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Pancreatic Neoplasms: HELP
Articles by Marianne Ellen Pavel
Based on 34 articles published since 2008
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Between 2008 and 2019, M. Pavel wrote the following 34 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. 2016

Pavel, M / O'Toole, D / Costa, F / Capdevila, J / Gross, D / Kianmanesh, R / Krenning, E / Knigge, U / Salazar, R / Pape, U-F / Öberg, K / Anonymous6880853. ·Charite Virchow Klinikum, Berlin, Germany. ·Neuroendocrinology · Pubmed #26731013.

ABSTRACT: -- No abstract --

2 Review Diagnostic imaging of pancreatic neuroendocrine neoplasms (pNEN): tumor detection, staging, prognosis, and response to treatment. 2016

Baur, Alexander D J / Pavel, Marianne / Prasad, Vikas / Denecke, Timm. ·Klinik für Strahlenheilkunde, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany alexander.baur@charite.de. · Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen), Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Klinik für Strahlenheilkunde, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany. ·Acta Radiol · Pubmed #25855665.

ABSTRACT: Pancreatic neuroendocrine neoplasms (pNEN) are rare malignancies arising from neuroendocrine cells of the pancreas. Functional tumors can present with specific clinical syndromes due to hormonal secretion. These tumors can present as incidental findings on imaging performed for unrelated purposes or they are diagnosed when workup is initiated in patients with specific syndromes or metastases. This article presents an overview of available imaging techniques focusing on computed tomography and magnetic resonance imaging. Recommendations regarding examination protocols are given. Typical imaging features of pNEN and metastases are described. Their potential value for the evaluation of prognosis as well as tumor response under treatment is discussed.

3 Review The Role of Chemotherapy in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors. 2015

Strosberg, Jonathan / Goldman, Jamie / Costa, Frederico / Pavel, Marianne. ·Moffitt Cancer Center and Research Institute, Tampa, Fla., USA. ·Front Horm Res · Pubmed #26303716.

ABSTRACT: Even though the neuroendocrine tumor (NET) field has entered the era of 'targeted therapy', the role of cytotoxic chemotherapy continues to be debated. High response rates, ranging from 30 to 70% depending on the line of therapy, are consistently observed in the treatment of pancreatic NETs, with lesser evidence of activity in other foregut tumors. Activity in midgut carcinoid tumors appears to be negligible. Unfortunately, placebo-controlled randomized controlled trials using modern response criteria are lacking: the bulk of the literature consists of small phase II trials and retrospective series. There are also no completed trials comparing modern chemotherapy regimens, and therefore little data exist to favor the use of streptozocin- versus temozolomide- versus oxaliplatin-based therapies. Due to the absence of high-level evidence, it is difficult to generate data-based guidelines on the appropriate sequencing of cytotoxic drugs versus targeted agents. Although conventional wisdom holds that targeted agents such as everolimus or sunitinib are more tolerable than cytotoxic drugs, there is no evidence to support this perception. As a general principle, chemotherapy may be more appropriate as early-line therapy in patients with bulky and/or symptomatic and/or rapidly progressive tumors, particularly of pancreatic origin. In patients with low-volume disease or slow-growing tumors, noncytotoxic drugs may be preferable in early lines of therapy, reserving chemotherapy for the salvage setting. Validation of predictive factors is imperative in order to appropriately match patients with optimal treatment. Methyl-guanine-methyl-transferase (MGMT) deficiency is likely to be a positive predictive factor for alkylating agents, but needs to be evaluated prospectively. It is also unclear whether immunostaining for MGMT expression, which can be somewhat subjective, is superior to PCR-based techniques, which assess MGMT methylation status. Other basic predictive factors, such as ki-67 index, need to be evaluated in prospective clinical trials. It will also be important to evaluate whether newly discovered mutations in pancreatic NETs, such as DAXX/ATRX, are associated with response to chemotherapy.

4 Review Systemic therapeutic strategies for GEP-NETS: what can we expect in the future? 2014

Raymond, E / García-Carbonero, R / Wiedenmann, B / Grande, E / Pavel, M. ·Department of Medical Oncology, Beaujon University Hospital, Clichy, France, eric.raymond@bjn.aphp.fr. ·Cancer Metastasis Rev · Pubmed #24375390.

