Presence of Extra-Hepatic Disease Should Not Preclude Transarterial Chemoembolization for Metastatic Carcinoid
Arrese David, Feria-Arias Enrique, Hatzaras Ioannis, Guy Gregory, Khabiri Hooman, Schmidt Carl, Shah Manisha, Bloomston Mark. The Ohio State University Medical Center, 410 W 10th Ave N924 Doan, Columbus, OH 43210.
Background: Transarterial chemoembolization (TACE) is the locoregional therapy of choice for the management of patients with inoperable carcinoid liver metastases. Often, metastatic disease is not limited to the liver. The impact of extra-hepatic metastases on response and outcomes following TACE has not been described.
Objective: We hypothesized that patients who, at the time of TACE, have extra-hepatic disease would have similar tumor response and symptom control following TACE.
Methods: We reviewed 198 patients that underwent TACE for incurable carcinoid liver metastases. Two groups were identified, those with (N = 129) and without (N = 69) evidence of extra-hepatic disease at the time of TACE. Demographics, clinicopathologic characteristics, response to TACE, complications, and survival were compared.
Results: The two groups were similar in demographics and histopathologic characteristics. Complications following TACE were similar. There was no difference between the groups with and without evidence of extrahepatic disease in symptomatic (76% vs 71%), biochemical (78% vs 90%) or radiographic response (35.0% vs 46%) to TACE. The group without extra-hepatic disease had a median survival of 88 vs 35 months with five-year survival of 65% vs 30% compared to patients with extra-hepatic disease at the time of TACE.
Conclusion: As expected, patients with extrahepatic metastatic disease from carcinoid tumor experienced shorter overall survival following TACE compared to those without extrahepatic disease. However, patients with extra-hepatic disease had similar symptomatic, biochemical and radiographic response to TACE compared to those with disease confined to the liver. Although the long-term prognosis for patients with extrahepatic disease is worse than those with liver-only metastasis, meaningful response to TACE is possible and should be considered in those with carcinoid syndrome.
Short Term Response to Systemic I-131 MIBG Therapy in Metastatic Carcinoid Tumors
Richard J. Campeau, MD,2,3,4 Lowell B. Anthony, MD,2,4 Eugene A. Woltering, MD,1,4 Yi-Zarn Wang, MD,1,4 J Phillip Boudreaux, MD.1,4LSU Health Sciences Center, Departments of 1Surgery, 2Medicine, and 3Radiology, New Orleans, Louisiana, 70112, and 4Ochsner Medical Center Kenner Neuroendocrine Tumor Clinic, Kenner, Louisiana, 70065.
Background: Purpose of study was to analyze short term response (< 2 yrs.) of systemic I-131MIBG therapy in terms of 1.) tumor biomarker response, including pancreastatin and neurokinin A (NKA), 2.) radiographic, and 3.) symptomatic responses in metastatic carcinoid tumor.
Methods: Retrospective chart review was performed in 24 patients who underwent 31 MIBG treatments from June, 2008 through March, 2010. Eligibility: Patients had to show intense uptake of MIBG on diagnostic scans, and had to demonstrate progressive metastatic disease on chemotherapy and/or octreotide. Four patients did not meet criteria and were excluded. Patients were analyzed for pre and post therapy tumor marker response utilizing conventional NET markers as well as pancreastatin and NKA. Radiographic and symptomatic response was evaluated with WHO and RECIST criteria.
Results: A symptomatic response after MIBG therapy was seen in 63% (12 of 19 evaluable patients). Fifteen of 20 patients (75%) had tumor biomarkers measured pre and post MIBG therapy. Among these 15 patients, 47% (7 of 15) had reductions of > 50% in pancreastatin and/or NKA post therapy. Only one of these patients showed progression of disease during the study period. All three patients with rapid rises of pancreastatin and/or NKA during MIBG treatment showed radiographic progression. Radiographic tumor response before and after treatment could be evaluated in 15 of 20 patients. A partial response was documented in only 13% (2 of 15 patients).
Conclusions: 63% of metastatic carcinoid patients improve symptoms after MIBG treatment; only a minority show radiographic response. Tumor markers decrease in 47% of patients, and suggest a favorable short term outcome. Rising NKA and/or pancreastatin levels during MIBG treatment were associated with rapid progression of disease. Previous studies have followed metastatic carcinoid response to MIBG therapy using 5-HIAA and chromogranin; pancreastatin and NKA appear to be more sensitive and prognostically significant.
Phase I Study of Pasireotide (SOM230) in Combination With Everolimus (RAD001) in Patients 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 Carolyn Casey, BS,1 Eileen Regan, RN, BSN, OCN,1 Kristen Cavanaugh, RN,1 Matthew H. Kulke, MD, MMSc.1,21Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, 2Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, 3Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114.
Background: Octreotide and 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: Patients received escalating doses of pasireotide and everolimus (Table 1). Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. DLT was defined as occurring within the first 56 days of therapy.
Results: Among 16 enrolled patients, 15 were evaluable for toxicity. Enrolled patients had the following characteristics: M:F = 10:6; median age 61 (range 38-76); ECOG PS 0/1/2 = 8/7/1; carcinoid/pancreatic NET = 12/4. Patients received a median of four 28-day cycles of treatment. No patients in cohorts 1 and 2 experienced DLT. 1 patient in cohort 3 experienced DLT (grade 3 rash); the cohort was expanded to 6 patients with no further observed DLTs. 1 patient in cohort 4 experienced DLT (grade 3 diarrhea). Other ≥ grade 3 treatment-related adverse events included hyperglycemia (n = 8), hypophosphatemia (n = 3), elevated alkaline phosphatase (n = 2), mucositis (n = 1), lymphopenia (n = 2), and thrombocytopenia (n = 1). Insulin was started in 4 patients due to hyperglycemia. Independently-reviewed best objective responses in 13 evaluable patients revealed stable disease in all 13 patients.
Conclusion: Combination therapy with pasireotide and everolimus is safe and feasible. Further enrollment with everolimus 10 mg daily in combination with pasireotide LAR 60 mg monthly is planned.
Phase I Study of Sorafenib in Combination With Everolimus (RAD001) in Patients With Advanced Neuroendocrine Tumors (NET)
Jennifer A. Chan, MD, MPH,1,2 Robert J. Mayer, MD,1,2 Nadine Jackson, MD, MPH,1,2 Paige Malinowski, BA,1 Eileen Regan, RN, BSN, OCN, 1Matthew H. Kulke, MD, MMSc.1,21Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, 2Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Background: Both sorafenib and everolimus have activity in NETs. We performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NETs.
Methods: Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg BID; dose level 2: 200 mg in the morning, 400 mg in the evening) using a standard phase I dose escalation design. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent.
Results: Enrolled patients had the following characteristics: M:F = 4:5; median age 56 (range 49-68); ECOG PS 0/1 = 5/4. All 9 patients had low-intermediate grade NETs (midgut, n = 6; bronchial, n = 2; gastric, n = 1). Patients received a median of 2 cycles of treatment (range 1-6). One patient at dose level 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLT. ≥ grade 3 treatment-related adverse events at dose level 1 included grade 3 thrombocytopenia (n = 2), grade 3 hypokalemia (n = 2), grade 3 hypophosphatemia (n = 1), grade 4 hypophosphatemia (n = 1), grade 4 hypocalcemia (n = 1). One patient with gastric carcinoid tumor treated at dose level 1 experienced fatal gastric perforation occurring after the DLT observation period. All 3 patients at dose level 2 experienced DLT (grade 3 thrombocytopenia requiring holding treatment for > 14 days, grade 3 hand-foot skin reaction, grade 3 skin rash/allergic reaction). Grade 3 hypophosphatemia (n = 1) was also observed at dose level 2. Independently-reviewed best objective responses in 5 evaluable patients at dose level 1 revealed stable disease in all 5 patients.
Conclusion: Sorafenib 200 mg BID in combination with everolimus 10 mg daily has been established as the MTD in patients with advanced NET. Further enrollment to evaluate safety and antitumor efficacy at this dose level is ongoing.
Incidental Diagnosis of Pancreatic Neuroendocrine Tumors
Asima Cheema, MD, Jill Weber, MPH, Larry Kvols, MD, Jonathan Strosberg, MD. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Background: Pancreatic neuroendocrine tumors are often discovered incidentally during radiologic or endoscopic examinations. The incidence of incidental detection is unknown. It is also unclear whether patients with incidentally discovered, asymptomatic tumors should be treated similarly to patients who present with tumor-related symptoms.
Methods: A database of 425 patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center was developed. Patient charts were reviewed to assess whether their diagnosis was incidental or prompted by tumor-related symptoms such as pain, jaundice or neuroendocrine hormone secretion. The frequency of "incidentalomas" was categorized by TNM stage (AJCC, 7th edition). Overall survival was stratified by "incidental" vs. "symptomatic" diagnosis.
Results: Amongst 425 patients with histologically proven pancreatic neuroendocrine tumors, 112 patients (26%) had tumors which were discovered incidentally. The majority of stage I tumors (55%) were incidentally discovered. Amongst patients with stage IV tumors, 20% were detected incidentally (table 1). Median survival of patients with incidentally discovered tumors was 103 months versus 84 months in patients who were symptomatic at diagnosis.
Conclusions: A sizeable fraction of patients with pancreatic neuroendocrine tumors are diagnosed incidentally during evaluations for other conditions or unrelated symptoms. The majority of patients with stage I tumors are incidentally diagnosed. The increased incidence of pancreatic neuroendocrine "incidentaloms" may be contributing to improving survival rates in this disease. This study highlights the necessity of developing guidelines for management of patients with incidentally discovered, early stage tumors.
Paraneoplastic Antigen Ma2 Autoantibodies as a Blood Biomarker for Diagnosis, Prognosis and Detection of Early Recurrence of Small Intestine Neuroendocrine Tumors
Tao Cui,1 Monica Hurtig,2 Graciela Elgue,3 Su-Chen Li,1 Giuseppe Pelosi,4 Ahmed Essaghir,5 Jean-Baptiste Demoulin,5 Giulia Veronesi,6 Mohammad Alimohammadi,2 Kjell Öberg,2 Valeria Giandomenico.,11Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala SE-75185, Sweden, 2Department of Medical Sciences, Uppsala University Hospital, Uppsala SE-75185, Sweden, 3Division of Clinical Immunology, Uppsala University, Uppsala SE-75185, Sweden, 4University of Milan, School of Medicine, Milan, Italy; Diagnostic Histopathology Unit, European Institute of Oncology, Milan IT-20141, Italy, 5Université Catholique de Louvain, de Duve Institute, Brussels B-1200, Belgium, 6Division of Thoracic Surgery, European Institute of Oncology, Milan IT-20141, Italy.
Background: Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancer. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. This finding prompted us to evaluate whether the detection of Ma2 autoantibodies in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs.
