Xanthohumol Reduces Notch and Induces Apoptosis in Neuroblastoma
Stephen Erickson, Mariappan Balamurugan, Selvi Kunnimalaiyaan, T. Clark Gamblin, Muthusamy Kunnimalaiyaan. Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin and Medical College of Wisconsin Cancer Center, Milwaukee, WI.
Background: Neuroblastoma (NB) is a highly malignant neuroendocrine cancer accounting for 15% of childhood cancer-related deaths. At diagnosis, more than 40% of patients present with aggressive disease and distant metastases, and 5 year disease-free survival remains below 50%. Recent studies have revealed deregulated expression of Notch signaling in NB; however, therapeutic targeting of Notch represents a significant challenge. Xanthohumol (XN), a prenylated chalcone, exerts anti-proliferative activity against various cancers. We have reported that growth suppression by XN in primary liver and pancreatic cancer is due to reduced Notch signaling. However, the effect of XN in NB has not yet been studied. We therefore hypothesized that XN could also reduce NB growth via downregulation of Notch.
Methods: The proliferation of several XN-treated human NB cell lines (SK-NA-S, NGP, and SH-5Y-SY) was assessed by MTT assay as well as real-time cellular proliferation assay using IncuCyte Live-Cell Imaging system. Expression levels of pro- and anti-apoptotic proteins were analyzed by Western blotting after XN treatment. The effects of XN treatment on Notch pathway proteins were studied via Western blotting and quantitative RT-PCR.
Results: NB cells treated with increasing concentrations of XN (0-30 μM) showed dose-dependent reduction in growth. Significant growth reduction was noted at or above 10 μM of XN in all three cell lines tested. This growth suppression appeared to be apoptotic as evidenced by increased expression of c-PARP and cleaved caspase-3 in addition to decreased levels of Bcl2 and survivin. Furthermore, XN treatment reduced levels of Notch3 and associated downstream targets Hes1 and ASCL1.
Conclusions: We report for the first time that XN targets Notch3 signaling in NB cells. Our data collectively establish that XN could potentially be used therapeutically.
Utilizing Fluorescent Transgenic Reporters to Trace the Metastatic Progression of Pancreatic Neuroendocrine Carcinoma
Sean T. Glenn,1 Calvin Sjaarda,2 Ping Liang,2 Karstin Webber,1 Michael Rusiniak,1 Caretta J. Reese,1 Maxwell M. Goodrich,1 Heinz Baumann,1 Dominic J. Smiraglia,1 Kenneth W. Gross,11Roswell Park Cancer Institute, Buffalo, NY; 2Brock University, Ontario, Canada.
Background: We have generated a unique mouse model of highly metastatic islet cell carcinoma by selectively abrogating floxed alleles of p53 and Rb using Cre-recombinase driven by the renin promoter. Incorporation of a multi-colored fluorescent reporter, Confetti, confers the ability to trace the lineage of individual renin-expressing cells allowing for observation of hyperplasia within pre-tumorigenic islets, clonality of primary tumor foci, and identification of the primary of origin for observed metastases.
Methods: RenCre activation of the Confetti reporter, randomly labels each cell with one of four fluorescent reporters in concert with concurrent homozygous deletion of Rb and p53. Clonal expansion of the rare cells that progress to primary tumors as a function of additional cooperating mutations results in color-coded primary tumors. Moreover, metastases are also color-coded and matched as clonal derivatives of the independent primary tumors in the same mouse. Next-Generation Sequencing technology is used to study genetic events responsible for progression to metastatic disease.
Results: Dissection of animals of appropriate genetic constitution reveals that most mice harbor multiple primary tumors of different fluorescent color. Remarkably, in the subset of animals that developed metastatic disease, all observed liver metastases are a single color suggesting they derive from only one of multiple primary tumors in each case. Whole Exome Sequencing of DNA from multiple sets of primary and metastatic tumors from individual animals has identified a mutation profile which allows for the tracing of a single primary responsible for seeding distant metastases in the liver, and confirms what is predicted by the reporter. A deeper investigation of both exome and transcriptome data will offer up insight into genes responsible for metastatic progression of disease.
Conclusions: Our utilization of multiple fluorescent reporters for cell lineage tracing of pancreatic renin-expressing cells, is providing unique insights into pancreatic islet carcinogenesis and metastasis.
Collection of Biological Samples of Neuroendocrine Tumors (NET) for Biomedical Research: The Discovery Project of GETNE Group
Paula Jimenez-Fonseca,1 Jaume Capdevila,2 Angel Castaño,3 Carlos López,4 Marta Benavent,5 Carles Villabona,6 Aurora Astudillo,1 Ignacio Matos,2 Raquel García Velasco,3 Santiago Montes,4 Ramón Salazar,6 Rocío García-Carbonero,51Hospital Universitario Central Asturias, Oviedo, Spain; 2Hospital Universitario Vall d’Hebron, Barcelona, Spain; 3Hospital Universitario de Fuenlabrada, Madrid, Spain; 4Hospital Universitario Marqués de Valdecilla, Santander, Spain; 5Hospital Universitario Virgen del Rocio/Instituto de Biomedicina de Sevilla (IBIS) [HUBVR, CSIC, US], Sevilla, Spain; 6Hospital Universitari Bellvitge-ICO, L'Hospitalet de Llobregat, Spain.
Background: The NET Discovery project of the Spanish Cooperative Group on NETs (GETNE) aims to build up a large nationwide biological sample collection linked to high quality clinical information of patients with NETs, through the cooperation of multiple institutions of the GETNE network. This initiative seeks to promote quality translational research adapted to clinical needs, including the identification of biomarkers of potential diagnostic, prognostic or therapeutic interest, and of predictive factors of efficacy and/or toxicity of therapy.
Methods: The collection was initiated in 2013 coordinated by GETNE, who has elaborated SOP for sampling, processing, storage and transfer of biological samples according to the legislation in force. This collection is structured based on 6 hubs or coordinating centers that are responsible for their own samples and for those referred from other centers from their geographic region. Biological samples collected include tumor tissue, whole blood, serum and saliva, and sample information is registered in a unified database linked to the clinical information from the national Spanish registry of gastroenteropancreatic NETs (RGETNE).
Results: As of June 2015, GETNE has over 2000 patients prospectively recorded in the clinical national registry RGETNE, with 339 samples linked to this registry (131 bloods, 122 serum, 119 tumor tissues). The first research project to be conducted within the NET Discovery Platform has been initiated (NETSEQ), which aims to analyze mRNA expression in midgut NETs using Nanostring Ncounter Technology. The results of this and other upcoming projects will be presented in future conferences and published accordingly.
Conclusions: The NET Discovery project has proven to be an efficient way to gather a significant number of adequately annotated biological samples that are of great value to carry out biomedical research with shall eventually improve the diagnosis and care of patients with different types of gastroenteropancreatic NETs.
Identification of Tumorigenic Cells and Therapeutic Targets in Pancreatic Neuroendocrine Cancers
Geoffrey W. Krampitz,1,2 Benson M. George,2 Stephen B. Willingham,2 Jens-Peter Volkmer,2 Kipp A. Weiskopf,2 Nadine S. Jahchan,2,5 Aaron M. Newman,2 Debashis Sahoo,2 Anne K. Volkmer,2 Norma F. Neff,3 Benedetto Passarelli,3 Hanlee P. Ji,4 Rebecca L. Yanovsky,2 Julia K. Nguyen,2 Peter J. Schnorr,2 Ingrid Ibarra,2 Pawel K. Mazur,2,5 Siddhartha S. Mitra,2 Julien Sage,2,5 Brendan C. Visser,1 George A. Poultsides,1 Stephen R. Quake,3 Jeffrey A. Norton,1 Irving L. Weissman,2,61Department of Surgery, 2Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA; 3Department of Applied Physics and Bioengineering, Stanford University, and Howard Hughes Medical Institute, Stanford, CA; 4Department of Medicine and Oncology, 5Department of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA; 6Ludwig Center for Cancer Stem Cell Biology and Medicine at Stanford University, Stanford, CA.
Background: Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells are responsible for tumor development, metastasis, and recurrence, and targeting these tumor initiating cells is necessary to eradicate tumors. However, tumor initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs.
Methods: We used 39 human tissue specimens, developed a novel cell line (APL1) from a well-differentiated patient PanNET, created xenograft models using primary tumors transplanted into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, and utilized a RIP-Cre Rb/p53/p130 genetic model of PanNETs to characterize tumorigenic cells in PanNETs and identify and validate potential therapeutic targets.
Results: Here we profile primary and metastatic well-differentiated tumors from a patient and identify MET as an important growth factor receptor for PanNET growth. Furthermore, we identify a highly tumorigenic cell population within primary patient, well-differentiated, low or intermediate grade PanNETs characterized by increased CD90 expression and ALDHA1 activity. We identify phenotypically distinct cellular subsets in well-differentiated PanNETs and provide evidence for the stem-like properties of the CD90hi cell fraction. All PanNETs analyzed express CD47, a “don’t eat me” signal co-opted by cancers to evade innate immune surveillance. Furthermore, we demonstrate that blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits tumor growth and prevents metastases in vivo.
Conclusions: Our findings provide a foundation for developing therapeutic strategies that eliminate tumor initiating cells in PanNETs and show how deep examination of individual cases can lead to potential therapies.
Patient-Derived Organoids as an In Vitro Model of Neuroendocrine Tumors
Iris H. Liu,1 James T. Neal,2 Allison J. Zemek,2 Pamela L. Kunz,2 Calvin J. Kuo,21Dartmouth College, Hanover, NH; 2Stanford University School of Medicine, Stanford, CA.
Background: Despite the major clinical advances made in treating neuroendocrine tumors (NETs) over the past decade, there remains a dearth of methods by which NETs can be studied in the laboratory. In particular, existing NET cell lines are believed to poorly represent NET biology and behavior. The advancement of 3D organoid culture over the past few years has opened the door to the use of organoids as models for recapitulating and experimenting on tumor properties in the setting of the laboratory.
Methods: Surgically resected NET samples were collected by the Stanford Tissue Bank from consented patients who had not undergone neoadjuvant therapy. Primary tissue was minced, then suspended in collagen for culture in the double-dish Air-Liquid Interface format. The primary tissue was cultured in supplemented basal medium, including the growth factors Wnt, EGF, Noggin, and R-Spondin. Media was changed 1-2 times per week, and cultures were passaged around once a month, according to the growth rate of individual cultures. Organoid samples were collected for histological analysis by hematoxylin and eosin staining, as well as NET-specific chromogranin A and synaptophysin staining.
Results: Thirteen NET samples were successfully initiated as expanding organoid cultures. Of the thirteen NETs, 9 originated from the pancreas, 2 from the lung, one from the small intestine, and one from the stomach. The NET organoids grew relatively slowly, compared to adenocarcinoma samples, in accordance with the indolent nature of NETs in vivo. While some of the slowest-growing samples began dying after 1-2 passages, robust cultures have survived up to 6 passages and continue to expand.
Conclusion: Patient-derived NET organoids offer the potential for establishing “lines” that more accurately recapitulate the biology and behavior of NETs. Further characterization of such cultures is necessary and may offer the opportunity to better understand NET biology and effect treatment in pre-clinical models.
Identification of Oxytocin Receptor (OXTR) as a Specific Theranostic Target in Ileal Neuroendocrine Tumors
Molly E. Martin,1 Blanca Schafer,1 James Howe,1 M. Sue O’Dorisio,11Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA.
Background: G protein-coupled receptors (GPCR) have emerged as candidates for molecular targeting in neuroendocrine tumors (NETs) and their ligands show promise as theranostic agents, where a single compound is used for both diagnosis and therapy. We hypothesize that peptides targeting OXTR can be radiolabeled with Ga-68 for diagnostic PET imaging and Y-90 for targeted therapy of OXTR-positive ileal NETs.
Methods: Fresh tumor and adjacent normal tissue was obtained at surgery from patients with ileal (16) and pancreatic (10) NET. Specimens were immediately preserved in RNA-later and frozen for isolation of RNA and conversion to cDNA. GPCR expression was quantitated for tumor and normal tissue. Expression level of OXTR in ileal and pancreatic NET was confirmed by immunohistochemistry. A library of oxytocin analogs, predicted to have OXTR agonist or antagonist activity, was synthesized using solid-phase chemistry and conjugated with fluorescein. Agonist/antagonist activity of synthetic peptides was measured by calcium influx assays in cell lines expressing OXTR.
Results: GPCR expression data demonstrate overexpression of OXTR in ileal with little or no expression in pancreatic NET. A library of peptides was generated to target OXTR; fluoro-oxytocin bound to ileal but not pancreatic NETs. Oxytocin induced a positive response in calcium influx assays using PC3 cells that express OXTR.
Conclusions: We have identified OXTR as a specific and highly expressed target in ileal NET. Preliminary studies demonstrate binding of fluoro-oxytocin in OXTR expressing ileal NETs as well as oxytocin-induced calcium flux in OXTR expressing cell lines.
Future Directions: Peptides in the oxytocin library will be used to characterize affinity, specificity, and agonist/antagonist activity for OXTR. Leading candidates will be tested as PET imaging agents and therapeutic radiopharmaceuticals in a mouse model of NET. GPCR targeted imaging and therapy is a powerful new THERANOSTIC tool in development of personalized treatment for patients with neuroendocrine tumors.
Somatic Alterations of CDKN1B Are Associated With Small Bowel and Pancreas Neuroendocrine Tumors
Jessica E. Maxwell, MD, MBA,1 Scott K. Sherman, MD,1 Guiying Li, MD,1 Allen B. Choi,1 Thomas M. O’Dorisio, MD,2 Andrew M. Bellizzi, MD,3 James R. Howe, MD,11University of Iowa Carver College of Medicine, Department of Surgery, Iowa City, IA; 2University of Iowa Carver College of Medicine, Department of Internal Medicine, Iowa City, IA; 3University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA.
Introduction:CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). Two groups found exonic somatic mutations of the gene in SBNET primary tumors at a combined rate of 7.4% (95% C.I.: 4.4-10.3%); hemizygous deletions were seen in 6.7%. Alterations of this gene have not been investigated in pancreatic neuroendocrine tumors (PNETs). We set out to confirm the role of mutations and copy number variants (CNVs) of CDKN1B in another large cohort of SBNET patients and also examined the importance of these changes in PNETs.
Methods: Genomic DNA was isolated from 86 primary SBNETs and 67 PNETs. Each exon and intron-exon boundary of CDKN1B was amplified by PCR, then bidirectionally sequenced. CNV analysis was performed by quantitative PCR using CDKN1B-specific probes at the 5’and 3’ ends of the gene. Results were evaluated using sequencing, CNV, and mutational analysis software. p27 expression was evaluated using immunohistochemistry.
Results: Three frameshifts, and 1 hemizygous deletion were observed in SBNETs, giving a total rate of CDKN1B alterations of 4.7% (95% C.I.: 0.2-9.1%; Table 1). The rate of frameshift mutations was 3.5% (95% C.I: 1.2-9.8%). p27 expression was reduced or lost in SBNETs with frameshift mutations. One likely deleterious missense mutation, and 4 CNVs were observed in PNETs, giving a total rate of CDKN1B alterations of 7.5% (95% C.I.: 1.2-13.8%). There were no frameshift mutations in the PNETs.
Conclusion: This study confirms that CDKN1B plays a role in SBNETs, with frameshift rates statistically similar to the previous reports. Conversely, frameshifts were not seen in PNETs, but a few had losses or duplications of unknown significance. Depression or loss of p27 expression in SBNETs with frameshift mutations suggests that these mutations may lead to cell cycle dysregulation and eventual tumor initiation.
Identification of MEN1 Mutation via Next Generation Sequencing in the Cancer Treatment Centers of America (CTCA) Database
Eyal Meiri,1 Navneet Dhillon,1 Altovise Ewing,1 Kim Kramer,21Cancer Treatment Centers of America Southeastern Region, Newnan, GA; 2Cancer Treatment Centers of America, Zion, IL.
Background: MEN1 is a syndrome associated with increased risk of non-endocrine related malignancies, including breast cancer and lung cancer. We attempted to correlate the MEN1 gene alteration incidence and the allelic frequency (AF) the MEN1 mutations detected.
Methods: A retrospective review of 15 specimens (6 breast, 4 lung, 2 pancreas, 1 small intestine, 2 unknown primary cancers) with MEN1 gene alteration detected by Foundation OneTM (Foundation Medicine, Inc., MA). Next generation sequencing (NGS) test was performed. DNA was extracted from biopsy specimens and sequencing was performed per previously described methodology. AF is calculated as percent of reads at the position of a variant, which support the alternate allele (Table 1). The reported value is not corrected for the specimen tumor content.
Results: N=2361, Breast Cancer N=414 (1.5%), Lung Cancer N= 369 (1.1%) (Table 1).
Conclusions: MEN1 mutations are found in a variety of neoplasms with the majority in breast and lung carcinomas. Additional studies are underway to determine if MEN1 alterations may have a more substantial role in carcinogenesis than previously surmised.
Higher Therapeutic Index In Vivo With Radiolabeled Somatostatin Receptor Antagonists May Broaden the Safety Window of PRRT
Guillaume P. Nicolas,1 Rosalba Mansi,1 Sandra Vomstein,1 Jens Kaufmann,2 Hakim Bouterfa,2 Helmut R Maecke,3 Damian Wild,1 Melpomeni Fani,11Division of Nuclear Medicine, University of Basel Hospital, Basel, Switzerland 2OctreoPharm Sciences GmbH, Berlin, Germany; 3Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
Background: Radiolabeled somatostatin (sst) receptor antagonists have been recently introduced in the clinic for treatment (PRRT) and imaging of neuroendocrine tumors. The therapeutic index, imaging contrast as well as the influence of the mass of OPS201 (a novel radiolabeled sst antagonist) is not known.
Methods: The sst2-antagonist 177Lu-OPS201 and the sst2-agonist 177Lu-DOTATATE were compared head-to-head in 2 sst2-expressing xenograft models (HEK-hsst2 and AR42J) in vivo. Biodistribution, pharmacokinetic and nano SPECT/CT imaging studies were performed. Influence of increasing peptide mass and use of octreotide were investigated in a theranostic approach.
Results: Besides a usual physiological pattern of uptake in the sst2-receptor expressing organs, the antagonist showed higher uptake (e.g. ~35% at 4 h, p < 0.05) and longer residence time in tumor in comparison with agonist (19.1 h vs 7.5 h) resulting in a 2.5 times higher tumor dose. The antagonist had higher kidney uptake, however the therapeutic index, defined as tumor-to-kidney dose ratio, remained by 34% in favor of 177Lu-OPS201. Increasing the mass of 177Lu-OPS201 from 10 to 2000 pmol caused no relevant saturation in the HEK-hsst2 tumor (19-24%IA/g, at 4 h, p > 0.05) but reduced significantly the background, except renal uptake (see nanoSPECT/CT images below). The improved image contrast and therapeutic index were confirmed with increased mass of 177Lu-OPS201 (from 10 to 200pmol) in AR42J xenografts. However tumor uptake significantly decreased after injecting 2000pmol. Co- and pre-injection of 200-fold excess of octreotide i.v. did not modify the distribution of the antagonist, including the tumor uptake.
Conclusion: The increased tumor uptake, prolonged tumor residence time as well as the more favorable differential washout of 177Lu-OPS201 improve the therapeutic index compared to 177Lu-DOTATATE. An optimized antagonist-mass will likely further reduce liver and bone marrow toxicity, while interrupting sst-analogs before PRRT may not any longer be needed with radiolabeled antagonists.
Is Next-Generation Sequencing (NGS) Ready for Routine Clinical Practice in Advanced Well Differentiated Pancreatic Neuroendocrine Tumors (WD panNETs): Results of a Prospective Study Utilizing MSK-IMPACT (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets)
Nitya Raj,1 Tara Soumerai,1 Emily Valentino,1 Diane Reidy-Lagunes,11Memorial Sloan-Kettering Cancer Center, New York, NY.