ABSTRACT: Over the last few years, there have been important advances in the understanding of the molecular biology of neuroendocrine tumors (NETs) that have already translated into relevant advances in the clinic. Several studies have extensively assessed the mutational profile of NETs, and have shown the key roles that angiogenesis and the PI3K-AKT-mTOR pathway play in the pathogenesis of these tumors. Recent data has also revealed the potential relevance of transcription factors such as death domain-associated protein, x-linked mental retardation, and α-thalassemia syndrome protein or ataxia telangiectasia-mutated in NETs of pancreatic origin. This fast progress is leading to a rapidly increasing number of new agents being explored in the field of NETs. However, and despite some unquestionable success, objective remission rates remain low, and evidence of a substantial survival impact is lacking. Thus, there is an important need to improve our ability to identify patients most likely to benefit from specific therapies, and to incorporate biomarkers in the management of NETs. In addition, further efforts to understand mechanisms of escape and acquired resistance to the different available agents is of utmost importance, and will likely require performing paired tumor biopsies (prior and after treatment) or sequential sampling of surrogate tissues. Combinations of approved agents with new agents, either in a rational or biomarker-driven manner, are certainly warranted in this field. Likewise, sequential strategies to modulate and compensate for escape phenomenons are also of great interest. It should also be noted, however, that targeted agents are not innocuous and frequently yield toxicities that need to be adequately addressed by experienced specialists, particularly when drug combinations are considered. This review summarizes the salient data on biomarker and new agent development for the treatment of NETs.

5 Review Neuroendocrine tumor disease: an evolving landscape. 2012

Frilling, Andrea / Akerström, Goran / Falconi, Massimo / Pavel, Marianne / Ramos, Jose / Kidd, Mark / Modlin, Irvin Mark. ·Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK. ·Endocr Relat Cancer · Pubmed #22645227.

ABSTRACT: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

6 Review Novel therapeutic agents for the treatment of gastroenteropancreatic neuroendocrine tumors. 2011

Pavel, M E / Wiedenmann, B. ·Charité Universitätsmedizin Berlin, Department of Gastroenterology & Hepatology, Endocrinology, Diabetes & Metabolic Diseases, Berlin, Germany. marianne.pavel@charite.de ·Horm Metab Res · Pubmed #22105475.

ABSTRACT: Neuroendocrine tumors (NET) are frequently diagnosed late and not amenable to curative surgery due to metastatic disease to the liver and lymph nodes. The disease is complex and heterogeneous given the various functionalities, distinct tumor growth patterns, and tumor spread upon diagnosis. Established therapies include somatostatin analogues, alpha-interferon, systemic chemotherapy, and loco-regional therapies of the liver. The availability of novel agents and expression of targets, such as growth factor receptors, different subtypes of somatostatin receptors, and the mammalian target of rapamycin (mTOR) have led to the exploration of different classes of drugs and offer new treatment opportunities in neuroendocrine tumors. This review provides an overview on novel drugs, focus on the impact of recently approved drugs on the management of NET disease, and outline future perspectives.

7 Review From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumors. 2011

Wiedenmann, Bertram / Pavel, Marianne / Kos-Kudla, Beata. ·Department of Hepatology, Gastroenterology and Endocrinology, Charité Medical School, Berlin, Germany. bertram.wiedenmann@charite.de ·Neuroendocrinology · Pubmed #21893937.

ABSTRACT: Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.

8 Review The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. 2011

Lawrence, Ben / Gustafsson, Bjorn I / Kidd, Mark / Pavel, Marianne / Svejda, Bernhard / Modlin, Irvin M. ·Gastrointestinal Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, 310 Cedar Street, PO Box 208602, New Haven, CT 06520-8062, USA. ·Endocrinol Metab Clin North Am · Pubmed #21349414.

ABSTRACT: Chromogranin A, although it exhibits limitations, is currently the most useful general tumor biomarker available for use in the diagnosis and management of gastroenteropancreatic neuroendocrine tumors (NETs). The value of the chromogranin A lies in its universal cosecretion by the majority of neuroendocrine cells that persists after malignant transformation. Clinicians aware of the physiologic role of chromogranin A and its secretion in a variety of non-NET-related pathologic conditions can use this protein as a moderately effective tumor biomarker in the management of GEP-NETs.

9 Review Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. 2010

Modlin, I M / Pavel, M / Kidd, M / Gustafsson, B I. ·Yale University School of Medicine, New Haven, CT 06520-8062, USA. imodlin@optonline.net ·Aliment Pharmacol Ther · Pubmed #19845567.

