Activin A in Carcinoid Heart Disease: A Possible Role in Diagnosis and Pathogenesis
Deidi Strickland Bergestuen,1 Thor Edvardsen,2,5 Svend Aakhus,2 Thor Ueland,4 Erik Øie,2,4 Morten Vatn,1,5 Pål Aukrust,3,4,5 Espen Thiis-Evensen11Section of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 2Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 3Section of Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo Norway; 4Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Faculty of Medicine, University of Oslo, Oslo, Norway.
Background: Carcinoid heart disease (CHD), a complication of NETs, is characterized by right heart fibrotic lesions. In addition to serotonin, cytokines and growth factors with fibrogenic properties may play a role. We sought to examine the relationship between plasma levels of fibrogenic cytokines and growth factors and CHD, to provide further insight into possible biomarkers of CHD and into the pathogenesis of CHD.
Methods: Plasma samples from 71 NET patients and 18 controls were analyzed using enzyme immunoassays. All patients underwent echocardiography. Tumor biopsies and a CHD lesion were analyzed via IHC.
Results: 15 patients had CHD. CHD patients were older (p=0.01), had larger (p=0.007) and more numerous liver metastases (p=0.04), and had elevated U-5HIAA (p=0.03) and serum chromogranin A levels (p=0.02). CHD patients had higher plasma levels of C-reactive protein (p=0.03), osteoprotegerin (p=0.005) and activin A (p=0.005) than patients without CHD. A direct correlation between activin A and U-5HIAA levels was observed in the total patient group (r=0.30, p=0.02). Activin A ≥0.34 ng/ml (OR 5.35 [1.01;28.17]) and age ≥69.5 (OR 6.10 [1.60;23.24]) were independent predictors of CHD. Activin A ≥0.34 ng/ml detected CHD with 87% sensitivity and 57% specificity. Tumor tissue and a CHD lesion showed positive staining for activin A.
Conclusion: Elevated plasma activin A levels are associated with the presence of CHD. Activin A is expressed in tumor tissue and in CHD lesions.
Effects of SDHB Mutant Genotypes on Neuroendocrine Tumor Progression
Adam J. Case,1 Bryan G. Allen,1 Melissa A. Fath,1 Anthony R. Cyr,1 Douglas R. Spitz,1 Frederick E. Domann11Free Radical & Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242.
Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare tumors of the neuroendocrine system with an underlying etiology that appears to be ∼70% sporadic and ∼30% hereditary in origin. A significant number of the hereditary PHEOs are caused by mutations in genes coding for the succinate dehydrogenase (SDH) subunits in mitochondrial electron transport chains including SDHB, SDHC, and SDHD. Interestingly PHEOs carrying SDHB gene mutations are more highly associated with extra-adrenal locations, overproduction of norepinephrine and dopamine, a high risk of malignancy, and poor therapeutic outcome. The autosomal dominant pattern of inheritance for SDHB related PHEOs suggests a potential dominant negative function of mutated SDHB proteins.
Methods: To test this hypothesis, we used reverse transcription and PCR cloning to construct an expression plasmid for wild type human SDHB. We then engineered into it, using site directed mutagenesis, several clinically relevant SDHB mutations including a point mutation (P197R), an exon 1 deletion, and a 4 bp deletion at nt847 that results in a frame shift and truncated protein. We also cloned a full-length SDHB antisense expression construct. These constructs were transfected into HEK293 cells to verify the expression of the mutated SDHB proteins from the mammalian expression plasmids by western blotting, and to determine the effect of the mutant SDHB proteins on SDH activity in the recipient cells.
Results: Expression of the mutated cDNAs was confirmed by RT-PCR and the proteins by western blotting. Effects of the mutant proteins on the activity of SDH and mitochondrial complex II will be presented.
Conclusion: Clinically relevant human SDHB mutants were transiently expressed in cells. These constructs will be useful to generate stable transfectants of adrenal medulla cells or established PHEO cell lines to determine the effects of perturbing SDH activity on malignant progression in neuroendocrine tumors. This work was supported by the Pheo/Para Alliance.
Cocoon Formation in Patients with Mid-Gut Neuroendocrine Tumors: A Rare and Unrecognized Final Pathway
Heather King, MD,1 Yi-Zarn Wang, DDS, MD11Louisiana State University Health Sciences Center, Department of Surgery, New Orleans, Louisiana 70130.
Background: Mid-gut neuroendocrine tumors are in general a rare disease with an indolent course. As a result, treatment is often delayed, passive or sometimes omitted. Although the natural history is poorly understood, there is a commonly accepted final pathway for patients with advanced carcinoid cancer. Disease progression leading to death from the sequelae of bowel obstruction, ischemia or liver failure secondary to massive liver metastasis is well described. We have recently recognized a rare and distinct final pathway for patients with long term disease, namely a cocoon formation.
Methods: Seven patients in our center developed this rare condition in the last three years. Patients’ charts, operative reports, lab results, pathology and tumor markers were reviewed in an attempt to recognize any common denominator. We will also discuss our dismal experience in attempts to intervene or halt disease progression, the results and outcome.
Results: No reliable predictor or precondition leading to the development of this condition was identified. Surgical treatment is only partially successful in dealing with these patients, namely those with a Type 1 cocoon. We propose that an advanced form of cocoon encasing the entire abdominal contents be included in the subtype 4.
Conclusion: Cocoon formation in long term NET survivors is a rare but lethal terminal disease progression that was not previously recognized or reported. The best treatment is yet to be discovered. Currently, the best approach is to recognize the condition preoperatively if possible and treat expectantly. In contrast to cocoon patients without NETS, surgical treatment is not advisable with the exception of patients with Type 1 abdominal cocoon.
Value of Islet 1 and PAX-8 in Identifying Metastatic Neuroendocrine Tumors of Pancreatic Origin
Jamie Koo,1 Richard Mertens,1 Deepti Dhall11Cedars-Sinai Medical Center, Los Angeles, CA, 90048.
Background: Neuroendocrine tumors (NETs) can present as liver metastases before discovery of the primary tumor. Immunohistochemical (IHC) staining with TTF-1 and CDX2 are currently used to identify NETs of pulmonary and gastrointestinal (GI) origin, respectively. Only recently have markers for NETs of pancreatic origin been proposed, including Islet 1 and PAX8. The purpose of this study was to (1) compare the utility of Islet 1 and PAX-8 in distinguishing pancreatic NETs from tumors of other sites; and (2) determine the usefulness of an IHC panel including TTF-1, CDX2, Islet 1, and/or PAX-8 in identifying metastatic pancreatic NETs.
Methods: A total of 110 primary NETs and 73 metastatic NETs were studied. Immunohistochemistry was performed using antibodies against Islet 1, PAX8, TTF-1 and CDX2. Tumors showing moderate to strong nuclear staining of at least 5% of cells, or tumors showing weak nuclear staining of at least 10% of cells were considered positive.
Results: Islet 1 and PAX8 were positive in 82% and 88% of primary pancreatic NETs, respectively, and negative in all primary ileal NETs. Immunoreactivity results for metastatic NETs are summarized in Table 1. A four-stain IHC panel including Islet 1, PAX8, TTF-1, and CDX2 identifies 75% of metastatic pancreatic NETs, which was significantly better than a three-stain panel of PAX8, TTF-1, and CDX2 and slightly better than a three-stain panel of Islet 1, TTF-1, and CDX2.
Conclusion: Both Islet 1 and PAX8 are reliable IHC markers for NETs of pancreatic origin and would be useful adjuncts to other markers (TTF-1, CDX2) currently used to work up a metastatic NET of unknown primary.
Alternative Splicing and Differential Gene Expression in Pancreatic NETs
Jan Lennart Körner,1,2 Bertram Wiedenmann,1 Carsten Grötzinger11Charité – Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology; 2Universität Stuttgart, Insitut für Zellbiologie und Immunologie.
Background: Alternative splicing is an important mechanism to increase the diversity of the proteome in higher organisms. Protein isoforms resulting from differentially spliced mRNA may constitute peculiar drug targets or markers for cancer diagnosis. We here present a new DNA array that allows identification of splice variation and differential expression for 357 G protein-coupled receptors (GPCR) and 11 proteins of the extracellular matrix. GPCRs like somatostatin and dopamine receptors are established targets in neuroendocrine tumor disease. However, a considerable fraction of patients cannot be treated or diagnosed adequately using currently available agents. The G protein-coupled receptor superfamily is the most important hub for drug therapies. In addition to their widespread expression and their important regulatory properties, GPCRs are located on the plasma membrane which makes them easily accessible for both contrast agents and therapeutics. Aim of this work is to identify tumor specific splice variants and overexpressed genes in pancreatic NETs. After validation, such targets can be used to develop targeted therapeutics and contrast agents for nuclear medicine.
Methods: We designed an array with 15k probes which either bind to exon, junction or intron regions. Eight pancreatic NETs and eight pancreatic control tissues where hybridized. Expression results were validated by qPCR, while splice variants where amplified by RT-PCR and sequenced.
Results: In the expression level analysis overexpressed genes were found and validated. Most of the overexpressed genes were not known to be differential expressed in pancreatic NETs (e.g. GPR158) but familiar GPCRs were also found to be overexpressed (e.g. DRD2, SSTR2). By calculating the splicing index for all probes, genes with a high probability for differentially expressed splice variants were selected and validated in RT-PCR. Novel variants specific for tumor as well as for the control tissues were identified.
Conclusions: This novel DNA microarray enables parallel identification of splicing events and gene expression in complex samples, providing a tool to identify targets for therapy and diagnostic biomarkers.
MicroRNA Signatures as Novel Biomarkers in Small Intestine Neuroendocrine Tumors
Su-Chen Li,1 Cécile Martijn,2 Ahmed Essaghir,1 Ricardo V. Lloyd,4 JeanBaptiste Demoulin,1 Kjell Öberg,1 Valeria Giandomenico11Uppsala University, Uppsala, Sweden; 2Université Catholique de Louvain, de Duve Institute, Brussels, Belgium; 3University of Wisconsin, Madison Wisconsin, USAl.
Background: Small intestinal neuroendocrine tumors (SI-NETs) arise from serotonin-producing enterochromaffin cells. SI-NETs are often well-differentiated tumors and most patients have regional or distant metastases at initial presentation. MicroRNAs (miRs) are post-transcriptional regulators which are important in diverse biological processes and can function as tumor suppressor genes or oncogenes. This study aims to identify an exclusive SI-NETs miR profile that may have a critical role in development, diagnosis, prognosis and progression of these malignancies.
Methods: Fifteen SI-NET specimens at different stage of malignancy, five primary tumors, five mesentery metastases and five liver metastases, were included in this study. Total RNA was hybridized onto Affymetrix GeneChip® miR arrays for genome-wide profiling. Array data summarization, normalization, and quality control were performed using miRNA QC Tool software. Differentially expressed miRs were then validated by quantitative real time PCR and Northern blot analyses on the initial specimens as well as on microdissected SI-NET cells. In addition a list of potential miR target genes was generated using TargetScan (www.targetscan.org).
Results: Array results show that the expression of nine miRs is significantly altered between primary tumors and metastases. Five of them (miR-96, -182, -183, -196a and -200a) are upregulated while the other four (miR-31, -129-5p, -133a and -215) are downregulated during tumor progression. All of them are specifically expressed by microdissected SI-NET cells and therefore may be potential novel biomarkers of tumor progression. In addition we address three bioinformatically selected potential target genes for each significant miR.
Conclusion: To date, little evidence of miRNA expression/ deregulation in SI-NETs has been reported. Our genome-wide SI-NET-miR expression profiling provides information about potential pivotal miRs, their involvement in tumor progression and their possible role as novel targets for therapy. Further analyses to clarify which genes are directly controlled by the selected miRs are ongoing.
Molecular Targeting of G Protein-Coupled Receptors MC1R and VPAC1 for Positron Emission Tomography Imaging of Pancreatic Neuroendocrine Tumors
Molly E. Martin,1 Erin A. Boese,1 M. Sue O’Dorisio,1 Blanca Schafer,1 Jennifer Carr,2 James Howe,2 Michael K. Schultz3University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242 1Department of Pediatrics; 2Department of Surgery; 3Department of Radiology.