Background: Whole exome sequencing in WD panNETs demonstrated an increased number of mutations in genes implicated in chromatin modeling (MEN1, DAXX, and ATRX), and in the PI3K/AKT/mTOR pathway. NGS allows us to bring this technology to the clinic but its relevance in clinical practice has been questioned. In this prospective, IRB-approved study (NCT01775072), we used the MSK-IMPACT assay to perform NGS on WD panNETs in a routine practice setting. MSK-IMPACT, performed in a CLIA-compliant laboratory, is a multiplexed assay (Illumina HiSeq) providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements.
Methods: After written consent, tumor and germline DNA were analyzed. Genomic alterations were catalogued. Actionable alterations were classified according to 5 levels (Table 1).
Results: MSK-IMPACT results are available in 29 patients with WD panNETs. Actionable alterations were identified in 13/29 patients (44.8%). No level 1 or level 2A alterations were identified. Two level 2B alterations were identified, both in BRAF V600E. Four level 3 alterations were identified, 1 in TSC1 and 3 in TSC2. Seven level 4 alterations were identified, 3 in PTEN, 1 in CDKN1B, 1 in CDKN2C, and 2 in ARID1A. 19/29 (65.5%) patients had alterations in MEN1, 8/29 (27.6%) patients had alterations in DAXX, and 9/29 patients (31.0%) had alterations in ATRX. Other notable findings included 2/29 patients (6.9%) with TP53 alterations, and 5/29 (17.2%) patients with SETD2 alterations.
Conclusion: The mutational landscape in our study was in line with prior work in whole exome sequencing. In almost half of the patient cohort, potentially actionable genomic alterations were identified through NGS but have not yet been shown to be therapeutically relevant or prognostic. An exploratory analysis to identify responses to different therapy types (chemotherapy, targeted agents) is ongoing and will be reported at the meeting.
Osteotropism of NETs: Role of CXCR4 in Regulating the EMT Process
Francesca Maria Rizzo,1 Mauro Cives,1 Valeria Simone,1 Ilaria Maggio,1 Davide Quaresmini,1 Claudia Felici,1 Morena D’Avenia,1 Franco Silvestris,11Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
Background: Neuroendocrine tumors (NETs) metastasize to the bone in up to 20% of patients with well/moderately differentiated disease. We have previously demonstrated that activation of the epithelial-to-mesenchymal transition (EMT) regulates the NET osteotropism. In particular, CXCR4 overexpression was related to increased risk of bone colonization. Here we investigated its activity in driving this process.
Methods: BON1, QGP1, CM, H727 and CNDT2.5 NET cell lines were evaluated by MTT test in their proliferative response to the CXCR4 ligand SDF1. The transcription and expression levels of a panel of EMT-related genes (CXCR4, SNAIL, TGF-β1, CTGF, EpCAM, E-Cadherin, N-Cadherin, IL-11, RANK) were screened by RT-PCR and immunocytochemistry at baseline and after 2 hr of SDF1 treatment. Migration and invasion of NET cells towards the bone were evaluated by functional assays, while the subcellular distribution of CXCR4 was investigated by confocal and electron microscopy. Western blot (WB) was used to detect CXCR4 isoforms in nuclei. Chromatin immunoprecipitation and nuclear calcium mobilization are underway to elucidate the CXCR4 function in nuclei.
Results: SDF1 was inert on NET cell proliferation. EMT-related genes were constitutively up-regulated in BON1 cells (p < 0.01), whereas their transcription and expression levels were inducible by SDF1 (p < 0.03) in CM and H727 cell lines, but not in QGP1 and CNDT2.5 cells. Overall, there was a defined correlation between mRNA and protein levels (r = 0.53, p = 0.04). Only BON1 cells showed an intrinsic tropism towards the bone (p < 0.0001), whereas CM and H727 cells significantly increased their migration only after incubation with SDF1 (p = 0.0025 and p = 0.01, respectively). Following agonist stimulation, CXCR4 migrated to the nuclear membrane and nucleoli of BON1, CM and H727 cells, where its nuclear levels increased up to 240%.
Conclusion: Stimulation of CXCR4 dramatically enhances the osteotropism of several NET cell lines by inducing the EMT. Migration of specific CXCR4 isoforms towards the nuclei may play a role in this process.
Establishment and Characterization of a New Well-Differentiated Pancreatic Neuroendocrine Tumor Cell Line
J. Schrader,1,2 Y. Behrang,1 D. Benten,1 M. Fahl,1 C. Rhotert,1 D. Perez,2 M. Bockhorn,2 J.R. Izbicki,2 A.W. Lohse,11I. Medical Department, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Background: The development of new therapeutic strategies for patients with pancreatic neuroendocrine tumors is impaired by the paucity of suitable pre-clinical models. Although the two available tumor cell lines BON and QGP have a neuroendocrine phenotype, the proliferation rates are far too high for a well differentiated neuroendocrine tumor. Hence, there is great need for the development of new neuroendocrine tumor cell lines.
Methods: We successfully established a new primary human neuroendocrine tumor cell line from a lymph node metastasis of a patient with a pancreatic neuroendocrine tumor. The expression profile, growth characteristic and treatment response in this cell line was analyzed in comparison to the established BON and QGP cells.
Results: The new cell line („NT-3“) has now been cultured for more than 18 month with a stable neuroendocrine tumor phenotype assessed by chromogranin A, synaptophysin and SSTR expression. The cells have a doubling time of 8 days in comparison to a doubling time of less than 2 days in the BON and QGP cells. In soft agar the NT-3 cells form small colonies after an incubation period of 8 weeks with a colony frequency of ~2% of plated cells. The expression of SSTR subtypes 1, 2, 3 and 5 is at least 10-fold higher in NT-3 cells compared to BON and QGP. Likewise, the expression of the pro-angiogenic factors VEGF A, VEGF B and Angiopoetin 2 is more than 5-fold higher in NT-3 cells. As a marker of functionality the NT-3 cells express and secrete insulin. The IC50 for treatment with streptozotozin was ~1 mM and >10 mM and with 5-FU was ~100 μM and >500 μM in NT-3 and QGP cells, respectively.
Conclusion: In summary, we have established a new slow growing, functional active pancreatic neuroendocrine tumor cell line with a well differentiated phenotype and high expression of pro-angiogenic factors.
mTOR Pathway Inhibition Sensitizes Insulinoma Cells to Streptozotocin Induced Apoptosis
C. Vercherat,1 F. Bourguillault,1 V. Hervieu,1,4 G. Poncet,1,5 P. Massoma-Peh,1 J. Bollard,1 I. Goddard,1 N. Gadot,2 M. Cordier-Bussat,1 J-Y. Scoazec,1,6 C. Roche,1 T. Walter,1,31INSERM U1052/CNRS UMR5286/Université de Lyon, Lyon1 UMR-S1052, Centre de Recherche en Cancérologie, Lyon, France; 2Anipath, Faculté de médecine Laënnec, Lyon, France; 3Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d’oncologie médicale, Lyon, France; 4Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Lyon, France; 5Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des spécialités digestives, Lyon, France; 6Département de Biopathologie, Gustave Roussy, Villejuif, France.
Background: Pancreatic neuroendocrine tumors (pNETs) are generally chemoresistants probably due to low proliferation rate and defects in apoptotic pathway. Targeted therapies are new encouraging options for pNETs however; clinical trials show limited objective response. Combination of chemotherapy and targeted therapy could be a new solution in therapeutic care. Streptozotocin (STZ) is the 1st line therapy for unresectable pNETs.
Methods: Based on the literature, we hypothesized that mTOR pathway over-activation could lead to resistance to STZ.
To evaluate this, we combined mTOR pathway inhibitors to STZ in in vitro and in vivo models. 4 mTOR pathway inhibitors (Everolimus, MK2206, BKM120 and BEZ235) were tested. Cell viability, proliferation and apoptosis were assessed in INS-1E and MIN6 cells (insulinoma cell lines). Development of tumor nodules was analyzed in an intra-splenic xenograft model. We also analyzed effects on these combinations on glycaemia and normal β cell mass to evaluate side effects.
Results: We show that all 4 combinations have synergistic effect in vitro. These combinations lead to heterogeneous mTOR pathway inhibition and increased apoptosis. In vivo, combinations lead to decreased tumor dissemination with variable efficacy depending on the inhibitor used. Hyperglycaemia and toxicity observed with BKM120 were avoided by decreasing doses.
Conclusions: These results suggest that combination of mTOR pathway inhibitors and STZ should be assessed in clinical trial.
Molecular Profiling Defines Subsets of Neuroendocrine Tumors (NETs) With Aggressive Disease: A Fox Chase Cancer Center (FCCC) Study
Namrata Vijayvergia,1 Steven J. Cohen,1 Patrick M. Boland,1 Karen. S. Gustafson,1 Fathima Sherrif,1 Harry Cooper,1 Igor Astaturov,1 Paul F. Engstrom,11Fox Chase Cancer Center, Philadelphia, PA.
Background: The rarity of NETs limits clinical trial accrual to develop new therapies. A better understanding of underlying biology is critical to development of and assignment of patients (pts) to clinical trials.
Methods: Patients with NETs at FCCC were enrolled onto a prospective IRB approved protocol that utilized an NGS platform to detect somatic mutations (SM) in 50 cancer-related genes on archived tissue. Genes tested included ABL1,AKT1,ALK,APC,ATM,BRAF,CDH1,CDKN2A,CSF1R,CTNNB1,EGFR,ERBB2,ERBB4,EZH2,FBXW7,FGFR,FGFR2,FGFR3,FLT3,GNA11,GNAQ,GNAS,NF1A,HRAS,IDH1,IDH2,JAK2,JAK3,KDR,KIT,KRAS,MET,MLH1,MPL,NOTCH1,NPM1,NRAS,PDGFRA,PIK3CA, PTEN,PTPN11,RB1,RET,SMAD4,SMARCB1SMO,SRC,STK11,TP53 and VHL.
Results: Sixty-six pts (median age 59, males 53%) were enrolled from 10/2013-02/2015. Gene profiling results were available on fifty-nine patients [21 (36%) high grade neuroendocrine carcinoma with Ki 67 > 20% (HG), 11(19%) pancreatic NETs (PNET), and 27(45%) carcinoid]. Twenty-seven (45%) pts were found to have SMs and 32 (55%) did not, with 5(10%) pts’ tumors having >1 SMs (3 HG and 2 PNETs). Incidence of SM was 77% (16/21) in HG NETs, 38% (4/11) in PNETs and 23% (6/24) in carcinoids. Most common SMs in HG NETs were TP53 (30%), BRAF (18%), KRAS (12%) and PIK3CA/PTEN (15%) (Table 1). Low grade (LG) NETs (Ki67 ≤ 2%) of small intestine origin didn’t harbor any mutations. Among the low-intermediate grade (LIG) NETs (Ki67 ≤ 20%), incidence of SMs was higher in pts with progressive disease in the 6 months preceding enrollment than those with stable disease [7/18 (33%) vs 2/20 (10%), p = 0.01].
Conclusion: SMs are seen frequently in HG-NETs but are rare in LG-NETs. TP53, KRAS, BRAF and PIK3CA/PTEN mutations are common in HG carcinomas and PNETs. Higher mutational load in LIG-NETs is associated with higher chance of progressive disease on prior regimen which may affect future treatment. These findings provide a basis to develop new targeted therapy trials for NETs. Analysis of relationship of SM to clinical outcome based on treatment received is ongoing to assess their prognostic/therapeutic implications.
Assessing Treatment Benefit of Telotristat Etiprate in Patients with Carcinoid Syndrome: Patient Exit Interviews
Lowell Anthony,1 Dieter Hörsch,2 Claire Ervin,3 Matthew H. Kulke,4 Marianne Pavel,5 Emily Bergsland,6 Martyn Caplin,7 Kjell Öberg,8 Richard Warner,9 Pamela Kunz,10 David C. Metz,11 Janice Pasieka,12 Nick Pavlakis,13 Dana DiBenedetti,3 Emily Haydysch,3Qi Melissa Yang,14 Shanna Jackson,14 Karie Arnold,14 Linda Law,14 Pablo Lapuerta,141University of Kentucky, Lexington, KY; 2Zentralklinik Bad Berka, Bad Berka, Germany; 3RTI Health Solutions, Research Triangle Park, NC; 4Dana-Farber Cancer Institute, Boston, MA; 5Charitè –Universitätsmedizin, Berlin, Germany; 6UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 7Royal Free Hospital, London, United Kingdom; 8Uppsala University, Uppsala, Sweden; 9Icahn School of Medicine at Mount Sinai, New York, NY; 10Stanford University, Palo Alto, CA; 11University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA; 12Tom Baker Cancer Centre Calgary, Canada; 13Royal North Shore Hospital, St Leonards, Australia; 14Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
Background: Telotristat etiprate (TE), an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome (CS) by reducing serotonin production. TE was evaluated in TELESTAR, a phase 3 study; the primary endpoint showed significant reductions in bowel movement (BM) frequency for 2 TE dosages + standard of care (SOC) vs. SOC. TELESTAR patients had CS inadequately controlled on somatostatin analog therapy with ≥4 BMs per day. They were interviewed about baseline symptoms and clinical trial experiences.
Materials and Methods: Participating sites were asked to invite all TELESTAR patients (consent obtained prior to randomization) to phone interviews scheduled between Weeks 12 and 14. Patients and interviewers remained blinded to treatment assignment. Interview data were summarized with standard qualitative analysis methods.
Results: All interview participants (N = 35) reported diarrhea and/or excessive BMs at baseline. Diarrhea (n = 17), followed by BM frequency (n = 9), and urgency (n = 5) were identified as the most bothersome and important symptoms to treat. BM frequency negatively affected emotional, social, physical, and occupational well-being. When probed, most participants reported that a reduction of ≥30% would be considered meaningful.
Improvements in CS symptoms were reported by 69% of participants. Among these, 88% reported reductions in BM frequency and 79% reported improvements in stool consistency. 95% who reported reductions in BM frequency noted that it was meaningful, describing a better ability to enjoy life, leave the house, and participate in social and other activities.
Among the 33 participants answering a question about treatment satisfaction, 55% reported being somewhat or very satisfied with TE in relieving CS symptoms. Reports of “very satisfied” were 0% (0/9) on placebo (SOC) and 50% (12/24) on TE, with similar results in the 2 TE dosage groups.
Conclusions: Diarrhea and BM frequency were identified as the most impactful CS symptoms. The primary endpoint of TELESTAR is very meaningful to patients.
Biomarkers in Late Stage Neuroendocrine Tumors of the Small Bowel
Joy Ardill,1 Wendy Stronge,1 David McCance,1 Brian Johnston,11Royal Victoria Hospital Belfast and Queen’s University Belfast, Northern Ireland, United Kingdom.
Background: Small bowel neuroendocrine tumors (SB-NETs) comprise 20-25% of all neuroendocrine tumors (NETs). They present early with obstruction or later with diarrhea, flushing and in some, right sided heart lesions (CHD). Biomarkers for MGC include serotonin or urinary 5 hydroxy indole acetic acid (U5HIAA), the general NET marker chromogranin A (CGA) and a specific marker, neurokinin A (NKA). We have shown that NKA >50 ng/l indicates poor prognosis. Many treatment options for MGC exist.
Methods: We reviewed clinical notes from 20 patients who died from SB-NETs to identify useful markers for late stage disease. We noted biomarkers for 2 years prior to death, at 24, 18, 12 & 6 m.
Results: All patients were symptomatic, 20/20 with diarrhea, 19/20 with flushing and 10/20 with CHD. All received somatostatin analogue therapy. Thirteen had surgery (5/20 right hemi-colectomy, 4/20 tumor resection). Eight received radio nucleotide therapy, 3 hepatic embolization and 7 IFA therapy.
From 24-6 m median U5HIAA (with ranges) rose through 285 (54.3-1,230), 274 (82.4-704), 397 (62-1,985) to 701 (78.1-1,995) umol/l, CGA 375 (140- > 1,200), 1,200 (40- > 1,200), >1,200 (220- > 1,200) to >1,200 175- > 1,200)U/l and NKA 57 (20-580), 109 (22-917), 112 (23-1,350) to 134 (30-2,425)ng/l. (Ref Ranges: U5HIAA <47umol/l, CGA <30U/l, NKA < 20 ng/l).
In 20 patients with 4 sample times, 4 specimens were missed for NKA, 6 for CGA and 15 for 5HIAA.
In 2 patients U5HIAA remained <150umol/l throughout and 6 had no sample at 6 m. In 4 patients CGA remained <500U/l throughout, 47% of CGAs were >1,200U/l. In 2 patients NKA remained <50 ng/l throughout and in all others NKA was >50 ng/l from 6 m.
Conclusion: The DACO Assay for CGA does not dilute parallel to standards above 1,200U/l making CGA difficult to measure in advanced disease. Missed sampling for U5HIAA is a problem in late disease. NKA and U5HIAA are both reliable tests for heralding terminal disease.
Response to Interferon Alpha (IFA) in Patients With Small Bowel Neuroendocrine Tumors (SB-NETs)
Joy Ardill,1 Brian Johnston,1 David McCance,11NET Group, Royal Victoria Hospital, Belfast, Northern Ireland.
Background: Small bowel NETs are uncommon with very variable survival outcome. Many therapeutic options are now available. Post-surgical resection and other proactive interventional procedures, somatostatin analogue (SA) therapy is used for symptom control and disease management. In some patients disease remains indolent while in others, when other therapeutic options are exhausted, disease progresses. For several decades some centers have used IFA concomitant with SA when SA alone is failing.
Methods: We report the findings from 15 patients who commenced SA concomitant with IFA, in order to control symptoms and disease progression. IFA (3MU) was administered 3 times weekly and in 6/15 patients the dose was increased to 6 or 10 MU3 times weekly.
Results: Male female ratio was 8:7. At the time of diagnosis at surgery or biopsy, Ki67 was <2% in 15/15 patients and 3/15 patients had carcinoid heart disease. All 15 patients had advanced symptomatic carcinoid disease on SA therapy. Two patients died within 1 month of starting IFA. Five patients did not tolerate the side effects of IFA and chose to discontinue within 3 months. A further patient stopped treatment at 6 months. Of these 6, 3/6 reported symptom response and 4/6 showed biomarker response during treatment. Survival was 12 (6-29) months post IFA commencement. Seven patients responded to IFA, 7/7 reported symptom control and 7/7 showed a significant reduction in circulating NKA 126(28-4500) to 48 (8-750) ng/L (median and range) with 6/7 showing significant reduction in urinary 5HIAA output 384(55-1180) to 78 (48-804) umol/L. Survival in these patients was 108 (21-207) months post commencement of IFA therapy. Radiology showed stable disease in all of these patients for between one and six years.
Conclusion: IFA concomitant with SA offers improved survival for many patients with late-stage small bowel NETs.
Complete Response to Combination Therapy With 177Lutetium PRRT and Capecitabine in the Treatment of Thymic Squamous Cell Carcinoma
Tannaz Armaghany, MD,1 Gelareh Vahdati, MD,2 Shelly Broline, MD,2 Mohammadali Hamiditabar, MD,2 Ran Goshen, MD, PhD,3 Moshe Rogosnitzky,3 Petros Giannikopoulos, MD,4 Aleah F. Caulin, PhD,4 William R. Polkinghorn, MD,4 Ebrahim Delpassand, MD,21Westchase Oncology Center, Houston, TX; 2Excel Nuclear Oncology Center, Houston, TX; 3Eliaso Holding Ltd., Israel; 4Driver Group, San Francisco, CA.
Background: Thymic carcinoma is a highly aggressive malignancy and carries a poor prognosis when metastatic. Some thymic carcinomas express somatostatin receptors. Peptide Receptor Radionuclide Therapy (PRRT) is currently utilized in clinical trials in the treatment of neuroendocrine tumors (NETs) due to somatostatin receptor expression. Capecitabine has shown tumor response in thymic carcinomas and it has also been used as a radiosensitizer during PRRT treatments in NETs.
Case Report: A 70 year old nonsmoker Caucasian male presented with cough and severe fatigue in August 2013. CT scan of his chest showed an anterior chest mass measuring 48x20 mm and multiple liver lesions.18 F-FDG- PET/CT scan confirmed the same findings. In 11/2013 a CT guided biopsy revealed moderately differentiated squamous cell carcinoma of the thymus. Chemotherapy with Cisplatin, Cyclophosphamide, Vincristine and Adriamycin (CVAP) was administered from 11/2013 to 2/2014. After initial mixed response he later on progressed in May of 2013. An Octrescan was performed in 5/2014, which showed intense somatostatin receptor activity in the same lesions seen on PET/CT scan. He was enrolled in a clinical trial of Peptide Receptor Radionuclide Therapy with 177Lutetium-DOTATATE in our center. Capecitabine was added in combination for the known antitumor and radio-sensitization properties. A baseline Ga68-DOTATATE PET/CT scan showed increased tracer uptake in the enlarged thymus also in the liver and the lung masses with SUVs of 15 and 7.10.