Methods: A novel indirect enzyme-linked immunosorbent assay (ELISA) was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. In total, 124 blood samples of SI-NET patients were included in the study. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. The analysis was extended to 66 blood samples of typical and atypical lung carcinoids (TLC and ALC) to evaluate whether Ma2 autoantibodies in the blood stream may become a general biomarker for NETs.
Results: The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence free survival compared to those with higher titers. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples.
Conclusion: Here we show that high Ma2 autoantibody titers in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.
Clinical Utility of Genomic Profiling of Pancreatic Neuroendocrine Tumors
Michael J. Demeure, MD, MBA,1,2 Lisa Evers, BSc,2 Elizabeth Lenkiewicz, MSc,2 Tara Holley, BSc,2 Lukas Bubendorf, MD,3 Christian Ruiz, PhD,3 Kimberly J. Bussey, PhD,2 Michael T. Barrett, PhD.21Virginia G Piper Cancer Center, Scottsdale AZ 85258, 2Translational Genomics Research Institute, Phoenix AZ 85004, 3Institute for Pathology, University Hospital Basel, Switzerland.
Background: Rare cancers pose particular difficulties for therapeutic development. We assessed the manner in which genomic information gained from novel technologies could be used clinically to improve the care of patients with pancreatic neuroendocrine tumors (PNETs).
Methods: We applied a novel technique using flow-cytometry to sort clonal populations of tumors cell for genomic profiling with array-based comparative genomic hybridization. We profiled the copy number aberrations present in the genomes of tumor cell populations from 7 PNETs.
Results: Of the 3 insulinomas studied, 2 had very simple genomes lacking significant aberrations at the genomic level predicting a benign phenotype. A third 8 mm low-grade insulinoma harbored numerous aberrations predicting malignant behavior including a focal amplicon within chromosome 11 containing GAB2, a known activator of the AKT pathway. A second PNET harbored a homozygous deletion of DISC1 at 1q42.1 that would also predict for activation of AKT. These tumors could be targeted with an AKT/PI3K inhibitor. In one PNET, we detected a focal deletion in 11p targeting 3 genes: IMMP1L an activator of the proapoptotic DIABLO, ELP4 a component of histone acetyltransferase, and PAX6, a key regulator of pancreatic islet hormone gene transcription necessary for normal islet cell development and an activator of c-MET, an oncogene. A glucagonoma harbored a deletion in CDX2. The CDX2 and CDX3complex with PAX6 and binds to the glucagon promoter. The same tumor harbored a deletion in CDKN2, a tumor suppressor gene that enhances p53-dependent apoptosis.
Conclusions: We have identified 3 potential ways in which clonal genomic profiling of PNETs by array CGH can assist in the clinical care of patients: 1) better definition of histopathology and determination of malignant phenotype, 2) provide insight into pathophysiology of excess hormone production, 3) expose therapeutic targets to guide decisions regarding selection of chemotherapy in patients with unresectable malignant PNETs.
Ki-67 Proliferative Index and the Tumor Grade Predict Progression Free Survival in Ileal Carcinoids
Deepti Dhall,1 Rugvedita Parakh,1 Richard Mertens,1 Girish Dhall,2 Catherine Bresee,4 Delma Ines,1 Fai Chung,1 Marissa Li,1 Steven D. Colquhoun,3 Nicholas N. Nissen,3 Run Yu,5 Hanlin Wang,1 Edward Wolin.61Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Hematology and nology, Children's Hospital of Los Angeles, Los Angeles, CA, United States, Liver Transplant Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 4Biostatistics, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 5Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 6Medical Oncology, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, United States.
Background: Ki-67 proliferative index (Ki-67) is suggested to be an important prognostic variable in neuroendocrine tumors and is included as one of the grading parameters in small bowel carcinoid tumors. The aim of this study is to determine the usefulness of Ki-67 and the corresponding tumor grade in predicting progression free survival in ileal carcinoids, especially in a metastatic setting.
Methods: Tumors from 60 patients with ileal carcinoids (well-differentiated neuroendocrine tumors) were studied. Ki-67 immunohistochemical stain was performed on the primary as well as selected metastatic tumor and quantitated by computer-assisted image analysis using Ariol™ system. The tumors were graded based on mitotic activity and Ki-67. Clinical and pathologic variables affecting the progression free survival were analyzed.
Results: There were 32 females and 28 males with a mean age of 58 years (range: 29-95 years). At the time of initial presentation, 9 (15%) patients had localized disease, 31 (52%) patients had regional (nodal/mesenteric) spread, and 20 (33%) patients had distant metastasis (stage IV). Fourteen out of 60 patients experienced disease progression. Patients with a higher initial stage were more likely to experience disease progression (p = 0.005), and a higher histologic grade was associated with a higher likelihood of disease progression (p < 0.001). Among the patients presenting with stage IV disease at the time of initial diagnosis, Ki-67 was significantly greater in patients who experienced disease progression (mean Ki-67 of primary and metastatic tumors were 10% and 15%, respectively, in patients with progression versus 1% and 2%, respectively, in patients with no progression). The mean time to progression in patients with Ki-67 > 2% in the primary tumor was significantly less when compared with patients with Ki-67 ≤ 2% (30.9 ± 10.9 months versus 134.0 ± 9.7 months, p < 0.001).
Conclusion: Ki-67 predicts progression free survival in patients with ileal carcinoids.
An Organ Slice Model to Evaluate Carcinoid Tumorogenesis in Liver
Priyodarshan Goswamee, Sasi Arunachalam, Riaz Nasim,1 Marthe Howard, David R. Giovannucci. Dept. Neuroscience, University of Toledo Medical Center, Toledo, OH, USA,1 Khyber Medical College, Peshawar, Pakistan.
Background: Midgut carcinoid cancers typically metastasize to the liver. However, cancer cell interactions with the liver tissue microenvironment are poorly understood. In combination with live-cell imaging methods and multi-photon microscopy, we developed an organ slice culture system that more closely resembles the three-dimensional, multicellular tumor microenvironment than does a dispersed cell culture system. Using this system we assessed cancer cell dynamics in situ and demonstrated that tumor-like structures are formed as a result of two concurrent processes - cell proliferation and aggregation.
Methods: Human carcinoid cancer cells, stably transfected with GFP were introduced to intact mouse liver via hepatic portal vein injection. A long-lasting vital dye was also introduced to mark the vasculature. The liver was sectioned into 200 μm thick slices and maintained in culture for up to two weeks. Cancer cell dynamics were assessed by immunofluorescence methods or by time-lapse imaging.
Results: The formation of tumor-like structures was observed by the 4th to 6th day in culture and it was revealed that more than half of the carcinoid cells were still dividing in the liver slices. Moreover, we found that tumor cells exhibited a variety of characteristic movements and rapidly inter-converted between elongated and rounded (blebbing) modes of locomotion. A rapid form of ameboid movement, observed only after several days in culture, was correlated to tumor cell aggregation in slices. These observations were consistent with in vitro experiments that demonstrated that liver tissue pieces or conditioned medium promoted carcinoid cancer cell aggregation in culture in a dose-dependent manner.
Conclusion: Proliferation and aggregation induced by an unidentified tissue-specific soluble factor contributed to the formation of tumor-like structures in mouse liver slices. This ex vivo model provides a tractable and cost efficient system for studying tumor formation in mouse liver.
Evaluation of Progression-Free Survival by Blinded Independent Central Review in Patients With Progressive, Well-Differentiated Pancreatic Neuroendocrine Tumors Treated With Sunitinib or Placebo
Pascal Hammel,1 Daniel Castellano,2 Eric Van Cutsem,3 Patricia Niccoli,4 Sandrine Faivre,1 Shem Patyna,5 Deno Klademenos,6 Dongrui Ray Lu,5 Richard Chao,5 Eric Raymond.11Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy 92118, France, 2Servicio de Oncologia, Hospital 12 de Octubre, Madrid 28041, Spain, 3University Hospital Gasthuisberg/Leuven, Leuven 3000, Belgium, 4Assistance Publique, Hôpitaux de Marseille CHU Timone, Institut Paoli-Calmettes and RENATEN Network, Marseille 13385, France, 5Pfizer Oncology, Development, La Jolla, CA 92037, USA, 6Pfizer Oncology, Development, New York, NY 10017, USA.
Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. In a phase III, double-blind, randomized trial of 171 patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET) (86 sunitinib, 85 placebo), median investigator-assessed progression-free survival (PFS, the primary endpoint) was 11.4 months for sunitinib 37.5 mg continuous daily dosing vs 5.5 months for placebo (hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P = 0.0001). Treatment-related adverse events (AEs) differed between the two arms, potentially effectively unblinding investigators. The effect of potential bias on PFS was evaluated by a retrospective, blinded independent central review (BICR) of tumor scans in a large subset of patients with available imaging data.
Methods: Baseline and on-study MRI/CT scans and radiology data were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Reading radiologists were blinded to investigator assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist.
Results: Retrospective BICR was conducted on the first 84 patients (49%) whose MRI/CT scans were available (41 sunitinib, 43 placebo). This subset was representative of the intent-to-treat population for demographics, baseline disease characteristics, prior treatment, on-study AEs, and investigator-assessed PFS. Median investigator-assessed PFS was 19.8 months for sunitinib vs 5.8 months for placebo (HR 0.449, 95% CI: 0.218, 0.924, P = 0.0249). In the analysis of PFS by BICR of scans, the median PFS was 20.6 months for sunitinib vs 6.2 months for placebo (HR 0.289, 95% CI: 0.117, 0.716, P = 0.0042).
Conclusions: This BICR of imaging data supported the investigator-assessed PFS benefit of sunitinib in the treatment of pancreatic NET, and argued against any bias favoring sunitinib. BICR on the remaining patients is ongoing.
Differential Protein Expression in Small Intestinal Carcinoids and Liver Metastases
Michelle Kang Kim,1 Daguan Wang,3 Miao Cui,3 Thomas Curran,1 Stephen Ward,3 Richard Warner,1 Sasan Roayaie,2 Michail Shafir,2 Myron Schwartz,2 David Zhang,3 Steven Itzkowitz.11Division of Gastroenterology, Mount Sinai School of Medicine, New York, New York, 2Division of Surgical Oncology, Mount Sinai School of Medicine, New York, New York, 3Department of Pathology, Mount Sinai School of Medicine, New York, New York
Background: Small intestinal carcinoids (SICs) are being increasingly detected, yet often late in their clinical course and with metastatic disease. Little is known about the molecular pathways important in the development of metastasis. We have recently developed a Protein Pathway Array to screen for changes in protein and phosphoprotein expression in tissues. The objective of our study was to identify key pathways important in the mechanism of SIC metastasis development.