Background: G protein-coupled receptors (GPCR) have emerged as candidates for molecular targeting in neuroendocrine tumors (NETs) due to their cell surface expression, exquisite specificity of ligand-receptor interactions, and key roles in NET signal transduction pathways. We hypothesize that the over-expression of MC1R and VPAC1 in pancreatic NETs can be exploited to develop tumor specific Positron Emission Tomography (PET) imaging agents.
Methods: Specimens of ileal and pancreatic NET plus adjacent normal tissue were obtained at surgery according to an IRB approved protocol. RNA was isolated from matched tissues, reverse transcribed, and applied to TaqMan Human GPCR arrays for quantitative PCR. Results were confirmed using genome wide EXON chip analysis. Data were analyzed using Relative Quantification Manager and StatMiner software. Unique, high affinity, stable peptide analogs of α-melanocyte stimulating hormone (α -MSH) and vasoactive intestinal peptide (VIP) were synthesized using solid phase chemistry, conjugated with DOTA, purified by HPLC, and radiolabeled with Gallium-68 for in vitro membrane binding and in vivo PET imaging.
Results: Melanocortin (MC1R) and vasoactive intestinal peptide (VPAC1) receptors were identified as tumor specific GPCR targets in pancreatic NETs. Analogs of α -MSH and VIP targeting MC1R and VPAC1, respectively, were synthesized and assayed for high affinity binding, metabolic stability, and stimulation of cAMP in vitro. Localization of MC1R-expressing xenografts was demonstrated in vivo using both fluorescence and PET imaging techniques.
Conclusions: GPCR TaqMan arrays have identified MC1R and VPAC1 as tumor specific molecular targets in pancreatic NETs that are distinct from adjacent normal tissue. Development of receptor specific ligands as PET imaging agents will enable more sensitive, non-invasive identification of primary tumors as well as quantitative assessment of response to therapy. Molecularly targeted PET imaging may also pave the way for development of tumor specific radiotherapy.
Rats Heterozygous for the MENX-Associated p27 Mutation Develop a MEN Phenotype
Sara Molatore,1 Frauke Neff,1 Tobias Wiedemann,1 Misu Lee,1 Natalia S. Pellegata11Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Background: MENX is a spontaneous multiple endocrine neoplasia syndrome in the rat showing phenotypic overlap with both MEN1 and MEN2 human syndromes. MENX is caused by a biallelic germline mutation of the Cdkn1b (p27) gene and it was described as recessively inherited. CDKN1B alterations have been also identified in human patients with MEN1-like features but no MEN1 mutations (MEN4).
Aims: Since MEN4 patients present germline CDKN1B monoallelic mutations and mice with only one null Cdkn1b allele are predisposed to tumor formation, we performed a detailed phenotypic characterization of rats heterozygous for the germline Cdkn1b mutation causing MENX.
Methods: We determined the overall survival of wild-type (p27+/+) and heterozygous (p27+/m) rats and performed histological and immunohistochemical analysis of their tissues.
Results: We observed that p27+/m rats die earlier than p27+/+ rats (average 17 vs. 24 months) and develop tumors earlier. p27+/m animals show bilateral pheochromocytoma, paraganglioma, thyroid C-cell and endocrine pancreas hyperplasias, parathyroid and anterior pituitary adenomas, similarly to double-mutant rats (p27m/m). Interestingly, we could observe all the phases of progression of medullary thyroid carcinoma (MTC), from C-cell hyperplasia to carcinoma, often within the same gland.
Conclusion: Heterozygous rats develop a MEN phenotype, like the double mutant animals. They could be exploited to gain information about neuroendocrine tumor progression and, in particular, about MTC development.
Comparative Study of DNA Repair and Cell Proliferation Markers in High Grade Neuroendocrine Carcinoma of the Uterine Cervix and Small Cell Carcinoma of the Lung
Boris G. Naraev, MD, PhD,1 Emilian V. Racila, MD,1 Michael J. Goodheart, MD,1 Sergei I. Syrbu, MD, PhD,1 Thomas M. O’Dorisio, MD,1 Thorvardur R. Halfdanarson, MD11University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242.
Background: The optimal treatment for high grade neuroendocrine carcinoma of the uterine cervix (cNEC) remains undetermined. Most patients (pts) are treated with chemotherapy regimens used for small cell lung cancer (SCLC) because of both tumors’ histological similarity and aggressive behavior. DNA replication and DNA damage repair processes could play a role in determining the tumors’ behavior and responses to treatment.
Methods: The rate of expression of thymidine kinase (TK), thymidylate synthetase (TS), proliferating cell nuclear antigen (PCNA), replication protein A (RPA), Ki-67, and DNA excision repair protein (ERCC-1) in tumor specimens from 20 pts with cNEC and 15 pts with SCLC seen at our institution in 1977-2010 was determined by using immunohistochemical methods. No pre-selection criteria other than the primary pathological diagnosis were used. Unpaired t-test analysis was performed and two-tailed P values were calculated to compare the means of the two groups.
Results: RPA and Ki-67 were expressed at significantly higher levels in SCLC than in cNEC (P=0.04 and 0.002, respectively). No significant difference in the expression of TK, TS, PCNA or ERCC-1 was found between the two groups. The mean percent of positive cells and standard error of the mean for SCLC vs. cNEC were 74.7% (9.4) and 48.3% (7.7) for RPA, 49.9% (8.4) and 16.9% (5.3) for Ki-67, 49.7% (10.8) and 58.4% (6.4) for TK, 45.0% (11.3) and 25.3% (6.7) for TS, 56.6% (7.9) and 64.5% (5.9) for PCNA, and 43.5% (9.3) and 29.9% (7.8) for ERCC-1, respectively. Eight pts (53.3%) with SCLC expressed very high levels of RPA (>80% cells positive), vs. only 2 pts (10%) with cNEC. High levels of Ki-67 expression (>80% cells positive) were observed in 4 pts (26.6%) with SCLC; none of the patients with cNEC had such high levels.
Conclusion: RPA and Ki-67 are both expressed at significantly higher levels in SCLC than in cNEC. The mean expression rate, although not statistically significant, possibly due to the small sample size, was higher in SCLC than in cNEC for all analyzed markers, with the sole exception of PCNA. Further studies are needed to determine possible correlation between these markers and clinical outcomes, including survival, as well as response to therapy.
A Pilot Study on the Immunohistochemical Expression of Chromogranin and/or Synaptophysin in Moderate to Poorly Differentiated Gastroenteropancreatic Carcinomas
Tony W.H. Shek,1 W.Y. Lam,2 H. Yao,3 V. Tang,4 S.M. Mak5Department of Pathology, 1Queen Mary Hospital, Hong Kong; 2Queen Elizabeth Hospital; 3Princess Margaret Hospital; 4Pemela Youde Eastern Nethersole Hospital; 5North District Hospital.
Background: Recent advances in specific treatment for neuroendocrine tumors (NET) prompted us to reinvestigate the old phenomenon of neuroendocrine differentiation in carcinomas of the GI tract which has previously been shown to carry no prognostic significance. We studied the immunohisotchemical expressions of chromogranin and synaptophysin in a group of ordinary moderate to poorly differentiated adenocarcinomas of the gastrointestinal tract including the pancreas.
Methods: A total of 100 cases of moderate to poorly differentiated adenocarcinomas of the stomach (8), colon and rectum (83), pancreas (8) and duodenum (1) were identified and tumor tissues were retrieved for immunohistochemical staining for chromogranin and synaptophysin.
Results: 15 of the 100 cases (15%) of adenocarcinoma of the GI tract (colon ×12, stomach ×1 and duodenum ×1) or pancreas (×1) showed focal evidence of neuroendocrine differentiation based on immunohistochemical staining. All these 15 cases were focally positive for synaptophysin and 3 cases (3%) were positive for both synaptophysin and chromogranin.
Conclusions: Synaptophysin seems to be a more sensitive neuroendocrine marker. The expression of neuroendocrine markers in 15% of cancers that would otherwise be classified as moderate to poorly differentiated adenocarcinoma raises the question whether the neuroendocrine component in these carcinomas could show response to specific treatment for NET. Further clinical trials may be targeted to this group of patients to see if they can benefit from the specific drug treatment for their NET component.
The Synergistic Effect of Pasireotide (SOM230) and a Raf-1 Activating Agent in Carcinoids
Yash Somnay, BS,1 Herbert Chen, MD, FACS,1 Muthusamy Kunnimalaiyaan, PhD11Section of Endocrine Surgery, Department of Surgery and the University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health; Endocrine Surgery Research Laboratories, Wisconsin Institutes for Medical Research Madison, WI 53705.
Background: Somatostatin analogs are mainstay for carcinoid treatment and management. The new somatostatin analog Pasireotide (SOM230) may be more effective given its relatively elevated receptor affinity and broader binding spectrum. Data suggest ERK1/2 phosphorylation may potentiate the anti-tumor effects of somatostatin analogs in carcinoids. We’ve shown that ERK1/2 phosphorylation suppresses carcinoid biomarker expression. Therefore, Raf-1/MEK/ERK1/2 pathway activating drugs may synergize with somatostatin analogs like SOM230. Here, we investigate the effects of SOM230 combined with Teriflunomide (TFN), a Raf-1 activator, in vitro.
Methods: Human GI carcinoids (BON) were incubated in TFN, SOM230 or both, for 96 hours. Cell growth was measured using methylthiazolyldiphenyl-tetrazolium bromide (MTT) colorimetric assay. Western analysis showed expression levels of achaete-scute complex-like1 (ASCL1) and Chromogranin A (CgA), known carcinoid malignancy markers, along with phosphorylated and total ERK1/2, and other apoptotic and cell survival markers.
Results: Combination treatment with SOM230 and TFN reduced cell growth beyond their sum individual effects. Combination indices confirmed synergy. TFN alone dose dependently reduced ASCL1 and CgA by approximately 20% and 50% with 35μM and 50μM TFN respectively, while SOM230 alone had no affect. Notably, addition of SOM230 following these TFN doses inhibited ASCL1 and CgA levels well beyond their added individual effects- 0.5μM SOM230 following 50μM TFN reduced ASCL1 and CgA levels over 75%. Combination treatment increased phospho-ERK1/2, cleaved poly (ADP)-ribose polymerase and cleaved caspase-3 levels, and reduced total caspase-3, X-linked inhibitor of apoptosis, survivin and Mcl-1 levels.
Conclusions: Combined SOM230 and TFN treatment of BON cells synergistically inhibits cell proliferation and biomarker expression through induction of apoptosis. Since treatment efficacy can be achieved at lower doses of either drug, combination therapy may presumably palliate carcinoid syndrome symptomatology at toxicity levels that are safer and tolerable. Because each drug has already been evaluated in clinical trials, animal models and combinatorial drug trials are warranted.
Prognostic Value of Chromogranin A and Alkaline Phosphatase in Patients with Advanced Neuroendocrine Tumor
Monica Ter-Minassian,1 Jennifer A. Chan,1 Susanne M. Hooshmand,1 Lauren K. Brais,1 Anastassia Daskalova,1 Rachel Heafield,1 Xihong Lin,2 David C. Christiani,3 Matthew H. Kulke11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; 2Department of Biostatistics; and 3Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115.
Background: Serum chromogranin A (CgA) or alkaline phosphatase (AlkPhos) are routinely assessed in patients with advanced neuroendocrine tumor (NET) patients but their prognostic significance continues to be debated. We evaluated whether CgA or AlkPhos were associated with overall survival in a large, prospectively collected cohort of NET patients.
Methods: We identified patients with metastatic NET enrolled in an institutional database between 2003-10. CgA and AlkPhos levels, together with demographic features including age, gender, tumor histology, and tumor subtype were obtained and correlated with overall survival using the log-rank test. Hazard ratios for each serum biomarker were calculated using multivariate Cox regression, adjusting for these baseline characteristics. Each biomarker was modeled as a time-varying covariate to account for variability in time from initial metastatic diagnosis to time of biomarker test.
Results: We identified 526 patients who presented at our institution with metastatic NET. Of these, we obtained CgA values for 349 patients and obtained AlkPhos values for 350 patients. There were 146 and 153 deaths among those tested for CgA and AlkPhos, respectively. The median survival time from time of test (yrs, (95%CI)) for patients with advanced NET and an elevated CgA was 4.95 (3.96, 5.47), as compared to 7.85 (6.14, -) for those at normal CgA limits (p<0.0001). The median survival time from time of test (yrs, (95%CI)) for patients with an elevated AlkPhos was 3.27 (2.48, 4.08), as compared to 7.13 (6.05, 9.37) for those at normal AlkPhos levels (p<0.0001). Using the adjusted time-varying model, either elevated CgA (aHR 3.97 (2.73, 5.75) p=3.15E-13) or elevated AlkPhos (aHR 2.4 (1.7, 3.4) p=7.96E-07) were adverse prognostic factors for patients with advanced NET.