After the first cycle of PRRT plus Capecitabine treatment his repeat images with MRI and Ga89 PET/CT scan showed a dramatic response and near to complete resolution of liver and lung lesions.
Ga68 PET/CT DOTATATE was repeated before initiation of Cycle 3 in 9/2014. Complete resolution of the abnormal uptake throughout the liver was seen. Abdominal MRI also showed total resolution of the conglomerate mass in the liver with a residual lesion measuring 15 mm in the right lobe of the liver.
Imaging was repeated in 2 month intervals. At 7 month post end of the treatment he remains free of detectable disease on imagines and he clinically improves dramatically.
Conclusion: Thymic carcinoma with squamous cell differentiation is a rare but highly aggressive malignancy. Chemotherapy options are limited and the response is modest and short. This cancer is known to express somatostatin receptors. The combination of capecitabine and 177Lu-DOTATATE PRRT showed dramatic response in our case. To our knowledge this is the first case reported of a patient treated with this combination with complete response on imaging and laboratory evaluation. PRRT with or without Capecitabine should be further investigated in the treatment of this malignancy.
Treatment of High Grade Metastatic Neuroendocrine Tumor (mNET) With Peptide Receptor Radionuclide Therapy (PRRT) Retrospective Analysis in a Single Referral Center
Tannaz Armaghany, MD,2 Gelareh Vahdati, MD,1 Reza Amerinia, MD,1 Mohammadali Hamiditabar, MD,1 Sanjay Tamaski, PhD,2 Ebrahim Delpassand, MD,11Excel Nuclear Oncology, Houston, TX; 2Westchase Oncology Center, Houston, TX.
Background: The purpose of this study was to retrospectively evaluate the efficacy of PRRT with 111In- Octreotide or 177Lu- Octreotate in the treatment of high grade mNETS. Poorly differentiated high grade NETs are characterized by aggressive histologic features (high mitotic rate, extensive necrosis and nuclear atypia) and a poor prognosis. They are rarely express somatostatin receptors. Somatostatin receptor expression is seen in some of high grade NETs and this can be the basis of PRRT as a treatment modality to control this disease.
Methods: Based on chart review we selected a subgroup of patients with the diagnosis of somatostatin receptor positive high grade mNETs who were referred to our center for PRRT treatment. We used differentiation (poorly differentiated) or Ki67 index >20% (either one that was available). RECIST criteria were used to determine the status of disease at base line and last follow up at defined intervals and survival was calculated. Patients were treated up to maximum of 4 PRRT cycles. Biological response was assessed by calculating the median SUV change of 3 target lesions by comparing baseline and the last repeated PET scan SUVs and reported as percent.
Results: A total of 262 charts were reviewed and 17 patients were evaluable. Median age was 53 ranging from 37 to 70 years of age. Primary lesions were divided to pancreatic NET (PNET) n = 9 (53%), gastrointestinal NET n = 4 (23%), pulmonary n = 1 (6%), prostate cancer n = 1 (6%) and unknown primary n = 2 (12%). 7 patients (41%) had carcinoid syndrome, and among these patients 4 (57%) were PNET and 3 (43%) were gastrointestinal NET 59% (n = 10) of patients received Lutetium and 41% (n = 7) received Indium. During 12 months follow up 29% of patients had stable disease or partial response. Medium progression free survival was 12 months (Figure1). 6 patients had 30% SUV intensity reduction by PET/CT scan.
Conclusion: PRRT is a viable option for metastatic high grade NETs that express sandostatin receptors. The median progression free survival in our study is comparable to standard first line chemotherapy treatment. The efficacy of PRRT on the survival of the population studied is limited by small population size, patient selection and heterogeneity of origin of primary site.
Economic Evaluation of Octreotide LAR versus Lanreotide Depot in the Treatment of Metastatic Gastrointestinal Neuroendocrine Tumors
Rajeev Ayyagari, PhD,1 Maureen Neary, PhD, MS,2 Shang Li, MS,3 Chen Zhao, PhD,3 Keiko Higuchi, MPH,2 Jipan Xie, MD, PhD,3 Al B. Benson III, MD, FACP, FASCO,41Analysis Group Inc., Boston, MA; 2Novartis Pharmaceuticals, East Hanover, NJ; 3Analysis Group Inc., New York, NY; 4Northwestern University, Chicago, IL.
Background: The long-acting somatostatin analogs octreotide LAR and lanreotide depot are recommended in National Comprehensive Cancer Network (NCCN) guidelines for patients with functional and nonfunctional metastatic GI-NETs. This study estimated the cost and effectiveness of treating metastatic GI-NETs with long-acting octreotide versus lanreotide from a US payer perspective.
Methods: An economic model was constructed to compare octreotide versus lanreotide among functional and nonfunctional patients with GI-NETs over 3-year and lifetime horizons. Costs, life-years and quality-adjusted life years (QALYs) were estimated in the model using an annual discount of 3%. A partitioned survival model was used, including stable, progressed, and death states; breakthrough symptoms were possible for functional patients. Efficacy inputs for octreotide were obtained from the PROMID trial. Lanreotide was assumed to be identical in efficacy to octreotide because of a lack of data comparing these drugs. This assumption is supported by the fact that the NCCN guidelines do not differentiate between these drugs. Utilities for stable and progressive disease were obtained from a published study estimating utilities for NET. The costs for treatments, hospitalizations, physician visits, procedures, and end-of-life treatment were obtained from standard sources and the literature.
Results: The total life-years and QALYs were identical for the 2 drugs because of equal efficacy assumptions. Over 3 years, patients lived 1.8 years with stable disease, 0.8 years with progressive disease, and spent 0.2 years with breakthrough symptoms requiring additional treatment. The estimated QALYs were 1.8, and the overall costs were $247,820 and $221,709 for patients receiving lanreotide and octreotide, respectively. Overall, patients receiving octreotide lived 7.9 years on average and incurred $81,745 less in lifetime costs than patients receiving lanreotide.
Conclusions: For patients with metastatic GI-NETs, the cost of treatment with octreotide LAR was considerably lower than the corresponding cost for treatment with lanreotide depot over the 3-year and lifetime horizons.
A Study of BP Variability Utilizing 24 Hour Ambulatory BP Monitoring in Patients With Catecholamine Secreting Neuroendocrine Tumors Before and After Tumor Resection
Bonita J. Bennett, RN,1 Anirban Ganguli, MD,1 Debbie L. Cohen, MD,1 Raymond R. Townsend, MD,11Renal, Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA.
Background: Blood pressure variability in hypertension is known to cause target organ damage. The role of the sympathetic nervous system in this variability is unknown. We studied blood pressure and heart rate changes before and after surgery for catecholamine producing neuroendocrine tumors using 24 hour ambulatory blood pressure monitoring (ABPM) to assess the impact of exaggerated sympathetic activity on hemodynamic variability.
Methods: We performed a prospective observational study of patients with histological confirmation of a secretory pheochromocytoma/paraganglioma who were evaluated at the Hypertension Clinic, University of Pennsylvania from January to October 2014 for pre-operative alpha blockade prior to tumor resection. All patients had routine biochemical evaluations and 24 hour ABPM (Spacelab monitor) 1-3 weeks prior to surgery and 6-8 weeks after surgery during outpatient follow up. Variability was measured using standard deviation(SD) and by average real variability(ARV) on 24 hour Systolic BP(SBP), Diastolic BP(DBP), Mean Arterial Pressure(MAP), Pulse Pressure(PP) and heart rate(HR).
Results: 13 patients whose catecholamines normalized after surgery have been studied thus far. Mean age was 59.3 ± 9.4 years with 69.2% females (n=9), 10 Caucasians (77%), 2 African American (38%) and 1 Asian. (n=1.8%) with mean BMI of 25.37± 4.36 kg/m2. Office SBP and DBP significantly improved after surgery (127.7 ±16.2 vs 115.7± 11.7mmHg, p=0.005) and (74.3± 9.6 vs 66.6±6.2 mmHg, p=0.0008). ABPM recordings showed that 24 hr average PP was significantly lower (p=0.0501) and HR was significantly higher (p=0.001) post-surgery while PP during awake hours was significantly higher before surgery (p=0.029). Hemodynamic variability as measured using ARV and SD for 24 hr SBP, DBP, MAP, PP and HR did not change significantly post-surgery.
Conclusion: Despite normalization of hemodynamic parameters consistent with successful surgery in patients with catecholamine secreting neuroendocrine tumors, the variability persists, which may be real or due to a small sample size.
Nutritional Status and Nutritional Risk in Patients With Neuroendocrine Tumors
Mette Borre, RD,1 Anne Wilkens Knudsen, RD, MSc,2 Gitte Dam, MD, PhD,1 Henning Grønbæk, MD, PhD,11Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; 2Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Background: Malnutrition is common in patients with cancer and is associated with impaired function and reduced quality of life. No data are available on nutritional status and nutritional risk in patients with neuroendocrine tumors (NET). Therefore we aimed to assess: 1) nutritional status, 2) nutritional risk and 3) whether nutrition impact symptoms (NIS) encompassing nausea, dry mouth, pain affecting appetite, swallowing difficulties, changes in taste and early satiety are related to nutritional status or nutritional risk in NET patients.
Methods: We performed a cross-sectional study in NET outpatients at department of Hepatology and Gastroenterology, Aarhus University Hospital, ENETS NET Center of Excellence. We measured the body mass index (BMI). Handgrip strength (HGS) was used as a marker of nutritional status. Nutritional risk was determined by the NRS-2002. NIS was assessed by the eating symptoms questionnaire (ESQ), and the disease related appetite questionnaire (DRAQ). Data are presented as median (IQR) or %.
Results: We included 139 patients (53% w). Age 66 (19-91) years, BMI 24.5 (15-44) kg/m2. A BMI<20.5 was found in 15.1%. A Low HGS (w<20 kg, m<30 kg) was found in 24.5% and 27.5% were at nutritional risk. Patients with BMI<20.5 had increased risk of having a dry mouth (p< 0.05). Low HGS was associated with a higher risk of the NIS (p< 0.05). Patients at nutritional risk more often had a stomach ache, dry mouth, pain affecting appetite, changes in taste, chewing difficulties, poor appetite, early satiety, rare hunger and reported that their disease influenced their appetite for more than 3 months (all < 0.05).
Conclusions: Almost 1/3 of NET outpatients were at nutritional risk or had impaired nutritional status and this was associated to specific NIS in NET patients. We recommend that NET outpatients should be screened with HGS and NRS-2002.
The Cost Impact of Non-Infectious Diarrhea in Patients With Carcinoid Syndrome
Michael S. Broder, MD, MSHS,1 Eunice Chang, PhD,1 Dasha Cherepanov, PhD,1 Maureen P. Neary, PhD,21Partnership for Health Analytic Research, LLC, Beverly Hills, CA; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: Carcinoid syndrome (CS) refers to the hormonal effects of carcinoid tumors, and typically includes non-infectious diarrhea (NID). Despite their high frequency in patients with CS, the healthcare costs and utilization associated with NID has not been elucidated.
Methods: Using MarketScan® (11/2002-12/31/2012) commercial insurance claims, we identified newly-diagnosed CS patients with a first medical claim for CS (ICD-9-CM code 259.2) and either an additional claim for CS and/or a claim for carcinoid tumor (209.x). Patients had to be CS free for 1 year prior to index CS diagnosis date. Multiple measures of healthcare utilization and cost were reported for the first year post index diagnosis of CS, stratified by evidence of NID (ICD-9-CM codes 564.5, 787.91). Results were reported before and after adjusting for demographics, US region, and conditions.
Results: Of 2,822 newly-diagnosed CS patients (mean age: 51.5 years; women: 56.9%; mean Charlson Comorbidity Index: 3.6), 534 (18.9%) had NID after CS diagnosis. Annual healthcare costs in patients with NID were $82,032 versus $52,621 in patients without NID. After adjusting for baseline differences between groups, patients with NID had higher mean number of office visits, inpatient hospitalizations, and ED visits (all p<0.001) one year post CS diagnosis. Adjusted risk of hospitalization was 49.3% in patients with NID vs. 39.7% in patients without NID (odds ratio: 1.48; 95%-CI: 1.22-1.79). Patients with NID had higher adjusted total annual costs (+$28,645), pharmacy costs (+$2,441), non-pharmacy costs (+$26,205), visit costs (+$15,718), and inpatient hospitalization costs (+$11,425) compared to those without NID (all p<0.001).
Conclusion: NID in CS patients is associated with a significantly increased healthcare utilization the year following initial CS diagnosis and an additional $30,000. The odds of hospitalization among CS patients with NID are about 1.5 times of those without NID. Future studies should focus on the humanistic burden of NID symptoms on CS patients’ lives.
Relationship Between Lanreotide Autogel, Chromogranin A and Progression-Free Survival in Patients With Gastroenteropancreatic Neuroendocrine Tumors
Núria Buil-Bruna,1 Marion Dehez,2 Amandine Manon,2 Thi Xuan Quyen Nguyen,2 Iñaki F. Trocóniz,11Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; 2Dept. of Pharmacokinetics and Drug Metabolism, Ipsen, Les Ulis, France.
Background: Antitumor efficacy and safety of lanreotide Autogel (Depot in US) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was demonstrated in the CLARINET study in which 204 patients received deep subcutaneous injections of lanreotide 120 mg (n=101) or placebo (n=103) every 4 weeks for 96 weeks. Plasma chromogranin A (CgA) may reflect tumor growth and could be a prognostic indicator for progression-free survival (PFS). We developed an integrated pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of lanreotide Autogel on serum CgA and PFS in patients with nonfunctioning GEP-NETs.
Methods: Data from 810 lanreotide and 1298 CgA serum samples (n=632 placebo; n=666 lanreotide) were used. Of patients with available serum samples 76 experienced disease progression (n=49 placebo; n=27 lanreotide). The population approach in NONMEM v7.2 was used for analysis.
Results: Lanreotide serum profiles were described by a one-compartment disposition model with absorption characterized by two parallel pathways following first- and zero-order kinetics. CgA levels increased continuously in the placebo group, reflecting disease progression as a function of time from study initiation. A direct inhibitory relationship between lanreotide serum concentrations and CgA levels was described by the standard maximum effect (EMAX) PD model.
The estimated lanreotide concentration required to achieve half-maximum effect (C50) on CgA was 5.6 ng/mL (approximately nadir in NET patients on lanreotide 120 mg). Baseline target lesions and patient age correlated with baseline CgA levels. When PFS was treated as a time-to-event response and modelled by Weibull distribution, a decrease in CgA from baseline reduced progression hazard (p<0.001). Pancreatic tumor location and hepatic tumor load >25% were associated with a higher hazard of progression (p<0.001).
Conclusions: This is the first analysis to quantify the relationship between serum lanreotide, plasma CgA and PFS in patients with GEP-NET. Our results confirm the antitumor efficacy of lanreotide Autogel in these tumors.
Embolotherapy for Neuroendocrine Tumor Liver Metastases: Prognostic Factors for Hepatic Progression-free Survival and Overall Survival
James X. Chen, MD,1 Steven Rose, MD,2 Sarah B. White, MD,3 Ghassan El-Haddad, MD,4 Nicholas Fidelman, MD,5 Hooman Yarmohammadi, MD,6 Daniel Sze, MD, PhD,7 Riad Salem, MD,8 David Metz, MD,9 Michael C. Soulen, MD,11Division of Interventional Radiology, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA; 2Division of Interventional Radiology, Department of Radiology, University of San Diego Medical Center, San Diego, CA; 3Division of Interventional Radiology, Department of Radiology, University of Wisconsin School of Medicine, Madison WI; 4Division of Interventional Radiology, Department of Radiology, Moffitt Cancer Center, Tampa, FL; 5Division of Interventional Radiology, Department of Radiology, University of San Francisco Medical Center, San Francisco, CA; 6Division of Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY; 7Division of Interventional Radiology, Department of Radiology, Stanford University Medical Center, Stanford, CA; 8Division of Interventional Radiology, Department of Radiology, Northwestern Memorial Hospital, Chicago, IL; 9Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
Background: Embolotherapies play an important role in the management of neuroendocrine tumor (NET) liver metastases, but available data on prognostic factors remains limited and controversial, leading to wide practice variations and uncertainty regarding optimal embolotherapy modality. The purpose of this study was to evaluate disease and treatment related variables in a modern context for factors affecting outcomes following embolotherapy.
Methods: This was a multicenter retrospective study of patients with NET liver metastases, who were treated with conventional transarterial chemoembolization (TACE), transarterial embolization (TAE), or selective internal radiation therapy (SIRT) between 2004-2015. The primary endpoints were hepatic progression-free survival (HPFS) and overall survival (OS). Survival analysis with Cox proportional hazards models was performed to evaluate tumor and treatment related factors including WHO 2010 grade, tumor type, and embolotherapy modality.
Results: 184 cases with mean follow-up time of 28 months were analyzed. Univariate and multivariate Cox proportional hazards models are shown in table 1. Higher tumor grade conferred significantly higher hazard ratios (HR) for HPFS and OS on univariate analysis, but the associations weaken on multivariate analysis. Tumor burden of 50% liver volume or greater conferred significantly higher HRs for HPFS and OS in multivariate analyses. No significant differences in HRs for HPFS or OS were seen among tumor types. In grade 1 and 2 tumors, SIRT conferred significantly lower HR for HPFS. In grade 3 tumors, SIRT conferred significantly higher HR for HPFS and OS than TACE.
Conclusion: Higher WHO 2010 grade and hepatic tumor burden of 50% or greater were negative prognostic factors for HPFS and OS following liver-directed embolotherapy. Tumor type was not a significant prognostic factor for HPFS or OS. SIRT demonstrated improved HPFS for grade 1 and 2 tumors, but worsened OS versus TACE for grade 3 tumors.
Multiple Endocrine Neoplasia (MEN1) Patients Need Close Monitoring and Aggressive Management
Ioannis Christakis,1 Lee Starker,1 Cote Gilbert,2 Claudius Conrad,1 Matthew Katz,1 Wei Qiu,1 Angelica Silva,1 Bryan Fellman,3 Paul Graham,1 Elizabeth Grubbs,1 James Yao,4 Jeffrey E. Lee,1 Nancy Perrier,11Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX; 2Department of Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, Houston, TX; 3Department of Biostatistics, MD Anderson Cancer Center, Houston, TX; 4Department of GI Medical Oncology, MD Anderson Cancer Center, Houston, TX.
Background: Multiple Endocrine Neoplasia (MEN1) patients develop primary hyperparathyroidism, pituitary adenomas and pancreatic neuroendocrine tumors (PNETs; functioning or non-functioning). The major source of disease-specific mortality is liver metastasis from PNETs. In 2006 we showed that early diagnosis and intervention could increase overall disease free survival. To further expand on this work we have revisited our experience with patients with MEN1 and PNET who underwent at least one pancreatic operation.
Methods: All patients had either radiographic and ± histologic PNET in the setting of genetically or clinically confirmed MEN1. Patients who had pancreatic resection were included in the study.
Results: 171 cases had a PNET out of a total of 487 patients with confirmed MEN1. 103 patients (52 males: 51 females) met the inclusion criteria. Median age was 43.08 years old, (SD:13.5). The most common mutation identified was 210_211delCC in 5 cases. Mutations in menin exon numbers 2 and 10 were the most frequent (19 and 15 cases respectively). Nonsense mutations occurred in 24 cases. The type of PNETs identified included nonfunctioning (NF, 45.6%), insulinoma (20.5%), glucagonoma (2.9%), PPoma (2.9%), and VIPoma (1.0%). In addition, 27.2% of patients presented clinically with synchrononous duoduodenal gastrinoma together with NF PNET. Disease status at presentation was local-regional (LR) in 91.3% and distant metastasis (DM) in 8.7%. The median OS for LR patients was 22.27 years and for DM patients was 12.80 years (p < 0.001). OS was statistically different between different types of PNETs [Median OS for Insulinoma, Glucagonoma, non-functioning tumors were 44.04, 19.55, 22.27 years respectively (p=0.027)].
