lanreotide.

Treatment of advanced, metastatic NETs is challenging but can increase patient survival rates. The final session, chaired by William J. Maples, covered available therapies for patients with advanced disease. These include standard chemotherapy, novel therapies that interfere with growth pathways and therapies directly targeted to the liver.

Streptozocin-Based Therapy and Oral Temozolomide — The role of systemic chemotherapy in NET treatment is complicated, and no standard of care has been established, especially for low-grade tumors. The response rate to chemotherapy is typically low, but difficult to determine from available studies. Emily Bergsland assessed the value of systemic chemotherapeutic options by reviewing studies of streptozocin- and temozolomide-based therapy. In general, streptozocin-based therapy appears to be more useful in treating pancreatic NETs than carcinoid tumors. Temozolomide also appears to be effective for NETs but is associated with severe lymphopenia.

A poster presentation by Christine Frauenhoffer supported the value of temozolomide therapy for patients with pancreatic NETs. [Frauenhoffer C8] In a retrospective chart review of 101 patients treated with temozolomide-based therapy, the cohort with pancreatic NETs had a better tumor response rate, median progression-free survival and overall survival than the cohort of carcinoid patients.

Interferon — An overview of interferon treatment, which is a popular antitumor agent in Europe, was presented by Kjell E. Öberg. Interferon is effective for low-proliferating, well-differentiating NETs and has an advantage over other chemotherapy due to its relatively low cost and moderate side effects. One targeting technique in development is expression of interferon from a plasmid vector within a nanotube. The nanotube is directed to and selectively internalized by the tumor, resulting in localized interferon production.

Targeting the VEGF Pathway in Neuroendocrine Tumors — Matthew H. Kulke discussed novel antiangiogenic therapies targeting the VEGF pathway. VEGF and its receptor are highly expressed in carcinoid and pancreatic NET cells. Several phase II studies support the antitumor activity of the VEGF pathway inhibitors bevacizumab, sorafenib and sunitinib in NET patients. Large, randomized trials are also underway to better evaluate these agents alone or in combination with other treatment modalities.

Alexandria Phan presented a phase II study of depot octreotide plus bevacizumab and/or PEG-interferon for treatment of advanced carcinoid. [Phan C18] Octreotide plus bevacizumab increased tumor response rates and progression-free survival. A larger study is currently underway.

Regulation and Function of the mTOR Pathway — James C. Yao described the regulation and function of the mammalian target of rapamycin (mTOR) signaling pathway in NETs. The mTOR pathway is dysregulated in certain syndromes associated with NETs. RAD001, an mTOR inhibitor, is currently in clinical trials and appears to result in tumor response or stabilization, biochemical reduction and improved survival. RAD001 treatment was associated with metabolic disturbances, such as hyperglycemia and hyperlipidemia.

The effect of RAD001 on metabolism was exploited in a study presented by Carmen Jacobs of Dr. Yao’s group. [Jacobs C11] Treatment with RAD001 improved glycemic control in 3 of 4 patients with malignant insulinoma and refractory hypoglycemia.

Chemoembolization and Chemoinfusion — Rodney F. Pommier described options and outcomes for chemoembolization and chemoinfusion. These techniques offer a high probability of an objective tumor response and symptomatic improvement to patients with widespread metastases. New therapies include drug-eluting beads; however, the treatment course and response rates for this modality remain to be determined.

Abstract presentations showed good response rates and survival outcomes in patients with unresectable hepatic metastases treated with (1) hepatic artery chemoinfusion plus embolization during maximal octreotide therapy (D. Christante [Christante C4]) or (2) high-dose melphalan delivered by isolated hepatic perfusion and percutaneous hepatic perfusion (James F. Pingpank [Pingpank C20]). A study by Alexander T. Ruutiainen showed trends toward better efficacy with transarterial chemoembolization compared to bland embolism. [Ruutiainen C21]

Microspheres, RFA/Cryoablation, Cytoreduction — Charles Nutting reviewed cytoreduction techniques that can be used when complete surgical resection is not possible. Radiofrequency ablation and cryoablation can provide relief to patients with small, stable tumors. A retrospective review of 148 patients with unresectable liver metastases treated by targeted 90Y-microsphere radioembolization suggested that this outpatient procedure is tolerable and has considerable benefit. Drs. Nutting and Pommier both emphasized that radioembolization and chemoembolization limit further treatment options and so should only be considered when other treatments, such as liver resection and transplantation, no longer can be used.

As promised by the meeting subtitle, the first annual NANETS symposium provided numerous opportunities to “think differently, explore possibilities and share ideas.” Despite sobering reminders of the poor progress toward improving patient survival over the past 30 years, attendees were given promising glimpses of novel diagnostic and therapeutic options in development. In keeping with the NANETS mission, there was evidence of more collaboration among specialties, facilities and organizations both in the United States and across borders. In fact, conference speakers constantly re-enforced the need for cooperative, multidisciplinary strategies to benefit the individual patient as well as the research community. Teamwork is critical!

For every discussion topic, information is lacking and controversies exist, even among the experts in the field. Needs range from a thorough understanding of the prognostic factors of NETs, to the best ways to gather and interpret data, to optimal long-term disease management. NANETS is already playing a pivotal role in addressing these issues by providing an annual educational symposium as a forum for exchanging information. In addition, NANETS is continuing efforts to improve NET disease diagnosis, treatment and management through ongoing initiatives and partnerships. Please consider becoming a NANETS member and being part of the solution. Expect to hear updates soon! And please join us at the 2009 NANETS symposium, to be held October 2–3 in Charlotte, North Carolina.