Conclusion: In patients with advanced disease, elevated serum CgA or elevated AlkPhos are associated with shorter survival times, independent of other prognostic factors.
Evaluation of the Efficacy and Safety of Lanreotide on Tumor Growth Stabilization in Patients with Progressive NETs Who Are Not Eligible for Treatment with Surgery or Chemotherapy
Vicente Alonso,1 Maribel Marmol,2 Daniel Castellano,3 Emilio Fonseca,4 Amalia Velasco,5 José Luis García López,6 Eva Pineda,7 Pascal Maisonobe,8 Bertomeu Massutí,9 Marta Martín-Richard,10 on behalf of the TTD Study Group 1Hospital Miguel Servet, 50009 Zaragoza, Spain; 2Hospital Clinic, 08036 Barcelona, Spain; 3Hospital Universitario 12 de Octubre, 28041 Madrid, Spain; 4Hospital Universitario, 37007 Salamanca, Spain; 5Hospital Universitario de la Princesa, 28006 Madrid, Spain; 6Hospital Ramón y Cajal, 28034 Madrid, Spain; 7IPSEN PHARMA, S.A, 08908 Barcelona, Spain; 8IPSEN, 92100 Paris, France; 9Hospital General de Alicante, 03010 Alicante, Spain; 10Hospital de la Santa Creu y Sant Pau, 08025 Barcelona, Spain.
Background: Somatostatin analogs (SSAs) are the treatments of choice for hormonal symptoms associated with NETs. Clinical studies have suggested stabilization of or, in rare cases, a partial response in the tumor mass. No data have been presented previously relating to the antitumoral activity of SSAs as sole treatment in documented progressive NETs. Thus, we undertook a phase II trial (NCT0032646) to evaluate the efficacy of lanreotide Autogel 120 mg on tumor growth stabilization in this patient population.
Methods: Thirty Caucasian patients from 17 Spanish hospitals with advanced and/or metastatic well-differentiated NETs that were progressive within the last 6 months were treated with lanreotide Autogel 120 mg every 28 days until progression. Exclusion criteria: SSA treatment during the previous 6 months; chemotherapy/interferon treatment during the previous 4 weeks. Radiologic evaluation was performed every three cycles. The primary endpoint was progression-free survival (PFS) per central blind review (using RECIST criteria). Clinical baseline characteristics were: median (range) age, 63 (40-78) years; male/female, 50%/50%; median (range) time since diagnosis, 5.5 (0.2-22.2) years; ECOG 0/1/2, 63%/30%/ 7%; foregut/midgut/unknown, 47%/40%/ 13%; median (range) Ki index, 2.0 (0.0 - 20.0); functioning/non-functioning, 63%/37%; previous pharmacologic treatment naive/chemotherapy/ interferon/SSAs, 50%/33%/23%/20%.
Results: Median PFS (95% CI) was 12.9 (7.9-16.5) months both in intention-to-treat and per-protocol populations. Best tumor responses were: 4% partial response/89% stable disease/7% disease progression. Ki 67 index was the most likely prognostic factor for PFS (n=21; hazard ratio, 1.17; p=0.018). One patient discontinued treatment due to adverse events (AE). Only one severe treatment-related AE was detected (aerophagia). No impairment in EORTC QLQ-C30 for the whole group was detected during treatment.
Conclusions: In this study, sole treatment with lanreotide Autogel 120 mg in progressive NET patients provided a median PFS >12 months with very low toxicity. This apparent tumoral control effect should be confirmed in an ongoing phase III trial (CLARINET, NCT00842348).
Impact of Prior Somatostatin Analog Use on PFS in the Phase III RADIANT-2 Trial of Everolimus + Octreotide LAR vs Placebo + Octreotide LAR in Patients with Advanced Neuroendocrine Tumors
Lowell Anthony,1 Neha Singh,-2 Vanessa Q. Passos,3 Marianne Pavel,4 Kjell Oberg,5 James C. Yao61Ochsner Kenner Medical Center, Kenner, LA 70065; 2Novartis Healthcare Pvt. Ltd., Madhapur, Hyderabad, India 500 081; 3Novartis Pharmaceuticals Corporation, Florham Park, NJ 07932; 4Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany 13353; 5Department of Endocrine Oncology, University Hospital, Uppsala, Sweden S-751 85; 6MD Anderson Cancer Center, Houston, TX 77030.
Background: In the phase III RADIANT-2 study, everolimus plus octreotide LAR provided a clinically meaningful 5.1-month increase in median progression-free survival (PFS) vs placebo plus octreotide LAR in patients with advanced, low- or intermediate-grade NET and a history of secretory symptoms (flushing and/or diarrhea). The effect of previous treatment with a long-acting somatostatin analog (SSA) on PFS in RADIANT-2 is presented here.
Methods: Patients (N=429) were randomized to the combination of everolimus 10 mg/d orally + octreotide LAR 30 mg intramuscularly q28d (E+O; n=216) or placebo + octreotide LAR (P+O; n=213). The primary endpoint was PFS per adjudicated central review by RECIST (v1.0). SSA treatment before study entry was permitted, although the prior doses used are not available at this time.
Results: Of the 429 patients randomized to treatment, 339 (79%) had received SSA before study entry, including 173 (80%) in the E+O group and 166 (78%) in the P+O group. Among patients with prior SSA therapy, the median duration of prior SSA exposure was 1.7 years for E+O and 1.8 years for P+O. The time since diagnosis was >6 months for 96% of patients who received prior SSA therapy vs. 73% of patients who did not. E+O improved median PFS vs. P+O in patients with and without previous SSA treatment (Table 1). Although not statistically significant, E+O dramatically improved median PFS vs P+O in patients who did not receive prior SSA therapy (25.2 vs 13.6 months, respectively).
Conclusions: In RADIANT-2, E+O prolonged PFS regardless of previous SSA use in patients with advanced NET and a history of secretory symptoms.
A Phase II Study to Evaluate the Safety and Efficacy of RAD001 plus Erlotinib in Patients with Well-Differentiated Neuroendocrine Tumors (NET)
Emily Bergsland,1 Lindsey Watt,1 Andrew Ko,1 Margaret Tempero,1 W. Michael Korn,1,2 Robin K. Kelley,1 Tom Weber,1 Iche Siah,1 Jimmy Hwang,3 Eric Nakakura,4 Alan Venook1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115 1Division of Hematology/Oncology; 2Division of Gastroenterology; 3Biostatistics and Computational Biology Core; 4Department of Surgery.
Background: Building on strong preclinical data, we hypothesized that concomitantly targeting mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) signaling pathways will inhibit neuroendocrine tumors (NET) more effectively than targeting either pathway alone (thus improving likelihood of shrinkage). We initiated a prospective, phase II study to assess the safety and efficacy of RAD001 plus erlotinib in patients (pts) with advanced NET.
Methods: Pts with well-differentiated NET were enrolled using a Simon 2-stage design with 2 groups: pancreatic NET (PNET) and other low-grade NET/ carcinoid (CARC). Eligibility criteria included histological diagnosis of a well- to moderately-differentiated NET and no prior mTOR- or EGFR-inhibitor. Pts treated with RAD001 5 mg PO QD and erlotinib 100 mg PO QD without scheduled breaks (1 cycle = 28 d). Pts followed for toxicity and radiographic response, with first planned analysis after 8 evaluable pt / group.
Results: Since 6/09, 17 pt enrolled: M/F 9/8; PNET/CARC 8/9. Pts on octreotide remained on drug. All pt had PD at enrollment. Median # cycles: 12 in CARC (range 2-20); 5.5 (to date) in PNET (range 0.5-18). Excessive toxicity in first 7 pts prompted reduction in starting erlotinib dose from 150 to 100 mg/d, resulting in improved tolerability: Gr 3 stomatitis in 3/7 initial pts (43%) vs 1/10 (10%) after new starting dose. Overall, the most common side effects include diarrhea, stomatitis, rash, anorexia, and fatigue. Enrollment to CARC cohort stopped after first stage due to insufficient efficacy (7/9 SD, 2/9 PD; 0 PR).
Conclusions: RAD001 plus erlotinib appears to be associated with radiographic stability, but not shrinkage, in CARC. Combining the two agents has proven challenging; toxicity precludes administration of either agent at full dose. Interim efficacy analysis for PNET stratum pending. Correlation with expression of mTOR pathway components in archived tissue planned.
The CLARINET Study – Assessing the Effect of Lanreotide Autogel on Tumor Progression-Free Survival in Patients with Non-Functioning Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
Blumberg Joelle,1 Liyanage Nilani,1 Caplin Martyn,2 on behalf of UK & Ireland Neuroendocrine Tumour Society/European Neuroendocrine Tumor Society1Ipsen Innovation, 91940 Les Ulis, France; 2Royal Free Hospital, NW3 2QG London, UK.
Background: Somatostatin analogs (SSAs) provide good symptom control in NET patients. Clinical studies suggest SSAs also stabilize tumor growth. In a previous double-blind study (PROMID) in a mixed functioning and non-functioning gastroenteroNET population (n=85), octreotide LAR significantly increased time to tumor progression versus placebo. No similar well-controlled study has previously been conducted with lanreotide Autogel (lan-ATG). Thus, the CLARINET study, a double-blind, placebo-controlled trial, has been undertaken to assess the effect of lan-ATG 120 mg on progression-free survival in patients with non-functioning GEP-NETs.
Methods: CLARINET is a 96-week, multinational study being conducted in collaboration with UKI NETS and ENETS in 200 patients with well or moderately differentiated non-functioning GEP-NETs and Ki67 <10%. Patients are stratified by prior tumor progression status and presence/absence of previous therapies, and treated with lan-ATG 120 mg. The primary endpoint is time to either disease progression (using RECIST criteria) or death. Two baseline CT scans (≥12 weeks apart) are performed, followed by additional scans at intervals up to 96 weeks. Secondary endpoints include proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, safety, quality of life, plasma chromogranin A levels and pharmacokinetic parameters.
Results: By mid-June 2011, 203 patients were included. Preliminary baseline data for the first 186 patients (95 males; mean [SD] age, 62.5 [10.3] years) are available: tumors most commonly originated in the pancreas (n=81, 44%) or small intestine (n=62, 33%), with the location of the primary unknown in 22 patients; seven patients had progressive disease; and 28 had received previous therapy. Thus far, the drug safety monitoring committee has identified no safety concerns. Final results are expected in 2013.
Conclusion: CLARINET will provide important information on the anti-tumoral activity and safety of lan-ATG, specifically in a large cohort of patients with non-functioning GEP-NETs.
Improved Tumor Dosimetry by Combining 131I-MIBG and 90Y-DOTATOC in Patients with Carcinoid Tumors
David Bushnell,1,3 Mark Madsen,1 Tom O’Dorisio,2 Yusuf Menda,1 Beth Schmitt,3 Thorvardur Halfdanarson,2,3 Sue O’Dorisio21University of Iowa Hospital and Clinics, department of Radiology; 2University of Iowa Hospital and Clinics, department of Medicine; 3Iowa City Veterans administration Medical Center, Diagnostic Imaging Service.
Background:131I-MIBG and 90Y-DOTATOC are used as radiotherapeutic agents for neuroendocrine tumors. The tumor dose delivered by either of these agents individually is often insufficient to cure disease. Since the activity limiting tissues are different for each (kidney for 90Y-DOTATOC and marrow for 131I-MIBG) we have previously demonstrated that combining them may lead to increased tumor dose without exceeding critical organ limits. The goal of this work is to establish whether patients with advanced stage carcinoid tumors could benefit dosimetrically from combining 131I-MIBG and 90Y-DOTATOC.
Methods: In patients with advanced stage midgut carcinoid tumors, Individual patient tracer kinetics and uptake measurements were used to calculate radiation dose values per unit of administered activity for both 131I-MIBG and 90Y-DOTATOC for the kidneys, bone marrow, and tumor sites. These results were then used with previously derived equations to calculate the optimal/safe administered activity levels for each drug, individually and in combination, to achieve maximum tumor dose in each subject.