ABSTRACT: BACKGROUND: The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours (GEP-NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth. AIM: To review 35 years of experience regarding the clinical application and efficacy of SST analogues. METHODS: The PubMed database (1972-2009) was searched using somatostatin as a search term with combinations of terms including 'treatment'; 'neuroendocrine'; 'carcinoid'; 'tumor'; 'octreotide'; 'lanreotide' and 'pasireotide'. RESULTS: In a review of 15 studies including 481 patients, the slow-release formulations Sandostatin LAR and Somatuline SR/Autogel achieved symptomatic relief in 74.2% (61.9-92.8%) and 67.5% (40.0-100%), biochemical response in 51.4% (31.5-100%) and 39.0% (17.9-58%), and tumour response in 69.8% (47.0-87.5%) and 64.4% (48.0-87.0%) respectively. Novel SST analogues like SOM230 (pasireotide) that exhibit pan SST receptor activity and analogues with high affinity to specific somatostatin receptor (sstr) subtypes may further advance the field, but efficacy studies are lacking. CONCLUSION: As more precise understanding of NET cell biology evolves and molecular biological tools advance, more accurate identification of individual tumours sstr profile will probably facilitate a more precise delineation of SST analogue treatment.

10 Clinical Trial Everolimus Effect on Gastrin and Glucagon in Pancreatic Neuroendocrine Tumors. 2017

Pavel, Marianne E / Chen, David / He, Wei / Cushman, Stephanie / Voi, Maurizio / de Vries, Elisabeth G E / Baudin, Eric / Yao, James C. ·From the *Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany; †Novartis Pharmaceuticals Corporation, East Hanover, NJ; ‡Department of Medical Oncology, University Medical Center, University of Groningen, Groningen, The Netherlands; §Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave-Roussy, Villejuif, France; and ∥Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #28609362.

ABSTRACT: OBJECTIVES: The pharmacodynamic effects of everolimus on gastrointestinal hormone levels have not been described in patients with pancreatic neuroendocrine tumors (pNETs). We report the effects of everolimus on gastrin and glucagon levels in patients with progressive pNET in RADIANT-1 (a single-arm phase II trial) and RADIANT-3 (a placebo-controlled, randomized, phase III trial). METHODS: Serum gastrin and glucagon levels were determined by immunoassay at baseline and at predose in subsequent treatment cycles in patients with elevated baseline hormone levels. The analyses included 158 patients from RADIANT-1 and 404 patients from RADIANT-3. RESULTS: In RADIANT-1, everolimus induced a rapid, sustained decrease in median gastrin and glucagon levels to approximately 60% and 70% of baseline levels, respectively. In RADIANT-3, everolimus consistently reduced median gastrin and glucagon levels by greater than 50% and approximately 40%, respectively (everolimus vs placebo, P < 0.0001), whereas with placebo, both hormones at each time point were essentially the same as their baseline levels. In patients with concomitant octreotide long-acting repeatable treatment, the moderate pharmacodynamic effect on lowering gastrin was greater than that seen with everolimus alone. CONCLUSIONS: In addition to prolonging progression-free survival in patients with pNET, everolimus down-regulates excess production of 2 gastrointestinal hormones, which may help control their associated clinical syndromes.

11 Clinical Trial A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. 2017

Kulke, M H / Ruszniewski, P / Van Cutsem, E / Lombard-Bohas, C / Valle, J W / De Herder, W W / Pavel, M / Degtyarev, E / Brase, J C / Bubuteishvili-Pacaud, L / Voi, M / Salazar, R / Borbath, I / Fazio, N / Smith, D / Capdevila, J / Riechelmann, R P / Yao, J C. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. · Department of Gastroenterology and Pancreatology University of Paris VII and Beaujon Hospital, Paris, France. · Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France. · Department of Medical Oncology, University of Manchester/The Christie Hospital, Manchester, UK. · Department of Endocrine Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Hepatology and Gastroenterology, Charité University of Medicine, Berlin, Germany. · Department of Oncology, Novartis AG, Basel, Switzerland. · Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, USA. · Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, Hospital of Barcelona, Barcelona, Spain. · Department of Gastroenterology Saint-Luc University Hospital, Brussels, Belgium. · Department of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · Department of Oncology, St. Andrew Hospital, Bordeaux, France. · Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. · Department of Oncology, Cancer Institute of the State of São Paulo, São Paulo, Brazil. · Department of Gastrointestinal and Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28327907.