Conclusions: Overall survival of PNETs is related to the functional status of the tumor and the aggressiveness of the disease at presentation. PNETs in patients with MEN1 should be diagnosed as early as possible and managed with surgical resection in appropriate candidates.
Identification of Response Predictors to Capecitabine/Temozolomide in Metastatic Pancreatic Neuroendocrine Tumors
Mauro Cives,1 Masoumeh Ghayouri,1 Marjorie Brelsford,1 Michael Black,1 Anthony Rizzo,2 Alan Meeker,2 Jonathan Strosberg,11H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2Johns Hopkins University School of Medicine, Baltimore, MD.
Background: Capecitabine and temozolomide (CAPTEM) are active in the treatment of metastatic pNETs, with response rates ranging from 30% to 70%. Several small retrospective series have suggested that MGMT deficiency may predict response to temozolomide, however expression of MGMT has not been validated as a predictive biomarker. Cytotoxic chemotherapy is thought to be most active in aggressive tumors, however the ki-67 index has not been formally evaluated as a predictive factor. It is unclear whether chromosomal instability (which correlates with alternate lengthening of telomeres) predicts response.
Methods: 143 patients with metastatic pNET who underwent treatment with CAPTEM were retrospectively evaluated for radiographic and biochemical response as well as survival outcomes. The predictive/prognostic role of tumor grade, ki-67% and MGMT by IHC as well as ALT activation by FISH was assessed on up to 128 evaluable archival specimens. Frequently altered genes in pNETs were also sequenced and their status was correlated to the radiographic response.
Results: Treatment with CAPTEM was associated with partial response and stable disease by RECIST 1.1 in 54% and 35% of patients respectively. On waterfall plot analysis, 78% of patients showed some degree of tumor shrinkage. Major reductions (>50%) in CgA levels were recorded in 61% of cases. After a median of 9 cycles of treatment and a follow-up duration ranging from 5.6 to 112.8 months, the median OS was 73.2 months (95% CI, 51.9-81.1 months), while the median PFS was 17 months (95% CI, 15-25 months). Response to CAPTEM was not significantly influenced by tumor grade (p=0.19), mitotic count (p=0.06) or ki67% (p=0.1). MGMT status (p=0.1) and ALT pathway activation (p=0.37) were not predictive of response. Low mitotic rate (p=0.007) and ALT-positive phenotype (p=0.02) were significant predictors of better prognosis.
Conclusions: CAPTEM is an effective treatment regimen in pNETs. MGMT status appears to have no correlation with response.
A Population Based Pathology Analysis on Application of WHO-Nomenclature in Pulmonary Neuroendocrine Tumors
Jules L. Derks,1 Robert Jan van Suylen,2 Erik Thunnissen,3 Michael A. den Bakker,4 Egbert F. Smit,5 Harry J.M. Groen,6 PALGA: Dutch Pathology Registry7 Ernst-Jan. M. Speel,8,* Anne-Marie C. Dingemans,1,* 1Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands; 2Department of Pathology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands; 3Department of Pathology, VU medical Center, Amsterdam, the Netherlands; 4Department of Pathology, Maasstad Hospital, Rotterdam, the Netherlands; 5Department of Pulmonary Diseases, VU Medical Center, Amsterdam, the Netherlands; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre, Groningen, the Netherlands; 7PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands, Houten, the Netherlands; 8Department of Pathology, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands. *Authors contributed equally.
Background: Pulmonary neuroendocrine tumors (pNETs) are a cluster of rare diseases that are difficult to classify. We performed a population-based analysis to investigate pNETs nomenclature application in daily pathology practice.
Methods: Conclusions from pathology reports (2003-2012) describing carcinoids, (large cell) neuroendocrine carcinomas ((LC)NEC) or carcinomas with neuroendocrine features/differentiation were retrieved from the Dutch Pathology Registry by queries on origin/location, diagnosis and keywords, and screened for terminology. Cases with non-pulmonary/unknown origin and small cell lung cancer (SCLC) were excluded. Diagnoses were clustered into subgroups and retrieved terminology was compared to WHO 2004 diagnoses. Interpretation of non-WHO nomenclature by treating physicians (N=35) and certified pathologists (N=19) was evaluated by an online questionnaire; participants were requested to cluster retrieved diagnoses into the established WHO categories or as ‘unknown’. Uniform interpretation was scored for diagnoses with ≥50% agreement.
Results: 7989 conclusions were retrieved. After exclusion, the final pathology conclusion of 3216 unique patients, including 55 distinctive diagnoses (in N=3052) and 20 uncertain diagnoses (in N=164), were analyzed. Non-WHO nomenclature was used in 15% (N=448) of diagnoses and was observed more often when results of biopsy/cytology specimens were reported as compared to resections (Table 1). Diagnoses could be clustered into four groups: carcinoids (N=1086), NEC (N=1316), carcinomas with neuroendocrine features/differentiation (N=624) and unspecified NETs (N=26). Non-WHO nomenclature was found in 7% of carcinoid, 20% of NEC, 13% of carcinomas with neuroendocrine features/differentiation and 100% of unspecified NETs (Table 1). Uniform interpretation was achieved on 4/19 non-WHO nomenclature diagnoses by physicians and 10/19 non-WHO diagnoses by pathologists.
Conclusion: In 15% of pNETs other than SCLC, a non-WHO nomenclature diagnosis was applied by certified pathologists, more often on limited tissue specimens. The interpretation was different between treating physicians and pathologists. Application of uniform nomenclature is advocated to improve reporting of results of treatment in patients with pNET.
Clinical Features of Large Cell Neuroendocrine Carcinoma: A Population Based Overview
Jules L. Derks,1 Lizza. E. Hendriks,1 Wieneke A. Buikhuisen,2 Harry J.M. Groen,3 Erik Thunnissen,4 Robert Jan van Suylen,5 Ruud Houben,6 Ronald A. Damhuis,7 Ernst-Jan M. Speel,8 Anne-Marie C. Dingemans,11Department of Pulmonary Diseases, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands; 2Department of Thorax Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; 3Department of Pulmonary Diseases, University of Groningen and University Medical Centre, Groningen, the Netherlands; 4Department of Pathology, VU University Medical Centre, Amsterdam, the Netherlands; 5Department of Pathology, Jeroen Bosch Hospital, ‘s Hertogenbosch, the Netherlands; 6Department of Radiation Oncology (MAASTRO Clinic), Maastricht, the Netherlands; 7Department of Registry and Research, Comprehensive Cancer Centre, Rotterdam, the Netherlands; 8Department of Pathology, GROW school for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an orphan disease and few data are available on clinical characteristics. Therefore, we analyzed LCNEC registered in the Netherlands Cancer Registry (NCR) and compared data with small cell lung cancer (SCLC), squamous cell (SqCC) and adenocarcinoma (AdC).
Patients and Methods: Histologically confirmed LCNEC (N=952), SCLC (11,844), SqCC (19,633) and AdC (24,253) cases were selected from the NCR (2003-2012). Patient characteristics, metastases at diagnosis (≥2006) and overall survival (OS) were compared for stage I-II, III and IV disease. Multivariate COX regression analysis was performed including age, sex, TNM edition and T/N-stage for stage I-II, III and IV disease. Additionally, stage I/II surgically treated patients including the co-variate adjuvant chemotherapy (yes/no), and stage IV chemotherapy treated patients were analyzed separately. Non-proportionality was observed in stage I-II disease and therefore time-dependent Hazard ratios were reported.
Results: LCNEC increased from 56 patients in 2003 to 143 patients in 2012, attributing 0.9% of all lung cancers in this time period. Stage IV LCNEC patients (N=383) commonly had metastasis in liver (47%), bone (32%) and brain (23%), resembling SCLC. Median OS (95% confidence interval) of stage I-II, III and IV LCNEC was 32.4 (22.0-42.9), 12.6 (10.3-15.0) and 4.0 (3.5-4.6) months, respectively. In stage I-II surgically treated and stage IV chemotherapy treated LCNEC patients, the multivariate adjusted OS resembled SCLC and was poorer than that of SqCC and AdC (Table 1). However, frequency of treatment with adjuvant chemotherapy in surgically resected stage I-II LCNEC (23%) resembled SqCC (15%) and AdC (14%) more than SCLC (75%).
Conclusions: Diagnosis of LCNEC increased over the past 10 years. Metastatic pattern of LCNEC resembles SCLC as does OS in multivariate analysis. However, early stage treatment strategies seem more comparable to SqCC and AdC.
Treatment Patterns and Outcomes in Metastatic Neuroendocrine Tumors: Results From a Retrospective Community Oncology Database
Maxine D. Fisher,1 Sonia Pulgar,2 Matthew H. Kulke,3 Susan Pitman Lowenthal,2 David Cox,2 Paul J. Miller,1 Mark S. Walker,1 Lee S. Schwartzberg,41Vector Oncology, Memphis, TN; 2Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ; 3Program in Neuroendocrine and Carcinoid Tumors, Dana Farber Cancer Institute, Boston, MA; 4The West Clinic, Memphis, TN.
Background: As the incidence of neuroendocrine tumors (NET) has increased and new treatment options have emerged, there has been interest in studying the real-world experience of NET patients, with a focus on the academic center setting. This study describes the treatment patterns and outcomes of metastatic NET (mNET) patients in the community oncology setting.
Methods: Patient-level data including demographic and clinical information, treatments, and outcomes were collected from medical records of adult patients with mNET from the Vector Oncology Data Warehouse, a comprehensive cancer patient database representing a network of community oncology practices in the US.
Results: 265 patients with mNET were included in the analysis; median age was 65 (range 22-92) and median follow-up was 22 months. Most patients (81%) were initially diagnosed with stage IV NET, and 74% had liver metastases. Of the 181 patients with tumor grade recorded, 53% had well-differentiated (G1), 13% had moderately-differentiated (G2), and 34% had poorly-differentiated (G3) tumors. 38% of patients had intestinal NET, 31% had pancreatic NET, and 32% had other NET. The most frequently observed symptoms were diarrhea (44%) and abdominal pain (36%). Carcinoid syndrome or related symptoms were recorded for 43% of patients. The most common therapeutic classes utilized were somatostatin analogs (SSA) (58%), cytotoxics (35%), and targeted therapies (11%). Of 155 patients treated with SSA (all octreotide LAR), 34% received above-labeled dosing. Median progression-free survival (PFS) and overall survival (OS) from diagnosis were 9.9 months and 56.94 months, respectively. From diagnosis, patients with G1 or G2 tumors had a median OS of 83.93 months while patients with G3 tumors had a median OS of 12.43 months.
Conclusions: This is the first analysis of patients with mNET from a community oncology database in the US, and the results provide a real-world view of patient characteristics, treatment patterns, and outcomes.
Efficacy and Safety of Lanreotide Depot vs Placebo in Patients With Neuroendocrine Tumor and a History of Carcinoid Syndrome and Prior Octreotide Therapy
George A. Fisher, Jr,1 Edward M. Wolin,2 Pamela Kunz,1 Nilani Liyanage,3 Edda Gomez-Panzani,4 Susan Pitman Lowenthal,4 Rodney F. Pommier,5 Montaser Shaheen,6 Aaron Vinik,71Stanford University School of Medicine, Stanford, CA; 2Markey Cancer Center University of Kentucky, Lexington, KY; 3Ipsen Biopharmaceuticals, Inc., Boulogne-Billancourt, France; 4Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ; 5Oregon Health & Science University, Portland, OR; 6University of New Mexico Cancer Center, Albuquerque, NM; 7Eastern Virginia Medical School, Norfolk, VA.
Background: In the ELECT double-blind study, treatment with lanreotide depot, a long-acting somatostatin analog (SSA), significantly reduced the need for short-acting octreotide rescue medication for symptomatic control of carcinoid syndrome (CS) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) compared with placebo. This subanalysis assessed the efficacy and safety of lanreotide depot in patients with prior octreotide use.
Methods: Adults with histopathologically-confirmed GEP-NET or NET of unknown location with liver metastases and a history of CS (flushing and/or diarrhea) were included. Patients SSA-naïve or responsive to conventional doses of octreotide LAR (≤30 mg q4W) or short-acting octreotide (≤600 μg daily) were randomized to receive lanreotide depot 120 mg (SC q4W) or placebo. Efficacy assessment included complete treatment success, defined as 0 days of rescue short-acting octreotide between weeks 12-15 during double-blind.
Results: 64 patients (n=33 lanreotide; n=31 placebo) were previously treated with octreotide LAR (n=56), short-acting octreotide (n=24), or both (n=6). Patient mean age was 58.8 years, 45% were male, and 84% had been diagnosed ≥1 year before the study. Among the lanreotide-treated patients, 52% experienced complete treatment success vs 26% of placebo patients (RR = 1.996 [95% CI: 1.009, 3.950], P=0.0471). As expected, the mean daily frequency of diarrhea and/or flushing events was similar between treatment groups because both received SSAs (lanreotide and/or octreotide rescue). Most treatment-emergent adverse events were mild or moderate in severity (Table). One patient receiving lanreotide experienced serious TEAEs (small intestinal obstruction and urinary infection).
Conclusions: The relative chance for achieving complete treatment success was 2 times greater with lanreotide treatment than placebo in patients with GEP-NETs who were previously treated with octreotide for CS. Transition to lanreotide depot 120 mg was well-tolerated with no new safety signals detected.
A Phase I/II Study of TKM-080301, a RNAi Therapeutic Directed Against Polo-Like Kinase 1 (PLK1), in Patients With Gastrointestinal Neuroendocrine Tumors (GI-NET)
Thorvardur R Halfdanarson,1 Tannaz Armaghany,2 Samuel Ejadi,3 Donald W Northfelt,4 Ramesh K Ramanathan,4 Jonathan Strosberg,5 David C Smith,6 Daniel Vaena,7 Paul Fredlund,8 Sean C Semple,8 Sarabjit S Gahir,8 Andrew Dye,8 Mark Kowalski,81Mayo Clinic, Rochester, MN; 2Westchase Clinical Associates Houston, TX; 3Virginia G. Piper Cancer Center/TGen, Scottsdale, AZ; 4Mayo Clinic Scottsdale, AZ; 5Moffitt Cancer Center, Tampa, FL; 6University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 7Holden Comprehensive Cancer Center, Iowa City, IA; 8Tekmira Pharmaceuticals Corporation, Burnaby, BC, Canada.
Background: Polo-like kinase 1 (PLK1) regulates multiple critical aspects of cell progression, is highly expressed in many human tumors, and correlates negatively with patient outcome. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis.
Methods: The previously reported dose escalation portion of this phase I/II open-label study supported a maximum tolerated dose (MTD) of 0.75 mg/kg/week. The study included an initial expansion cohort at the MTD in subjects with advanced solid tumors, and subsequent expansion cohorts in subjects with adrenocortical carcinoma (ACC) and GI-NET. TKM-080301 was administered as a 30-minute IV infusion on Days 1, 8, and 15 of a 28-day cycle. Disease response according to RECIST 1.1 criteria was assessed following every two cycles of treatment.
Results: Fifteen previously treated subjects with GI-NET received TKM-080301; one subject was enrolled during the dose escalation phase and received two doses at 0.9 mg/kg and subsequently 0.6 mg/kg, one subject was enrolled during the initial expansion cohort at 0.75 mg/kg, the remaining 13 subjects were enrolled in the GI-NET expansion cohort at 0.75 mg/kg. In 13 GI-NET subjects who were evaluable, the best response observed was partial response (PR) for one subject (>60% reduction in tumor) and stable disease (SD) for 11 subjects (duration 1-52 weeks). Overall, 7/13 (54%) of subjects showed a best response of decrease in target tumor size (2.8% to 61%). The most common adverse events were: chills, nausea, vomiting, pyrexia, hypertension, fatigue, and increased AST. Serious adverse events considered at least possibly related to TKM-080301 were observed for three subjects in total included myocardial infarction (2 subjects), atrial fibrillation, and pulmonary edema.
Conclusion: This first-in-human trial indicates TKM-080301 was generally well-tolerated by the majority of subjects. In addition, promising evidence of anti-tumor effect has been observed in GI-NET. ClinicalTrials.gov Identifier: NCT01262235.
Real-World Treatment Patterns in Advanced Pancreatic Neuroendocrine Tumors in the Era of Targeted Therapy: Perspectives From an Academic Tertiary Center and Community Oncology Practices
Maurice Herring,1 Lynn Huynh, MPH, MBA, DrPH,2 Mei Sheng Duh, MPH, ScD,2 Francis Vekeman, MA,3 Audrey Tiew,2 Maureen P. Neary, PhD, MS,4 Emily Bergsland, MD,11UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, CA; 2Analysis Group, Inc., Boston, MA; 3Groupe d’Analyse, Ltée, Montreal, Canada; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Background: Pancreatic neuroendocrine tumors (PanNETs) are rare, slow-growing cancers. Optimal treatment of advanced PanNETs is unclear. For unresectable disease, somatostatin analogs (SSAs), targeted agents (everolimus, sunitinib), chemotherapy, and liver-directed therapy are routinely administered. We aim to evaluate treatment patterns in the era of targeted therapy among patients with newly-diagnosed advanced PanNETs in both academic and community practice settings.
Methods: Retrospective chart review identified patients at an academic cancer center (University of California, San Francisco [UCSF]) and a large network of community oncology practices with locations throughout 36 states in the US (Altos Solutions’ OncoEMR database; ALTOS). Eligible patients were ≥18 years and newly-diagnosed with advanced (i.e. locally advanced or metastatic) and well- to moderately-differentiated PanNET between 2010-2013. Patients were actively followed for ≥6 months after advanced PanNET diagnosis date, with ≥2 visits in 12 months.
Results: Fifty-four eligible patients (NUCSF=23; NALTOS=31) were identified out of 159 charts screened. Overall mean age at advanced PanNETs diagnosis was 60.6 years (ALTOS patients were non-significantly older than UCSF, p=0.11); 61.1% were male; median time to treatment initiation was 1.1 months; median follow-up time was 22.9 months. UCSF patients underwent more lines of therapy than ALTOS patients despite similar median follow-up times. Table 1 summarizes clinical and treatment characteristics by practice setting. The most common first-line treatments were SSA, everolimus, or chemotherapy at ALTOS and surgery, SSA, or chemotherapy at UCSF. The median time to treatment discontinuation for first/second-line was statistically significantly shorter for patients on chemotherapy than targeted therapy at both UCSF and ALTOS (chemotherapy=2.2 months vs. targeted=18.6 months, p<0.01).
Conclusion: Treatment patterns and durations for newly-diagnosed advanced PanNETs vary widely both within and between different practice settings. Limitations related to study methodology (e.g., incomplete information in the EMRs) preclude making definitive conclusions. Prospective studies are needed to more completely examine factors affecting choice of therapy.
Impact of Gene Expression Profiling Using the 92-gene Assay on Management of Neuroendocrine Carcinoma of Unknown Primary Site
Talal Hilal, MD,1 Scott R. Silva, MD, PhD,2 Lowell B. Anthony, MD,11Division of Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, KY; 2Department of Radiation Oncology, Loyola University, Maywood, IL.
Background: Neuroendocrine tumors (NETs) are slow growing and can be undetected until patients present with metastasis. Although pathologic examination is adequate for diagnosis, the identification of site of origin can be challenging. We aimed to retrospectively analyze the impact of the 92-gene assay on therapeutic decision making. Specifically, whether testing allowed for the use of molecularly targeted therapy, which otherwise may not have been utilized.
Methods: Forty patients from Louisiana State University and the University of Kentucky with metastatic neuroendocrine carcinoma of unknown primary site (NEC-UPS) after initial diagnostic evaluation were selected for retrospective analysis. Biopsy specimens were sent to bioTheranostics, Inc. (San Diego, CA) for molecular cancer classification with the 92-gene assay. Patient and tumor characteristics were collected and impact of the 92-gene assay results on clinical therapeutic decision making were evaluated.