Results: We have completed the data analysis for 3 patients to date. We have 5 additional patients in this study. In 1 of these 3 patients, the radiation dose (to a carcinoid tumor site) that would be delivered using an optimized combination of 131I-MIBG and 90Y-DOTATOC was found to be higher by 24% than the achievable tumor dose with either 131I-MIBG or 90Y-DOTATOC alone without exceeding dose limits to kidneys or marrow. The optimized combination of administered activities for this subject was found to be 20 GBq 131I-MIBG plus 11 GBq 90Y-DOTATOC. In practice these levels of activity would be delivered over multiple cycles.
Conclusion: These findings support the premise that combining 131I-MIBG and 90Y-DOTATOC can increase the delivered tumor radiation dose in some patients with metastatic midgut carcinoid above that achievable with either agent alone.
Impact of Progression on Resource Utilization in the Treatment of Advanced Neuroendocrine Tumor
R. Casciano,1 X. Wang,2 Z. Liu,3 R. Parikh,1 J. Strosberg,4 R. Riechelmann51Analytica International, Global Outcomes Research & Pricing, New York NY 10018, USA; 2Novartis Oncology, Global Health Economics & Pricing, Florham Park NJ, USA 07932; 3Novartis Oncology, Health Economics & Outcomes Research, Florham Park NJ, USA 07932; 4H. Lee Moffitt Cancer Center & Research Institute, Experimental Therapeutics Gastrointestinal Tumor, Tampa FL, USA 33612; 5Instituto do Cancer do Estado de Sao Paulo, Clinical Research, Sao Paulo, Brazil 02146.
Background: Advanced neuroendocrine tumors (aNET) are associated with high morbidity and mortality; however, literature on resource utilization upon disease progression is scarce. This study aims to compare resource use in aNET patients at diagnosis versus post-progression.
Methods: An online survey was administered to physicians across the US, UK, Germany, France, Brazil and Italy. The survey collected resource utilization during the baseline (time post-diagnosis but pre-progression), 1st, and 2nd progression periods. Progression was defined as measurable/radiographic evidence of tumor progression.
Results: 197 physicians participated, providing data on 394 patients. Average durations in baseline, 1st and 2nd progression were 12.8, 8.7 and 12 months, respectively. aNET subtypes included Gastrointestinal (GI) (45%), lung (24%), and pancreas (31%). Resource utilization consistently increased from baseline through progression (Table 1).
Conclusions: It is important to characterize the burden posed by disease progression in a NET. Findings suggest that progression results in increased use of chemotherapy, PRRT, targeted therapies, and hospitalization rates.
Updated Results of a Phase I Study of Pasireotide (SOM230) in Combination with Everolimus in Patients (pts) with Advanced Neuroendocrine Tumors (NET)
Jennifer A. Chan, MD, MPH,1,2 David P. Ryan, MD,3 Charles S. Fuchs, MD, MPH,1,2 Andrew X. Zhu, MD, PhD,3 Thomas A. Abrams, MD,1,2 Brian M. Wolpin, MD, MPH,1,2 Paige Malinowski, BA,1 Eileen Regan, RN, BSN, OCN,1 Matthew H. Kulke, MD, MMSc1,21Dana-Farber Cancer Institute, Boston, MA 02215; 2Brigham and Women’s Hospital, Boston, MA 02115; 3Massachusetts General Hospital, Boston, MA 02114.
Background: Octreotide and the mTOR inhibitor everolimus have antitumor activity in NETs. Pasireotide is a novel somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate safety and feasibility of combining pasireotide and everolimus in patients with advanced NETs.
Methods: Pts received escalating doses of pasireotide and everolimus. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Dose-limiting toxicity (DLT) was defined within the first 56 days of therapy.
Results: Among 22 enrolled pts, 21 were evaluable for toxicity. Enrolled pts had the following characteristics: M/F = 14/8; median age 60 (range 35-76); ECOG PS 0/1/2 = 16/5/1; carcinoid/pancreatic NET = 18/4. Pts have received a median of 6 cycles of treatment (range 1-29). No pts at dose level (DL) 1 and DL 2 experienced DLT. DLT was experienced by 1 pt at DL 3 (gr 3 rash) and 1 pt at DL 4 (gr 3 diarrhea). Dose escalation was halted at DL 4 to further assess safety and toxicity at DL 3; no further DLT was observed in 6 additional patients treated at DL3. Other gr 3 or higher treatment-related adverse events across all cycles included hyperglycemia (n=8; 1 at DL1, 1 at DL2, 4 at DL3, 2 at DL4), hypophosphatemia (n=6; 1 at DL1, 1 at DL2, 3 at DL3, 1 at DL4), thrombocytopenia (n=3; 2 at DL3, 1 at DL4), lymphopenia (n=2; 1 at DL1, 1 at DL3), elevated alkaline phosphatase (n=2; 1 at DL2, 1 at DL3), mucositis (n=1 at DL3), prolonged QTc (n=1 at DL3), and joint pain (n=1 at DL4). Independently-reviewed best objective responses in 21 evaluable pts revealed partial response in 1 pt, stable disease in 19 pts, and progressive disease in 1 pt.
Conclusion: Combination therapy with pasireotide and everolimus is feasible and associated with preliminary evidence of antitumor activity in NET. Pasireotide 60 mg IM monthly combined with everolimus 10 mg daily should be further investigated in future NET studies.
The Use of Intraoperative Ultrasound Guided Radiofrequency Ablation for Cytoreductive Surgery of Liver Metastases from Pancreatic Neuroendocrine Tumors
Junsung Choi, MD, Pamela J. Hodul, MD, Larry K. Kvols, MD, Jonathan Strosberg, MD, Mokenge P. Malafa, MD Department of Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA.
Background: Surgical cytoreduction is an important option for management of hepatic metastases from pancreatic neuroendocrine tumors (PNET). However, optimal cytoreduction by resection alone is often limited by the extent of tumor volume or tumor distribution within the liver. The purpose of this study was to assess the utilization of intraoperative ultrasound guided radiofrequency ablation (RFA) to achieve optimal cytoreduction in patients with PNET and to assess for disease progression following treatment.
Methods: A prospective database of 84 consecutive metastatic neuroendocrine carcinoma patients undergoing surgical treatment at our institution from 1999 to 2010 was retrospectively queried for radiofrequency ablation of liver metastases for cytoreduction from PNET. Patients were evaluated for the use of radiofrequency ablation alone or in combination with resection to achieve optimal (greater than 80% to 90%) cytoreduction. Progression of disease following surgery was evaluated by cross-sectional imaging studies.
Results: 23 patients were identified with a diagnosis of pancreatic neuroendocrine carcinoma with biopsy proven or suspected liver metastases. Of those patients IOUS demonstrated no liver lesion in one patient. Biopsy of liver lesions in two patients demonstrated hemangiomas and bile duct hamartoma in a third patient. IOUS guided RFA was performed in 20 patients. The median age at diagnosis was 48.7 years and at the time of cytoreductive surgery was 50.6 years. The average time of follow up was 6.7 years from diagnosis (range 2.3 to 15 years). Of the 20 patients undergoing cytoreduction with RFA a total of 73 ablations were performed (range 1 to 9 ablations). 16 of these patients also had one or more segmental or wedge resections with RFA and 9 patients having distal pancreatectomy and splenectomy. Optimal cytoreduction was achieved as assessed by IOUS in 16 of 20 patients. On follow up imaging 5 patients remained without disease progression and one patient had no evidence of disease in the liver. 14 patients demonstrated disease progression (enlarging residual tumors or new liver metastases) at 0.3 to 4.5 years (average 1.9 years). 2 of these patients had repeat cytoreductive surgery. Multiple additional treatment options were provided for disease progression including chemotherapy, embolization, radioembolization, external beam radiation, and lutetium.
Conclusions: The use of intraoperative ultrasound guided radiofrequency ablation is a reasonable option to increase the likelihood of achieving optimal cytoreduction of liver metastases in PNET. Additional treatment options become necessary for the management of disease recurrence or progression in the majority of these patients.
Comparison of Clinicopathologic Factors in 122 Patients with Resected Pancreatic and Ileal Neuroendocrine Tumors from a Single Institution
Fadi S. Dahdaleh, MD,1 Daniel Calva-Cerqueira, MD,1 Jennifer C. Carr, MD,1 Junlin Liao, PhD,1 James J. Mezhir, MD,1 Thomas M. O’Dorisio, MD,2 James R. Howe, MD11Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA 52242; 2Department of Internal Medicine, Division of Endocrinology and Diabetes, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.
Background: Recent population-based studies have demonstrated significant differences in outcome between patients with pancreatic and ileal neuroendocrine tumors. The objective of this study was to examine the clinicopathologic differences between ileal and pancreatic neuroendocrine tumors following resection.
Methods: A retrospective chart review was performed and data on clinicopathologic variables, biochemical markers, and follow-up of patients with resected ileal (INETs) and pancreatic (PNETs) neuroendocrine tumors were collected. The Student’s t-test or analyses of variance (ANOVA) were used to compare means. Survival analysis was performed using the Kaplan-Meier method.
Results: Between 1998 and 2010, 122 patients with PNETs and INETs were explored (70 PNETs and 52 INETs). Several variables were found to be significantly different between patients in both groups. INETs were more often associated with flushing (44% vs. 14%; p<0.001) and diarrhea (63% vs. 16%; p<0.001) and were more often associated with elevation in preoperative serum levels of pancreastatin (90% vs. 50%; p<0.001), chromogranin A (78% vs. 53%; p=0.036) and serotonin (96% vs. 51%; p<0.001). INETs more frequently had vascular invasion on pathology (96% vs. 60%; p<0.001), and presented more often with nodal and/or distant metastases (77% vs. 36%; p<0.001). There was no significant difference in overall survival between patients in both groups.
Conclusion: In this series, patients with INETs presented with a more advanced stage of disease as compared to PNETs, higher preoperative levels of three markers, and were more often symptomatic. Despite these factors, there was no significant difference in overall survival between patients with these two tumor types.
Neurokinin A Levels Predict Survival in Patients with Well Differentiated Small Bowel Neuroendocrine Tumors
Anne E. Diebold, BS,1,2 J. Philip Boudreaux, MD,1,2 Yi-Zarn Wang, DDS, MD,1,2 Lowell B. Anthony, MD,2,3 Ann Porter Uhlhorn, RN,2,4 Pamela Ryan, BSN, RN,2,4 Eugene A. Woltering, MD1,21Department of Surgery, Section of Surgical Endocrinology, The Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States; 2New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), Ochsner-Kenner Medical Center, Kenner, LA 70065, United States; 3Department of Medicine, Section of Hematology and Oncology, The Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States; 4Ochsner-Kenner Medical Center-Kenner, Kenner, LA 70065, United States.
Background: Recent European investigations demonstrated that persistently elevated (> 50 pg/ml) plasma neurokinin A (NKA) levels are associated with a poor short term survival in patients with midgut neuroendocrine tumors (NETS). We hypothesized that US patients with persistently elevated NKA levels (> 50 pg/ml) will also have a poor short term survival.
Methods: Serial plasma NKA levels were collected from the charts of 183 patients with midgut NETS. Patients were grouped according to their NKA values, and median, six, twelve, and eighteen month survival rates were calculated. Group one had NKA levels < 50pg/ml. Group two at one point had NKA levels >50 pg/ml but subsequently fell to < 50pg/ml. Group three had NKA values currently >50pg/ml.
Results: Group one patients (n=145) have not yet reached their median survival and their eighteen month survival rate is 95%. Thirteen of the fourteen (93%) group two patients are currently alive. Group three patients (n=24) have a median survival of 20 months and an eighteen month survival rate of 57%.
Conclusion: Patients with midgut NETS who have serial NKA levels <50 pg/ml have an excellent short term prognosis, while patients with NKA levels>50 pg/ml have a poor short term prognosis.
Comparison of Hepatic Artery Embolization and Selective Internal Radiation Therapy for Metastatic Neuroendocrine Tumors
Eric S. Engelman, DO,1 Roberto Leon-Ferre, MD,2 Boris G. Naraev, MD, PhD,1 Nancy Sharma, MD,1 Shiliang Sun, MD,3 Thomas M. O’Dorisio, MD,4 Thorvardur R. Halfdanarson, MD11Division of Hematology, Oncology, and Blood and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242; 2Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242; 3Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242; 4Division of Endocrinology and Metabolism and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242.