Methods: From 5 patients undergoing surgical resection for metastatic SIC, tissue was harvested from the primary tumor and adjacent normal small intestine, and from liver metastases and adjacent normal liver from the same patient. Extracted proteins were separated by SDS gel, and Western blots were performed with 136 antibodies. Band densities were determined using BioRad Image system. Significant Analysis of Microarray (SAM) (http://www-stat.stanford.edu/∼tibs/SAM/) was used to select the proteins differentially expressed between different groups. Unsupervised hierarchical clustering analysis was performed using BRB Array Tools software v.3.3.0 (htt://linus.nci.nih.gov/BRB-ArrayTools.html).
Results: Of the 136 proteins analyzed, 52 proteins were expressed in these samples. 9 proteins were up-regulated in primary SICs compared with matched normal small bowel mucosa. Cyclin E was down-regulated in primary SIC tissue compared to normal small bowel mucosa. Compared to normal liver tissue, SIC liver metastases demonstrated up-regulation of P-ERK and p27 but down-regulation of CDK2 and CDC25B. When comparing primary SIC with their paired liver metastases, cyclin E demonstrated a significant up-regulation in the liver metastasis.
Conclusion: Few studies have compared gene or protein expression in primary and metastatic SIC tumors resected simultaneously. Our findings using Protein Pathway Array reveal changes in a limited number of proteins, suggesting that these may be targets for therapy. Future studies are needed to validate these findings.
Phase I/II Study of Everolimus (RAD001) in Combination With Temozolomide (TMZ) in Patients With Advanced Pancreatic Neuroendocrine Tumors (NET)
Matthew H. Kulke, MD, MMSc,1,2 Lawrence Blaszkowsky, MD,3 Andrew X. Zhu, MD, PhD,3 Sarah Florio, BS,1 Eileen Regan, RN, BSN, OCN,1 David P. Ryan, MD,3 Jennifer A. Chan, MD, MPH.1,21Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, 2Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, 3Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA 02114.
Background: Both the mTOR inhibitor RAD001 and TMZ have antitumor activity in NETs. We performed a phase I/II study to evaluate tolerability and efficacy of RAD001 in combination with TMZ in patients with advanced pancreatic NETs.
Methods: Patients were enrolled at 2 dose levels: TMZ 150 mg/m2 daily, administered for 7 consecutive days every other week, in combination with RAD001 5 mg daily (Cohort 1) or RAD001 10 mg daily (Cohort 2). TMZ with RAD001 10 mg daily was established as the phase II dose. TMZ was administered in combination with RAD001 for a maximum of six 4-week treatment cycles, at which point patients with response or stable disease continued treatment with RAD001 alone. Patients received prophylaxis with trimethoprim-sulfamethoxazole. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent.
Results: In Phase I, 1 patient in cohort 1 experienced DLT consisting of grade 4 thrombocytopenia, and the cohort was expanded to 6 patients. No further DLTs have been observed. A total of 27 patients have been enrolled; 7 in cohort 1 (6 evaluable) and 20 in cohort 2 (19 evaluable). Enrolled patients have the following characteristics: M:F =15:12; median age 52 (range 29-87); ECOG PS 0/1 = 13/14. Patients received a median of 5 cycles of treatment. Observed grade 3/4 toxicities included thrombocytopenia (n = 5), lymphopenia (n = 7), neutropenia (n = 2), diarrhea (n = 1), hyperglycemia (n = 1), elevated transaminases (n = 2), elevated triglycerides (n = 2), skin rash (n = 1), fatigue (n = 1), hyper/hypokalemia (n = 1 /1), and hyponatremia (n = 1). 22 patients were evaluable for response. Responses include 7 patients with PR (32%), 13 with SD (59%), and 2 with PD (9%). 17/22 patients had elevated CGA levels (>225 ng/ml) at baseline; 5 (29%) experienced CGA decreases of >50% from baseline on 2 consecutive assessments.
Conclusions: The combination of RAD001 and TMZ can be safely administered and shows promising activity in patients with advanced pancreatic NET. Further enrollment is planned.
The Efficacy and Safety of Pasireotide (SOM230) in the Treatment of Patients With Metastatic Neuroendocrine Tumors (NET) Refractory or Resistant to Octreotide LAR
Larry Kvols,1 Bertram Wiedenmann,2 Kjell Öberg,3 Pharis Mohideen,4 Thomas M. O'Dorisio,5 Wouter W. de Herder,6 Gareth Hughes,7 Rudolf Arnold,8 Lowell Anthony.91H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA, 2Universitätsklinikum Charité-Virchow-Klinikum, Berlin, Germany, 3Department of Endocrine Oncology, University Hospital, Uppsala, Sweden, 4Oncology Clinical Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA, 5University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, 52242, USA, 6Erasmus Medical Center, Rotterdam, The Netherlands, 7Novartis Pharma AG, Basel, Switzerland, 8Philipps-Universität, Marburg, Germany, 9Louisiana State University Medical Center, New Orleans, LA, 70112, USA.
Background: Pasireotide (SOM230) is a novel multi-receptor targeted somatostatin analogue with high binding affinity for sst1,2,3 and sst5. Therefore, pasireotide may offer improved efficacy compared with other somatostatin analogues in patients with NET unresponsive to octreotide LAR.
Methods: A phase II, open-label, multicenter study of pasireotide was initiated in patients with metastatic NET whose symptoms of carcinoid syndrome were inadequately controlled by octreotide LAR. Patients had histopathologically confirmed metastatic NET, elevated 5-HIAA and/or chromogranin A levels, and at least one measurable lesion (excluding bone). Pasireotide was initiated at 150 μg sc bid, escalated to a maximum of 1200 μg sc bid in patients with suboptimal response. Symptom control on a fixed-dose of pasireotide was defined as: complete (a mean of ≤3 bowel movements [BM]/day, with ≤3 BM on any day, with no flushing episodes) or partial (a mean of <4 BM/day with ≤6 BM on any day, and a mean of <2 flushing episodes/day).
Results: Forty-five patients received ≥1 dose of pasireotide and 44 qualified for efficacy assessment. The median treatment duration was 13 weeks (range 0-85). Complete or partial symptom control was achieved by 12 (27%) patients at a dose of 600-900 μg bid; three (7%) patients achieved complete symptom control and nine patients (20%) experienced partial symptom control. Mean duration of complete or partial symptom control was 43.7 and 72.0 days, respectively. Evaluation of tumor response (RECIST) in 23 patients showed 13 with stable disease and 10 with progressive disease at study end. The most common drug-related adverse events were: nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%).
Conclusions: Pasireotide 600-900 μg sc bid was effective and generally well tolerated in controlling symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.
An Aggressive Multi-Disciplinary Approach to Advanced Neuroendocrine Tumors
Shawn MacKenzie, Kambiz Kosari, Timothy Sielaff. Virginia Piper Cancer Institute, Minneapolis, Minnesota
Background: Neuroendocrine tumors continue to be a difficult to treat cancer with a less then 70% 5 year survival, with little improvement over the last few decades. A multi-disciplinary approach to neuroendocrine cancer in essential.
Methods: A 53-year-old female with jaundice; and was found to have a 13 cm tumor occupying the pancreatic head. The unresectable tumor occluded the portal vein and incased the hepatic artery. Inital neoadjuvant therapy included external beam radiation and chemotherapy. Subsequent, radioactive octreotide (In111) was used to decrease the tumor size. The well-differentiated neuroendocrine tumor was resected with a pancreaticoduodenectomy, requiring a portal vein and a hepatic artery reconstruction (no perioperative complications; blood loss = 400cc; operative time = 636 min; and the LOS = 9 days). The pathology revealed islet cell tumor with microscopic islands of tumor in the peri-aortic tissue. The patient is doing well without clinical recurrence at 18 month follow up, with a planned 3rd cycle of radioactive octreotide.
A 41-year-old female with new onset abdominal pain, and was diagnosed with a 24cm neuroendocrine liver tumor. CT imaging reveals tumor replacement of the right lobe of the liver and additional left liver lesions. The patient underwent radioactive octreotide (In111) treatment to control the systemic disease. Surgery included resection of the primary jejunal lesion and a right hepatectomy (no peri-operative complications; blood loss = 250cc; LOS = 6 days). During a staged liver resection the left lobe of liver was cleared. A 3rd round of radioactive octreotide was utilized. The patient is doing well with minimal stable disease 18 months after diagnosis. Additional options for tumor progress will include Selective Internal Radiation Therapy (SIRT) and/or liver transplantation.
Conclusions: An aggressive mutli-disciplinary approach to neuroendocrine tumors can be performed safely and may provide a survival benefit.
Surgical Exploration Is Superior to All Other Modalities for Locating Primary Carcinoid Tumors
Kristen P. Massimino, Esther Han, SuEllen J. Pommier, Rodney F. Pommier. Oregon Health & Science University, Portland, OR 97239.
Background: Many patients with carcinoid tumors have liver metastases at diagnosis. However, even when extensive metastases are present, primary carcinoid tumors remain very small and difficult to locate. Recent studies indicate resection of the primary tumor is associated with improved survival rates, prompting extensive searches for these elusive tumors. We hypothesized that surgical exploration is superior to all other techniques for locating them.
Setting: University Hospital.
Methods: Records of carcinoid patients with liver metastases at diagnosis in years 2006-2010, in whom a search for the primary tumor was conducted, were retrospectively reviewed. Patients presenting with acute bowel obstruction were excluded. Results of preoperative procedures and surgical explorations were compared for their efficacy at finding primary tumors.
Results: 59 patients were identified. Most primary tumors (81% [n = 48]) were not located by preoperative testing. The sensitivities of preoperative colonoscopy (27% [n = 22]), CT scan (7.0% [n = 57]), and octreoscan (2.0% [n = 46]) were low. No tumors were found by MRI (n = 6), upper endoscopy (n = 22), capsule endoscopy (n = 2) or bronchoscopy (n = 4). Surgical exploration (76% [n = 59]) was the most sensitive method of tumor detection. 65% of successful localizations were laparoscopic. Fourteen tumors remained occult after an average follow up of 13 months with serial CT scans.
Conclusions: Surgical exploration was superior to all other modalities for locating primary tumors. A laparoscopic approach had a high probability of finding occult primary tumors and has the advantage of rapid recovery from negative exploration. Other tests can provide valuable information concerning extent of disease, but their sensitivity is too low to utilize them for primary tumor localization. Therefore, we recommend surgical exploration as the best method to locate primary carcinoid tumors.
Xanthohumol, a Novel Plant Extract, Alters Neuroendocrine Phenotype and Inhibits Growth of Carcinoid Cell Lines
Catherine M. McManus, BS, Mary Ndiaye, BS, Herbert Chen, MD, FACS, Muthusamy Kunnimalaiyaan, PhD. Department of Surgery, Wisconsin Institutes For Medical Research, University of Wisconsin, Madison, WI.