ABSTRACT: Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

12 Clinical Trial Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours. 2017

Lepage, Côme / Dahan, Laetitia / Bouarioua, Nadia / Toumpanakis, Christos / Legoux, Jean-Louis / Le Malicot, Karine / Guimbaud, Rosine / Smith, Denis / Tougeron, David / Lievre, Astrid / Cadiot, Guillaume / Di Fiore, Frédéric / Bouhier-Leporrier, Karine / Hentic, Olivia / Faroux, Roger / Pavel, Marianne / Borbath, Ivan / Valle, Juan W / Rinke, Anja / Scoazec, Jean-Yves / Ducreux, Michel / Walter, Thomas. ·Department of Digestive Oncology, Burgundy Franche-Conté University, University hospital Dijon, Dijon, France; Burgundy Franche-Conté University, EPICAD, INSERM LNC UMR1231, Dijon, France; French Federation of Digestive Oncology (FFCD), INSERM LNC UMR1231 EPICAD, Dijon, France. Electronic address: come.lepage@u-bourgogne.fr. · Department of Digestive Oncology, Aix-Marseille University - Assistance Publique Hôpitaux de Marseille, Marseille, France. · Department of Gastroenterology and Digestive Oncology, Saint Etienne, France. · Royal Free Hospital, Neuroendocrine Tumour Unit, Londres, Grande-Bretagne, UK. · Regional Hospital of Orleans, Orleans, France. · French Federation of Digestive Oncology (FFCD), INSERM LNC UMR1231 EPICAD, Dijon, France. · Hôpital Rangueil, Toulouse, France. · Hôpital Haut Lévêque, Service d'hépato-gastroentérologie, Pessac, France. · Hôpital de la Milétrie, Poitiers, France. · CHU de Rennes-Hôpital Pontchaillou, Rennes, France. · Hôpital Robert Debré, Reims, France. · CHU Charles Nicolle, Rouen, France. · CHU Côte de Nacre, Caen, France. · Hôpital Beaujon, Clichy, France. · CH Les Oudairies, La Roche sur Yon, France. · Charite Campus Virchow Kinikum, Berlin, Germany. · Cliniques universitaires Saint-Luc, Bruxelles, Belgium. · University of Manchester, Division of Cancer Sciences/The Christie NHS Foundation Trust, Manchester, UK. · University Hospital Marburg, Marburg, Germany. · Pathology Department, Gustave Roussy, Villejuif, France. · Gastrointestinal Oncology Department, Gustave Roussy Institute, Villejuif, France; Faculté de Médecine, Paris Sud University Le Kremlin Bicêtre, France. · Edouard Herriot Hospital, Department of Gastroenterology, Hospices Civils de Lyon, Lyon, France. ·Dig Liver Dis · Pubmed #28292641.

ABSTRACT: INTRODUCTION: Patients with metastatic or locally advanced, non-resectable, grade 1 or 2 well-differentiated duodeno-pancreatic (WDDP) NETs are treated following European guidelines. Patients (Pts) with aggressive disease, i.e. progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases, anti-tumour therapy should receive systemic combination of chemotherapy once disease control is obtained. AIM(S): The aim is to stop chemotherapy until progression. REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study designed to evaluate lanreotide (LAN) as maintenance treatment after L1 chemotherapy in G1-G2 WDDP NET. MATERIALS AND METHODS: Main eligibility criteria: adults pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs and documented control disease after L1 therapy at least 4 weeks prior to randomization. RESULTS: 222 patients will be randomly assigned in a 1:1 ratio to receive 120mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. The aim of the phase II part is to demonstrate a 6-months PFS >45% in LAN arm. Secondary endpoints are PFS according to central review, overall survival, safety and quality of life. A bio-bank of frozen blood will be constituted. CONCLUSION: The study is currently open in France, Germany, Belgium, United Kingdom and Ireland. A total of 25 patients are randomized (NCT02288377).

13 Clinical Trial Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. 2016

Yao, James C / Pavel, Marianne / Lombard-Bohas, Catherine / Van Cutsem, Eric / Voi, Maurizio / Brandt, Ulrike / He, Wei / Chen, David / Capdevila, Jaume / de Vries, Elisabeth G E / Tomassetti, Paola / Hobday, Timothy / Pommier, Rodney / Öberg, Kjell. ·James C. Yao, University of Texas MD Anderson Cancer Center, Houston, TX · Maurizio Voi, Wei He, and David Chen, Novartis, East Hanover, NJ · Timothy Hobday, Mayo Clinic College of Medicine, Rochester, MN · Rodney Pommier, Oregon Health & Science University, Portland, OR · Marianne Pavel, Charité Universitätsmedizin, Berlin, Germany · Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France · Eric Van Cutsem, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium · Ulrike Brandt, Novartis Pharma AG, Basel, Switzerland · Jaume Capdevila, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain · Elisabeth G. E. de Vries, UMCG, University of Groningen, Groningen, Netherlands · Paola Tomassetti, University of Bologna, Bologna, Italy · and Kjell Öberg, Uppsala University Hospital, Uppsala, Sweden. ·J Clin Oncol · Pubmed #27621394.