Background: Liver-directed therapies can be beneficial in reducing morbidity and mortality in patients with metastatic neuroendocrine tumors (mNETs). We compared the clinical outcomes of patients treated with hepatic artery embolization/chemoembolization (HA(C)E) or selective internal radiation therapy (SIRT) with SIR-Spheres at our institution over the last ten years.
Methods: Medical records of 42 mNET patients with hepatic metastases treated with either bland hepatic artery embolization (HAE), chemoembolization (HACE), or SIRT at the University of Iowa from 2001 to 2011 were analyzed. Chi-square and Wilcoxon rank-sum tests were performed to compare the groups. Time to progression (TTP) and overall survival (OS) were calculated using Kaplain-Meier analysis.
Results: The tumors were located in the small bowel in 21 patients (50%), pancreas in 8 (19%), lung in 2 (5%), and other locations in 11 patients (26%). Ten patients (24%) had extra-hepatic metastases. 13 patients had HAE, 17 patients had HACE and 12 patients had SIRT. 20 of these patients had a second procedure with 6 receiving SIRT, 9 HAE and 5 HACE. TTP was similar between SIRT (15.1 months) and HAE or HACE (19.6 months) (p= 0.968). There was a trend towards an increased TTP in patients receiving HACE (33.4 months), compared to HAE (12.1 months) or SIRT (15.1 months) (p = 0.512). The overall survival for all patients from the first intervention was 41.9 months.
Conclusion: There appears to be no significant difference in TTP in patients treated with SIRT compared to patients treated with HAE or HACE in this cohort; however, there may be a trend towards a longer time to disease progression in patients treated with chemoembolization compared to the other two modalities. Patients tend to have a prolonged survival after all three liver-directed therapies.
Analysis of Progression-Free Survival (PFS) by Prior Chemotherapy Use and Updated Safety in RADIANT-3: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Trial of Everolimus in Patients with Advanced Low- or Intermediate-Grade Pancreatic Neuroendocrine Tumors (pNET)
Timothy Hobday,1 Rodney Pommier,2 Eric Van Cutsem,3 Ashok Panneerselvam,4 Stephen Saletan,4 Robert E. Winkler,4 James C. Yao51Mayo Clinic, Rochester, MN, USA 55905; 2Oregon Health & Science University, Portland, Oregon, USA 97239; 3University Hospital Gasthuisberg/Leuven, Leuven, Belgium 3000; 4Novartis Oncology, Florham Park, NJ, USA 07932; 5The University of Texas MD Anderson Cancer Center, Houston, TX, USA 77030.
Background: In RADIANT-3, everolimus, an oral mTOR inhibitor, demonstrated superior median PFS vs placebo (11.0 vs 4.6 mo; HR=0.35; 95% CI, 0.27-0.45; P<0.0001) (ESMO 2010, Abstract #LBA9). Analysis of PFS by prior chemotherapy use and survival/safety updates are presented.
Methods: Patients with progressive low- or intermediate-grade pNET were randomized to receive everolimus 10 mg/d orally (n=207) or placebo (n=203); all received best supportive care. Patients were stratified by prior chemotherapy use. The primary endpoint was PFS per central review (RECIST v1.0). Upon disease progression, patients randomized to placebo could cross over to open-label everolimus.
Results: 206/410 (50%) patients received prior chemotherapy, with prior use balanced in both treatment arms. Everolimus significantly prolonged median PFS vs placebo in patients with prior chemotherapy (11 vs. 3.2 months) (HR=0.34; P<0.001) and in those without prior chemotherapy (11.4 vs. 5.4 months) (HR=0.42; P<0.001). Of 203 placebo patients, 172 (85%) crossed over to open-label everolimus. The updated OS analysis cutoff date was Feb 23, 2011 (146 events: 68 everolimus; 78 placebo). Median OS with placebo was 36.6 months and has not been reached with everolimus (HR, 0.89; 95% CI, 0.64–1.23). Median safety follow-up extended to 20.1 months and included 407 patients (204 everolimus; 203 placebo). Most common drug-related AEs with everolimus vs placebo remained stomatitis (52.9% vs 12.3%), rash (48.5% vs 10.3%), and diarrhea (34.3% vs 10.3%). Most common drug-related grade 3/4 events were anemia (5.9% vs 0%), hyperglycemia (5.9% vs 2.5%), and stomatitis (4.9% vs 0).
Conclusions: Everolimus significantly prolonged PFS vs placebo regardless of prior chemotherapy use. After 40 months of follow-up, median OS was not reached for everolimus. Median OS in the placebo arm, exceeded the previously reported median in metastatic pNET patients. Safety of everolimus was consistent with previous experience.
Hepatic Artery Radioembolization (HARE) in the Management of Progressive Metastatic Neuroendocrine Tumors (NETs): A Survival and Biochemical Response Analysis in Geriatric (G) and Young (Y) Populations
Khawaja Saad Jahangir, MD,1 Ryan Majoria, MD,2 Joe Hagan, PhD,1 Philip Boudreaux, MD,2 Yi-Zarn Wang, MD,2 Brian Boulmay, MD,1 Richard Campeau, MD,2 Eugene Woltering, MD,2 Lowell Anthony, MD21Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112; 2Ochsner Health Center, Kenner, Louisiana 70065.
Background: HARE (Y-90 SirSpheres™) in NETs has limited survival statistics, biochemical responses (BR) and factors influencing outcomes are lacking. Objectives: 1) determine if age (G ≥ 60yrs vs Y< 60yr) influences overall survival (OS) & progression free survival (PFS); 2) calculate biochemical response (BR); 3) identify predictive factors.
Methods: A retrospective chart analysis of consecutively treated patients was performed. Demographic, serial pre- & post-Rx (1,6,12,18 mos) Karnofsky Performance Status (KPS), biochemical (5-HIAA, chromogranin A, pancreastatin, neurokinin A (NKA)) & radiographic response data were collected and OS, PFS and BR calculated.
Results: Between 12/2004-8/2010, 73 pts (37 small bowel (SB), 12 pancreas (P), 6 rectum, 18 other) with a median age (range) of 60.4 yrs (39-75) underwent HARE. No differences in OS (p=0.759) & PFS (p=0.767) were seen in G vs Y pts. Primary site was not associated with OS (p=0.373), SB had better PFS (p<0.001). Higher Ki-67 had lower PFS, Hazard ratio (HR)=1,488,691, p=0.002. NKA level at 6 mos was directly proportional to radiographic progression, HR=1.05, p=0.047. Pre-Rx KPS was greater for alive pts, median KPS=85 vs median KPS=72 for dead pts, p=0.040.
Conclusion: HARE is equally effective for all ages. SB primary has a greater PFS than P. The Ki-67 index is inversely proportional to PFS. KPS correlates with outcomes. Six mos NKA level predicts progression.
Efficacy of Telotristat Etiprate in Refractory Carcinoid Syndrome: Preliminary Results of a Randomized, Placebo-Controlled, Multicenter Study
Matthew H. Kulke,1 Thomas O’Dorisio,2 Alexandria Phan,3 Robert Langdon Jr,4 Billie Marek,5 Nadeem Ikhlaque,6 Emily Bergsland,7 Joel Freiman,8 Linda Law,8 Phillip Banks,8 Kenny Frazier,8 Jessica Jackson,8 Brian Zambrowicz81Dana-Farber Cancer Institute, Boston, MA; 2University of Iowa Hospitals and Clinics, Iowa City, IA; 3The University of Texas M.D. Anderson Cancer Center, Houston, TX; 4Nebraska Methodist Hospital System, Omaha, NE; 5Texas Oncology, P.A., McAllen, TX; 6St. Francis Hospital, Grove Beach, IN; 7University of California – San Francisco Cancer Center, San Francisco, CA; 8Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
Background: Diarrhea associated with carcinoid syndrome has been attributed to excess serotonin. Telotristat etiprate (a.k.a. LX1032, LX1606) is an oral serotonin synthesis inhibitor that decreases peripheral serotonin production. This randomized study assessed the safety, tolerability, and efficacy of telotristat etiprate in carcinoid syndrome associated diarrhea.
Methods: Carcinoid patients with octreotide-refractory diarrhea (>4 bowel movements (BM)/day on stable-dose octreotide) were randomized 3:1 to receive telotristat etiprate or placebo. Patients enrolled in double-blind, placebo-controlled, sequential, escalating dose cohorts of 150, 250, 350, or 500mg tid, with an expansion cohort (500mg tid). Endpoints included safety, reduction in BMs, reduction in 24-hour urinary 5-HIAA (u5-HIAA) and self-reported clinical improvement, as measured by response to a weekly questionnaire. Upon completion of the initial 4-week assessment period, patients could receive open-label telotristat etiprate.
Results: 23 patients enrolled: 16 in the 4 escalating dose cohorts, 7 in the expansion cohort. 18 received telotristat etiprate and 5 received placebo. Patients had a median age of 62 yrs, mean 6.2 BMs/day (range 4-10), and mean u5-HIAA of 64.2 (range 0.03-246 mg). AEs (placebo/telotristat etiprate) included diarrhea (40%/39%), nausea (20%/28%), and abdominal pain (0%/17%); 1 patient was hospitalized with vomiting. Among evaluable telotristat etiprate -treated patients, 5/18 (28%) experienced a clinical (BM) response (≥30% reduction in frequency for ≥2 weeks), 9/16 (56%) experienced a biochemical (u5-HIAA) response (reduction of ≥50%), and 6/12 (50%) reported subjective relief of bowel symptoms at Week 4. No evaluable placebo patients experienced a BM response (0/5), u5-HIAA response, (0/4) or subjective relief of bowel symptoms at week 4 (0/4).
Conclusion: Treatment with telotristat etiprate was well tolerated and was associated with decreased BM frequency, decreased 24-hour u5-HIAA levels, and a high rate of self-reported subjective clinical improvement in carcinoid patients with octreotide refractory diarrhea. 18 of 19 eligible patients continued treatment under the extension protocol.
Resection of At-Risk Mesenteric Lymph Nodes Improves the Outcome of Patients with Small Bowel Neuroendocrine Tumors
Christine S. Landry, MD,1 Heather Y. Lin, PhD,2 Alexandria Phan, MD,2 Chusilp Charnsangavej, MD,2 Eddie K. Abdalla, MD,2 J. Nicolas Vauthey, MD,2 James C. Yao, MD,2 Jason B. Fleming, MD21Banner M. D. Anderson Cancer Center, Gilbert, AZ 85234; 2The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
Background: Neuroendocrine tumors of the small intestine commonly metastasize to regional lymph nodes. Single institutional reports suggest that removal of lymph nodes improves outcome, but comprehensive data is lacking. We hypothesized that the performance and extent of lymphadenectomy reported in a large administrative database would be associated with improved survival for jejunal and ileal neuroendocrine tumors.
Methods: A search of the SEER database was performed for patients with jejunal and ileal neuroendocrine tumors from 1977-2004. Descriptive patient characteristics were collected to include age at diagnosis, gender, race, grade, primary tumor size, lymph node status, number of lymph nodes resected, presence of distant metastasis, and operation. Statistical analyses were limited to patients with only 1 primary tumor to exclude patients with other malignancies. Univariate and multivariate analyses were performed to analyze the number of lymph nodes resected and the lymph node ratio (number of positive lymph nodes/total number of lymph nodes removed) to determine the effect on cancer-specific survival.
Results: Removal of any LNs was associated with improved cancer-specific survival when compared to patients with no LN removal reported (p=0.0027) on univariate analysis. Among those who had any LN removed, a median of 8 LNs were identified in resection specimens with a median LNR of 0.29 (range 0-1). On multivariate analysis (adjusting for age and tumor size), patients with >7LNs removed experienced an improved cancer-specific survival over those with ≤7LNs removed (median survival not reached vs. 140 months; HR=0.573 [0.402, 0.817], p=0.002) (figure 1).
Conclusions: This review of a large number of surgical patients suggests that a complete regional mesenteric lymphadenectomy in conjunction with resection of the primary tumor will improve the survival of patients with small bowel neuroendocrine tumors.