Background: Carcinoids produce excessive amounts of active hormones, which cause debilitating symptoms such as intractable diarrhea, flushing, skin breakdown, and abdominal pain. Though these secretions are generally controlled by somatostatin analogs or interferon, some patients are refractory to it. Thus, patients with incurable carcinoid syndrome have a poor quality of life. Therefore, new therapies are required to effectively treat carcinoids. Earlier we have shown that inhibition of AKT pathway resulted in decrease in growth and neuroendocrine (NE) markers in carcinoid cells. The purpose of this study was to determine the effectiveness of xanthohumol, a prenylflavonoid anti-oxidant, on carcinoid tumor cells growth and NE markers that correlate with severity of carcinoid syndrome.
Methods: Human gastrointestinal carcinoid BON and bronchopulmonary carcinoid H727 cells were treated with xanthohumol (0 to 20 μmol/L) or DMSO (solvent). Cellular proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) growth assay. Proteins were isolated after two days of treatment and were analyzed by Western blot for NE markers and the levels of expression of AKT pathway. Possible role of xanthohumol on this pathway was determined by over expression of active AKT with appropriate controls in the presence or absence of Xanthohumol treatment.
Results: Dose-dependent reduction in cell growth as well as markers CgA and achaete scute complex-like 1 (ASCL1), was observed with xanthohumol treatment. Inhibition of AKT pathway was evidenced by a decrease in the level of phosphorylated AKT. Importantly, cells transfected with AKT plasmid did not abrogate the effect of xanthohumol.
Conclusions: Treatment with xanthohumol decreases AKT phosphorylation, but over-expression of active AKT did not alter NE phenotype, indicating that AKT pathway regulates carcinoid syndrome markers. Our findings demonstrate for the first time the anti-proliferative and possible anti-carcinoid syndrome effects of xanthohumol in carcinoid cell lines. These results warrant further investigation of xanthohumol to treat and palliate patients with unresectable carcinoid cancer.
Small Cell Carcinoma of the Uterine Cervix: A Single-Center Experience
Boris G. Naraev, MD, PhD,1 Michael J. Goodheart, MD,2 Thomas M. O'Dorisio, MD,3 Thorvardur R. Halfdanarson, MD.11Division of Hematology, Oncology, and Bone and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242, 2Department of Obstetrics & Gynecology and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242, 3Division of Endocrinology and Metabolism and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, 52242.
Background: Small cell carcinoma of the uterine cervix (SCCUC) is a rare and aggressive malignancy of neuroendocrine origin. Given the rarity of this cancer, the optimal treatment remains uncertain. We report our experience with 36 cases seen at the University of Iowa between 1977 and 2009.
Methods: Cases were identified by searching our institutional database. Patients (pts) with pathology-confirmed SCCUC were included. Other histologies were excluded.
Results: We identified 36 cases where follow-up information was available. The median age of pts was 49 years (range 26-77). FIGO staging was IB1 for 14 pts (39%), IB2 for 3 pts (8%), II for 7 pts (19%), and 12 pts (34%) had stage III or higher. Fifteen pts (44%) underwent resection, 20 pts (56%) had radiation therapy (RT) and 27 pts (82%) received chemotherapy. The median survival (MS) for the entire cohort was 22.6 months with a 24% 5-year overall survival (5-OS). Stage was a strong predictor of survival. Patients deemed resectable (stage IB1 or less) had an improved MS and 5-OS compared to pts of higher stage (MS 42 vs. 11.1 months, p = 0.008, 47 vs. 6% respectively). RT did not seem to improve survival (MS 16 months for RT vs. 23 months for no RT, p = 0.6). Of the 15 resected patients, 7 recurred after a median time of 14 months from diagnosis and all but one patient died.
Conclusion: SCCUC is a rare malignancy with poor overall prognosis. Patients with advanced disease had the shortest MS and 5-OS. Surgery in early stages provided the best chance to increase survival. RT was not associated with improved survival in this study, but the impact of chemotherapy could not be clearly defined. Further exploration of the biology of this aggressive tumor, and search for possible prognostic factors, most likely on molecular level, is required.
Evaluation of Chromogranin A and Neuron-Specific Enolase as Predictors of Response to Everolimus Therapy in Patients With Advanced Pancreatic Neuroendocrine Tumors (pNET)
Kjell Öberg,1 Matthew Kulke,2 Marianne Pavel,3 Alexandria Phan,4 Sakina Hoosen,5 Jessica St. Peter,5 Azzeddine Cherfi,6 James C. Yao.41Uppsala University, Uppsala, Sweden, 2Dana-Farber Cancer Institute, Boston, MA, 02115, USA, 3Charité-University, Berlin, Germany, 4The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA, 5Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA, 6Novartis Pharma Services AG, Basel, Switzerland.
Background: The RADIANT-1 study reported the median progression-free survival (PFS) in patients with advanced pNET was 9.7 months with everolimus and 16.7 months in combination with octreotide LAR. With disease stabilization recognized as an established predictor of improved survival, the identification of biomarkers could further distinguish patients likely to respond to everolimus treatment. This examination of RADIANT-1 data evaluated chromogranin A (CgA) and/or neuron-specific enolase (NSE) to determine their value as prognostic and predictive biomarkers.
Methods: Patients received everolimus 10 mg/day (n = 115), or everolimus plus octreotide LAR ≤30 mg/28 days (n = 45), based on prior octreotide therapy. Elevated baseline CgA was defined as >2× upper limit of normal (ULN) and elevated baseline NSE as >ULN. Early biomarker response was defined as normalization or decrease of ≥30% after 4 weeks of therapy.
Results: Non-elevated CgA and NSE levels at baseline were associated with improvement in both PFS and overall survival (OS). Patients with elevated CgA and NSE levels at baseline demonstrated shorter PFS compared with non-elevated levels (9.3 vs 16.7 months, respectively [HR = 0.53; P = 0.01] for CgA and 7.5 vs 15.6 months, respectively [HR = 0.42; P = 0.0002] for NSE). Patients with elevated baseline levels, demonstrated OS of 20.2 months versus not reached in the non-elevated arm (HR = 0.29; P < 0.0001) for CgA and 16.6 months versus not reached in the non-elevated arm (HR = 0.33; P < 0.0001) for NSE. The median PFS was longer for everolimus-treated patients demonstrating an early biomarker response versus no early response (CgA, 12.3 vs 8.2 months, respectively [HR = 0.39; P = 0.002]; NSE, 8.3 vs 4.9 months, respectively [HR = 0.40; P = 0.03]).
Conclusions: This exploratory analysis determined that patients with early CgA and NSE response to everolimus-based therapy reported a longer PFS. In addition, non-elevated baseline biomarker levels predicted longer PFS and OS. The results of the RADIANT-3 study will further validate the prognostic value of the biomarkers CgA and NSE in patients with advanced pNET.
Cisplatin Plus Etoposide in the Management of Metastatic Neuroendocrine Tumors of the Colon and Rectum
Annie Patta,1 Marwan G. Fakih.1,21University at Buffalo, Buffalo, NY 14215, 2Roswell Park Cancer Institute, Buffalo, NY 14263.
Background: The combination of cisplatin and etoposide is effective in the treatment of small cell lung cancers and other high grade neuroendocrine tumors (NET). This combination has been considered as a default treatment for patients with high grade NET of the colon and rectum (CRC). Yet no formal series describe the activity of this regimen in this patient population. We report a single institute experience on treating 8 patients with metastatic colorectal NET with cisplatin and etoposide.
Methods: Using pharmacy records and tumor registry records, we searched for metastatic CRC NET patients treated with cisplatin and etoposide. Responses were categorized using RECIST 1.1 guidelines.
Results: We identified 8 patients with colon or rectal metastatic NET who were treated with cisplatin and etoposide between May of 2003 and August of 2010. All patients had high grade NET. Cisplatin was administered at 80 mg/m2 on Day 1 and etoposide at 80 mg/m2/day on Days 1-3, every 3 weeks. Patient characteristics were: median age of 64 yrs (31-83yrs), a male to female ratio of 5/3, and a rectal primary site in 5 patients. All patients had evidence of metastatic disease to the liver at presentation. One patient had concurrent lung metastases, and one patient had concurrent lung, bone, and distant lymph node involvement. Radiographic response consisted of complete response (CR) in 1 patient, partial response (PR) in 4 patients, and stable disease (SD) in 2 patients. The median time to progression was 4.5 months (2-9 months) and the median overall survival was 7.75 months (3.5-17 months). Two patients received second-line treatment consisting of cisplatin plus irinotecan, both with progressive disease.
Conclusion: Patients with high grade CRC NET have a high response rate to cisplatin and etoposide. The response is short lived and most patients die within 1 year from diagnosis.
A Phase II Clinical Ttrial of MK-0646, an Insulin-Like Growth Factor-1 Receptor Inhibitor (IGF-1R) in Patients With Metastatic Well Differentiated Neuroendocrine Tumors (NETs)
D. L. Reidy, E. Hollywood, M. Segal, L. Saltz. Memorial Sloan-Kettering Cancer Center, New York, NY.
Background: Preclinical studies have implicated the IGF-1 receptor in the progression of neuroendocrine tumors. A therapy directed at IGFR mediated signaling pathways has potential for conferring enhanced anti-tumor activity. We evaluated the safety and efficacy of MK-0646, a monoclonal antibody (mab) that blocks the insulin-like growth factor receptor (IGF-1R), as monotherapy in metastatic well differentiated neuroendocrine patients.
Methods: A phase II study was performed in which patients received MK-0646 at a dose of 10 mg/kg iv over 1 hour weekly. Archived pretreatment tumor tissue was obtained for putative biomarkers.
Results: A total of 25 patients were treated (15 carcinoid, 10 PNETs) female, 40%; median age, 61 years, (range 36-82). No antitumor activity was seen in these 25 patients treated with MK-0646 monotherapy. Progression free survival was 4.2 months in the PNET cohort (range 0.7-6.7 months) and 2.7 months (range 2-3 months) in the carcinoid cohort. The most common serious adverse event (SAE) thought to be potentially related to MK-0646 was hyperglycemia (7 patients, 25%). Other SAEs included one grade 2 infusion-related reaction (4%), and 2 patients with grade 3 fatigue (8%).
Conclusions: MK-0646 alone was well tolerated with the exception of hyperglycemia that was manageable with antihyperglycemic medications, however, the degree of activity seen was insufficient to warrant further study as a monotherapy in well differentiated neuroendocrine tumors.
The Addition of Octreotide Functional Imaging to CT or MRI Cross-Sectional Imaging for the Detection of Neuroendocrine Tumors (NETs) - Added Value or an Anachronism?
Diane L Reidy, Marc J Gollub, Leonard B Saltz. Memorial Sloan-Kettering Cancer Center, New York, NY.
Purpose: Somatostatin scintigraphy (OctreoScan, SRS, octreotide scan) detects somatostatin receptors and images disease in patients with NETs. We evaluated the benefit of an octreotide scan when used in conjunction with CT or MRI, to determine if it detected additional NET disease.