ABSTRACT: Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

14 Clinical Trial Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. 2016

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Gomez-Panzani, Edda / Ruszniewski, Philippe / Anonymous721030. ·Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France m.caplin@ucl.ac.uk. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. · Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France Royal Free HospitalLondon, UKCharité University Medicine BerlinBerlin, GermanyUniversity of Warmia and MazuryOlsztyn, PolandUniversity of Texas MD Anderson Cancer CenterHouston, Texas, USAUniversity HospitalVienna, AustriaDepartment of Oncology of the First Faculty of Medicine and General Teaching HospitalPrague, Czech RepublicRobert-Debré HospitalReims, FranceMarkey Cancer CenterUniversity of Kentucky, Lexington, Kentucky, USAVall d'Hebron University HospitalBarcelona, SpainWestern General HospitalEdinburgh, UKUniversità Cattolica del Sacro CuoreRome, ItalyIpsenLes Ulis, FranceIpsenBasking Ridge, New Jersey, USABeaujon HospitalClichy, FranceParis Diderot UniversityParis, France. ·Endocr Relat Cancer · Pubmed #26743120.

ABSTRACT: In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤ 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

15 Clinical Trial Lanreotide in metastatic enteropancreatic neuroendocrine tumors. 2014

Caplin, Martyn E / Pavel, Marianne / Ćwikła, Jarosław B / Phan, Alexandria T / Raderer, Markus / Sedláčková, Eva / Cadiot, Guillaume / Wolin, Edward M / Capdevila, Jaume / Wall, Lucy / Rindi, Guido / Langley, Alison / Martinez, Séverine / Blumberg, Joëlle / Ruszniewski, Philippe / Anonymous1220800. ·From Royal Free Hospital, London (M.E.C.) · Charité University Medicine Berlin, Berlin (M.P.) · University of Warmia and Mazury, Olsztyn, Poland (J.B.Ć.) · University of Texas M.D. Anderson Cancer Center, Houston (A.T.P.) · University Hospital, Vienna (M.R.) · Department of Oncology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic (E.S.) · Robert-Debré Hospital, Reims (G.C.), Ipsen, Les Ulis, (A.L., S.M., J.B.), Beaujon Hospital, Clichy (P.R.), and Paris Diderot University, Paris (P.R.) - all in France · Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles (E.M.W.) · Vall d'Hebron University Hospital, Barcelona (J.C.) · Western General Hospital, Edinburgh (L.W.) · and Università Cattolica del Sacro Cuore, Rome (G.R.). ·N Engl J Med · Pubmed #25014687.

ABSTRACT: BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

16 Clinical Trial Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. 2011

Yao, James C / Pavel, Marianne / Phan, Alexandria T / Kulke, Matthew H / Hoosen, Sakina / St Peter, Jessica / Cherfi, Azzeddine / Öberg, Kjell E. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, Texas 77030, USA. jyao@mdanderson.org ·J Clin Endocrinol Metab · Pubmed #21994954.

ABSTRACT: CONTEXT: Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors. OBJECTIVE: The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus. PATIENTS AND METHODS: Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels. RESULTS: In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study. CONCLUSIONS: Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.

17 Clinical Trial Everolimus for advanced pancreatic neuroendocrine tumors. 2011

Yao, James C / Shah, Manisha H / Ito, Tetsuhide / Bohas, Catherine Lombard / Wolin, Edward M / Van Cutsem, Eric / Hobday, Timothy J / Okusaka, Takuji / Capdevila, Jaume / de Vries, Elisabeth G E / Tomassetti, Paola / Pavel, Marianne E / Hoosen, Sakina / Haas, Tomas / Lincy, Jeremie / Lebwohl, David / Öberg, Kjell / Anonymous2070686. ·University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jyao@mdanderson.org ·N Engl J Med · Pubmed #21306238.