Results: Twenty-one men and 19 women were included in the study, with an age range of 37-75 years and a median age of 63 years. Of the 40 patients, 55% presented with only liver metastases; 17.5% had disseminated metastases within the liver and other sites, and 27.5% patients presented with metastases located outside of the liver. The most common presenting symptoms were non-specific: abdominal pain (n=14), and diarrhea (n=7). The most common positive serum biomarkers were 5-hydroxyindolacetic acid (n=17), chromogranin A (n=11), pancreastatin (n=11), neurokinin A (n=5), and serotonin (n=5). In all cases, the 92-gene assay predicted a site of origin with >90% certainty – 35% predicted to be gastrointestinal carcinoid, 27.5% pancreatic islet cell, 12.5% small/large cell, and 5% lung carcinoid. Identifying the site of origin with the 92-gene assay altered chemotherapy regimen in 47.5% of patients and confirmed it in 50% of patients. Molecularly targeted therapy was used in 55% of the patients whose chemotherapy regimen was altered (see Figure 1).
Conclusion: In this retrospective analysis, patients identified with pancreatic islet cell tumors are most likely to benefit from gene expression profiling. Analysis of the impact of the 92-gene assay on survival should be evaluated in future studies.
Multicenter Prospective Phase II Trial of Bevacizumab (bev) for Progressive Pancreatic Neuroendocrine Tumor (PNET)
Timothy Hobday, MD,1 Jun Yin, PhD,1 Adam Pettinger, MA,1 Jonathan Strosberg, MD,2 Diane Reidy-Lagunes, MD,3 Helen Chen, MD,4 Charles Erlichman, MD,11Mayo Clinic College of Medicine, Rochester, MN (Mayo Phase 2 Consortium (P2C); 2H Lee Moffit Cancer Center, Tampa, Fl (Southeast P2C); 3Memorial Sloan-Kettering Cancer Center, New York, NY; 4National Cancer Institute, Rockville, MD.
Background: Single agent trials of mTOR inhibitors and VEGF receptor TKIs in PNET yield response rates < 10%. We previously demonstrated a 41% PR rate in PNET with the combination of temsirolimus and bevacizumab in patients with progressive PNET1. There are no data regarding the efficacy of single agent bevacizumab in PNET.
Methods: We conducted a multicenter phase II trial of bevacizumab at a dose of 10 mg/kg IV q 2 weeks in patients (pts) with well or moderately differentiated PNET, adequate organ function, and ECOG PS of 0-1. Important eligibility criteria included requirement for progression of disease by RECIST within 7 months of study entry. No prior anti-VEGF pathway inhibitor therapy was allowed. Ongoing octreotide was allowed at stable dose if required for symptom control. Primary endpoint was response with null hypothesis of 10% and promising result was defined as 30%. Planned enrollment was 21 pts.
Results: 22 pts enrolled from 10/2012 through 6/2014 were eligible for response assessment. 7 patients remain on therapy. Confirmed PR rate is 14% (3/22). 6 month progression free survival (PFS) was 95% (20/22). 19 out of 22 pts have follow-up > 12 months. The Kaplan-Meier 12 month PFS was 65% (95% CI: 34-85%). Median PFS is 18 months (95% CI 10.7- NA). Therapy was well tolerated with no grade 3-4 AEs except 36% of patients with grade 3 hypertension.
Conclusion: Bevacizumab therapy for progressive PNET is associated with promising clinical activity and a favorable toxicity profile. A median PFS of 18 months and a 14% confirmed PR rate were demonstrated in this trial of patients required to have RECIST criteria progression within 7 months prior to study enrollment.
Cystic Neuroendocrine Tumors of the Pancreas (c-pNETs): A Single-Center Experience
Vishnu Kommineni,1 Maria F. Coakley,2 Rahul Pannala,3 Longwen Chen,3 Jun Zhang,4 Nabil Wasif,3 Thorvardur R. Halfdanarson,41University of Alabama Huntsville Regional Campus, Huntsville, AL; 2Cork University Hospital, Cork, Ireland; 3Mayo Clinic, Scottsdale, AZ; 4Mayo Clinic, Rochester, MN.
Background: c-pNETs are rare pancreatic neuroendocrine neoplasms which according to some studies are felt to be less aggressive than their solid counterparts.
Methods: We identified all patients diagnosed with a c-pNET at the Mayo Clinic during the period 1990 to 2014. Data on patient characteristics and outcomes of therapy were extracted and analyzed.
Results: 46 patients were identified, 30 males (65%) and 16 females. The median age at diagnosis was 59.5 years (range: 31 to 78 years). 26 (57%) patients had no symptoms at diagnosis. Among symptomatic patients, abdominal pain was the most common symptom. Five patients (12%) had symptoms attributed to hormonal secretion and 4 (9%) had metastases at diagnosis. 10 patients (22%) had a diagnosis of MEN1. The diagnosis was made on a surgical resection specimen in 63%, on a fine-needle aspirate in 26%, a core needle biopsy in 9% and an open biopsy in 2%. Fifteen tumors (33%) were of WHO grade 1, five (11%) of grade 2 and 26 (56%) were ungraded. The majority of patients (66%) had unifocal tumors. Most patients (93%) underwent resection, most often distal pancreatectomy (81%). Most tumors were located in the tail (52%) followed by the body and head (15% each). The ENETS T-stage was: T1: 30%; T2: 39%; T3: 28%; T4: 2%. Only 4 patients (9%) had nodal involvement. Among resected patients, recurrences occurred in 9 with a median time to recurrence being 68.9 months (range: 6 to 220 months). T-stage did not predict recurrences (p=0.31).
Conclusion: c-pNETs are a rare subset of pNETs. They are frequently discovered incidentally, and are usually unifocal, nonfunctional and located in the tail of the pancreas. The prognosis after resection is good with the majority of patients achieving a cure but late recurrences may occur.
Randomized Phase II Study of Everolimus (E) Versus Everolimus plus Bevacizumab (E+B) in Patients (Pts) With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors (pNET), CALGB 80701 (Alliance)
Matthew H. Kulke,1 Donna Niedzwiecki,2 Nathan R. Foster,3 Briant Fruth,3 Pamela L. Kunz,4 Hagen Kennecke,5 Edward M. Wolin,6 Alan P. Venook,71Dana-Farber Cancer Institute, Boston, MA; 2Alliance Statistics and Data Center and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC; 3Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN; 4Stanford Cancer Institute, Palo Alto, CA; 5Vancouver Center: BC Cancer Agency, Vancouver, CA; 6University of Kentucky, Lexington, KY; 7University of California San Francisco, San Francisco, CA.
Background: It is not known if the addition of a VEGF pathway inhibitor to an mTOR inhibitor enhances antitumor activity in pNET. This randomized phase II study evaluated E or E+B in pts with advanced pNET.
Methods: Pts were randomized 1:1 to E (10 mg po qd) or E (10 mg po qd) with B (10 mg/kg IV q 2 wks). All pts received octreotide. The primary endpoint was PFS. Potential superiority of E+B vs. E was assessed using a stratified log-rank test with 90% power (1-sided α=0.15) to detect a HR of 0.64. Secondary endpoints included overall survival (OS), response rate (RR), and safety.
Results: 150 pts were randomized: median age was 59 years (21-86), 56% male, ECOG PS 0 (57%)/1 (43%), prior chemotherapy 24%. Median number of 28-day treatment cycles were 13 (E+B) and 12 (E); range 1-44. Median follow up was 25.9 months. Pts on E+B experienced more grade 3 AEs, including diarrhea (14% vs. 3%; p = 0.01), hyponatremia (12% vs. 3%; p = 0.02), hypophosphatemia (11% vs. 3%; p=0.04), proteinuria (16% vs. 1%; p = 0.001), and hypertension (41% vs. 12%; p < 0.0001). The frequency of grade 4 AEs was 11% in both arms. Median PFS was 16.7 mos (E+B) vs. 14 mos (E); HR=0.80 (95% CI: 0.55, 1.17; 116 PFS events), 1-sided p= 0.12. Median OS was 36.7 mos (E+B) vs. 35.0 mos (E), HR =0.75 (95% CI: 0.42-1.33; 49 OS events), 1-sided p=0.16. E+B was associated with a significantly higher RR (31%) compared to E alone (12%), p=0.005).
Conclusions: Treatment with E+B led to superior PFS compared to E but with more adverse events in this randomized phase II study. The RR was significantly higher in pts treated with E+B. The combination of E+B warrants further investigation in pts with advanced pNET.
Telotristat Etiprate Shows Benefit in Treating Patients With Carcinoid Syndrome That is Inadequately Controlled by Somatostatin Analog Therapy in the Phase 3 TELESTAR Clinical Trial
Matthew H. Kulke,1 Dieter Hörsch,2 Martyn Caplin,3 Lowell Anthony,4 Emily Bergsland,5 Kjell Öberg,6 Staffan Welin,6 Richard Warner,7 Catherine Lombard-Bohas,8 Pamela Kunz,9 Enrique Grande,10 Juan W. Valle,11 Douglas Fleming,12 Pablo Lapuerta,13 Phillip Banks,13 Shanna Jackson,13 Darren Wheeler,13 Brian Zambrowicz,13 Arthur Sands,13 Marianne Pavel,141Dana-Farber Cancer Institute, Boston, MA; 2Zentralklinik Bad Berka, Bad Berka, Germany; 3Royal Free Hospital, London, United Kingdom; 4University of Kentucky, Lexington, KY; 5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 6Uppsala University, Uppsala, Sweden; 7Icahn School of Medicine at Mount Sinai, New York, NY; 8Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 9Stanford University, Palo Alto, CA; 10Hospital Universitario Ramón y Cajal, Madrid, Spain; 11University of Manchester/ The Christie NHS Foundation Trust, Manchester, United Kingdom; 12Ipsen BioScience, Cambridge, MA; 13Lexicon Pharmaceuticals, Inc. The Woodlands, TX; 14Charitè –Universitätsmedizin, Berlin, Germany.
Background: Overproduction of serotonin from within neuroendocrine tumors (NET) causes carcinoid syndrome (CS), which includes diarrhea, flushing, and heart valve damage. Telotristat etiprate (TE) inhibits tryptophan hydroxylase (TPH), an enzyme that converts tryptophan to serotonin in the NET cell. TELESTAR is a pivotal phase 3 global clinical trial.
Methods: Patients with metastatic NET and inadequately controlled CS (≥4 daily BMs despite SSA therapy) were randomized (1:1:1) to receive TE (250 or 500 mg) or placebo (PBO) given tid, while continuing SSA. The primary endpoint was the reduction in the mean number of daily BMs averaged over the 12-week double-blind period of the trial.
Results: 135 patients (baseline mean BMs/day 5.7, baseline urinary 5-HIAA 88 mg/24hr) were randomized. The primary objective was met; BM frequency in both treatment groups was less than PBO (Hodges Lehman Estimator TE minus placebo of -0.813 (TE 250) and -0.689 (TE 500) BM/day, (p<0.001 for both comparisons). Decrease in mean daily BMs at Week 12 was 17% (PBO), 29% (TE 250), and 35% (TE 500). The proportion of patients with durable response (≥30% reduction in BM frequency for ≥50% of study) was 20% (PBO), 44% (TE 250) and 42% (TE 500), (p≤0.040 for both comparisons). Week 12 reductions in 24-hr u5-HIAA were 30.1 mg (TE 250), and 33.8 mg (TE 500) compared to PBO (p<0.001 for both dosages). Overall AE frequency was similar in all 3 groups. Mild/moderate depression was reported in 3 (PBO), 2 (TE 250), and 6 patients (TE 500), all events resolved while continuing therapy; 87% of randomized patients continued onto open-label treatment with TE 500 mg tid.
Conclusions: Telotristat etiprate provided statistically significant and clinically meaningful reductions in BM frequency and represents a promising potential new class of treatment for patients with CS inadequately controlled by standard of care SSA therapy.
Phase 2 Study of Fosbretabulin Tromethamine (CA4P) for the Treatment of Well-Differentiated, Low-to-Intermediate-Grade Unresectable, Recurrent or Metastatic Pancreatic or Gastrointestinal Neuroendocrine Tumors/Carcinoid with Elevated Biomarkers
Steven K. Libutti, MD,1 Lowell Anthony, MD,2 Julie Ann Sosa, MD,3 Pamela Kunz, MD,4 James Thomas, MD,5 Susan Cruikshank,6 Alice Varga,6 David J. Chaplin, PhD,6 James Burke, MD,6 Edward M. Wolin, MD,21Montefiore Medical Center, Bronx, NY; 2Markey Cancer Center, Lexington, KY; 3Duke University Medical Center, Durham, NC; 4Stanford University School of Medicine, Stanford, CA; 5Frodtert and Medical College of Wisconsin Clinical Cancer Center, Milwaukee, WI; 6OXiGENE Inc., South San Francisco, CA.
Background: Fosbretabulin is a reversible tubulin depolymerizing agent that targets tumor vascular endothelial cells leading to selective tumor vascular shutdown. As highly vascular tumors, GI-NETs are rational clinical targets for VDAs such as fosbretabulin. Based on the propensity for GI-NETs to produce bioactive compounds that mediate systemic symptoms, fosbretabulin induced tumor vascular shutdown may result in a reduction in the production of these biologically active compounds, and potentially lead to improved patient symptoms, quality of life, and long term outcomes.
Methods: This Phase 2 open label, multi-center trial, will include 20 patients with well-differentiated, low-to-intermediate-grade, advanced PNET or GI-NET who have relapsed after receiving prior treatment, including octreotide, chemotherapy or targeted therapy. Treatment will consist of weekly fosbretabulin for 9 weeks at which point subjects, if benefiting from therapy based on biomarker reduction or symptom control, may continue fosbretabulin in a separate study.
The primary objective is biochemical response as determined by tumor marker change from baseline. Secondary objectives include safety and symptom control (using QLQ-C30 and QLQ-GINET21). ORR and evaluation of pretreatment serum VEGF-A as a potential predictive biomarker are exploratory endpoints.
Main inclusion criteria: biopsy-proven well-differentiated, low-to-intermediate-grade PNET or GI-NET with elevated biomarkers; if symptomatic, prior or ongoing SSA or serotonin synthesis inhibitor treatment; ECOG PS 0-2; adequate hematologic and organ function; radiographically evaluable disease. Key exclusion criteria: inadequately controlled hypertension; significant cardiac or vascular disease; active CNS metastasis; acquired or congenital QTc prolongation or treatment with agents definitely associated with QTc prolongation or torsades de pointes. Statistical analysis of the primary and other study endpoints will chiefly be descriptive.
Results: This trial is currently ongoing with results expected in 2016.
Conclusion: Fosbretabulin represents a promising agent for PNET and GI-NET based on preclinical data. Results of this early phase study are eagerly awaited.
Results of Liver-Directed Surgery in Neuroendocrine Metastases: Support for Use of Parenchymal-Sparing Debulking Procedures
Jessica E. Maxwell, MD, MBA,1 Scott K. Sherman, MD,1 Thomas M. O’Dorisio, MD,1 Andrew M. Bellizzi, MD,2 James R. Howe, MD,11Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; 2University of Iowa Carver College of Medicine, Department of Pathology, Iowa City, IA.
Introduction: Neuroendocrine tumors (NETs) frequently metastasize to the liver. Surgical debulking offers symptomatic relief and improved survival. However, the frequent presence of multifocal, bilobar disease and high recurrence rates introduce doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection, while minimizing morbidity and preserving functional liver tissue.
Methods: Clinicopathologic variables from 226 patients with primary and/or metastatic small bowel (SBNETs) or pancreatic neuroendocrine tumors (PNETs) who were managed surgically at one institution were collected. Liver-directed surgery (LDS) with primarily PSD procedures was carried out when 70% debulking was deemed feasible. Survival was assessed using the Kaplan-Meier method.
Results: 108 patients with PNETs or SBNETs underwent LDS, 91 (84.2%) of whom had concurrent resection of their primaries or recurrences. The median number of lesions treated by PSD was 6.0 (range 0–36). Approximately two-thirds of patients achieved 70% hepatic cytoreduction. The 30-day major complication rate was 12.9%. There were no 30-day operative mortalities. PNET patients having LDS (n = 28) had a median overall survival (OS) of 126 months (OS of PNET M1 patients in SEER, 24 months). Median OS was not reached in the 80 SBNET patients undergoing LDS (OS of SBNET M1 patients in SEER, 56 months). SBNET and PNET patients that achieved 70% hepatic cytoreduction enjoyed significantly improved progression free survival (median 3.2 years, p < 0.001) and overall survival (median not reached, p = 0.009) (Figure 1).
Conclusion: Hepatic resection improves survival in NET patients, but disease recurrence is nearly universal. PSD procedures are safe, reduce the loss of functional liver tissue, and can treat bilobar disease. In this series, patients with SBNET and PNET hepatic metastases undergoing PSD procedures had improved PFS and OS, with minimal morbidity and no mortality. Lowering the debulking target threshold to 70% will benefit NET patients by increasing eligibility for cytoreduction.
Histological Classification of Pancreatic Neuroendocrine Tumors: Optimizing the Ki67 Range for Grade of Tumors
L. Mills,1 J.K. Ramage,1,2 A. Prachalias,1,3 P. Srinivasan,1,3 K. Menon,1,3 A. Quaglia,1,4 G. Vivian,1 N. Heaton,3 D. Sarker,1 P. Ross,1 R. Srirajaskanthan,1,51ENETS Centre of Excellence, Institute of Liver Studies, King’s College Hospital, London, United Kingdom; 2Department of Gastroenterology, Hampshire Hospitals NHS Trust, Hampshire, United Kingdom; 3Hepatopancreatobiliary Surgery, Institute of Liver Studies, King’s College Hospital, London, United Kingdom; 4Department of Histopathology, Institute of Liver Studies, King’s College Hospital, London, United Kingdom; 5Department of Gastroenterology, University Hospital Lewisham, London, United Kingdom.
Background: Pancreatic neuroendocrine tumors are graded using the Ki67 antigen in accordance with the WHO 2010 classification. Despite the system’s widespread use, a wide variety of tumor behaviors have been described leading to various proposed revisions. Specifically: a) the use of 5% rather than 2% as the boundary between Grades 1 and 2, b) the use of 55% rather than 20% as the boundary between Grades 2 and 3, c) the subdivision of Grade 3 using poorly vs well-differentiated appearances.
Methods: Of 223 patients who visited our institution between 2004 and 2013, Ki67 values were known for 168. Where data was available for the pancreas and liver metastases, the highest value was used. The significance of each system was investigated using Kaplan-Meier survival curves and specific Ki67 values searched for using ROC.
Results: a) G1 vs G2 prognostic significance was not improved using 5% instead of 2%. G3 vs G1/G2 remained significant (p < 0.001). b) G2 vs G3 remained significant using 55% (p < .001). G1 vs G2 significance improved compared to 20% (p = .019 vs .193). ROC analysis showed that Ki67 = 55% has 100% specificity, but that Ki67 values between 10% and 20% offer the best specificity/sensitivity balance. c) Defining G3 using poor-differentiation rather than >20% improved G1 vs G2 (p = .133 vs .195).
Conclusions: 1) Prognostic relevance of Grades 2 and 3 may be improved by using either 55% or poor-differentiation as criteria. 2) There is no evidence to suggest that 5% offers increased prognostic relevance for Grade 1.
Gastroenteropancreatic Neuroendocrine Tumor Patients Imaged Favorably With Somatostatin Receptor Antagonist: Results of a Phase I/II Study Comparing 68Ga-OPS202 With 68Ga-DOTATOC PET/CT
Guillaume P. Nicolas,1 Felix Kaul,1 Ramon Mena,2 Hakim Bouterfa,2 Michael Lassmann,3 Nils Schreiter,4 Melpomeni Fani,1 Damian Wild,11Division of Nuclear Medicine, University of Basel Hospital, Basel, Switzerland; 2OctreoPharm Sciences GmbH, Berlin, Germany; 3Department of Nuclear Medicine, University Hospital, Wuerzburg, Germany; 4Department of Radiology, Charité, Universitätsmedizin Berlin, Germany.
Background: Radiolabeled somatostatin (sst) receptor antagonists are a promising class of radiotracer for imaging and treatment of neuroendocrine tumor patients. We report here the first clinical data on 68Ga-OPS202 PET/CT in gastroenteropancreatic neuroendocrine tumors (GEP-NET) (ClinicalTrials.gov NCT02162446).