Methods: Computerized medical records were used to identify all NET patients who underwent an octreotide scan in addition to either a CT or MRI within a 30-day time period, at MSKCC from 1/1/2003 through 12/1/2009. Reports of the scans and clinical history were reviewed.
Results: 121 evaluable patients were identified, of whom 107 had metastatic disease. Twenty-one patients were classified as high-grade, 13 intermediate-grade, 78 low-grade and 9 had unspecified grade classification. Twenty-two patients had a negative octreotide scan in the setting of metastatic disease on CT or MRI. Of those, 14 were high-grade, 3 intermediate-grade, 3 low-grade and 2 unspecified grade. An additional 9 low-grade patients had findings of primary NET on CT or MRI that were not seen on octreotide scan. In six patients, bone lesions were revealed on octreotide scan that were not seen on CT or MRI imaging; all of these findings were in the setting of metastatic disease.
Conclusion: Modern CT and MRI were able to identify soft tissue lesions with greater sensitivity than octreotide scan. 6% of patients had octreotide scan avid bone metastases not seen on CT or MR. These data suggest that, contrary to current practice, octreotide scanning is not a useful adjunct for defining extent of soft tissue disease in NET tumors, and should not be used routinely for this purpose.
Mitotic Index and Somatostatin Receptor Status Are Independent Predictors of Survival After Resection of Neuroendocrine Tumors Metastatic to the Liver
Sasan Roayaie,1 Paramjeet Singh, Hongfa Zhu,2 Lihui Qin,2 Daniel Labow,1 Michelle Kim,3 Richard R. P. Warner,3 Myron Schwartz.11Mount Sinai Liver Cancer Program, Department of Pathology, 2Division of Gastroenterology, Department of Medicine3, Mount Sinai Medical Center, New York, NY 10029.
Background: Mitotic activity of neuroendocrine tumors (NET) has been shown to predict survival after resection. However, other markers of outcome are lacking.
Methods: Patients undergoing resection of hepatic metastases of NET between Jan1988 and Jan 2009 were reviewed. Inclusion criteria required the surgeon to feel he/she could treat all gross disease with a combination of resection and ablation. The primary and metastatic tumors were histologically and immunohistochemichally examined. Survival was estimated with the Kaplan-Meier method and compared using log rank. Multivariate analysis was conducted with Cox regression.
Results: 70 patients underwent hepatic resection of NET. There have been 29 deaths including 3 (4%) within 30 days. The median survival was 96.5 months with 5yr and 10 yr survivals of 72% and 43%. Mitoses per 10 high power field (HPF) and percentage of cells staining positive for Ki67 were significantly higher in the liver metastases than in the primary tumors on paired T-test. On univariate analysis of the primary tumors, a pancreatic primary, size>3cm, >2 mitoses/10HPF, Ki67 staining >1% of cells, weak staining for somatostatin receptor, and strong staining for CEA were significantly associated with shorter survival. On univariate analysis of the liver metastases, >2 mitoses/10HPF, Ki67 staining >1% of cells, and weak staining for somatostatin receptor were all significantly associated with shorter survival. Multivariate analysis of the primary tumors found no independent predictor of survival.
Multivariate analysis of the metastatic tumors showed:
Conclusions: Resection of hepatic metastases of NET can achieve excellent results. Mitotic activity was significantly higher in the liver metastases than in the primary tumors. Mitoses per 10 HPF and staining for somatostatin receptors in the liver metastases are significant and independent predictors of survival.
Methods in the Development of Human Carcinoid Cell Lines
Eric Sceusi,1 Asif Rashid,3 Yunfei Zhou,2 Shaija Samuel,2 Fan Fan,2 Ling Xia,2 Xiang-Cang Ye,2 Jia Lu,2 Federico Tozzi,1 Puja Gaur,1 Patrick Zweidler-McKay,6 Raymond Meyn,5 James Yao,4 Lee M. Ellis.1,2Departments of 1Surgical Oncology, 2Cancer Biology, 3Pathology, 4Medical Oncology, 5Experimental Radiation Oncology and 6Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Background: Research in carcinoid and neuroendocrine tumors (NETs) is limited by the lack of midgut derived cell lines. The existing foregut NET lines, BON and H727, are phenotypically distinct from midgut NETs; highlighting the importance of establishing midgut derived NET cell lines. NETs are difficult to culture and we are developing methods to improve primary NET cell culture.
Methods: Sterile human NET surgical specimens were digested to a single cell suspension and fibroblast depleted using magnetic beads. The NET cells were maintained on collagen I coated plates for 1) culture and 2) immortalization. FACS was performed with a portion of cells using the Aldefluor assay to isolate potential cancer stem cells (CSCs). Sorted cells were grown in serum-free media on low attachment plates to assess sphere formation. Subcutaneous xenografts in nude and NOD/SCID gamma mice using fresh tumor implants and NET cell suspensions were performed.
Results: 1% serum improves primary cultured cell survival compared with 10% serum media. The effect of low serum reverses after approximately one week. Subcutaneous xenografts formed tumors in 5/59 mice over 4-10 months. FACS sorting has identified an ALDH+ population of NET cells, which can form spheres (a characteristic of CSCs) more frequently than ALDH(-) negative cells, which did not proliferate in sphere forming media. NET markers, somatostatin receptor 2 and chromogranin A, were detectable in cultures from a midgut carcinoid liver metastasis at passage 3 and 5, as well as in one mouse xenograft tumor; however both lines failed to grow beyond this point. We are now studying tumor xenografts in more immunodeficient NOD/SCID gamma mice.
Conclusions: We have developed a system allowing for NET primary culture up to 4 weeks. These techniques are the first step in obtaining cells for in vitro studies. Supported by the The Raymond and Beverly Sackler Foundation.
Extensive "Multitasking" Surgery for Advanced Enteropancreatic Neuroendocrine Tumors (NETS): A Safe and Effective Approach
Michail Shafir, MD, Richard PR Warner, MD, Sheilah Gonsalves, MD, Jerome J Zacks, MD, Lynn Ratner, MD, Michelle Kim, MD. Mount Sinai School of Medicine and the Carcinoid Cancer Foundation, New York.
Introduction: Management of advanced-metastatic-NETs is controversial. Our Center's philosophy is to offer a systematic, planned multimodality treatment for such patients, with major "debulking "surgery, representing a major component of the therapeutic strategy.
Aims: To demonstrate that this surgical tumor reductive component achieves a major Improvement in symptoms and quality of life.
Materials and Methods: From 1994 to 2007, 57 patients (ages 26 to 78, mean 56), 21 males and 36 females underwent extensive surgery for advanced metastatic NETs; Minimal follow-up was of three years, with median of 8 years. 35/57 presented with typical and significant carcinoid syndrome, mostly originating in small bowel. All patients were fully evaluated by serum markers, nuclear and radiological imaging and echocardiogram to assess for cardiac valvular involvement. All surgeries in this series were performed by one surgeon (MS), and included: Resection of primary tumor(s), lymph nodes, peritoneal and retroperitoneal metastases, liver resection(s), cryoablation/radiofrequency ablation for liver metastases and all patients had a cholecystectomy. Several patients underwent pancreatectomy and hysterectomy/salpingo-oophorectomy. 8/57 had significant tricuspid and pulmonary valvular disease and underwent cardiac valvular replacement prior to abdominal surgery. Samples of all resected tissues were collected for expression of growth factors such as EGF and VEGF and for in vitro tumor cell culture to assess for chemosensitivity and chemoresistance, to help personalize postoperative treatment options. All patients were pretreated with short and long acting Octreotide. Perioperative high dose continuous infusion was administered intravenously and tapered progressively after surgery.
Results: There were no operative mortalities. Four major complications were treated non operatively: 1 pancreatitis, 1 biliary fistula, 1 pancreatic fistula and 1 upper abdominal hematoma. No patients developed "carcinoid crisis "Blood pressure and pulse rate fluctuations intraoperatively were treated by increasing dosage of intravenous Octreotide.. Postoperatively there was an immediate and prolonged symptomatic relief in all patients. Long term survival is presently being evaluated.
Conclusions: Treatment of advanced, metastatic, NETs by "multitasking" surgery in one operative session, including major extensive debulking, is safe, efficacious and well tolerated.
Treatment of Pancreatic Neuroendocrine Tumors (pNET) With Everolimus: Improved Progression-Free Survival Compared With Placebo (RADIANT-3)
Manisha H. Shah,1 Kjell Öberg,2 Tetsuhide Ito,3 Catherine Lombard-Bohas,4 Edward M. Wolin,5 Eric Van Cutsem,6 Carolin Sachs,7 Robert Winkler,7 Jeremie Lincy,7 Timothy Hobday,8 James C. Yao.91Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA, 2Uppsala University, Uppsala, Sweden, 3Graduate School of Medical Sciences, Kyushu University, Japan, 4Hôpital E. Herriot, Hospices Civils de Lyon, Lyon, France, 5Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA, 6University Hospital Gasthuisberg/Leuven, Leuven, Belgium, 7Novartis Oncology Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA, 8Mayo Clinic, Rochester, MN, 55905, USA, 9The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Background: The incidence of pNET is increasing steadily; however, there is no established systemic treatment for patients with advanced pNET after chemotherapy failure. Two recent phase II studies demonstrated the antitumor activity of everolimus (RAD001) in patients with advanced NET.
Methods: A multi-center, international, randomized, double-blind, placebo-controlled, phase III trial to evaluate the efficacy and safety of oral everolimus (10 mg/day) plus best supportive care (BSC) [n = 207]; compared with placebo plus BSC (n = 203) in patients with advanced pNET whose disease has progressed within the past 12 months. The primary endpoint was progression-free survival (PFS). At progression (RECIST), patients could be unblinded and the placebo arm was offered open-label everolimus.
Results: Compared with placebo, everolimus was associated with a 65% reduction in the risk of progression and 6.4-month increase in median PFS (4.6 vs 11.0 months, respectively [HR 0.35; 95% CI: 0.27, 0.45; P < 0.0001]). Eighteen-month PFS rate was 34% (95% CI: 26, 43) for everolimus versus 9% (95% CI: 4, 16) for placebo. Median PFS by adjudicated central assessment was consistent (HR 0.34; 95% CI: 0.26, 0.44; P < 0.001). The most common adverse event (AE, all grades) for everolimus versus placebo was stomatitis (64% vs 17%, respectively). The most frequent grade 3/4 AEs for everolimus were: stomatitis (6.9%), anemia (6%), and hyperglycemia (5%). Treatment discontinuation for AEs was 17.4% in the everolimus arm versus 3.4% in the placebo arm.