ABSTRACT: BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

18 Article Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors. 2019

Dromain, Clarisse / Pavel, Marianne E / Ruszniewski, Philippe / Langley, Alison / Massien, Christine / Baudin, Eric / Caplin, Martyn E / Anonymous2211132. ·Department of Diagnostic and Interventional Radiology, CHUV University Hospital, Lausanne, Switzerland. Clarisse.Dromain@chuv.ch. · Department of Medicine 1, Division of Endocrinology and Diabetology, Friedrich-Alexander Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany. · Division of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France. · Faculty of Medicine, Paris Diderot University, Paris, France. · Ipsen, Boulogne-Billancourt, France. · APHP, Hypertension unit, Georges Pompidou European Hospital, F-75015, Paris, France. · Endocrine Tumour and Nuclear Medicine Unit, Gustave-Roussy Cancer Campus, Villejuif, France. · Neuroendocrine Tumour Unit, Department of Gastroenterology, Royal Free Hospital, London, UK. ·BMC Cancer · Pubmed #30642293.

ABSTRACT: BACKGROUND: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. METHODS: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR RESULTS: TGR CONCLUSIONS: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. TRIAL REGISTRATION: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

19 Article Functional Imaging in the Follow-Up of Enteropancreatic Neuroendocrine Tumors: Clinical Usefulness and Indications. 2017

Merola, Elettra / Pavel, Marianne E / Panzuto, Francesco / Capurso, Gabriele / Cicchese, Noemi / Rinke, Anja / Gress, Thomas M / Iannicelli, Elsa / Prosperi, Daniela / Pizzichini, Patrizia / Prasad, Vikas / Kump, Patrizia / Lipp, Rainer / Partelli, Stefano / Falconi, Massimo / Wiedenmann, Bertram / Delle Fave, Gianfranco. ·Digestive and Liver Diseases Unit, Sant'Andrea Hospital, 00189 Rome, Italy. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, 13353 Berlin, Germany. · Department of Gastroenterology, University Hospital, 35043 Marburg, Germany. · Department of Radiology, Sant'Andrea Hospital, 00189 Rome, Italy. · Division of Nuclear Medicine, Sant'Andrea Hospital, 00189 Rome, Italy. · Department of Nuclear Medicine, Campus Virchow-Klinikum, Charité Universitätsmedizin, 13353 Berlin, Germany. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University, 8036 Graz Austria. · Division of Nuclear Medicine, Department of Radiology, Medical University, 8036 Graz Austria. · Pancreatic Surgery Unit, Vita-Salute University, San Raffaele Hospital Istituto di Ricovero e Cura a Carattere Scientifico, 20132 Milan, Italy. ·J Clin Endocrinol Metab · Pubmed #28324047.

ABSTRACT: Context: Functional imaging tests (FITs) detecting somatostatin receptor expression [i.e., somatostatin receptor scintigraphy, 68Ga-DOTA positron emission tomography/computed tomography (CT)] have a pivotal role in the diagnosis of neuroendocrine tumors (NETs), although their indication during follow-up still needs to be clarified. Objective: Investigate the role of FITs after diagnosis of metastatic enteropancreatic NETs, identifying patients who might benefit from these exams. Design: Multicenter retrospective analysis of metastatic enteropancreatic NETs. Setting: Analysis of imaging tests performed between January 1995 and December 2015 in Rome, Berlin, Milan, Marburg, or Graz. Subjects: One hundred forty-three patients with metastatic pancreatic NETs and small intestine NETs, at least 2-year follow-up, and positive FITs. Interventions: Patients had received CT every 6 months (unless clinical conditions and tumor behavior required shorter intervals) and FIT every 12 months. Main Outcome Measures: Clinical usefulness of FITs, defined as changes in patient management (indication to biopsy, medical therapy, surgery, or further imaging tests) due only to FITs. Results: FITs affected management in 73.4% of patients, mostly when G2 vs G1 [odds ratio (OR), 2.40; 95% confidence interval (CI), 1.09 to 5.27; P = 0.03]. Changes were observed in a 12-month time frame especially with pancreatic NETs vs small intestine NETs (OR, 2.89; 95% CI, 1.09 - 7.67; P = 0.03) or metastases since diagnosis vs developed during follow-up (OR, 4.00; 95% CI, 1.43 to 11.17; P < 0.01). Conclusions: FITs used in addition to CT in the follow-up of stage IV enteropancreatic NETs improve patient management (especially for G2 tumors). Follow-up program should be tailored according to tumor features.