Single Dose Prophylactic Octreotide Does Not Prevent Intraoperative Carcinoid Crisis
Kristen P. Massimino,1 Ola Harrskog,1 SuEllen J. Pommier,1 Rodney F. Pommier11Oregon Health & Science University, Portland, Oregon, 97212.
Background: Surgery and anesthesia in carcinoid patients can provoke a carcinoid crisis, which can have serious sequelae, including death. Octreotide prophylaxis is recommended to prevent carcinoid crisis, however there are few reports of outcomes and no large series examining its efficacy. We hypothesized that prophylactic octreotide alone is not sufficient to prevent carcinoid crisis.
Methods: Records of carcinoid patients undergoing abdominal operations during years 2007-2011 were retrospectively reviewed. Effect of clinical factors including octreotide use on intraoperative hemodynamic events (systolic blood pressure < 80 for > 10 minutes or report of hemodynamic instability including hypotension, hypertension, tachycardia or carcinoid crisis) was determined. Association of intraoperative hemodynamic events with postoperative outcomes was evaluated. Rates of intraoperative events in patients treated with octreotide prophylaxis were compared to historic controls.
Results: Ninety-seven intraabdominal operations performed by a single surgeon were reviewed. Ninety percent of patients received preoperative prophylactic octreotide. Fifty six percent received at least one additional intraoperative dose. Twenty three patients (24%) all of whom received prophylactic octreotide experienced a major intraoperative hemodynamic event. This rate is higher than previously published. Intraoperative hemodynamic events correlated with presence of hepatic metastases but not presence of carcinoid syndrome. Post operative complications occurred in 60% of patients with intraoperative hemodynamic events versus 31% of those with none (p=0.01).
Conclusions: Significant intraoperative hemodynamic events occur frequently in carcinoid patients with hepatic metastases regardless of presence of carcinoid syndrome and despite single dose prophylactic octreotide. Occurrence of such events correlates strongly with post-operative complications. Randomized controlled trials are needed to determine whether the administration of prophylactic octreotide is beneficial.
Reproducibility of [68Ga]DOTATOC Imaging in Neuroendocrine Tumors
Yusuf Menda, MD,1 Laura L. Boles Ponto, PhD,1 Thomas O’Dorisio, MD,1 Michael K. Schultz, PhD,1 G. Leonard Watkins, PhD,1 John Sunderland, PhD,1 Michael Graham, MD PhD,1 David Bushnell, MD,1,4 M. Sue O’Dorisio, MD, PhD11University of Iowa Carver College of Medicine, Iowa City, IA; 2Veteran’s Affairs Medical Center Iowa City. 115 VA Newton Road, Iowa City, IA.
Background: The potential utility of Gallium-68-labeled DOTA-D-Phe1-Tyr3-octreotide Positron Emission Tomography ([68Ga]DOTATOC PET) to effectively monitor response to therapy is dependent on the reproducibility of [68Ga]DOTATOC uptake.
Objective: To evaluate the reproducibility of uptake parameters of [68Ga]DOTATOC in patients with neuroendocrine tumors by PET.
Methods: Five subjects with metastatic neuroendocrine tumors were imaged with [68Ga]DOTATOC PET on two occasions. The interval between two scans was 1-5 days. Dynamic images of the chest or abdomen were obtained for 60 minutes followed by a whole-body PET/CT scan. Maximum pixel standardized uptake values (SUVmax) and the average SUV based on 50% thresholding of the maximum pixel SUV (SUVmean) were calculated for up to 10 target lesions for each patient. Time-activity curves were determined for lesions identified on the dynamic frames with arterial plasma input functions generated from regions over major vessels (e.g., aorta). Patlak coefficients (K-Patlak) and K-influx derived from a two-tissue compartment model were calculated for each target volume of interest (VOI). The reproducibility (i.e., percent difference) was calculated for each parameter.
Results: [68Ga]DOTATOC uptake in lesions was highly reproducible. The correlation coefficient for SUVmax and SUVmean between the first and second scan was 0.99. The mean difference for SUVmax and SUVmean between two scans (n=47) were 9.8± 7.9% and 12.1±12.3%, respectively. Kinetic parameters (n=21) had poorer reproducibility due to variability in the input function determination. The mean difference was 20.9±16.2% for K-Patlak and 31.1±33.5% for K-influx.
Conclusions: These data suggest that an 18-24% difference (mean +1 SD) in SUVmax or SUVmean is needed to confirm a biological change in tumor uptake of [68Ga]DOTATOC between two studies.
High Grade Neuroendocrine Carcinoma of the Uterine Cervix: Outcomes and the Role of Radiation and Chemotherapy – The University of Iowa Experience
Boris G. Naraev, MD, PhD,1 Nancy Sharma, MD,1 Michael J. Goodheart, MD,1 Thomas M. O’Dorisio, MD,1 Thorvardur R. Halfdanarson, MD11University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242.
Background: High-grade neuroendocrine carcinoma of the uterine cervix (cNEC) is a rare and aggressive cancer, and the optimal treatment remains uncertain. We report 36 cases seen at the University of Iowa between 1977 and 2010.
Methods: Cases were identified by searching our institutional database. Only patients (pts) with pathology-confirmed cNEC were included.
Results: 36 cases with follow-up information were identified. The median age at diagnosis was 49 years (range 26 – 77). FIGO staging was IB1 for 14 pts (39%), IB2 for 3 (8%), II for 7 (19%), and 12 (34%) had stage III or higher. 17 pts (47.2%) underwent resection, 20 pts (56%) had radiation therapy (RT), and 27 pts (82%) received chemotherapy (ChT). The median survival (MS) for the entire cohort was 20.7 months (ms) with 23% 5-year overall survival (5-OS) and 8% 10-year OS. Stage was a strong predictor of survival. Pts with stage IB1 or less had longer MS and 5-OS compared to those with higher stage (MS 42 vs. 11.1 ms, p=0.008, 5-OS 47 vs. 6%). Complete resection predicted better outcome (MS: 50 vs 9.3 ms, p=0.0004, 5-OS: 50 vs. 0%). Of 17 resected pts, 7 recurred after a median of 19.4 ms (range 7.5 – 43), and all but 1 died. RT did not seem to improve survival (MS 16 months for RT vs. 23 months for no RT, p=0.6). RT was not associated with outcome regardless of surgery. Resected pts had MS of 43.8 ms with RT vs. 128.5 ms without RT, (p=0.76). Pts with unresectable disease demonstrated MS of 11.8 ms with, and 10.5 ms without RT (p=0.8). ChT was associated with better survival in pts with unresectable disease. Pts receiving ChT had MS of 10.8 ms vs. 2.7 ms (p=0.006) in those who did not. None of these pts survived > 5 years. Platinum with etoposide was used in 73%. Partial response or stable disease were seen in 50% with mean duration of response of 9.1 ms. Second line ChT at progression was used in 44.4%. Pre- and post-operative ChT in resectable disease did not impact survival (MS 45 ms on ChT vs. 156.5 ms with no ChT (p=0.37).
Conclusion: The prognosis of advanced cNEC is very poor and surgery in early stages resulted in the best outcome. RT was not associated with improved survival in this study. ChT seems beneficial in unresectable disease, but the effect of the second line ChT remains undefined. Overall, the treatment outcomes remain unsatisfactory; better treatment options are needed.
Outcomes of Peptide Receptor Radionuclide Therapy (PRRT) in Patients with Metastatic Low Grade Neuroendocrine Tumors (mNETs)
Boris G. Naraev, MD, PhD,1 Nancy Sharma, MD,1 Eric S. Engelman, DO,1 David L. Bushnell Jr., MD,1,2 Thomas M. O’Dorisio, MD,4 Thorvardur R. Halfdanarson, MD11University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242; 2Iowa City Veterans Administration Medical Center, Diagnostic Imaging Service.
Background: PRRT is frequently used for patients (pts) with mNETs but PRRT is not readily available in the US. We report on 108 patients seen at the University of Iowa who underwent PRRT.
Methods: Cases were identified by searching our institutional NET database. Early stage (AJCC 1-3) and high-grade tumors were excluded. Groups were compared using a Wilcoxon rank-sum test and survival calculated with the Kaplan-Meier method.
Results: Men were 62% and women 38%; median age at diagnosis was 52 years (25 – 78). The origin of the primary tumor was small bowel (SBNET) 43.5%, pancreas (PNET) 27.8%, lung 4.6%, unknown primary 11.1%, other sites 13%. PRRT was performed at the University of Basel, Switzerland in 72%, University of Iowa in 26% and elsewhere in 2%. 97 patients received two treatments. 90Y was used in 86% and 177Lu in 13% for the first PRRT. The survival of patients is shown in Table 1. Radiographic responses (any) at 1-6 months after PRRT were observed in 62%, 11% had a mixed response and 18% progressed. A biochemical response (>50% reduction) in chromogranin A and pancreastatin was seen in 16% and 19% respectively but data was frequently missing.
Conclusion: Patients with mNETs enjoy a relatively long survival. The OS from 1st PRRT was considerably less than OS after diagnosis, suggesting that PRRT is used late in the disease course. PRRT appears to be a valuable treatment option for mNETs, especially SBNETS, and its role earlier in the disease course warrants investigation.
Pattern and Clinical Predictors of Lymph Node Involvement in Neuroendocrine Neoplasms of the Pancreas
Stefano Partelli,1 Rim Cherif,3 Letizia Boninsegna,1 Sebastien Gaujoux,3 Stefano Crippa,1 Anne Couvelard,4 Aldo Scarpa,2 Alain Sauvanet,3 Philippe Ruszniewski51Department of Surgery, University of Verona, Verona, Italy; 2Pathology, University of Verona, Verona, Italy; 3Department of HPB Surgery – PMAD, Hopital Beaujon - Clichy - AP-HP; 4Department of Pathology, Hopital Beaujon - Clichy - AP-HP; 5Gastroenterology - Hopital Beaujon - Clichy - AP-HP.
Background: Pancreatic neuroendocrine neoplasms (PNENs) are often indolent without pathological lymph node metastasis (pN1). Therefore, in patients with low risk of pN1, a lymphadenectomy could be avoided. Aim of this study was to construct a model for predicting the risk of pN1 prior to surgical resection.
Methods: Databases from the University of Verona and the Beaujon Hospital were queried. Data of all patients with resected (R0 or R1) non-functioning PNEN between 1993 and 2009 were analyzed.
Results: Data were analyzed for 194 patients. Metastases were present in the dissected lymph nodes of 58 patients (30%). The 5-year disease free survival for pN1 patients was significantly lower than for pN0 (66% vs 93%, P<0.0001). Multivariable analysis suggested the independent predictors of pN1 were radiological nodal status (rN) (OR 3.4, P=0.008), localization in the pancreatic head (OR 3.4, P=0.002) and the degree of differentiation (G2 vs G1 OR 3.5, P=0.001). When the degree of differentiation was excluded, on multivariable analysis rN1 (odds ratio 4.1, P=0.001), localization in the pancreatic head (odds ratio 3.2, P=0.002), and radiological size > 4 cm (odds ratio 2.5, P=0.012) were independent predictors of pN1.
Conclusion: Patients with PNEN-G1 of the pancreatic body, in the absence of radiological node involvement, have a low risk of pN1. If a preoperative cytological diagnosis is not achieved, radiological size of the lesion is a powerful alternative predictor of pN1.
Telotristat Etiprate Produces Clinical and Biochemical Responses in Patients with Symptomatic Carcinoid Syndrome: Preliminary Results of an Ongoing Phase 2, Multicenter, Open-Label, Serial-Ascending, European Study
Marianne Pavel,1 Bertram Wiedenmann,1 Thomas Seufferlein,2 Joel Freiman,3 Linda Law,3 Phillip Banks,3 Kenny Frazier,3 Jessica Jackson,3 Brian Zambrowicz31Charité - Universitätsmedizin, Berlin, Germany; 2Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany; 3Lexicon Pharmaceuticals, Inc., The Woodlands, TX USA.
Background: Excess serotonin (5-HT) may contribute to gastrointestinal (GI) symptoms such as diarrhea in carcinoid syndrome (CS) patients. Telotristat etiprate / LX1032/ a.k.a. LX1606, an oral serotonin synthesis inhibitor (SSI), is designed to reduce peripheral 5-HT levels and alleviate GI distress.