Conclusions: Treatment with everolimus met the primary endpoint with a highly statistically significant reduction in the risk of disease progression compared with placebo. Furthermore, everolimus produced a clinically meaningful 6.4-month prolongation in median PFS. The AEs reported for everolimus were consistent with previous reports of everolimus treatment. These results validate earlier trials and represent important progress towards the use of everolimus as an effective treatment alternative for patients with progressive advanced pNET.
Hypo/Achlorhydria Is Associated With False-Positive Secretin Stimulation Testing (SST) for Zollinger-Ellison Syndrome (ZES)
Pari Shah,1 Yu-Xiao Yang,1,2 David Metz.11Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, 2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.
Background: The hallmark of ZES is inappropriate hypergastrinemia, manifest by elevated fasting serum gastrin levels in the presence of elevated levels of gastric acid production. However, since gastric analysis is not routinely available, SST is widely used instead. SST is considered positive when a diagnostic rise in serum gastrin concentration after intravenous secretin injection occurs (>110 pg/ml or >200 pg/ml). However, case reports have documented false-positive SST in patients who are achlorhydric due either to atrophic gastritis or therapy with proton pump inhibitors (PPIs).
Aim: To review our experience with SST in hypo/achlorhydric patients.
Methods: We examined the charts of all patients who underwent gastric analysis and SST from Jan 1994 to Sept 2009 with a basal acid output (BAO) < 5 mEq/hr in the absence of prior gastric acid reducing surgery to determine the frequency of false positive SST results.
Results: Of 330 patients who underwent gastric analysis during the testing period, we identified 40 that potentially fit the above criteria. Thirteen patients were excluded because they had incomplete data. Of the 27 patients with complete information available, the mean age was 47.9 years ± 15.4 years, 19 were female and 8 were male; the mean basal fasting gastrin level was 247.3 ± 304.0 pg/ml and the mean BAO value was 1.6 ± 1.8 mEq/hr. Twenty patients were studied in the absence of all anti-secretory therapy and 7 were studied on therapy. We identified 2 patients with false-positive SST using a cutoff of >200 pg/mL for a positive result; one with gastric atrophy (BAO 0 mEq/hr) and one with drug-induced hypochlorhydria (acid output 0.5 mEq/hr on rabeprazole 20 mg BID). Using a cutoff >110 pg/mL we identified two additional false-positive test results, both with atrophy (BAO 0 mEq/hr for both). The false-positive test results were confirmed in all instances on additional follow up including structural and functional imaging. In addition, we found 3 true positive SSTs in patients with previously diagnosed ZES on medication therapy (acid outputs of 0.4, 1.2 and 1.3 mEq/hr on lansoprazole 60 mg BID, esomeprazole 40 mg BID and omprazole 20 mg BID, respectively).
Conclusions: We identified 4/27 false positive secretin tests (14.8%) in patients who were hypo/achlorhydric. Positive SST should be interpreted carefully and in context in individuals in whom gastric acid secretion is suppressed, depressed or unknown.
Multidisciplinary Reference Centers: A Beneficial Approach for Neuroendocrine Tumor Disease Management
Simron Singh, Yael Fineberg, Calvin Law. Toronto Sunnybrook Odette Cancer Center, University of Toronto, Toronto, Ontario, Canada.
Background: Neuroendocrine tumors (NET) can be challenging to diagnose and treat as they are a heterogeneous and complex group of malignancies that are uncommon and poorly understood. Treatment of patients with NET in a multidisciplinary reference center (MRC) may improve clinical outcome by integrating expert care from multiple specialties, reducing delays in treatments and referrals, facilitating clinical trial enrollment, and improving patient satisfaction. Although improved outcomes in ovarian, breast, and lung cancers have been achieved with the MRC approach, MRCs focusing on NET are uncommon.
Methods: A PubMed (Medline) literature search was performed to assess the experience and potential benefits of NET MRCs.
Results: A single-center analysis of treatment patterns and survival of patients with metastatic NET managed by a medical oncology unit (MOU; a MRC surrogate) [n = 28] compared with patients managed by individual specialists (n = 21) demonstrated that MOU patients had better disease monitoring, increased likelihood of chemotherapy (7% vs 0%) and octreotide LAR (79% vs 10%) treatments, were frequently enrolled in clinical trials (7% vs 0%), and achieved a longer overall survival (112 vs 32 months). In a single-center analysis of 146 patients with metastatic intestinal NET treated with multidisciplinary care, median and 5-year survival was 103 months and 75%, respectively, which represents a favorable outcome from multidisciplinary care. In 2007, the US National Cancer Institute determined regional MRCs with experienced clinicians were needed. Recently, NCCN and NANETS guidelines stated that effective NET diagnosis requires collaboration between specialists and that a multidisciplinary approach to treatment can lead to improvement in the patient's quality of life, survival, and a positive outcome.
Conclusions: NET treatment in an MRC can improve patient outcome, including reducing the time between diagnosis and treatment and increasing patient survival time. Multidisciplinary treatment is recommended by recent treatment guidelines and should be a goal of healthcare systems.
Phase II Study of Sunitinib Malate Following Hepatic Artery Embolization for Metastatic Neuroendocrine Tumors
Jonathan Strosberg, MD, Asima Cheema, MD, Tiffany Campos, Tiffany Valone PA, Larry Kvols, MD. H. Lee Moffitt Cancer Center and Research Institute, Dept. of GI Oncology, Tampa, FL.
Background: Neuroendocrine tumors (NETs) frequently metastasize to the liver. Hepatic arterial embolization is an important therapeutic modality in treating patients with liver-predominant metastases. NETs are highly vascular and are known to express both VEGF and VEGFR. We hypothesize that administration of Sunitinib, a VEGFR inhibitor, following hepatic artery embolization will delay tumor revascularization and extend progression-free survival.
Methods: Patients with metastatic neuroendocrine tumors to the liver underwent a series of selective arterial embolizations followed by sunitinib (one week after each embolization, and continued until disease progression or up to a maximum of 8 cycles). Radiographic response rates were assessed by RECIST criteria. PFS and OS were calculated using Kaplan-Meier methodology.
Results: 39 patients with metastatic NETs were enrolled. Primary tumor sites included the small intestine (26), pancreas (10), rectum (2) and lung (1). The initial starting dose of sunitinib was 50 mg, however all five patients enrolled at this dose required dose reductions, and the starting dose was subsequently lowered to 37.5 mg. The majority of patients required further dose reductions to 25mg. Twenty eight patients (72%) experienced a partial radiographic response (PR), eight patients (20%) had stable disease and three patients (8%) had progressive disease as their best response. Median PFS was 18 months and the rate of 1-year PFS was 72%. The rates of overall survival (OS) at one-year and two-years were 94% and 78%. Serum VEGF levels increased by an average of 51pg/ml (34%) after embolization.
Conclusions: Hepatic artery embolization is a highly active treatment option for patients with metastatic neuroendocrine tumors to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib can be administered following hepatic artery embolization. The high rates of progression-free survival and overall survival associated with this sequence of therapies are encouraging.
Prognostic Relevance of a Novel AJCC Staging Classification for Neuroendocrine Tumors of the Pancreas
Jonathan Strosberg, MD, Asima Cheema, MD, Jill Weber, MPH, Domenico Coppola, MD, Larry Kvols, MD. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Background: The AJCC Cancer Staging Manual (7th edition, 2010) has introduced a novel TNM staging classification for pancreatic neuroendocrine tumors which is derived from the staging system for exocrine pancreatic adenocarcinomas. This classification has not yet been validated.
Methods: Patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-IV) based on the new AJCC classification. Overall survival from time of initial diagnosis was measured and statistical significance calculated using the log-rank test. The prognostic relevance of the AJCC staging classification was compared to the relevance of a staging classification proposed recently by the European Neuroendocrine Tumor Society (ENETS).
Results: 425 patients with histologically proven pancreatic neuroendocrine tumors were identified. Both the novel AJCC classification and the ENETS classification were highly prognostic for survival (p < 0.00001; table 1).
Conclusions: The novel AJCC 7th Edition TNM classification for pancreatic neuroendocrine tumors is highly prognostic for overall survival and should be adopted in clinical practice.
Risk of Metastatic Spread in Patients With Early-Stage, Surgically Resected Pancreatic Neuroendocrine Tumors
Jonathan Strosberg, MD, Asima Cheema, MD, Jill Weber, MPH, Domenico Coppola, MD, Larry Kvols, MD. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Background: The risk of metastatic spread among patients with early-stage surgically resected pancreatic neuroendocrine tumors has not been well established.
Methods: Patients with surgically resected localized or locally advanced pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I-III) based on the new AJCC classification. Recurrence-free survival was measured for each stage. A separate analysis was performed excluding patients who had been referred to Moffitt Cancer Center after metastatic recurrence.
Results: 123 patients with non-metastatic, surgically-resected pancreatic neuroendocrine tumors were identified. 5-year recurrence-free survival correlated with AJCC stage (p = 0.01; table 1).
Conclusions: The novel AJCC 7th Edition TNM classification for pancreatic neuroendocrine tumors is highly prognostic for recurrence in patients with surgically resected non-metastatic tumors.
Stage I Non-Functioning Neuroendocrine Tumors of the Pancreas: Surgery or Surveillance?
Jonathan Strosberg, MD, Asima Cheema, MD, Larry Kvols, MD. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Background: An increasing number of non-functioning, early-stage pancreatic neuroendocrine tumors are detected incidentally as patients undergo radiographic procedures for unrelated indications. Endoscopic sonography with fine-needle aspiration now enables non-operative biopsy of tumors smaller than 1cm in diameter. It is unclear whether the risks of partial pancreatectomy or enucleation exceed the risks of surveillance in patients with these neoplasms.
Methods: We performed a database search of patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center in order to evaluate outcomes of patients with stage I tumors who did not undergo surgical resection.
Results: Four patients were identified who elected to undergo surveillance of their stage I tumors instead of surgical resection. All had been diagnosed via endoscopic ultrasound-guided fine-needle aspiration. The tumor sizes were 7 mm, 12 mm, 13 mm and 15 mm at initial diagnosis. Three tumors were cystic and one was solid. Three were located in the body of the pancreas and one in the tail. In two patients, the Ki-67 index was measured and was <1%. With a median of follow-up of two years, none of the patients experienced tumor growth. All three patients with cystic tumors experienced shrinkage of their tumors following the diagnostic needle aspiration and did not experience subsequent increase in size (table 1).
Conclusions: Surveillance may be an appropriate strategy for management of incidentally discovered, stage I pancreatic neuroendocrine tumors.
Survival Analyses of Pancreatic Neuroendocrine Tumors: Contrasting Institutional Databases With Population-Based Studies
Jonathan Strosberg MD, 1 Thorvardur Halfdanarson, MD.21H. Lee Moffitt Cancer Center, Tampa, Florida, USA 33612, 2University of Iowa, Iowa City, Iowa, USA 52242.