Methods: Metastatic G1/G2 GEP-NET patients, with at least 1 tumor focus on previous 68Ga-DOTATOC PET/CT, were screened for eligibility in an open-label, micro-dosing study. Safety, biodistribution, dosimetry of two single doses of 68Ga-OPS202 (A: 15 μg & B: 50 μg) and preliminary efficacy in comparison with 68Ga-DOTATOC PET/CT were investigated. 68Ga-OPS202 doses were given within 3-4 weeks interval. All PET/CT were performed on the same scanner, >4 weeks after sst-analogs had been stopped and 1 h after i.v. injection of the radiotracer.
Results: Twelve patients were recruited (7 male, 5 female). No grade 3 or serious adverse event (AE) related to 68Ga-OPS202 occurred. Both 68Ga-OPS202 doses (A & B) showed significantly lower uptake in the liver (mean SUVmax ± σ) 3.2 ± 0.8 (A)/2.9 ± 0.7 (B), in the spleen 11.7 ± 4.2 (A)/10.1 ± 2.3 (B), in the intestine 3.5 ± 1.3 (A)/2.9 ± 0.7 (B) and in the pancreas 3.2 ± 2.0(A)/2.6 ± 1.4 than 68Ga-DOTATOC, respectively 6.8 ± 2.3, 29.1 ± 10.0, 5.4 ± 1.0 and 4.9 ± 3.2 (p < 0.05). Matched lesions (lesions visible on all 3 scans) did not differ significantly in terms of tumor uptake (median SUVmax [range]) 10.2[1.4 – 155.5] (A)/9.6 [1.3 – 130.2] (B) vs 10.7[1.2-141.7] for 68Ga-DOTATOC. Liver-metastases-to-liver-background uptake ratios consistently improved >2-fold (mean ± σ) 5.7 ± 6.9 (A)/6.0 ± 7.4 (B) vs 3.0 ± 1.9 for 68Ga-DOTATOC resulting in a higher detection rate of liver metastases for 68Ga-OPS202 PET/CT (median) 13 (A), 15 (B) vs 4 liver metastases for 68Ga-DOTATOC. The effective dose for an injection of 150 MBq Ga-68-OPS202 is 3.6 mSv (mean ± σ: 2.4 ± 1.78E-02 mSv/MBq).
Conclusion:68Ga-OPS202 is well tolerated and shows increased image contrast compared to 68Ga-DOTATOC PET/CT. The lower hepatic and intestinal and pancreatic uptake may increase the sensitivity and diagnostic confidence in staging GEP-NETs.
Long-Term Outcome of Conservative Management Versus Surgery for Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤ 2 cm in Patients With Multiple Endocrine Neoplasia Type 1
Stefano Partelli,1 Domenico Tamburrino,2 Caroline Lopez,3 Max Albers,3 Anna Caterina Milanetto,4 Claudio Pasquali,4 Marco Manzoni,1 Christos Toumpanakis,2 Giuseppe Fusai,2 Detlef Bartsch,3 Massimo Falconi,11Pancreas Surgery Unit (SP, MF) and Endocrine Tumors Unit (MM), Department of Internal Medicine, IRCCS San Raffaele Hospital, “Salute e Vita” University, Milan, Italy; 2HPB and Liver Transplant Unit (DT,GF) and Neuroendocrine Tumor Unit (CT), Royal Free Hospital, London, United Kingdom; 3Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University Marburg, Germany; 4Pancreatic and Digestive Endocrine Surgical Unit, University of Padua, Padua, Italy.
Background: Surgery represents the best treatment for both functioning and NF-pNEN > 2 cm but many controversies still remain on the optimal management of NF-pNEN ≤ 2 cm. Aim of this study was to evaluate the efficacy of a conservative treatment for NF-pNEN ≤ 2 cm in MEN1-affected patients compared with a surgical treatment.
Methods: This was a retrospective study conducted between 1997 and 2013. Databases of 4 tertiary-referral institutions (San Raffaele Scientific Institute, Milan; University of Marburg, Marburg; University of Padua, Padua; The Royal Free Hospital, London) were interrogated. We included 60 patients affected by MEN1 syndrome with NF-pNEN ≤ 2 cm. Comparison of conservative management versus surgery at initial diagnosis of NF-pNEN ≤ 2 cm was performed.
Results: Overall, 27 patients (45%) underwent up-front surgery and 33 patients (55%) were followed-up at initial diagnosis. A higher proportion of patients in the surgery group were female (70% versus 33%, P = 0.004). Patients were mainly operated in the period 1997-2007 (n = 17, 63% versus 37%, P = 0.040). The rate of multifocal tumors was higher in the surgical group (n = 24, 89%) compared with no surgery group (n = 22, 67%, P = 0.043). The radiological tumor size was larger in the surgery group (16 mm versus 10.5 mm, P < 0.0001). After a median follow-up of 126 months, one patient deceased for postoperative complications. The 5-, 10-, and 15-year the PFS rates were 63%, 39%, and 10%, respectively. The median PFS were similar between the two groups. Overall, 13 patients (32.5%) were operated after an initial surgical or conservative treatment. The majority of surgical treated patients had stage 1 (77.5%), T1 (77.5%) and G1 (85%) tumors.
Conclusions: NF-pNEN ≤ 20 mm in MEN1 patients are indolent neoplasms with a low oncological risk. Surgical treatment of these tumors at initial diagnosis is rarely justified in favor of a conservative treatment.
Identification of SETD2 Genetic Alterations in Patients With Advanced Well Differentiated Pancreatic Neuroendocrine Tumors (WD panNETs)
Nitya Raj,1 Tara Soumerai,1 Emily Valentino,1 Diane Reidy-Lagunes,11Memorial Sloan Kettering Cancer Center, New York, NY.
Background: SETD2 is a histone methyltransferase specific for lysine-36 of histone H3, and has a role in chromatin remodeling. SETD2 also has a tumor suppressor role. SETD2 is frequently altered in clear cell renal cell carcinoma (ccRCC); in ccRCC, SETD2 alterations have been linked to poorer cancer specific and overall survival. A role for SETD2 in WD panNETs has not been described; based on ccRCC data, SETD2 alterations may contribute to tumorigenesis and disease aggressiveness.
Methods: A next-generation sequencing platform developed at Memorial Sloan Kettering Cancer Center, MSK-IMPACT (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets), was utilized. This platform screens for 410 cancer related genes, including SETD2. MSK-IMPACT results are available in 29 patients with advanced WD panNETs.
Results: 5/29 (17.2%) patients demonstrated SETD2 alterations. All 5 patients had metastatic disease to the liver. No tumors were low grade; 4/5 (80%) tumors were intermediate grade and 1/5 (20%) tumors were high grade. All 5 patients harboring tumors with SETD2 alterations received capecitabine/temozolomide (cape/tem) chemotherapy; looking at best therapy response with cape/tem, 4/5 (80%) patients had disease shrinkage and 1/5 (20%) patients had stable disease. One patient exhibited a dramatic response to cape/tem and underwent surgical resection of the primary pancreatic lesion; after surgery, this patient has minimal liver disease remaining, with no evidence of disease progression more than one year after surgery and stopping cape/tem.
Conclusion: SETD2 alterations have not been previously reported in WD panNETs but have been observed in ccRCC, where they are thought to play a role in tumorigenesis. Interestingly, all WD panNETs with SETD2 alterations were intermediate to high grade, and responded to cytotoxic therapy with cape/tem. Further investigation is warranted to determine the role of SETD2 in panNETs, and the clinical significance of these observations. Evaluation using panNET tissue microarrays is ongoing.
Treatment Response and Outcomes of Metastatic Grade 3 (G3) Pancreatic Neuroendocrine Carcinomas (HGNEC) Based on Pathologic Differentiation (Well Differentiated (WDNEC) Versus Poorly Differentiated (PDNEC))
Nitya Raj,1 Emily Valentino,1 Laura Tang,1 Marinela Capanu,1 Olca Basturk,1 David Klimstra,1 Diane Reidy-Lagunes,11Memorial Sloan Kettering Cancer Center, New York, NY.
Background: WHO criteria define HGNEC as tumors with Ki-67 index >20%. However, it is unknown if treatment response/outcomes vary based on cellular differentiation (WDNEC versus PDNEC). We conducted a retrospective review of pancreatic HGNEC treated at MSKCC to evaluate response to therapy, progression free survival (PFS), and overall survival (OS).
Methods: G3 pancreatic WDNEC or PDNEC patients treated from 2000-2014 were identified. Demographics, response to 3 lines of systemic therapy (by RECIST criteria based on radiology reports), PFS, and OS were determined.
Results: 45 patients were identified, 16 WDNEC (mean age 46.8, 43.8% male) and 29 PDNEC (mean age 58.2, 65.5% male). Median OS was 52.0 months in WDNEC versus 10.1 months in PDNEC (p = 0.0009). 10/16 (62.5%) WDNEC received platinum agents, 1/10 (10.0%) with partial response (PR), 5/10 (50.0%) with stable disease (SD), and 4/10 (40.0%) with progressive disease (PD). 27/29 (93.1%) PDNEC received platinum agents, 1/27 (3.7%) with complete response, 9/27 (33.3%) with PR, 10/27 (37.0%) with SD, and 7/27 (25.9%) with PD. Median PFS was 4.4 months for WDNEC versus 3.3 months for PDNEC (p = 0.16). 12/16 (75.0%) WDNEC received alkylating agents, 6/12 (50.0%) with PR, 3/12 (25.0%) with SD, 3/12 (25.0%) with PD. 6/29 (20.7%) PDNEC received alkylating agents, 3/6 (50.0%) with PR, 1/6 (16.7%) with SD, 2/6 (33.3%) with PD. Median PFS was 5.6 months for WDNEC versus 4.2 months for PDNEC (p = 0.27). 6/16 (37.5%) WDNEC received targeted agents, 1/6 (16.7%) with SD and 5/6 (83.3%) with PD. 1/29 (3.4%) PDNEC received a targeted agent; this patient had a PR.
Conclusion: In this series, WDNEC had significantly improved OS compared to PDNEC. Both WDNEC and PDNEC responded to alkylating agents; PDNEC had a higher response to platinum agents. Targeted agents were rarely used with signal of activity noted in few patients.
The Role of Capecitabine/Temozolomide (CAPTEM) in Metastatic Neuroendocrine Tumors: A Neuroendocrine Tumor Program Experience
Robert A. Ramirez,1,4 Aman Chauhan,2,4 David T. Beyer,3,4 J. Philip Boudreaux,3,4 Yi-Zarn Wang,3,4 Eugene A. Woltering,3,41Department of Oncology, Ochsner Medical Center, New Orleans, LA; 2Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA; 3Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA; 4Ochsner Kenner, Neuroendocrine Clinic, Kenner, LA.
Background: Neuroendocrine tumors (NETs) are commonly treated with multimodality therapy including surgery, somatostatin analogues, targeted agents, chemotherapy and others. The combination of capecitabine and temozolomide has been suggested as a treatment option for patients with metastatic NETs. We present a review of our patient population’s experience with CAPTEM treatment.
Methods: This retrospective review included patients diagnosed with NETs at the Louisiana State University/Ochsner NET clinic. Appropriate institutional review board approval was obtained. Patients were identified via a VELOS database. Only NET patients who had been placed on CAPTEM and received at least one cycle were included for review. Response rate (RR) was evaluated by RECIST 1.1, progression-free survival (PFS) was calculated by the Kaplan-Meier survival method.
Results: This review included twenty-nine patients (17 male and 12 female). The median age of CAPTEM initiation was 58 (range: 26-77) years. Primary tumors included 9 small bowel (29%), 15 pancreas (52%), 3 lung (13%) and 2 rectum (7%). Overall partial response (PR) occurred in 5 patients (5/29, 17%), 14 patients (13/29, 48%) had stable disease (SD), and 10 patients (10/29, 35%) had progressive disease (PD). RR by Ki-67 proliferative index and primary tumor site is shown in Table 1. Median number of CAPTEM cycles was 8 (range: 1-55). Sixty-six percent of patients experienced clinical benefit (partial response or stable disease). Median PFS was 12 months. Adverse reactions included fatigue (10/29, 34%), nausea (13/29, 45%), cytopenias (19/29, 66%) and hand foot syndrome (9/29, 31%) resulting is dose reductions in 24% of patients.
Conclusions: Although adverse reactions were experienced, most patients tolerated this regimen. CAPTEM provided clinical benefit to the majority of patients regardless of site of disease or Ki-67. Additional prospective data is eagerly awaited but CAPTEM should be considered a reasonable option for treatment of patients with metastatic NETs.
Design of a Phase 2, Prospective, Randomized, Double-Blind, Placebo-Controlled Study Assessing the Efficacy and Safety of Lanreotide Depot 120 mg in Patients With Well Differentiated, Advanced Lung, or Thymus Neuroendocrine Tumors (NETs)
Diane Reidy-Lagunes,1 Edward M. Wolin,2 Susan Pitman- Lowenthal,3 David Cox,3 Matthew H. Kulke,41Memorial Sloan Kettering Cancer Center, New York, NY; 2Markey Cancer Center, University of Kentucky, Lexington, KY; 3Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ; 4Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber Cancer Institute, Boston, MA.
Background: The randomized, double-blind, placebo-Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) showed that treatment with the somatostatin analog (SSA) lanreotide depot was associated with significantly prolonged progression-free survival (PFS) vs placebo in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lanreotide depot injection subsequently became the first FDA-approved somatostatin analog (SSA) for this indication. Like GEP-NETs, lung and thymic NETs express somatostatin receptors. We designed a randomized phase II study to assess whether lanreotide depot may prolong progression-free survival (PFS) in these NET tumor subtypes.
Methods: This multi-institutional study will enroll an anticipated 126 patients with advanced lung or thymic NETs. The study will include patients with grade 1 or 2 tumors who have positive somatostatin scintigraphy and are somatostatin-analog naïve. Tumor progression within the last 12 months will be assessed for eligible patients. Patients will be randomized 2:1 to receive lanreotide depot 120 mg via deep subcutaneous injection plus best standard of care (BSC) or placebo (BSC). With a 2:1 randomization, an estimated 100 PFS events (disease progression or death) on both arms will provide an 80% power to detect a statistically significant treatment effect using a two-sided log rank test at a significance level of α = 0.05.
Results: Anticipated results include data on the primary endpoint of PFS in both arms, as well as data on secondary endpoints which include objective radiologic response rate, overall survival, effects on plasma chromogranin A, and safety/tolerability.
Conclusions: Therapeutic agents for the treatment of patients with advanced lung or thymus NETs treatment are currently limited. This study will provide data on the efficacy of lanreotide depot for patients with these understudied malignancies.
Surgical Resection of the Primary Tumor in Patients With Metastatic Pheochromocytoma and Sympathetic Paraganglioma: Impact on Survival and Quality of Life
Alejandro Roman-Gonzalez,1,2 Montserrat Ayala-Ramirez,2 Ioannis Christaki,3 Wei Qiu,3 Steven Waguespack,2 Mouhammed Habra,2 Nancy Perrier,3 Camilo Jimenez,21Department of Endocrinology, Hospital Universitario San Vicente Fundacion-Universidad de Antioquia. Medellin, Colombia; 2Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX.
Background: Patients with metastatic pheochromocytoma and paraganglioma (PPG) exhibit a decreased overall survival. Current treatments for these tumors are not curative. The role of surgical resection of the primary tumor in patients with metastatic disease is still to be determined.
Methods: We performed a retrospective of MD Anderson Cancer Center database of patients with metastatic pheochromocytoma and paraganglioma. Demographic, clinical, biochemical, imaging, and pathological variables were analyzed.
Results: There were 113 patients with metastatic PPG; 89 had surgical removal of the primary tumor. 53 patients had synchronous metastases; of these 33 had resection of the primary tumor. The median diameter of the primary tumor in the whole cohort was 8.45 centimeters (range 1.90-24 cms). Survival rates were longer in patients who underwent removal of the primary tumor when compared with patients who did not undergo resection (148 months, 95% CI 112.7-183.2 vs 36 months, 95% CI 27.2-44.8; p < 0.001). In patients with synchronous metastases treated with surgery for the primary tumor, the survival rates were longer that in patients that were not treated with surgery (85 months, 95% CI 64.5 – 104.5 vs 36 months, 95% CI 29.7 – 42.3; p < 0.001). No differences in age, race, primary tumor size or genetic background were noted in these cohorts. Survival rates in patients with metastatic disease were independent of the location of the primary tumor. In patients with hormonally active tumors treated with primary tumor resection, the symptoms of catecholamine excess including hypertension improved. Tumor burden rather than hormonal secretion is a more important determinant of overall survival in patients hormonally active metastatic PPG.
Conclusions: Resection of the primary tumor in patients with metastatic PPG is associated with an improved overall survival. In patients with hormonally active tumors, surgical resection is associated with better blood pressure control and symptom improvement.
68Ga-DOTATOC PET/CT Effectiveness for Diagnosis and Staging in Neuroendocrine Tumors in Comparison With Octreoscan and High-Resolution, Contrast-Enhanced CT
Blanca Schafer,1 Yusuf Menda,2 Thomas M. O’Dorisio,3 Joseph S. Dillon,3 David W. Dick,4 Gideon K. Zamba,5 M. Sue O’Dorisio,11University of Iowa, Department of Pediatrics, Iowa City, IA; 2University of Iowa, Department of Radiology, Iowa City, IA; 3University of Iowa, Department of Internal Medicine, Iowa City, IA; 4University of Iowa, PET Center, Iowa City, IA; 5University of Iowa, Department of Biostatistics, Iowa City, IA.
Background: Neuroendocrine tumors (NETs) affect children, adolescents, and adults. The incidence of NETs has been rising; surgery remains the only curative treatment. With great variability in primary tumor location and symptomatology, a sensitive and specific method for diagnosis and staging is a critical need. Positron emission tomography (PET) is more sensitive than single photon emission tomography (SPECT) and can be completed in one visit. Furthermore, Gallium-68 (68 min half-life) provides sensitive imaging with less radiation exposure than Indium-111 (2.8 day half-life). We hypothesize that 68Ga-DOTA0-Tyr3 octreotide (68Ga-DOTATOC) PET/CT will be more sensitive, accurate, and convenient than OctreoScan (111In-DTPA-Octreotide) SPECT/CT for diagnosis and staging of neuroendocrine tumors.
Methods: Volunteers (3 to 92 years old) have enrolled in this University of Iowa, IRB approved study. Subjects received a 68Ga-DOTATOC PET/CT, and an 111In-DTPA-Octreotide SPECT, high-resolution, contrast-enhanced CT or MRI within 120 days. Scans were read and compared by a board certified nuclear medicine physician. Discordant and newly observed lesions detected on PET/CT but not on 111In-DTPA-Octreotide SPECT/CT were confirmed by surgery or a second 68Ga-DOTATOC PET/CT. Kidney and liver function were assessed pre- and post-scan. SSTR2 status of each subject’s tumor was confirmed by immunohistochemistry with a specific anti-SSTR2 monoclonal antibody.
Results:68Ga-DOTATOC PET/CT detected at least one positive lesion not found on Octreoscan SPECT/CT in 18 of 52 subjects (34.6%) (Table 1); 13 were confirmed with a second PET/CT and 3 by surgical exploration. Two subjects declined. Grade I increases in kidney and liver function tests were seen in eight subjects. Reported side-effects included flushing, nausea, and pain/discomfort associated with lying still.
Conclusions: The 68Ga-DOTATOC PET/CT is a safe, specific, and sensitive alternative to OctreoScan SPECT/CT. 68Ga-DOTATOC PET/CT enables diagnosis and staging of NETs with a single exam that is more convenient for the patient and decreases radiation exposure compared to OctreoScan SPECT/CT.
Functional Status and Resource Utilization of Elderly Patients With Neuroendocrine Tumors
Ya-Chen Tina Shih,1 Chan Shen,1,2 Ying Xu,1 James C. Yao,31Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; 3University of Texas MD Anderson Cancer Center, Department of Gastrointestinal (GI) Medical Oncology, Houston, TX.
Background: Neuroendocrine tumors (NETs) are often classified by functional status. Functional tumors secrete hormonal peptides which lead to additional symptom burdens. The incidence of functional disease among the general NET population is not well-established. Further, it is largely unknown whether the resource utilization patterns differ by functional status. The current analysis estimates the incidence of functional NETs and the associated resource utilizations.