20 Article Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome. 2017

Panzuto, Francesco / Merola, Elettra / Pavel, Marianne Ellen / Rinke, Anja / Kump, Patrizia / Partelli, Stefano / Rinzivillo, Maria / Rodriguez-Laval, Victor / Pape, Ulrich Frank / Lipp, Rainer / Gress, Thomas / Wiedenmann, Bertram / Falconi, Massimo / Delle Fave, Gianfranco. ·Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany. · Department of Gastroenterology, Philipps-University of Marburg, Germany. · Clinical Division of Gastroenterology, Medical University Graz, Austria. · Division of Pancreatic Surgery, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy. · Department of Radiology Charité University, Campus Virchow Klinikum, Berlin, Germany. · Clinical Division of Oncology, Medical University Graz, Austria. · Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy gianfranco.dellefave@uniroma1.it. ·Oncologist · Pubmed #28232598.

ABSTRACT: BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs.

21 Article NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive. 2017

Pavel, Marianne / Jann, Henning / Prasad, Vikas / Drozdov, Ignat / Modlin, Irvin M / Kidd, Mark. ·Department of Hepatology and Gastroenterology, Campus-Virchow-Klinikum, Berlin, Germany. ·Neuroendocrinology · Pubmed #27078712.

ABSTRACT: BACKGROUND/AIMS: A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study. METHODS: GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low <40% and high activity risk cutoffs >80%); chromogranin A (CgA) was measured by radioimmunoassay (normal <150 µg/l); progression-free survival (PFS) was analyzed by Cox proportional-hazard regression and Kaplan-Meier analysis. RESULTS: At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with <40% levels). The NETest was more informative (96%) than CgA changes (>25%) in consistently predicting disease alterations (40%, p < 2 × 10-5, χ2 = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ2 = 5, p < 0.03). Baseline NETest values <40% accurately (100%) predicted stability over 5 years (p = 0.05, χ2 = 3.8 vs. CgA). CONCLUSION: The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has predictive and prognostic utility for GEP-NETs identifying clinically actionable alterations ∼1 year before image-based evidence of progression.

22 Article Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. 2015

Heetfeld, M / Chougnet, C N / Olsen, I H / Rinke, A / Borbath, I / Crespo, G / Barriuso, J / Pavel, M / O'Toole, D / Walter, T / Anonymous4090834. ·Department of Hepatology and GastroenterologyCharité University Hospital Berlin, Berlin, GermanyDepartment of Nuclear MedicineHopital Saint Louis, Paris, FranceDepartment of Surgical GastroenterologyEuropean NET Center of Excellence, Rigshospitalet, DenmarkDepartment of Internal MedicineDivision of Gastroenterology and Endocrinology, Philipps University, Marburg, GermanyDepartment of GastroenterologyCliniques Universitaires Saint-Luc, Bruxelles, BelgiumDepartment of Medical OncologyHospital Universitario de Burgos, Burgos, SpainDepartment of Medical OncologyHospital Univeristario La Paz, Madrid, SpainDepartment of Clinical Medicine and GastroenterologySt James's and St Vincent's Hospitals and TCD, Dublin, IrelandDepartment of Hepatology and GastroenterologyEdouard Herriot Hospital, University of Lyon, 69437 Lyon Cedex 03, France. · Department of Hepatology and GastroenterologyCharité University Hospital Berlin, Berlin, GermanyDepartment of Nuclear MedicineHopital Saint Louis, Paris, FranceDepartment of Surgical GastroenterologyEuropean NET Center of Excellence, Rigshospitalet, DenmarkDepartment of Internal MedicineDivision of Gastroenterology and Endocrinology, Philipps University, Marburg, GermanyDepartment of GastroenterologyCliniques Universitaires Saint-Luc, Bruxelles, BelgiumDepartment of Medical OncologyHospital Universitario de Burgos, Burgos, SpainDepartment of Medical OncologyHospital Univeristario La Paz, Madrid, SpainDepartment of Clinical Medicine and GastroenterologySt James's and St Vincent's Hospitals and TCD, Dublin, IrelandDepartment of Hepatology and GastroenterologyEdouard Herriot Hospital, University of Lyon, 69437 Lyon Cedex 03, France thomas.walter@chu-lyon.fr. ·Endocr Relat Cancer · Pubmed #26113608.

ABSTRACT: Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

23 Article Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. 2015

Dilz, Lisa-Marie / Denecke, Timm / Steffen, Ingo G / Prasad, Vikas / von Weikersthal, Ludwig Fischer / Pape, Ulrich-Frank / Wiedenmann, Bertram / Pavel, Marianne. ·Dept. of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Germany. · Dept. of Radiology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Germany. · Dept. of Nuclear Medicine, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Germany. · Klinikum St. Marien, Dept. of Internal Medicine, Amberg, Germany. · Dept. of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Germany. Electronic address: marianne.pavel@charite.de. ·Eur J Cancer · Pubmed #25935542.