Background: Prognostic data in pancreatic neuroendocrine tumors derives from population-based studies as well as from institutional databases.
Methods: The stage-stratified rates of 5-year survival derived from two institutional databases were contrasted with rates of 5-year survival derived from two national population-based studies (SEER 1973-2000 and National Cancer Data Base 1985-2004).
Results: The 5-year survival rates derived from the two separate institutional databases were concordant with each other, but markedly higher than the 5-year survival rates derived from the population databases (table 1). 5-year survival rates amongst stage IV patients were 55% and 57% in the institutional databases versus 15% and 19% in the population databases.
Conclusions: Survival rates derived from institutional databases are substantially higher than survival rates derived from national population databases. The causes of these differences have yet to be clarified.
Genetic Associations With Sporadic Neuroendocrine Tumor Risk
Monica Ter-Minassian,1,6 Zhaoxi Wang,1 Kofi Asomaning,1 Michael C. Wu,3 Chen-Yu Liu,1 Jessica K. Paulus,2 Geoffrey Liu,5 Penelope A. Bradbury,5 Rihong Zhai,1 Li Su,1 Christine S. Frauenhoffer,6 Susanne M. Hooshmand,6 Immaculata DeVivo,2 Xihong Lin,3 David C. Christiani,1,2,4 Matthew H. Kulke.61Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, 2Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, 3Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 4Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, 5Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON M5G 2C1, Canada, 6Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Background: Genetic risk factors for sporadic neuroendocrine tumors (NET) remain poorly understood. To identify single nucleotide polymorphisms (SNPs) associated with NET risk, we performed a large-scale assessment of common SNPs in candidate genes in independent discovery and replication sets of incident and prevalent Caucasian NET cases and controls.
Methods: We designed a custom array containing 1536 tagging and functional SNPs in 355 candidate genes implicated in established cancer pathways. We tested risk associations using multiple logistic regression, adjusting for age and gender and smoking, with dominant and additive models in a 261 NET case and 319 control discovery set. We then evaluated the top associated SNPs in a 235 case and 113 control replication set. We also evaluated associations in subgroups of small bowel carcinoid and pancreatic NET.
Results: The discovery phase revealed that 18 SNPs were associated with NET risk at a p-value<0.01, meeting the criterion for replication. Two of these SNPs were also found to be significantly associated with NET risk in our independent replication set at a p-value <0.05. IL12A rs2243123 replicated with an adjusted odd ratio (95%CI) (aOR) = 1.47 (1.03, 2.11) p-trend = 0.036. DAD1 rs8005354 replicated at aOR = 1.43 (1.02, 2.02) p-trend = 0.04. In a combined analysis of 181 small bowel cases or 99 pancreatic NET vs. 432 controls, IL12A rs2243123 was associated with both small bowel and pancreatic NET, and DAD1 rs8005354 only with small bowel NET.
Conclusions: Our findings suggest that variation in IL12A and DAD1, genes involved in inflammation and apoptosis respectively, is associated with NET risk.
Prospective Analysis of Clinical Outcomes and Prognostic Factors in Patients With Neuroendocrine Tumors (NETs)
Monica Ter-Minassian,1,3 Jennifer A. Chan,3 Christine S. Frauenhoffer,3 Susanne M. Hooshmand,3 Kofi Asomaning,1 Xihong Lin,2 David C. Christiani,1 Matthew H. Kulke.31Environmental and Occupational Medicine and Epidemiology (EOME) Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, 2Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Background: The clinical course of patients with neuroendocrine tumor remains poorly defined. A number of prognostic factors have been identified that we evaluated in a large prospective cohort.
Methods: We evaluated prognostic factors of 853 neuroendocrine tumor patients from the Dana-Farber Cancer Institute with a log-rank test and multivariate Cox regression analysis including age, gender, metastasis at initial diagnoses (stage M0 completely resected (reference) and M1 with metastases), tumor type (pancreatic (PET), small bowel carcinoid and other carcinoid (reference)), histologic grade (unknown, poor, moderate and well (reference)) and octreotide treatment (yes/no). Overall survival (OS) and time to recurrence (DFS) were also considered in NET subgroups.
Results: Among 853 neuroendocrine tumor patients, we identified 321 small bowel carcinoids and 190 PET and 342 tumors arising at other sites. Median overall follow-up time was 4.45 years. 210 (24.6%) deaths occurred with a median OS of 12.8 years. Patients had the following characteristics, 396 (46%) male, 457 (54%) female, 375 (44%) M0, 476 (55.9%) M1. Among M0 patients, the median OS was not reached and five and ten year OS rates were 94% and 75% respectively. Five and ten year DFS rates were 65% and 37% respectively. Median DFS was 7.9 years (9 yrs for small bowel carcinoid and 4.6 yrs for PET, and 10 yrs for other carcinoid). Factors predictive of recurrence were older age, male gender, PET and higher histologic grade. Among M1 patients, median OS was 7.6 yrs (12.5 for small bowel and 4.7 yrs for PET); five and ten year OS rates were 61% and 40% respectively. Octreotide treatment was associated with a non-significantly protective OS HR of 0.87 (0.63, 1.19), p=0.37 in all patients.
Conclusion: Overall survival for NET patients may differ depending on tumor site of origin. Recurrences, when they develop, may occur more than 5 years from time of original resection.
Correlation Between Gene Expression Profile and Tumor Behavior of Pancreatic Neuroendocrine Tumors and Carcinoids
Yunguang Tong PhD,1 Nicholas N. Nissen, MD,2 Vijay Menon, MD,2 Edward Wolin, MD,3 Run Yu, MD, PhD.31Division of Endocrinology, 2Department of Surgery, 3Division of Oncology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Background: Clinical parameters are often inadequate to predict the behavior of common neuroendocrine tumors (NETs) such as non-functioning pancreatic NETs (NF PNETs) and mid-gut carcinoid tumors (carcinoids). Molecular markers of tumor behavior are not clear but needed to assist clinical decision making.
Methods: Gene expression profile of 7 NF-PNETs and 6 carcinoids was obtained through Affymetrix Human Gene 1.0 ST Array. The tumors were clinically classified by aggressiveness (indolent v. aggressive). The microarray data were analyzed using Genespring 11. Microarray data files were preprocessed with RMA algorithm. Genes were ranked according to expression levels and only those presented in top 80% in at least one sample were included for unpaired t-test. Benjamini Hochberg false discovery rate control was used for multiple test correction.
Results: For NF-PETs, 322 genes were differentially expressed >3-fold in indolent v. aggressive tumors, and 112 genes were differentially expressed with p < 0.005. ACMSD (Aminocarboxymuconate semialdehyde decarboxylase), FGB (fibrinogen beta chain), AGT (angiotensinogen), APOH (apolipoprotein H), HAO1 (hydroxyacid oxidase 1) were >8 fold upregulated in aggressive tumors. For carcinoids, 159 genes were differentially expressed >3-fold in indolent v. aggressive tumors, and 47 genes were differentially expressed with p < 0.005. SLC38A3 (solute carrier family 38, member 3) was 15-fold upregulated in aggressive tumors and MX2 (myxovirus resistance 2) was 5-fold upregulated in indolent tumors. When taken as a group, 68 genes were differentially expressed >3-fold in indolent v. aggressive tumors, and 38 genes were differentially expressed with p < 0.005. MEP1B (meprin A, beta) was ∼10-fold upregulated in aggressive tumors. Pathway analysis suggested interleukin 4 and `9 pathways were differentially regulated between indolent and aggressive NF-PETs.
Conclusion: Indolent and aggressive NETs, especially pancreatic ones, exhibit distinct gene expression profile. Specific genes are differentially expressed in indolent v. aggressive NETs and may serve as markers for tumor behavior.
Sunitinib for Treatment of Pancreatic Neuroendocrine Tumors: Patient-Reported Outcomes and Efficacy Across Patient Subgroups in a Phase III Trial
Aaron Vinik,1 Yung-Jue Bang,2 Jean-Luc Raoul,3 Juan Valle,4 Peter Metrakos,5 Dieter Hörsch,6 Beata Korytowsky,7 Rajiv Mundayat,8 Richard Chao,9 Eric Raymond.101EVMS Strelitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, VA 23510, USA, 2Seoul National University Hospital, Seoul 138-736, Korea, 3Eugène Marquis Centre and European University in Brittany, Rennes 35062, France, 4Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK, 5McGill University Hospital Center, Montreal H2W 1S6, Canada, 6Clinic for Internal Medicine, Gastroenterology, Oncology and Endocrinology, Center for Neuroendocrine Tumors, Bad Berka Central Clinic, Bad Berka 99437, Germany, 7Pfizer Oncology, Outcomes Research, New York, NY 10017, USA, 8Pfizer Oncology, Outcomes Research Statistics, New York, NY 10017, USA, 9Pfizer Oncology, Development, La Jolla, CA 92037, USA, 10Service Inter-Hospitalier de Cancerologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy 92118, France.
Background: Sunitinib 37.5 mg continuous daily dosing was compared with placebo in 171 patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NET) in a phase III trial. Sunitinib significantly prolonged median progression-free survival (PFS) vs placebo (11.4 vs 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; p = 0.0001) and was well tolerated. Here we present patient-reported outcomes (PROs) and exploratory subgroup analyses evaluating the impact of baseline characteristics on treatment efficacy.
Methods: PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Repeated measures mixed-effects models were used as the primary model for between-treatment comparison. Statistical significance (2-sided p value; 0.05 level) and clinical significance (minimally important difference, defined as ≥10 points) were assessed. The influence of baseline characteristics on treatment effect was explored using Cox proportional hazards model.
Results: In subgroup analyses, sunitinib was associated with a statistically significant improvement in PFS regardless of age, race, gender, ECOG status, number of metastatic sites or time from diagnosis to study enrollment. Hazard ratios for PFS favored sunitinib regardless of prior and/or concurrent use of somatostatin analogues, and prior treatment with chemotherapy. Global health related quality of life (HRQoL), as well as cognitive, emotional, physical, role, and social functioning domains were not clinically or statistically different between the sunitinib and placebo arms. However, among symptoms and other scales, patients receiving sunitinib experienced clinically and statistically significant worsening of diarrhea, and statistically significant worsening of insomnia vs placebo. Improvement in PFS with sunitinib delayed deterioration in emotional and physical functioning and global HRQoL.
Conclusions: Sunitinib resulted in significant PFS improvement vs placebo and maintained HRQoL in patients with pancreatic NET. The PFS improvement was clinically meaningful across all subgroups studied, indicating that its use was independent of baseline characteristics.