Methods: We identified NET patients diagnosed between 1/1999 and 12/2009 from the SEER-Medicare database, excluding those under age 65, enrolled in HMOs, or without continuous enrollment in Medicare Parts A and B. We defined functional NETs as patients who had any claims with a diagnosis indicative of carcinoid syndrome during the 3 months before and after the NET diagnosis. We quantified resource utilization as counts of events and Medicare payment, stratified by type of care (inpatient, outpatient, and emergency room) and compared patterns of resource utilization between patients with and without functional NETs. We used Cochran-Armitage trend test to test the trend in the incidence of functional NETs; and used Wilcoxon two-sample test to compare resource utilizations between patients with and without functional NETs.
Results: Among the study cohort of 16,929 elderly NET patients, 3586 (21%) had carcinoid syndrome. The incidence of functional NET steadily increased throughout the study period, growing from 7.3% in 1991 to 34.1% in 2009. The trend is statistically significant with p-value < 0.001. Compared to patients without syndrome, patients with functional NET had higher resource utilizations in terms of all the measures we considered (Table 1). All the p-values were less than 0.001.
Conclusions: This population-based study reported an upward trend in the incidence of functional NET. The study also found that patients with functional NET consumed more healthcare resource.
Feasibility of Combining Capecitabine and Temozolomide With Yttrium 90 Radioembolization (CapTemY90) for Intermediate-Grade Metastatic Neuroendocrine Tumors
Michael C. Soulen, MD,1 Ursina Teitelbaum, MD,1 David Metz, MD,1 Jeffrey I Mondschein, MD,1 Bruce Giantonio, MD,1 S. William Stavropoulos, MD,1 Tracy Evans, MD,1 Nevena Damjanov, MD,11Divisions of Interventional Radiology, GI Medical Oncology, and Gastroenterology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Purpose: Grade 2 neuroendocrine tumors (NET) have an intermediate proliferative rate and progress more aggressively than low-grade NETs. The combination of capecitabine and temozolomide (CapTem) has been shown to achieve response rates of 61% in well-differentiated NETs. Capecitabine is synergistic with radiation and often used concurrently in other malignancies. We investigated the safety and tolerability of combining CapTem with Y90 radioembolization for progressive Grade 2 NETs with liver-dominant metastases.
Methods: Patients were treated with capecitabine 600 mg/m2 twice daily for 14 days and temozolomide 150-200 mg/m2 in two divided doses on Days 10-14, with 14 days between cycles. Simulation angiography and MAA scan for Y90 planning were performed during the first cycle of chemotherapy. During the second cycle, Y90 radioembolization with resin microspheres was performed to one lobe on Day 7. The other lobe was treated if needed on Day 7 of the 3rd or 4th cycle. CapTem was continued monthly. Clinical and laboratory toxicities were assessed monthly. Imaging was performed 3 months after the first radioembolization, then every 3 months. This retrospective analysis was IRB approved.
Results: 14 patients were treated. Primary NETs were pancreatic (6), bronchial (3), small bowel (3), and rectal (2). 12/14 patients completed the prescribed combination of oral chemotherapy and radioembolization. One heavily pre-treated patient developed Grade 2 hyperbilirubinemia after the first radioembolization and did not have the other lobe treated. One had severe post-embolization syndrome after the first radioembolization and declined the second one. 10/14 patients stopped CapTem at 3-31 months due to toxicity or progression, the other 4 remain on CapTem for 2 months – 4 years. As expected, G1-G2 fatigue, nausea, or thrombocytopenia was observed in most patients. Three patients had G3 toxicities, one each thrombocytopenia, fatigue, and pain. Mean decrease in CgA was 80%. One patient progressed in the liver at 21 months, the remainder are free from intrahepatic progression at 6-25 months. Three patients died, two from extrahepatic progression (7, 32 months) and one from REILD (17 months).
Conclusion: CapTemY90 is a tolerable regimen with toxicities similar to those reported for CapTem or Y90 alone. Responses are encouraging and supports further evaluation in a multicenter Phase 2 trial.
Clinical and Pathologic Characteristics of Gastric Neuroendocrine Tumors in a Tertiary Care Center
Kristen M Stashek,1 Robert E Roses,2 Emma E Furth,1 David C Metz,31Department of Pathology, University of Pennsylvania, Philadelphia, PA; 2Department of Endocrine and Oncologic Surgery, University of Pennsylvania, Philadelphia, PA; 3Department of Internal Medicine/Gastroenterology, University of Pennsylvania, Philadelphia, PA.
Background: Gastric neuroendocrine tumors (NETs) are categorized into one of three types. Type 1 lesions arise in association with autoimmune metaplastic atrophic gastritis (AMAG) and appropriate hypergastrinemia, type 2 lesions occur in patients with multiple endocrine neoplasia (MEN) type 1 with gastrinomas and inappropriate hypergastrinemia and type 3 lesions occur sporadically with normal serum gastrin levels. We report the clinical and pathologic characteristics of gastric NETs treated at our center over a five year period.
Methods: A CERNER pathology database search from 1/2010 to 6/2015 revealed 49 discreet gastric carcinoid patients. Five were excluded because of incomplete data or a known NET metastasis from a non-gastric site. Clinical and pathologic features were recorded for the remaining 44 patients (61 total tumors).
Results: Type 1 gastric NETs accounted for 66% (29/44) of cases. As expected, these lesions were low grade, well-differentiated and multiple, occurring in older women with other autoimmune disorders. Metastases were rare but did occur (7%). Adenomatous dysplasia in the surrounding mucosa was uncommon. No synchronous or metachronous gastric adenocarcinomas were noted. Type 2 gastric NETs were uncommonly seen (2/44; 4%) despite a well-established MEN-1 and gastrinoma program. Type 3 gastric NETs accounted for 30% (13/44) of cases. As expected, these lesions were solitary, and were more frequently found in older men, of higher grade and associated with metastasis. See Table 1 for comparative data according to carcinoid type.
Conclusions: These data confirm many previously identified clinical and pathologic features of gastric NETs. However, we also show that type 1 lesions can metastasize, that degree of differentiation can vary in patients with multiple lesions and that long term PPI therapy may be an independent cause of type 1 lesions.
177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors: Results of the Phase III NETTER-1 Trial
Jonathan Strosberg,1 Edward Wolin,2 Beth Chasen,3 Matthew Kulke,4 David Bushnell,5 Martyn Caplin,6 Richard P. Baum,7 Erik Mittra,8 Timothy Hobday,9 Andrew Hendifar,10 Kjell Oberg,11 Maribel Lopera Sierra,12 Dik Kwekkeboom,13 Philippe Ruszniewski,14 Eric Krenning,131Moffitt Cancer Center, Tampa, FL; 2Markey Cancer Center, University of Kentucky, Lexington, KY; 3University of Texas MD Anderson Cancer Center, Houston, TX; 4Dana-Farber Cancer Institute, Boston, MA; 5University of Iowa, Iowa City, IA; 6Royal Free Hospital, London, United Kingdom; 7Zentralklinik, Bad Berka, Germany; 8Stanford University Medical Center, Stanford, CA; 9Mayo Clinic College of Medicine, Rochester, MN; 10Cedars Sinai Medical Center, Los Angeles, CA; 11University Hospital, Uppsala University, Uppsala, Sweden; 12Advanced Accelerator Applications, New York, NY; 13Erasmus Medical Center, Rotterdam, Netherlands; 14Hopital Beaujon, Clichy, France.
Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors (20-45% of NETs) progressing on first-line somatostatin analog therapy. Since 2000, thousands of patients have been treated with 177Lu-DOTA0-Tyr3-Octreotate (Lutathera®) peptide receptor radionuclide therapy (PRRT) with promising results.
Methods: NETTER-1 is the first Phase III multicentric, stratified, open, randomized, controlled trial evaluating Lutathera® in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) with renal protection (amino acid solution infusion) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks until tumor progression. Secondary objectives included objective response rate, overall survival, TTP, safety, tolerability and health-related quality of life. An independent Data Safety Monitoring Board regularly assessed the safety outcome.
Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 35 European and 15 sites in the United States. At the time of the statistical analysis, the median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p<0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. The number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The safety profile observed in the study was consistent with the safety information generated in the Phase I-II clinical trial.
Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS in patients with advanced midgut neuroendocrine tumors treated with Lutathera.
Association of Progression-Free Survival With Overall Survival in Patients With Neuroendocrine Tumor Treated With Somatostatin Analogs
Monica Ter-Minassian,1 Nichole V. Brooks,1 Lauren K. Brais,1 Jennifer A. Chan,1 David C. Christiani,2 Xihong Lin,3 Sylvie Gabriel,4 Jérôme Dinet,4 Matthew H. Kulke,11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2Department of Environmental Health, Harvard School of Public Health, Boston, MA; 3Department of Biostatistics, Harvard School of Public Health, Boston, MA; 4Ipsen Pharma, Boulogne-Billancourt, France.
Background: Progression-free survival (PFS) is commonly used as a primary endpoint in NET clinical trials. Whether PFS is associated with OS is uncertain. We assessed the association between PFS and OS in a large observational cohort of patients with NETs treated with somatostatin analogs (SSA).
Methods: We identified 440 patients at our institution who had received single-agent SSA for metastatic NETs and were evaluable for tumor progression and overall survival. We used a landmark analysis to assess OS in patients with progressive disease (PD) or without PD at 6 month intervals, from 6 to 24 months after treatment initiation. Adjusted hazard ratios were assessed with Cox proportional hazards models. Kaplan-Meier estimates were used to calculate median OS for patients with PD vs. those without PD at each landmark time. PFS was defined as time of treatment initiation to time of first progression, death or censoring. OS was measured from landmark time to time of death, or censoring.
Results: Of the 440 pts, 224 had small bowel NETs, 93 had pancreatic NETs and 123 other NETs. 311 patients progressed and 215 died. Median follow-up was 7.1 yrs. PFS was associated with OS at the 6, 12, 18 month landmarks (see Table 1): those who progressed by each landmark time had shorter median OS times than those who did not progress.
Conclusions: In this observational cohort of patients with metastatic NETs treated with SSA, PFS was associated with OS. Our findings support the use of PFS as an endpoint in NET clinical trials.
Patterns and Sequencing of Systemic Therapies in Patients With Advanced Neuroendocrine Tumors (NET)
Monica Ter-Minassian,1 Nichole V. Brooks,1 Lauren K. Brais,1 Jennifer A. Chan,1 David C. Christiani,2 Xihong Lin,3 Sylvie Gabriel,4 Jérôme Dinet,4 Matthew H. Kulke,11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2Department of Environmental Health, Harvard School of Public Health, Boston, MA; 3Department of Biostatistics, Harvard School of Public Health, Boston, MA; 4Ipsen Pharma, Boulogne-Billancourt, France.
Background: Systemic treatments for patients with advanced NET are evolving, and current treatment patterns are not well described.
Methods: We evaluated treatment patterns in 593 patients with advanced NET treated at our institution between 2003 and 2013, including 215 small intestinal NET (SINET), 162 pancreatic NET (PanNET) and 216 other NET. Time on treatment was defined as date of treatment initiation to last known follow up, treatment completion, or death, whichever came first, and was estimated using Kaplan-Meier analysis.
Results: The median number of lines received (in patients followed for their entire disease course) was 2 (1-6) for SINET, 3 (1-8) for PanNET and 2 (1-7) for other NET. Somatostatin analogs (SSA) were used first-line in 92% of SINET, 46% of PanNET and 49% of other NET. Median time on SSA after initiation in the first line setting was 95 mos for SINET, 62 mos for PanNET and 68 mos for other NET. Cytoxic chemotherapy comprised first-line treatment in 5% of SINET, 41% of PanNET, and 45% of other NET. mTOR inhibitors (mTORi) or tyrosine kinase inhibitors (TKI) were used for first line treatment in 1% of SINET, 9% of PanNET, and 4% of other NET. An increase in the use of mTORi/TKI’s was observed after 2011, particularly in the second and third line. In the second line, mTORi/TKI use increased from 20% to 36% for SINET, 15 to 62% for PanNET, and 9 to 30% for other NET. In third line, mTORi/TKI use increased from 7% to 29% in SINET, 22 to 52% in PanNET and 15 to 43% in other NET.
Conclusions: Multiple lines of therapy are common in patients with advanced NET. Treatment patterns differ markedly depending on tumor subtype.
Recurrence Patterns Following Surgical Resection of Gastroenteropancreatic Neuroendocrine Tumors: An Analysis From the NCCN Oncology Outcomes Database
Katherine Van Loon, MD, MPH,1 Li Zhang, PhD,1 Jennifer Creasman, MSPH,1 Sarah Bobiak, PhD,2 Carrie C. Zornosa,2 Michael A. Choti, MD, MBA,3 Matthew Kulke, MD,4 James C. Yao, MD,5 Eric K. Nakakura, MD, PhD,1 Mark Bloomston, MD,6 Al B. Benson, MD,7 Manisha H. Shah, MBBS,6 Jonathan R. Strosberg, MD,8 Emily K. Bergsland, MD,11UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 2National Comprehensive Cancer Network, Fort Washington, PA; 3The University of Texas Southwestern Medical Center, Dallas, TX; 4Dana-Farber Cancer Institute, Boston, MA; 5The University of Texas MD Anderson Cancer Center, Houston, TX; 6The Ohio State University Comprehensive Cancer Center, Columbus, OH; 7Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 8Moffitt Cancer Center, Tampa, FL.
Background: Resection of gastroenteropancreatic NETs is known to prolong survival. Current NCCN guidelines recommend that complete surgical resection of the primary tumor and metastases should be performed if possible. However, large multicenter studies of recurrence patterns following resection have not been performed.
Methods: Patients ≥18 years who presented to 7 participating NCCN institutions after 2004 with a new diagnosis of a small bowel, pancreas, or colorectal NET were included. All underwent complete (R0) resection of the primary tumor and of synchronous metastases if present. Descriptive statistics were used to determine recurrence rates. Kaplan-Meier estimates were used to calculate time-associated endpoints. Comparisons were assessed by the log-rank test.
Results: Of 1125 patients with small bowel, pancreas, or colorectal NETs in the database, 294 patients underwent R0 resection. 51% of patients included in the analysis were male, 88% were Caucasian, and 99% had an ECOG PS 0-1. The median age at diagnosis was 55 (range 20-90); however, patients with a colorectal NET were younger (p<0.001). Median follow-up time from R0 resection was 62.1 months. Among patients with small bowel NET (n=110), 18% recurred. Among patients with pancreatic NET (n=138), 26% recurred. Among patients with colorectal NET (n=46), 11% recurred. Disease-free survival according to stage is shown in Figure 1. Data on frequency and type of surveillance imaging performed will be reported to describe surveillance strategies of the member NCCN institutions.
Conclusions: R0 resection was associated with variable risk of recurrence across subtypes during 5 years of follow-up. Greater than 90% of patients who underwent an R0 resection were alive at 5-year follow-up, regardless of primary site. The presence of metastatic disease should not deter an attempt at R0 resection, when feasible. Median follow-up time was limited by database closure. Further inquiry into appropriate frequency and duration of surveillance following R0 resection is needed.
Neuroendocrine Tumor of the Appendix in Children
Rajkumar Venkatramani,1 Hao Wu,2 Murali Chintagumpala,11Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX; 2Department of Pathology, Baylor College of Medicine, Houston, TX.
Background: Neuroendocrine tumor (NET) of the appendix is the most common gastrointestinal epithelial tumor in children. It is usually diagnosed as an incidental finding in appendectomy specimens. The utility of serum markers or the indication for hemicolectomy have not been established in children.
Methods: The presentation, treatment and outcome of all children <18 years of age diagnosed at Texas Children’s Hospital between 1995 and 2014 were retrospectively reviewed. Pathology slides from the appendectomy and hemicolectomy, when available, were reviewed to determine tumor size, location, invasiveness and presence of metastasis.
Results: Forty-five children with a median age of 12 years (range 6-17 years) were identified. The majority (56%) were female. NET was an incidental finding following appendectomy performed for suspected acute appendicitis (89%) or incidental appendectomy during other surgical procedures (11%). Somatostatin scan (n=5), serum chromogranin A (n=4), and Urine 5-HIAA (n=9) were obtained post-operatively and were within normal limits. The pathology slides of 43 patients were reviewed. The median tumor size was 0.5 cm, and 42% of tumors were located in the tip of the appendix. Invasion of mesoappendix was seen in 26%. Perineural invasion and vascular invasion were seen in 63% and 12% respectively. Seven patients (16%) underwent hemicolectomy. The indications for hemicolectomy were invasion of mesoappendix (4), tumor infiltration near the serosal margin (1), tumor size 1.5 cm with vascular invasion (1) and persistence of previously unrecognized carcinoid syndrome post-surgery (1). Only two hemicolectomy specimens showed disease; one in the appendiceal mesentery and other a micro metastasis in a mesenteric lymph node. There were no recurrences and all patients were alive at last follow-up.
Conclusions: NET of the appendix in children is a benign disease with excellent prognosis. In the absence of carcinoid syndrome, post-operative scans and serum biomarkers are not useful. In completely resected tumors, the indication for hemicolectomy is unclear.
Does the Addition of Adjuvant Intraoperative Post-Dissection Tumor Bed Chemotherapy During GI Neuroendocrine Tumor Debulking Benefit Patients?
Yi-Zarn Wang,1 Aman Chauhan,2 Robert A Ramirez,3 David T Beyer,1 Melissa A Stevens,1 Eugene A Woltering,1 J Philip Boudreaux,11Department of Surgery, LSUHSC-Ochsner Neuroendocrine Clinic, Kenner, LA; 2Department of Hematology and Oncology, University of Kentucky, Lexington, KY; 3Division of Neuroendocrine Oncology, Ochsner Health, New Orleans, LA.
Background: Midgut neuroendocrine tumor (NET) patients are often diagnosed at an advanced stage with extensive mesenteric lymph node and liver metastasis. The only treatment for potential cure and durable results is resection with extensive debulking. However, even with the most elegant resection, macro and microscopic residual disease at the tumor resection bed remains possible. We hypothesize that local application of 5-florouracil within tumor bed will eliminate the microscopic residual disease post-operatively.
Method: Records of 189 patients who underwent extensive cytoreductive surgeries for stage IV, small bowel NETs with boggy mesenteric lymphadenopathy during 2003-2012 were reviewed. Eighty-six patients who had 5-Florouracil saturated gelfoam strips secured into their mesenteric resection defects served as the study group and 103 patients who did not receive intra-operative chemotherapy as the control. Survival from time of diagnosis, postoperative morbidity and mortality between the two groups were compared.
Results: Mortality rates at immediate, 30, 60 and 90 days post-operative period were 4, 0, 0, 0 and 0, 2, 0, 2 for the study and control groups, respectively. Minor complications (Clavien-Dindo Grades I & II) at 30, 60 and 90 day post-operative period were 12, 0, 0 and 9, 3, 3 for study and control groups, respectively. Major complications (Grade III & IV) at the same time intervals were 0, 0, 1 and 2, 3, 2 for study and control groups, respectively. Median Kaplan-Meier survival, 5-year and 10-year survival rates are shown in Table 1 for the study and control groups.
Conclusion: Intra-operative tumor resection bed chemotherapy is a safe adjuvant without any discernible toxicity. Furthermore, it might provide survival benefit to midgut NET patients with extensive mesenteric lymphadenopathy undergoing extensive cytoreductive surgery without additional complications.
Is Surgical Cytoreduction for Stage IV Pancreatic Neuroendocrine Tumors Justifiable?
Yi-Zarn Wang, MD,1 Elizabeth McCord, BS,1 Melissa Aycock Stevens, MPH,1 Anne Diebold, BS,1 Robert A. Ramirez, DO,2 J. Philip Boudreaux, MD,1 Eugene A. Woltering, MD,11Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA; 2Department of Neuroendocrine Oncology, Ochsner Health, New Orleans, LA.
Background: Pancreatic neuroendocrine tumors (pNETS) comprise <2% of all pancreatic tumors. They can be functioning or nonfunctioning. Long-term survival in patients with metastatic disease is generally poor, with recent SEER data citing 5- and 10- year survival of 19.5% and 7.1% respectively. We hypothesized that surgical cytoreduction of stage IV pNETS would improve survival.