ABSTRACT: BACKGROUND: The role of systemic chemotherapy for pancreatic neuroendocrine tumours (pNET) is controversially discussed. Objective response rates (RR) reported for streptozocin (STZ)-based chemotherapy are variable and novel targeted drugs have recently been approved. However, the sequence of treatment remains unclear. We aimed to evaluate the efficacy of STZ plus 5-fluorouracil (STZ/5-FU) in a large pNET cohort. METHODS: Data from 96 pNET patients treated with STZ/5-FU were analysed retrospectively. Endpoints of the study were RR, time to tumour progression (TTP) and overall survival (OS). RESULTS: Mean age of patients at the start of chemotherapy was 57.6years (range, 32.1-80.4). STZ/5-FU was the 1st line treatment in 56.3%. 11.5% had G1, 79.2% G2 and 6.3% G3 neoplasms. Baseline progression was evident in 74%. Objective response rate was 42.7%. 40.6% of patients showed stable disease as best response while 16.7% showed progressive disease. Treatment was discontinued due to toxicity in 16 patients. Median TTP and OS were 19.4 (95% confidence interval (CI), 13.6-25.2) and 54.8months (95% CI, 34.7-74.9), respectively. In Cox regression analysis, Ki67>15% was the only negative prognostic factor for TTP (hazard ratio (HR), 3.3; P<0.001), confirmed by multivariate analysis (HR, 6.7; P=0.001). CONCLUSIONS: STZ/5-FU was associated with considerable RR. Treatment was associated with durable TTP especially in patients with Ki67-index of ⩽15%. These findings along with good tolerability strengthen the value of this two-drug chemotherapy for the management of unresectable pNET.

24 Article Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms. 2014

Schmitt, Anja Maria / Pavel, Marianne / Rudolph, Thomas / Dawson, Heather / Blank, Annika / Komminoth, Paul / Vassella, Erik / Perren, Aurel. ·Department of Pathology, Institute of Clinical Pathology, University of Bern, Bern, Switzerland. ·Neuroendocrinology · Pubmed #25012122.

ABSTRACT: BACKGROUND/AIMS: O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. METHODS: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. RESULTS: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. CONCLUSION: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.

25 Article Evaluation of radiological prognostic factors of hepatic metastases in patients with non-functional pancreatic neuroendocrine tumors. 2013

Denecke, Timm / Baur, Alexander D J / Ihm, Claudia / Steffen, Ingo G / Tischer, Elisabeth / Arsenic, Ruza / Pascher, Andreas / Wiedenmann, Bertram / Pavel, Marianne. ·Klinik für Radiologie, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Germany. ·Eur J Radiol · Pubmed #23891296.

ABSTRACT: PURPOSE: There are different therapeutic options in non-functional well to moderately differentiated (G1 and G2) pancreatic neuroendocrine tumors (pNET) with unresectable hepatic metastases including systemic chemotherapy and novel molecular targeted therapies. Treatment with somatostatin analogs (SSA) as antiproliferative agents is optional. At initial diagnosis watchful waiting until tumor progression is a well-established approach. Goal of this study was to evaluate imaging features as potential prognostic factors predicting early tumor progression in order to select patients that might benefit from an earlier initiation of medical treatment. PATIENTS AND METHODS: In 44 patients we correlated tumor grade, chromogranin A (CgA) levels, treatment with SSA and imaging features of hepatic metastases on contrast-enhanced multiphase CT and MR imaging with time to tumor progression (TTP) according to RECIST 1.0. RESULTS: In the total patient cohort none of the tested imaging features was found to be a statistically significant prognostic factor for TTP. Since treatment with SSA was associated with an increased TTP we also analyzed a subgroup of 30 patients not treated with SSA. In this subgroup of patients hypoenhancement of hepatic metastases during early contrast phases was found to be a negative prognostic factor for early tumor progression within 12 months (p=0.039). The other evaluated parameters including hepatic tumor load, number of metastases, and presence of regressive morphological changes did not reveal significant results. CONCLUSION: Hypovascularization of liver metastases from G1 and G2 pNET reflected by hypoenhancement during the early contrast phases seems to be associated with early tumor progression. In patients with hypoenhancing metastases repeated biopsy for reassessment of grading of these metastases, and early initiation of therapy should be considered.

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