Radio-Guided Exploration Facilitates Surgical Cytoreduction of Neuroendocrine Tumors
Yi-Zarn Wang, DDS, MD,1,4 Abby E Gandolfi, BS, MS,1 Lowell B. Anthony, MD,2,4 Richard Campeau, MD,3 Eugene Woltering, MD,1,4 J. Philip Boudreaux, MD. 1,41Louisiana State University Health Sciences Center, the Department of Surgery, Section of Surgical Endocrinology1, the Department of Medicine, Section of Medical Oncology 2, the Department of Radiology, Section of Nuclear Medicine3, and the LSUHSC Stanley S. Scott Cancer Center New Orleans, LA 701124.
Introduction: Radio-guided exploration can be an essential tool in the successful cytoreduction of neuroendocrine tumors.
Hypothesis: The choice of the proper radioisotope, dose and time interval between injection and exploration are the major factors responsible for attaining a successful outcome.
Methods: 244 patients undergoing cytoreduction between November 2006 and July 2009 were reviewed to determine optimal dose and interval between injection and exploration and the impact of radio-guided exploration.
Results: 46 patients had gamma probe guided explorations including 3 patients injected with 99mTc, 3 patients injected with 123I MIBG (3) and 111 In pentetreotide in 40 patients with midgut carcinoid. In 37 out of 40 (93%) of the111 In-pentetreotide guided explorations the gamma probe was deemed helpful in localizing and differentiating tumor from normal tissue. In 5 out of 6 neck and mediastinum explorations the gamma probe was essential for completing a quick, safe and minimally invasive procedures. 123I MIBG was not useful in all three patients included in this review. The optimal doses and interval between injection and exploration of 111 In pentetreotide is 6 mCi, injected 6-7days prior to surgery.
Conclusion: Radio-guided exploration is a useful adjunct and sometime an essential tool for resecting neuroendocrine tumors with the right isotope injected at the optimal dosage and time.
Staged Second Look Laparaproscopy: A New Approach for Evaluating Ischemic Bowel Following Extensive Mesenteric Lymphadenectomy for Midgut Carcinoid
Yi-Zarn Wang, DDS, MD, Eugene Woltering, MD, J. Philp Boudreaux, MD. Department of Surgery, LSUMC- New Orleans.
Background and Objectives: Midgut carcinoid has a strong tendency to metastasize toward mesenteric lymph nodes to encase the mesenteric vessels and creates bowel ischemia. For having a durable surgical intervention, extensive mesenteric lymphadenectomy is often required to relieve such encasement and relieve the partial or complete bowel obstruction. In so doing, the integrity of the blood supply to segments of intestine may become questionable. It then becomes a major dilemma confounding the surgeon in terms of the intra-operative management. Traditionally, intestine with questionable blood supply will be removed and anastomosis created between intestine segments carrying sound blood supply. To avoid short gut syndrome, however, more conservative measures will often call upon. Often, a second-look operation becomes mandatory. Open 2nd look is time consuming and traumatic. It might delay healing and prolong hospital stay. Laparoscopic 2nd look has been adopted in recent years. It has its own pitfall in the process of reentering the post-operative abdominal cavity. Easy, speedy and safe way to conduct a second look operation is direly needed. The authors have developed an easy access to achieve such a goal using JP drain tubing as insufflation port and the JP tract itself as troche site to conduct the 2nd look operation.
Method: Patients" charts and operating reports are reviewed between 7/2006 and 2/2010. A total of 12 patients underwent staged 2nd look laparoscopies. Six patients underwent staged 2nd look laparoscopies for ischemic bowel following extensive mesenteric lymph node dissection for midgut carcinoid.
Results: All laparoscopies were conducted successfully and safely in a speedy fashion without any complications or prolonging hospital stay.
Conclusion: Staged 2nd look laparoscopy can be easy conducted by leaving a JP drain at the conclusion of primary operations. It is easy and safe and can potentially done at the bedside as indicated.
RADIANT-2: A Phase III Trial of Everolimus + Octreotide LAR in Patients With Advanced Neuroendocrine Tumors (NET)
James C. Yao,1 John D. Hainsworth,2 Eric Baudin,3 Marc Peeters,4 Dieter Hoersch,5 Lowell Anthony,5 Judith Klimovsky,6 Jessica St. Peter,6 Valentine Jehl,7 Marianne Pavel.81The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA, 2Sarah Cannon Cancer Center, Nashville, TN, 37203, USA, 3Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France, 4Department of Oncology, Antwerp University Hospital, Edegem, Belgium, 5Division of Hematology/Oncology, Louisiana State University, New Orleans, LA, 70112, USA, 6Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA; 7Novartis Pharma AG, Basel, Switzerland, 8Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany.
Background: Patients with advanced NET have limited treatment options. Recent phase II studies demonstrated evidence of antitumor activity for everolimus alone or in combination with octreotide LAR among patients with NET.
Methods: A randomized, double-blind, placebo-controlled, phase III trial included patients with progressing low- to intermediate-grade advanced NET and a history of carcinoid symptoms. 429 patients were assigned everolimus (10 mg/day) plus octreotide LAR (30 mg/28days) [E + O, n = 216] or placebo plus octreotide LAR (P + O, n = 213). The primary endpoint was progression-free survival (PFS) [RECIST]. Crossover from P + O to open-label E + O was allowed at disease progression.
Results: Patients treated with E+O demonstrated a median PFS (95% CI) of 16.4 months (13.67, 21.19) versus 11.3 months (8.44, 14.59) for P + O by adjudicated central radiology review. E + O resulted in a 23% reduction in the risk of progression (HR 0.77; 95% CI:0.59, 1.00; one-sided P = 0.026; did not meet the pre-specified significance level of P = 0.0246). Median PFS (95% CI) by investigator review was 12.0 months (10.61, 16.13) for E + O and 8.6 months (8.08, 11.14) for P + O (HR 0.78; 95% CI:0.62, 0.98; one-sided P = 0.018). The most frequent drug-related AEs for E+O treated patients were mostly grade 1-2 and included: stomatitis, rash, fatigue, and diarrhea. Grade 3-4 drug-related AEs (≥ 6%) were stomatitis (6.5% vs 0%), fatigue (6.5% vs 2.8%), diarrhea (6.0% vs 2.4%) for E + O vs P + O, respectively. The following patient characteristics were more frequent in the E + O group: lung primary (15% vs 5%); WHO PS >0 (45% vs 34%); and prior chemotherapy (35% vs 26%) [E + O vs P + O, respectively].
Conclusions: Treatment with E+O provided a clinically meaningful 5.1-month increase in median PFS compared with P+O and a reduction in the risk of tumor progression with mild AEs. Analysis of the treatment arms revealed a disproportionate patient distribution for several important prognostic characteristics occurring in the placebo arm.
Randomized Run-In Study of Bevacizumab and Everolimus in Low- to Intermediate- Grade Neuroendocrine Tumors (LGNETs) Using Perfusion CT (pCT) as Functional Biomarker
James C. Yao,1 Alexandria Phan,1 Kenneth R. Hess,2 David Fogelman,1 Carmen Jacobs,1 Cecile G. Dagohoy,1 Colleen C. Leary,1 Chaan S. Ng.31Departments of Gastrointestinal Medical Oncology, 2Biostatistics, 3Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
Background: Studies have shown promising results for mTOR inhibitor, everolimus, and VEGF inhibitor, bevacizumab, in LGNETs. In our prior study, decrease in tumor blood flow (BF) following bevacizumab was proportional to baseline BF suggesting bevacizumab decreased BF by a fixed percentage.
Methods: LGNET patients with lesion(s) ≥ 3 cm were randomized to bevacizumab or everolimus for one 21-day cycle. On Cycle 2 day 1, the alternate agent was added. pCTs assessing tumor BF, blood volume (BV), mean transit time (MTT), and permeability surface (PS) were mandatory. Primary objectives were to determine the effects of bevacizumab or everolimus as well as bevacizumab + everolimus on BF.
Results: 112 pCTs were performed among 39 patients. 65 lesions among 36 patients were evaluated at 3 time points. Bevacizumab led to 47% decrease in BF (P <.01). Everolimus was associated with 13% increase in MTT (P =.02) and 12% decrease in BF (P =.16). Addition of everolimus to bevacizumab led to a further decrease in BF (15%; P =.02). Addition of bevacizumab to everolimus resulted in 28% further decrease in BF (P <.01) and no significant change in MTT. By ITT analyses, there were 10 PR (26%), 27 SD (69%), 1 PD (3%), 1 unknown (3%). PFS rate at 6-month was 92%; median was 14.6 months. The 12- and 24-month overall survival rates were 92% and 80%. pCT parameters (all P <.05) associated with RECIST response included: high baseline permeability surface, higher post-treatment MTT, higher percentage decrease in BF, BV, and higher percentage increase in MTT. CTC G3/4 AE occurring in ≥10% patients included: neutropenia (15%), proteinuria (12%), hyperglycemia (10%).
Conclusions: Bevacizumab decreased tumor BF. Addition of everolimus was associated with further decrease in BF. Bevacizumab + everolimus demonstrated anti-tumor activity in LGNET. fCT is a promising for selection of patients likely to benefit from therapy.
Calcium Entry and Maintenance of Oscillatory Ca2+ Signals in Human Carcinoid Cell Lines
Tetyana Zhelay, Sasi Arunachalam, David R. Giovannucci. Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA.
Background: Cytosolic Ca2+ oscillations evoked by G protein-coupled receptor activation can regulate cell cycle, migration and apoptosis in some cancer cells including those of neuroendocrine phenotype. Typically, oscillatory signals depend on release of Ca2+ from internal stores as well as entry through plasma membrane channels. However, little is known regarding the role and molecular underpinnings of this Ca2+ entry in carcinoid cell lines. In the current study we elucidated the role of STIM and ORAI (key components of a Ca2+ permeable channel that we have previously identified in carcinoid cell lines) in agonist induced Ca2+ entry.
Methods: BON and H727 cell lines were loaded with Ca2+ sensitive dyes and monitored by fluorescence imaging. Carbachol (CCh) application was used to activate Ca2+ oscillations and pharmacological inhibition, targeted gene silencing and over expression techniques were used to probe the effect of ORAI-mediated Ca2+ entry on oscillatory Ca2+ signals. In other experiments, multi-photon microscopy was used to assess the role of ORAI on the kinetics of tumor formation in cultured mouse liver slices.
Results: Activation of muscarinic acetylcholine receptors in BON and H727 cells evoked Ca2+ oscillations in a dose- and extracellular Ca2+-dependent fashion. Inhibition of Ca2+ entry, silencing of ORAI or STIM or over-expression of a dominant negative ORAI significantly diminished the frequency and maintenance of Ca2+ oscillations, whereas over-expression of wild-type ORAI protein enhanced both frequency and amplitude of Ca2+ oscillations. In addition, BON cells deficient in ORAI were unable to reliably form tumors in our organ slice model.
Conclusions: These data indicated that ORAI is required for agonist induced Ca2+ entry, maintenance and frequency of Ca2+ oscillations in human carcinoid cancer cell lines and support a role for ORAI 1 in formation of tumors in mouse liver.