Methods: Eighty-nine charts of consecutive well-differentiated pancreatic NET patients seen in our clinic from 5/2006 through 7/2012 were reviewed. Only patients with liver metastases were included in this study (n=64). Tumor characteristics and surgical procedures were reviewed and Kaplan-Meier survival curves were generated.
Results: Fifty-one (51/64, 80%) patients had nonfunctional pNETS vs. 13 (13/64, 20%) with functional pNETS. Sixteen (16/64, 25%) patients had pancreatic primary resected without concurrent liver resection, 27 (27/64, 42%) patients underwent combined pancreatic and liver resection, 5 patients (5/64, 8%) underwent resection of their liver metastases only without resection of their primary. Sixteen (16/64, 25%) patients did not undergo any NET-related surgeries.
The 5- and 10-year survival rates for the whole cohort were 62% and 48% respectively; survival in the surgical group was 66% and 49% vs. 54% and 45% in non-surgical group. Patients who underwent surgical cytoreduction had a median survival of 81 months in contrast to nonsurgical group with a survival of 61 months.
Conclusions: Aggressive surgical cytoreduction for patients with stage IV pNETS is warranted and should be recommended for all low risk surgical candidates.
Lanreotide Depot/Autogel in Intestinal and Pancreatic Neuroendocrine Tumors According to Body Mass Index: Subgroup Analyses From the CLARINET Study
Edward M. Wolin, MD,1 Martyn E. Caplin, DM,2 Marianne E. Pavel, MD,3 Jarosław B. Ćwikła, MD, PhD,4 Alexandria T. Phan, MD,5 Markus Raderer, MD,6 Eva Sedláčková, MD,7 Guillaume Cadiot, MD, PhD,8 Jaume Capdevila, MD,9 Lucy Wall, MD,10 Guido Rindi, MD, PhD,11 Alison Langley, MSc,12 Edda Gomez-Panzani, MD,12 Philippe B. Ruszniewski, MD, PhD,13 on behalf of the CLARINET Study Group. 1Markey Cancer Center, Lexington, KY; 2Royal Free Hospital, London, United Kingdom; 3Charité University Medicine Berlin, Berlin, Germany; 4University of Varmia and Masuria, Olsztyn, Poland; 5The Methodist Hospital, Houston, TX; 6University Hospital, Vienna, Austria; 7First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 8Robert-Debré Hospital, Reims, France; 9Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; 10Western General Hospital, Edinburgh, United Kingdom; 11Università Cattolica del Sacro Cuore, Rome, Italy; 12Ipsen, Les Ulis, France; 13Beaujon Hospital, Clichy, France.
Background: CLARINET showed antitumor effects with lanreotide Autogel (Depot in USA) 120 mg in metastatic intestinal/pancreatic neuroendocrine tumors (NETs). Here, we characterize treatment effects within subgroups defined post hoc by baseline body mass index (BMI).
Methods: CLARINET was a 96-week randomized trial of patients with metastatic grade 1/2 (Ki-67 <10%) nonfunctioning intestinal/pancreatic NETs (NCT00353496). Patients received lanreotide Autogel 120 mg (n=101) or placebo (placebo; n=103) every 4 weeks. Patient subgroups were based on well-known WHO BMI categories. Median progression-free survival (PFS) [95% confidence interval (CI)] was determined by Kaplan–Meier analysis, and hazard ratios (HRs) and CIs by using a Cox proportional hazards model with a single term for treatment (both on the intent-to-treat population); summary statistics were used for adverse events (AEs; safety population). PFS analyses investigated only the consistency of treatment effects across subgroups as the study was not otherwise powered for such analyses.
Results: In the lanreotide group median PFS was not reached in any BMI subgroup (vs 13–24 months for placebo); HRs favored lanreotide and were generally consistent with the overall population (Table 1). Incidences of AEs overall were similar across BMI and treatment groups; the most common AE was diarrhea (Table 1).
Conclusions: CLARINET subgroup analyses suggest that lanreotide has antitumor effects and a favorable safety/tolerability profile regardless of patient BMI.
Lung Neuroendocrine Tumor (NET) US Patient-Reported Experience: Results from the First Global NET Patient Survey: A Collaboration Between the International Neuroendocrine Cancer Alliance (INCA) and Novartis
Edward Wolin,1 Maia Sissons,2 Grace Goldstein,3 John Leyden,4 Teodora Kolarova,51University of Kentucky, Lexington, KY; 2NET Patient Foundation, Hockley Heath, United Kingdom; 3The Carcinoid Cancer Foundation, Inc., White Plains, NY; 4The Unicorn Foundation, Mosman, Australia; 5APOZ & Friends, Sofia, Bulgaria.
Background: Lung NETs are rare, diverse tumors that are often asymptomatic, resulting in treatment delays and reduced survival. The burden of lung NETs on patients’ lives has not previously been described.
Methods: In 2014, 1928 NET patients from >12 countries including the United States (n=758) participated in a survey, conducted by Hall & Partners on behalf of INCA/Novartis, funded by Novartis, on the NET patient experience (comparisons significant at P<0.05).
Results: 15% of US patients had lung NETs, primarily nonfunctional/asymptomatic (53% of patients who knew status, n=79) and low grade (G1; 57%, n=70). 56% required ≥2 years for diagnosis; 49% were diagnosed with other conditions prior to NETs, most often asthma (56%) and pneumonia (35%). Most had not visited (64%)/been diagnosed (96%) at a NET specialist center. Lung NET patients were more likely to be given the impression their cancer was curable (32%) and not something to worry about (40%) vs GI/pNETs (9%/14% and 23%/14%). However, similar to GI/pNETs (73%/74%), most lung NET patients (67%) experienced a moderate/large negative impact on quality of life and were more likely to temporarily stop working because of NETs (31%) vs GI/pNETs (12%/12%). Overall, patients with lung NETs had more negative feelings regarding health care provider expertise/knowledge and quality of care and were more likely to desire better access to NET experts (56%)/knowledgeable health care team (52%). Following diagnosis, fewer lung NET patients were satisfied they received answers to questions (43%) or sufficient information (33%) vs GI/pNETs (62%/59% and 48%/52%). 45% regarded quality of available treatments as poor/very poor (vs GI/pNETs [28%/33%]). Many (71%) expressed the need for more immediate access to NET specialists and transfers to NET centers of expertise (45%).
Conclusion: This large patient survey demonstrated the substantial burden of a lung NET diagnosis in the United States and identified areas for improvement.
Multivariate Analysis of Progression-Free Survival in the CLARINET Study of Lanreotide Autogel/Depot vs Placebo Identifies Prognostic Factors in Neuroendocrine Tumors
Edward M.Wolin, MD,1 Martyn E. Caplin, DM,2 Marianne E. Pavel, MD,3 Jarosław B. Ćwikła, MD, PhD,4 Alexandria T. Phan, MD,5 Markus Raderer, MD,6 Eva Sedláčková, MD,7 Guillaume Cadiot, MD, PhD,8 Jaume Capdevila, MD,9 Lucy Wall, MD,10 Guido Rindi, MD, PhD,11 Alison Langley, MSc,12 Edda Gomez-Panzani, MD,12 Philippe B. Ruszniewski, MD, PhD,13 on behalf of the CLARINET Study Group. 1Markey Cancer Center, Lexington, KY; 2Royal Free Hospital, London, United Kingdom; 3Charité University Medicine Berlin, Berlin, Germany; 4University of Varmia and Masuria, Olsztyn, Poland; 5The Methodist Hospital, Houston, TX; 6University Hospital, Vienna, Austria; 7First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 8Robert-Debré Hospital, Reims, France; 9Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; 10Western General Hospital, Edinburgh, United Kingdom; 11Università Cattolica del Sacro Cuore, Rome, Italy; 12Ipsen, Les Ulis, France; 13Beaujon Hospital, Clichy, France.
Background: Progression-free survival (PFS) in metastatic pancreatic and intestinal neuroendocrine tumors (NETs) was significantly increased with lanreotide Autogel (Depot in USA) 120 mg vs placebo (hazard ratio [HR] for progressive disease [PD]/death 0.47 [95% CI: 0.30, 0.73]) in the CLARINET study. This was a preplanned exploratory covariate analysis to identify prognostic factors for PFS.
Methods: Patients with metastatic grade 1/2 (Ki-67<10%) nonfunctioning pancreatic/intestinal NETs received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until PD/death (NCT00353496), with data analyses stratified according to PD (yes/no) and prior therapy for NET (yes/no) at baseline. These factors, alongside treatment, were tested here in separate Cox proportional hazards (PH) models for several baseline covariates (as listed in the table). Factors potentially significant in univariate analysis (p≤0.1, Wald chi-square test) were included in stepwise multivariate analysis to obtain a final model. Treatment interaction was investigated.
Results: With adjustment for covariates, treatment with lanreotide vs placebo reduced the risk of PD/death by 60% in the final model (Table). The adjusted effect of prior therapy was not significant, whereas PD at baseline was associated with higher risk of PD/death. Other baseline factors associated with an increased risk of PD/death were: hepatic tumor load (HTL) >25%; primary tumor type of pancreas (risk increased by 20–60% vs midgut, hindgut and other types); and below-median BMI (Table 1). No covariate-by-treatment interaction was significant.
Conclusions: Lanreotide extends PFS across patient subgroups; patients without PD at baseline have the lowest risk of PD. Among other potential prognostic factors in this exploratory analysis, several covariates (including tumor grade, prior therapy and time since diagnosis) had no effect. Conversely, HTL and primary tumor type were identified as the most important prognostic factors for PFS.
Incidence of Nodal Positivity in Appendiceal Neuroendocrine Tumors (NETs) and Its Effect on Survival
Eugene A. Woltering,1 David T. Beyer,1 Ramcharan Thiagarajan,1 Yi-Zarn Wang,1 Robert A. Ramirez,2 J. Philip Boudreaux,11Department of Surgery, LSU Health Sciences Center & Ochsner Medical Center – Kenner Neuroendocrine Clinic, Kenner, LA; 2Department of Neuroendocrine Oncology, Ochsner Health, New Orleans, LA.
Background: NETs of the appendix are rare neoplasms most often discovered during incidental appendectomy. We determined the incidence of nodal positivity and its effect on survival in primary NETs of the appendix.
Methods: Data from all patients diagnosed with a primary appendiceal NET was queried. Patients that underwent appendectomy and/or right hemicolectomy were included. Patients diagnosed with goblet cell carcinoid or appendiceal adenocarcinoma, or those with inadequate data were excluded.
Results: Forty-eight patients met inclusion criteria (5/1998 - 2/2014). Twenty-five percent of patients (12/48) had tumors less than 1 cm in size, thirty-five percent (17/48) had tumors between 1 and 2 cm in size, and forty percent (19/48) had tumors greater than 2 cm in size. Lymph nodes were positive in 38% of overall patients (18/48). 42%, 29%, and 42% of patients had positive lymph nodes in tumors less than 1 cm, 1-2 cm, and greater than 2 cm, respectively. Median, 5-year and 10-year Kaplan-Meier survival sorted by nodal involvement is shown below in Table 1. Survival sorted by nodal involvement sub-sorted by tumor size was also calculated. Survival sorted by presence of lymphovascular invasion, perineural invasion, or mesoappendiceal invasion was found to be statistically insignificant.
Conclusions: Patients with appendiceal NETs experience high 5- and 10-year survival rates. However, nodal positively adversely impacts survival only in well-differentiated appendiceal NETs.
Predicting Post-Therapy Response Using Computational Image Analysis
Yan Wu,1,2 Rebecca A. Moss,3 Omar Hasan,2 Pamela L. Kunz,4 John L. Nosher,2 David J. Foran,1,21Center for Biomedical Imaging and Informatics, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; 2Department of Radiology, Robert Wood Johnson Medical School, Rutgers University; New Brunswick, NJ; 3Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; 4Medical Oncology, Stanford University Medical Center, Stanford, CA.
Background: Yttrium 90 radioembolization (Y90RE) is a promising antiangiogenic therapy for neuroendocrine tumor (NET) liver metastases, but responses are variable. In other liver tumors, texture analysis of pre-therapy triphasic CT scans has predictive power for response to Y90RE.
Methods: In this pilot study, 17 patients with NET liver metastases were treated with Y90RE at Robert Wood Johnson University Hospital, and images were collected as part of an IRB-approved protocol. Tumor texture information was extracted from the arterial and venous phase of baseline triphasic CT images using the local binary pattern method (LBP). A Support Vector Machine (SVM) model based on baseline texture characteristics (LBP histograms) and other features was used to predict whether a patient’s time to progression (TTP) would be longer than a preset threshold, and predictions were compared with clinical outcomes.
Results: The median patient age was 64 (41-82). TTP (Figure A) ranged from 100 days to 1521 days (12 patients); the remaining 5 patients did not progress during the time of study (>2000 days) or had complete response. We chose a TTP of 1095 days (3 years) to define a threshold for differentiating responders from nonresponders. LBP histogram was generated for each tumor region (Figure B) as texture features. The SVM predicted TTP with 88% accuracy using arterial phase data (Figure C). Adding tumor volume, gender, and patient age did not improve prediction accuracy. Triphasic data was significantly more accurate than venous phase data in identifying responders, which we independently confirmed using conventional contrast enhanced CT of 5 patients undergoing antiangiogenic therapy at Stanford Medical School in a set of parallel experiments.
Conclusion: SVM classification from arterial, but not venous, phase texture analysis shows promise in predicting post-therapy TTP for patients presenting with NET liver metastases. Prediction of treatment response by this method could provide decision support for recommending Y90RE on the basis of pretreatment triphasic CT.
Safety and Efficacy of Everolimus in Advanced Nonfunctional Neuroendocrine Tumors (NET) of Lung or Gastrointestinal (GI) Origin: Findings of the Randomized, Placebo-Controlled, Double-blind, Multicenter, Phase 3 RADIANT-4 Study
James C. Yao,1 Nicola Fazio,2 Simron Singh,3 Roberto Buzzoni,4 Carlo Carnaghi,5 Edward Wolin,6 Jiri Tomasek,7 Markus Raderer,8 Harald Lahner,9 Maurizio Voi,10 Lida Pacaud,11 Nicolas Rouyrre,11 Carolin Sachs,11 Juan W. Valle,12 Gianfranco Delle Fave,13 Eric Van Cutsem,14 M.E.T. Tesselaar,15 Yasuhiro Shimada,16 Do-Youn Oh,17 Jonathan Strosberg,18 Matthew H. Kulke,19 Marianne E. Pavel,20 for the RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4) Study Group. 1University of Texas/MD Anderson Cancer Center, Houston, TX; 2Istituto Europeo di Oncologia - IRCCS, Milano, Italy; 3Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 4Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 5IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 6Markey Cancer Center, University of Kentucky, Lexington, KY; 7Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Univ. Klinik f. Innere Medizin I, AKH, Wien, Austria; 9Universitaetsklinikum Essen, Zentrum f. Innere Medizin, Essen, Germany; 10Novartis Pharmaceuticals Corporation, East Hanover, NJ; 11Novartis Pharma AG, Basel, Switzerland; 12Institute of Cancer Studies, University of Manchester, The Christie Hospital, Manchester, United Kingdom; 13Azienda Ospedaliera Sant'Andrea - Università La Sapienza, Roma, Italy; 14Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KULeuven, Leuven, Belgium; 15Nederlands Kanker Instituut - Antoni van Leeuwenhoek, Amsterdam, Netherlands; 16National Cancer Center Hospital, Tokyo, Japan; 17Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 18Department of Medicine, Moffitt Cancer Center, Tampa, FL; 19Dana Farber Cancer Institute, Boston, MA; 20Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
Background: Everolimus (EVE), an oral mTOR inhibitor, is approved in advanced pancreatic NET. Advanced, nonfunctional NET of lung/GI origin however remains an area of significant unmet medical need. The RADIANT-4 study evaluated the efficacy and safety of EVE in this NET population.
Methods: Patients with advanced, progressive, well-differentiated, nonfunctional lung/GI NET were randomized (2:1) to EVE (10 mg/d) or placebo (PBO), both with best supportive care. Patients were stratified by tumor origin, WHO performance status (PS), and prior somatostatin analogue (SSA) treatment. Primary endpoint was progression free survival (PFS) assessed by central radiology review (modified RECIST 1.0). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.
Results: 302 patients were randomized to EVE (n=205) or PBO (n=97); median age, 63 yrs; 53% females; G1/G2: 64%/35%; WHO PS: 0, 74% or 1, 26%; majority (76%) were Caucasian; most common tumor sites: lung (30%), ileum (24%). EVE demonstrated a statistically significant increase in median PFS of 7.1 months over placebo in this patient population (table). Subgroup analyses of PFS by stratification factors were consistent with the primary efficacy analysis. A preplanned interim OS analysis showed an HR of 0.64 (95% CI, 0.40–1.05; P=0.037) in favor of EVE although not statistical significant (threshold P-value for significance, 0.000213). Drug-related adverse events (AEs) were mainly G1/2; most common AEs included stomatitis, diarrhea, fatigue, infections, rash and peripheral edema. Most frequent drug-related G3/4 AEs are listed below (Table 1).
Conclusions: RADIANT-4, the first large, PBO-controlled, phase 3 study in patients with advanced, progressive, nonfunctional lung/GI NET, provided unequivocal evidence for the efficacy of EVE in this population. EVE demonstrated a statistically significant 52% risk reduction in progression or death along with clinically meaningful 7.1-month prolongation of PFS vs PBO. AEs were consistent with the known safety profile of EVE.
Clinical and Immunohistochemical Features of Non-Pancreatic Gastrointestinal Neuroendocrine Neoplasms
Allison J Zemek,1 Michael A DiMaio,1 John Allen,2 Hemamalini Vairamuthu,2 Raymond R Balise,2 Teri A Longacre,1 Pamela L Kunz,21Department of Pathology, Stanford University Medical Center, Stanford, CA; 2Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA.
Background: Non-pancreatic gastrointestinal neuroendocrine neoplasms are classified in the WHO 2010 system into three grades, using mitotic figure counts and Ki-67 indices. There is increasing evidence that immunohistochemical expression of p16 and p53; and/or loss of chromogranin may provide additional prognostic information predicting worse clinical outcome.
Methods: Non-pancreatic gastrointestinal neuroendocrine neoplasms were identified in a retrospective search of the surgical pathology database of a large academic medical center from 1992-2013, and compiled in a tissue microarray. H&E and Ki67-stained sections were examined to classify the lesions as well-differentiated neuroendocrine tumors, including WHO grades 1 and 2 (WDNET), versus poorly-differentiated neuroendocrine carcinoma, WHO grade 3 (PDNEC). Immunohistochemistry for p16, p53 and chromogranin was performed. Kaplan-Meier analysis was used to calculate overall survival (OS). Cox proportional hazards models were constructed to assess significance of differentiation, p16, p53 and chromogranin with survival.
Results: 178 non-pancreatic gastrointestinal neuroendocrine neoplasms were identified. Median age was 58.5 years, 94 (53%) were female, 169 (95%) were WDNETs, 9 (5%) were PDNETs. The majority of cases were p16/p53 negative and chromogranin positive. The 5-year OS rate for the entire cohort was 75%. Of the PDNECs, p16/53 positive cases had worse OS. Univariate Cox regression analysis demonstrated that PDNEC was associated with an increased hazard of death with a HR of 18.1 (p<0.0001), as was p53 expression with a HR of 8.6 (p<0.0001). However, only poor differentiation (PDNEC) maintained this association by bivariate COX analysis (p<0.001).
Conclusion: In a population of non-pancreatic gastrointestinal neuroendocrine neoplasms, patients were predominantly young, female, and had WDNETs. As expected, PDNEC had poorer OS compared to WDNET. Of PDNEC, p16/53 positive cases had poorer OS compared to p16/53 negative cases. In univariate Cox regression analysis, both PDNEC and p53 expression were associated with increased hazard of death. In bivariate Cox analysis, only PDNEC maintained this association. Our analysis was limited by low case numbers for PDNEC and p16/53 expression. Further studies are needed to determine if p16, p53 and chromogranin may aid grading of neuroendocrine neoplasms.