Methods: This study evaluates the safety and tolerability of ascending doses (150 mg, 250 mg, 350 mg, and 500 mg tid) of telotristat etiprate in symptomatic CS patients, averaging ≥4 bowel movements (BM)/day, either therapy-naïve or receiving somatostatin analogs. Secondary objectives include symptomatic response (change in: number of BM/day, stool form/consistency, sensation of urgency to defecate, sensation/severity of nausea, global assessment of symptoms, assessment of abdominal pain/discomfort, reduction of cutaneous flushing episodes), and assessment of plasma drug concentrations, pharmacokinetics, and pharmacodynamics (urinary 5-hydroxyindolacetic acid [u5-HIAA] and blood 5-HT). All patients began dosing at 150 mg. Dose strength was increased following 2 weeks of therapy with no dose-limiting toxicity. If dose-limiting toxicities occur, the dose will be reduced to prior level. Treatment will continue at the individual maximum-tolerated dose for 4 weeks; patients can continue in an extension phase.
Results: Currently, 5 patients have completed the ascending dose study and 1 of 3 eligible subjects has enrolled into the long-term extension, up to 48 weeks; 2 more subject are eligible for the long-term extension. Mean age 61 years (range, 51-81), mean BM/day was 6.4 (range, 4-8). Upon completion of 12 weeks dosing, 84% (5/6) had sustained reductions of ≥30% in BM/day (50% [3/6] had multiple assessments indicating ≥50% BM reductions).
Conclusion: Telotristat etiprate produced biochemical and clinical responses/benefit in refractory CS. No major safety issues were detected. As of 9/2011, 8 patients have been treated with an additional 8 patients required to complete enrollment. Accrual is ongoing.
Generator Produced 68Ga for Clinical Preparations of [68Ga]DOTATOC for Imaging Neuroendocrine Tumor Patients: Initial Studies at the University of Iowa
Michael K. Schultz,1 Yusuf Menda,1 Thomas O’Dorisio,1 Laura L. Boles Ponto,1 Kathy Thedes-Reynolds,1 John J. Sunderland,1 David L. Bushnell,2 G. Leonard Watkins,1 M. Sue O’Dorisio11The University of Iowa Hospitals and Clinics, Iowa City, IA 52240; 2Veteran’s Affairs Medical Center Iowa City, IA 52242.
Background and Objectives: Gallium-68 (68Ga) somatostatin analogs are the gold standard for PET imaging of neuroendocrine tumors, yet have not been embraced in the United States. In this study, an automated system for preparation of a 68Ga labeled somatostatin analog ([68Ga]DOTA-Tyr3-octreotide or [68Ga]DOTATOC) is evaluated based on system performance and quality control parameters. The system was used to prepare patient doses for biodistribution research studies in human subjects and results compared to Octreoscan™ SPECT.
Methods: The automated system (ModularLab PharmTracer, Eckert-Ziegler, Berlin, Germany) combines a titanium dioxide based germanium-68 (68Ge)/68Ga generator (IGG100 Eckert-Ziegler) with a computer-controlled system that employs complete, single-use, sterile, GMP-grade, cassettes. In this study, 1.85 GBq 68Ga was eluted to an in-line cation exchange resin, which retains 68Ga. Purified 68Ga was eluted with acetone/0.02 M HCl to a glass reaction vessel containing 30 μg DOTATOC (acetate buffer, pH 4). Radiolabeling was carried out for 6 min (95 °C). Acetone is removed by vent to waste. Final [68Ga]DOTATOC was purified by C-18 cartridge and eluted in 1:1 95% ethanol:water to the product vial through a sterilizing filter (and diluted with saline). QC parameters were measured by standard techniques.
Results: Sterile, pyrogen-free [68Ga]DOTATOC was prepared in 32 min. Reagent preparation and system setup requires about 30 minutes of technician effort. QC metrics were acceptable: specific activity > 25 MBq nmole-1, radiochemical purity >98%; pH 6; acetone, ethanol, and pyrogen levels within limits. Excellent tumor contrast was observed in these initial biodistribution studies in human subjects.
Conclusions: The system enabled rapid [68Ga]DOTATOC preparation. QC parameters were well-within specifications. Initial studies in human subjects displayed excellent tumor contrast. PET/CT images were clearly superior to matched patient paired SPECT images obtained using Octreoscan. The system and integrated software can be adapted readily for training of personnel and daily operations.
Neuroendocrine Tumor Collaborative Registry
Oleg Shats,1 Jean F. Botha,1 Jean Grem,1 Lucienne Case,1 Alexander Sherman,1 Janmin Feng,1 Greg Wilson,2 Simon Sherman11University of Nebraska Medical Center, Omaha, NE 68198; 2Digital Health Technology, LLC, Papillion, NE 68133.
Background: Neuroendocrine tumors (NET) are a diverse and rare group of diseases that can be: (i) benign or highly malignant; (ii) asymptomatic or cause debilitating syndromes; (iii) indolent or require highly aggressive therapies; and (iii) originated almost anywhere in the body. To increase understanding of NET, it is necessary to create a standardized, user-friendly, HIPAA-compliant registry that will allow researchers from multiple centers to collect, mine, and share NET-related data.
Methods: The Neuroendocrine Tumor Registry (NETR, http://netr.unmc.edu) utilizes a multi-tier web-based architecture and a secure web server communication. All Protected Health Information is stored encrypted in an Oracle 11g Database. The system employs a principle of the federated model: all centers input data in the central repository using the same questionnaire and procedures, while each center manages and has access only to its own data. This model protects the confidentiality of each center’s data, while laying a foundation for collaborative research. If desired, each center has the capability to share all or selected portions of data.
Results: The NETR has been created and tested. Its questionnaire includes patient socio-demographic, lifestyle, environmental, family history, and clinical forms that are designed with predetermined selection choices to assist users with accuracy and ease of completion. The validation components of the NETR prevent users from entering erroneous information. The NETR’s end-users are patients, clinicians, researchers and center administrators that have corresponding levels of authority to enter and use data.
Conclusion: The NETR is ready for implementation. Future developments should include: (i) recruitment of new participating centers and subjects; (ii) creation of a Steering Committee (consisting from representatives from participating centers and a patient advocate) to govern the NETR; (iii) refinement of the NETR’s questionnaire by incorporating suggestions from the clinical and research community; (iv) coupling the NETR with a biospecimen management system.
RADIANT-2: A Randomized, Double-Blind, Multicenter, Phase III Trial of Everolimus + Octreotide LAR vs Placebo + Octreotide LAR in Patients with Advanced Neuroendocrine Tumors: Progression-Free Survival by Primary Tumor Site and Updated Safety Results
Jonathan Strosberg,1 Sergio Ricci,2 Philippe Ruszniewski,3 Paola Tomassetti,4 Valentine Jehl,5 Stephen Saletan,6 Marianne Pavel,7 James Yao81H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612; 2Oncology Unit, Santa Chiara Hospital, Pisa, Italy 56126; 3University of Paris VII and Beaujon Hospital, Paris, France F-92118; 4University of Bologna, Bologna, Italy 40126; 5Novartis Pharma, Basel, Switzerland 4057; 6Novartis Oncology, Florham Park, NJ, USA 07932; 7Charité Universitätsmedizin Berlin, Berlin, Germany 13353; 8University of Texas, MD Cancer Center, Houston, TX, USA 77030.
Background: In the RADIANT-2 trial, everolimus + octreotide LAR demonstrated a clinically meaningful increase in progression-free survival (PFS) of 5.1 months vs. placebo + octreotide LAR in patients with advanced low- or intermediate-grade neuroendocrine tumors (NET) and a history of secretory symptoms (ie, flushing, diarrhea). Inferior prognoses are associated with pulmonary and colorectal primary sites. We present here an exploratory analysis of PFS by primary tumor site and an updated safety analysis.
Methods: Patients (N=429) were randomly assigned to receive everolimus 10 mg/d orally + octreotide LAR 30 mg IM q 28 days (E+O; n=216) or placebo + octreotide LAR (P+O; n=213). Primary endpoint was PFS per adjudicated central review (RECIST v1.0). At disease progression, P+O patients could cross over to open-label E+O.
Results: E+O improved median PFS compared with P+O by 4.6 months (18.6 months [n=111] vs 14.0 months [n=113]) in the small intestine subgroup, by 8.0 months (13.6 months [n=33] vs 5.6 months [n=11]) in the lung subgroup, and by 23.3 months (29.9 months [n= 19] vs 6.6 months [n= 20]) in the colorectal subgroup. As of the 7/2/2010 safety data cut-off, median follow-up was 31.1 months. Most frequent drug-related AEs (E+O vs P+O, %) were stomatitis (61.9 vs 14.2), rash (37.2 vs 12.3), and fatigue (31.6 vs 24.2). Most frequent drug-related grade 3/4 AEs (E+O vs P+O, %) were fatigue (6.5 vs 2.8), diarrhea (6.0 vs 2.4), and hyperglycemia (5.1 vs 0.5). These updated safety results are consistent with previous experience.
Conclusions: E+O demonstrated a clinically meaningful prolongation of median PFS in advanced NET patients, particularly those with primary tumor sites associated with poor survival rates. These findings, together with a favorable safety profile, support the benefit of everolimus in patients with advanced NET and a history of secretory symptoms.
Multi-Feature Method for Ascertaining NET Cases in a Clinical Data Warehouse
Marie Synnestvedt, PhD,1 Bonnie Bennett, RN, BSN,1 Hillary Faust, MD,1 Mark Weiner, MD,1 David C. Metz, MD11The Perelman School of Medicine at University of Pennsylvania, Philadelphia PA 19104.
Background: A multidisciplinary program should be the standard of care for neuroendocrine tumors (NETs) but care is often fragmented across multiple specialties. We developed a method to ascertain how many NET patients existed in our health care system in order to establish a registry for future clinical care and research.
Methods: A knowledge discovery approach was undertaken to identify a trial set of criteria by examining terminologies within electronic NET resources such as NANETS and SNOMED and performing statistical and text analysis of a sample of 364 known NET cases (128 GI NETs and 236 pheochromocytoma/paragangliomas). The criteria selected included laboratory (any abnormal 5HIAA, chromogranin A, epinephrines, metanephrines, norepinephrines, pancreatic polypeptides, serotonin, or VMA), pathology (positive keywords in diagnosis), radiology (non-negative MIBG or Octreoscan), medications for pheochromocytoma, or ICD9 codes (for genetic diagnoses such as MEN). These criteria yielded 5262 potential NET cases going back to 1999. A 10% random sample of 302 cases was selected from 3017 unclassified cases with activity since 2008 for review and classification of true NET status.
Results: The search method retrieved 90% of known NET cases. Missed cases were primarily older cases that predated searchable electronic data or that were diagnosed using historical terminology such as glomus tumor. The true case rate in the random sample was 132/302 (44%) – 56 GI NETs, 14 phaeochromocytoma/paragangliomas, 27 lung carcinoids and 35 other NETs (170 were not NETs). The least specific univariate criteria were the pathology keyword synaptophysin or abnormal metanephrines or norepinephrines. Removal of cases having single non-specific criteria increased the true positive rate to 127/226 (56.2%) with 3.7% missed true positives.
Conclusion: This methodology can be improved with further modeling, and in its current form can help institutions identify a larger cohort of previously unidentified patients with NETs who are suitable for inclusion in a registry for follow-up, management, and improved research capabilities.
Comparison of 68Ga-somatostatin Analogues, 18F-DOPA and 18F-FDG PET/CT in Patients with Recurrent Medullary Thyroid Carcinoma
Giorgio Treglia,1 Paola Castaldi,1 Maria Felicia Villani,1 Angelina Filice,2 Valentina Ambrosini,3 Nadia Cremonini,4 Diana Salvo,2 Stefano Fanti,3 Alessandro Giordano,1 Vittoria Rufini11Nuclear Medicine Institute, Catholic University of the Sacred Heart, Rome, Italy; 2Nuclear Medicine Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy; 3Nuclear Medicine Institute, PET Center, Policlinico S. Orsola-Malpighi, Bologna, Italy; 4Endocrinology Unit, Maggiore Hospital, Bologna, Italy.