“New Horizons in NET Management”
February 8-9, 2008 - Southampton, Bermuda

Course Chairs
Rodney F. Pommier, MD Professor of Medicine Oregon Health & Science University Portland, OR		Eugene A. Woltering, MD, FACS Professor of Surgery Louisiana State University Health Sciences Center New Orleans, LA
Other Faculty
Lowell Anthony, MD, FACP Professor of Medicine Louisiana State University Health Sciences Center New Orleans, LA Al B. Benson III, MD, FACP Professor of Medicine Northwestern University Chicago, IL Emily Bergsland, MD Associate Professor University of California, San Francisco San Francisco, CA J. Philip Boudreaux, MD, FACS Professor of Surgery & Transplantation Louisiana State University Health Sciences Center New Orleans, LA David L. Bushnell, MD Professor of Radiology, Chief of Diagnostic Imaging University of Iowa Iowa City, IA Martyn E. Caplin, MD, FRCP Royal Free Hospital Neuroendocrine Tumour Unit London, England Herbert Chen, MD, FACS Chief of Endocrine Surgery University of Wisconsin Madison, WI JunSung Choi, MD Associate Professor of Radiology H. Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, FL R. Edward Coleman, MD Professor of Radiology Duke University School of Medicine Chapel Hill, NC Domenico Coppola, MD Chief, Anatomic Pathology H. Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, FL Wouter W. de Herder, MD, PhD Erasmus University Medical Center Department of Internal Medicine Rotterdam, The Netherlands Ebrahim S. Delpassand, MD Adjunct Associate Professor University of Texas & Baylor College of Medicine Houston, TX Magnus Essand, PhD Associate Professor Uppsala University Uppsala, Sweden Nancy Gardner, PhD, RN, NP Assistant Professor Rutgers University Newark, NJ Vay Liang W. (Bill) Go, MD Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, CA Stanley J. Goldsmith, MD Professor of Radiology Weill Cornell Medical School NY Presbyterian Hospital New York, NY Lynn H. Harrison Jr., MD Professor and Chief University of Massachusetts Worcester, MA Manal M. Hassan, PhD, MPH Assistant Professor M.D. Anderson Cancer Center University of Texas Houston, TX Timothy J. Hobday, MD Assistant Professor of Oncology Mayo Clinic Rochester, MN Christopher B. Hughes, MD Chair, Transplant Surgery Mayo Clinic Jacksonville, FL Robert T. Jensen, MD Chief, Cell Biology Section National Institutes of Health Bethesda, MD Michelle Kang Kim, MD, MSc Assistant Professor of Medicine Mount Sinai School of Medicine New York, NY		Walter I. Kocha, MD, FRCP Medical Oncologist London Regional Cancer Center London, Ontario, Canada Eric P. Krenning, MD, PhD, FRCP Professor Erasmus University Rotterdam Department of Nuclear Medicine & Nuclear Endocrinology & Oncology Rotterdam, The Netherlands Matthew H. Kulke, MD Assistant Professor of Medicine Dana Farber Cancer Institute Harvard Medical School Boston, MA Larry K. Kvols, MD Professor of Interdisciplinary Oncology H. Lee Moffitt Cancer Center & Research Institute University of South Florida Tampa, FL Ricardo V. Lloyd, MD, PhD Professor of Pathology Mayo Clinic Rochester, MN Stephen J. Marx, MD Chief of Metabolic Diseases NIDDK / National Institutes of Health Section Bethesda, MD Cesar A. Moran, MD Professor of Pathology MD Anderson Cancer Center University of Texas Houston, TX William J. Maples, MD Associate Professor of Medical Oncology Mayo Clinic Jacksonville, FL Jan Mϋller-Brand, MD, PhD Head, Institute of Nuclear Medicine University Hospital Basel Basel, Switzerland Charles Nutting, DO, FSIR Interventional Radiologist Skyridge Medical Center Lone Tree, CO M. Sue O'Dorisio, MD, PhD Distinguished Professor Carver College of Medicine University of Iowa Iowa City, IA Thomas M. O'Dorisio, MD Professor of Medicine Holden Comprehensive Cancer Center University of Iowa Iowa City, IA Kjell E. Öberg, MD, PhD Professor of Endocrine Oncology Uppsala University Hospital Uppsala, Sweden Janice L. Pasieka, MD Clinical Professor of Surgery & Oncology Department of Surgery North Tower University of Calgary Calgary, Alberta, Canada Asif Rashid, MD, PhD Professor M.D. Anderson Cancer Center University of Texas Houston, TX Robin Sommers, MS, APRN, BC, AOCNP Nurse Practitioner Dana Farber Cancer Institute Boston, MA Aaron I. Vinik, MD, PhD, FCP, MACP Director of Strelitz Research Institute Eastern Virginia Medical School Norfolk, VA Richard R.P. Warner, MD Professor of Medicine Mount Sinai School of Medicine New York, NY Joshua L. Weintrab, MD Chief, Division of Interventional Radiology Mount Sinai School of Medicine New York, NY Gregory Wiseman, MD Consultant in Nuclear Medicine Mayo Clinic Rochester, MN Edward M. Wolin, MD Medical Oncologist Cedars-Sinai Medical Center Los Angeles, CA James C. Yao, MD Associate Professor MD Anderson Cancer Center University of Texas Houston, TX