Background: Early detection of recurrences is a crucial step in the management of patients with medullary thyroid carcinoma (MTC). Currently, there is growing interest for PET tracers in MTC such as: 18F-FDG (reflecting glucose metabolism), 18F-DOPA (reflecting amine decarboxylation), 68Ga-somatostatin analogues (reflecting somatostatin receptors expression). Aim of our study was to compare PET/CT with 68Ga-somatostatin analogues, 18F-DOPA and 18F-FDG in a series of patients with suspected recurrent MTC on the basis of increased calcitonin levels during follow-up, but with conventional imaging inconclusive for loco-regional and/or metastatic spread.
Methods: Eighteen patients (6 male/12 female; mean age: 53.5 years) who had performed PET/CT with 68Ga-somatostatin analogues, 18F-DOPA and 18F-FDG within 3 months were selected. Comparison of the results was done on a per-patient and on a per-lesion basis. Verification of PET/CT findings was achieved by histopathology (13 cases) or imaging follow-up (5 cases).
Results: Foci of abnormal uptake were observed in 13/18 patients at 18F-DOPA PET/CT (sensitivity: 72%), 6/18 patients at 68Ga-somatostatin analogues PET/CT (sensitivity: 33%), in 3/18 patients at 18F-FDG PET/CT (sensitivity: 17%); 5/18 patients (28%) were negative with all procedures. 18F-DOPA PET/CT detected more lesions than 18F-FDG and 68Ga-somatostatin analogues PET/CT (61 vs 20 vs 14, respectively; p<0.05).
Conclusion:18F-DOPA PET/CT seems to be the most sensitive imaging method to detect recurrences in patients with MTC. Studies investigating larger patient population are needed to confirm these results and to explain the lack of abnormal uptake of all tracers in some cases. In any case, the different uptake patterns observed with the various PET tracers reflect different metabolic pathways (uptake of hormone precursors, receptor expression, glucose metabolism); this information may help to broaden knowledge of MTC and potentially to select the most appropriate treatment.
Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) and Updated Overall Survival (OS) of Sunitinib versus Placebo for Patients with Progressive, Unresectable, Well Differentiated Pancreatic Neuroendocrine Tumor (NET)
Aaron Vinik,1 Eric Van Cutsem,2 Patricia Niccoli,3 Jean-Luc Raoul,4 Yung-Jue Bang,5 Ivan Borbath,6 Catherine Lombard-Bohas,7 Juan W. Valle,8 Peter Metrakos,9 Denis Smith,10 Jen-Shi Chen,11 Dieter Hörsch,12 Daniel E. Castellano,13 Hagen F. Kennecke,14 Joel Picus,15 Guy Van Hazel,16 Shem Patyna,17 Dongrui Ray Lu,17 Richard C. Chao,17 Eric Raymond181EVMS Strelitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, VA; 2University Hospital Gasthuisberg, Leuven, Belgium; 3University Hospital Timone, Paoli-Calmettes Institute and RENATEN Network, Marseille, France; 4Paoli-Calmettes Institute, Marseille, France; 5Seoul National University Hospital, Seoul, Republic of Korea; 6Cliniques Universitaires Saint-Luc, Brussels, Belgium; 7Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 8The Christie NHS Foundation Trust, Manchester, United Kingdom; 9McGill University Hospital Centre, Montreal, QC, Canada; 10Medical oncology, University Hospital, Bordeaux, France; 11Chang Gung Memorial Hospital and Chang Gung University, Taipei, Republic of China; 12Zentralklinik Bad Berka GmbH, Bad Berka, Germany; 13Hospital Universitario 12 de Octubre, Madrid, Spain; 14British Columbia Cancer Agency, Vancouver, BC, Canada; 15Washington University School of Medicine, St. Louis, MO; 16University of Western Australia, Perth, Australia; 17Pfizer Oncology, La Jolla, CA; 18Beaujon University Hospital, Clichy, France.
Background: In a double-blind phase III trial, sunitinib improved PFS vs. placebo (11.4 vs. 5.5 months; HR: 0.418, 95% CI: 0.263–0.662; P=0.0001) and was well tolerated in patients with progressive, unresectable, well-differentiated pancreatic NET that had progressed ≤12 months before baseline (Raymond et al, NEJM 2011). Initial OS revealed a benefit for sunitinib over placebo, but median OS was not reached (NR). We now report PFS assessed by BICR and updated median OS.
Methods: Patients were randomized 1:1 to sunitinib 37.5 mg on a continuous-daily-dosing schedule or placebo, each with best supportive care. The primary endpoint was PFS; OS was a secondary endpoint. Baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Patients in the placebo arm with disease progression were eligible to receive sunitinib in an extension study.
Results: 171 patients were randomized (sunitinib, n=86; placebo, n=85) from 6/2007 to 4/2009. The trial ended when an independent data monitoring committee noted efficacy favoring sunitinib and more serious AEs and deaths with placebo. The study was unblinded at closure; patients were offered open-label sunitinib and followed for survival. Median PFS by BICR was 12.6 vs. 5.8 months, sunitinib vs. placebo, respectively (HR: 0.315, 95% CI: 0.181–0.546; P=0.000015). At study end, there were 9 and 21 deaths in the sunitinib and placebo arms (HR: 0.409, 95% CI: 0.187–0.894; P=0.0204). By 6/2010, there were 34 and 39 deaths; median OS was 30.5 (95% CI: 20.6–NR) and 24.4 (95% CI: 16.3–NR) months, respectively (HR: 0.737; 95% CI: 0.465–1.168; P=0.1926). 69% of patients crossed over to sunitinib on progression.
Conclusion: BICR of PFS demonstrated a 6.8-month improvement in median PFS with sunitinib, confirming the treatment effect reported with investigator assessment.
Cervical and Upper Mediastinal Lymph Node Metastasis from GI and Pancreatic Neuroendocrine Tumors: Incidence and Management
Yi-Zarn Wang, DDS, MD,1,4 George Mayhall,1 Lowell Anthony, MD,2,4 Richard Campeau, MD,3,4 J. Philip Boudreaux, MD,1,4 Eugene Woltering, MD1,41Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70012, 2Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70012, 3Department of Radiology, Louisiana State University Health Sciences Center, New Orleans, LA 70012, 4Ochsner Medical Center- Kenner, Neuroendocrine Tumor Clinic, Kenner, LA 70065.
Background: The incidence, clinical importance and optimal management of cervical and upper mediastinal lymph node metastases from gastrointestinal (GI) and pancreatic neuroendocrine tumors (NETS) are largely unknown. Historically, they have been regarded as asymptomatic and ignored. We hypothesized that these lesions have clinical implications, and should be surgically removed.
Methods: Consecutive 111In-pentetreotide scans (OctreoScans) performed at our institution from May 2008 to October 2010 were reviewed in order to determine the incidence of cervical and upper mediastinal lymph node metastases. The charts of surgically treated patients were reviewed to evaluate the clinical importance of these metastases and the subsequent outcome of surgical treatment.
Results: A total of 161 patients presented with positive OctreoScans. Fourteen patients (8.7%) scanned positive for cervical and upper mediastinal lymph node metastasis. Seven patients underwent surgical exploration; six had successful removal of their metastatic nodes. Five patients had clinical symptoms that were resolved by surgery.
Conclusion: Cervical and upper mediastinal lymph node metastases from GI and pancreatic NETS are seen in up to 8.7% of patients. In the past, these metastases were ignored. Our study clearly demonstrates that most, if not all, such metastases are symptomatic and their clinical implications should not be overlooked. Notably, these metastases can be easily and safely resolved by radio-guided surgery.
Correlation of Progression-Free Survival (PFS) with Early Response of Biomarkers Chromogranin A (CgA) and 5-Hhydroxyindoleacetic Acid (5-HIAA) Levels in Patients with Advanced Neuroendocrine Tumors: Phase III RADIANT-2 Study Results
Edward Wolin,1 Daniel Castellano,2 Gregory Kaltsas,3 David Gross,4 Ashok Panneerselvam,5 Judith Klimovsky,5 Stephen Saletan,5 James Yao,6 Eric Baudin71Cedars-Sinai Medical Center Medicine, Medical Oncology, Los Angeles, CA 90048; 2University Hospital 12 de Octubre, Madrid, Spain 28041; 3University of Athens, Athens, Greece 11527; 4Hadassah-Hebrew University Medical Center, Jerusalem, Israel 91120; 5Novartis Pharmaceuticals Corporation, Florham Park, NJ 07932; 6The University of Texas MD Anderson Cancer Center, Houston, TX 77030; 7Institut Gustave-Roussy, Villejuif Cedex, France 94805.
Background: In RADIANT-2, everolimus 10 mg/d (an oral mTOR inhibitor) + octreotide LAR 30 mg IM q28 days (E+O) demonstrated a clinically meaningful 5.1-mo increase in median progression-free survival (PFS) compared with placebo + octreotide LAR (P+O) in patients with low- or intermediate-grade advanced neuroendocrine tumors (NET) and a history of flushing/diarrhea. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are NET biomarkers correlating with tumor burden or symptoms. The effects of early CgA and 5-HIAA response on PFS were analyzed.
Materials: 429 patients were randomized to E+O (n=216) or P+O (n=213). Serum CgA and 24-h urinary 5-HIAA were collected at baseline and, if elevated (>ULN), on day 1 of each monthly cycle. Relationship between early CgA and 5-HIAA responses (≥30% reductions on the first day of cycle 2 after 4 weeks of treatment compared to baseline values) with PFS were assessed using Kaplan-Meier and Cox-proportional hazard modeling.
Results: Significantly more E+O patients had early CgA (36.3% vs 23.1%) and 5-HIAA (37.1% vs 24.3%) responses than P+O patients. Median PFS was significantly longer in early CgA responders (20.0 vs 10.8 months; HR, 0.49; P<0.001) than in nonresponders, and was longer in patients with early 5-HIAA response than those without (17.1 vs 12.0 months; HR, 0.76; P=0.193) [Table 1].
Conclusion: In RADIANT-2, E+O was associated with significantly more early CgA and 5-HIAA responses than P+O. Early CgA responses were associated with significant improvement in PFS regardless of treatment. A smaller, non-significant trend was seen for early 5-HIAA responses.
Treatment of Small Bowel Neuroendocrine Tumors (NETS) in a Multidisciplinary Specialty Center Increases Survival
Eugene A. Woltering, MD,1,2 Anne E. Diebold, BS,1,2 Yi-Zarn Wang, DDS, MD,1,2 Lowell B. Anthony, MD,2,3 John Philip Boudreaux, MD,1,2 Ann Porter Uhlhorn, RN,2 Pamela Ryan, BSN, RN,2 Leigh Anne Kamerman-Burns, RD, LDN,2,3 Daniel J. Frey, MD,1,2 Daniel Raines, MD,3 Ryan N. Majoria, MD,2 Richard J. Campeau, MD2,41Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA; 2New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), Ochsner Clinic Foundation, Ochsner Medical Center - Kenner, Kenner, LA; 3Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA; 4Department of Radiology, Louisiana State University Health Sciences Center, New Orleans, LA.
Background: Neuroendocrine tumors (NETS) of the gastrointestinal tract are rare, slow-growing neoplasms. While surgery and somatostatin analogs are the mainstays of treatment, we hypothesize that aggressive, long-term multidisciplinary management will improve treatment outcomes and maximize survival.
Methods: The charts of 401 patients with well-differentiated, small bowel NETS, treated by our multidisciplinary NET specialty team, were reviewed. Information relating to the extent of disease and all tumor-related surgeries was collected from the patient records. Kaplan-Meier survival curves were generated, and 5-year, 10-year, and median survival rates from histologic diagnosis were calculated.
Results: Our multidisciplinary NET clinic saw 14 patients with local disease, 68 patients with regional disease and 319 patients with distant disease. Patients with regional disease had significantly higher median survival rates when compared to the national Surveillance Epidemiology and End Results (SEER) database data (not yet reached vs. 107 months, p=.004). Ten year survival rates for patients with regional disease were 81% vs. 46%, comparing our clinic patients vs. SEER, respectively. Our clinic patients with distant disease also had significantly higher median survival rates when compared to SEER data (141 months vs. 65 months, p < .001). Ten year survival rates for patients with distant disease were 63% vs. 30%, for our clinic patients vs. SEER, respectively.
Conclusion: Survival rates seen in this study are objectively higher than compared to those seen in SEER. We believe that our data supports a multidisciplinary specialty approach to NET care. Future research should be done to investigate this concept.
NANETS would like to thank Ms Amy Trang for reformatting the abstracts in preparation for publication.