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Pancreatic Neoplasms: HELP
Articles by Jaume Capdevila
Based on 27 articles published since 2009
(Why 27 articles?)
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Between 2009 and 2019, J. Capdevila wrote the following 27 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors. 2018

Merino-Casabiel, X / Aller, J / Arbizu, J / García-Figueiras, R / González, C / Grande, E / Jiménez-Fonseca, P / Sevilla, M I / Capdevila, J. ·Radiology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain. · Endocrinology Department, Hospital Universitario Puerta de Hierro de Majadahonda, Madrid, Spain. · Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain. · Radiology Department, Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña, Spain. · Radiology Department, Hospital Universitario Puerta de Hierro de Majadahonda, Madrid, Spain. · Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain. · Medical Oncology Department, Investigación Clínica y Traslacional en Cáncer, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Hospital Universitario Regional y Virgen de la Victoria de Málaga, Malaga, Spain. · Medical Oncology Department and Gastrointestinal and Endocrine Tumor Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, 119-129, 08035, Barcelona, Spain. jacapdevila@vhebron.net. ·Clin Transl Oncol · Pubmed #29766455.

ABSTRACT: PURPOSE: Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. METHODS: To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. RESULTS: Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated.

2 Guideline ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. 2016

Falconi, M / Eriksson, B / Kaltsas, G / Bartsch, D K / Capdevila, J / Caplin, M / Kos-Kudla, B / Kwekkeboom, D / Rindi, G / Klöppel, G / Reed, N / Kianmanesh, R / Jensen, R T / Anonymous1590854. · ·Neuroendocrinology · Pubmed #26742109.

ABSTRACT: -- No abstract --

3 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 --

4 Review The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. 2017

Amair-Pinedo, Fabiola / Matos, Ignacio / Saurí, Tamara / Hernando, Jorge / Capdevila, Jaume. ·Vall d'Hebron University Hospital, Barcelona, Spain. · Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Vall d'Hebron University Hospital, Barcelona, Spain. jcapdevila@vhio.net. · Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. jcapdevila@vhio.net. ·Target Oncol · Pubmed #29143176.

ABSTRACT: Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.

5 Review Optimizing Somatostatin Analog Use in Well or Moderately Differentiated Gastroenteropancreatic Neuroendocrine Tumors. 2017

Carmona-Bayonas, Alberto / Jiménez-Fonseca, Paula / Custodio, Ana / Grande, Enrique / Capdevila, Jaume / López, Carlos / Teule, Alex / Garcia-Carbonero, Rocío / Anonymous24040919. ·Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Calle Marqués de los Vélez, s/n, CP 30008, Murcia, Spain. alberto.carmonabayonas@gmail.com. · Department of Medical Oncology, Central Asturias University Hospital, Oviedo, Spain. · Department of Medical Oncology, La Paz University Hospital, Madrid, Spain. · Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain. · Department of Medical Oncology, Vall D'Hebrón University Hospital, Vall D'Hebrón Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, center affiliated with the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Barcelona, Spain. · Department of Medical Oncology, Marqués de Valdecilla University Hospital, Santander, Spain. · Department of Medical Oncology, Institut Català d'Oncologia, L'Hospitalet de Llobregat, center affiliated with the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Barcelona, Spain. · Department of Medical Oncology, Doce de Octubre University Hospital, center affiliated with the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain. ·Curr Oncol Rep · Pubmed #28920153.

ABSTRACT: BACKGROUND: Somatostatin analogues, aiming to control tumor secretion or growth, constitute the most attractive therapeutic option for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The objective of this article is to provide a comprehensive review of the current state-of-the-art knowledge gaps and potential opportunities for future development and optimization of this therapeutic modality. METHOD: A contextualized systematic review with a narrative component was conducted using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Titles were screened, and non-English, duplicate, or irrelevant entries were excluded. Selection criteria for articles included the following: publication in English between 1995 and 2016, patients with GEP-NETs, analysis of efficacy, safety, practical management considerations, predictive factors, and/or strategies for overcoming resistance, concerning somatostatin analogs. RESULTS: Ninety-seven studies out of 2771 screened publications met the inclusion criteria (16 randomized clinical trials, 27 phase II trials, 3 phase I trials, 3 subgroup analyses of clinical trials, 1 open-label extension of a randomized trial, 1 phase IV trial, 32 observational studies, and 14 basic research articles). The nature and scope of literature was diverse with most articles dedicated to drug efficacy or indications of use (n = 49), pharmacological issues (n = 8), assessment or predictors of response (n = 4), practical management (n = 11), combination therapy or other means to overcome resistance (n = 19), receptors and signaling pathways (n = 3), and subgroup analyses (n = 3). CONCLUSION: In this appraisal, we have found some practical aspects that can help to the optimization of somatostatin analog (SSA) therapy in patients with well-differentiated GEP-NETs. We have also identified areas of uncertainty in an effort to guide clinical research in the coming years.

6 Review Translational research in neuroendocrine tumors: pitfalls and opportunities. 2017

Capdevila, J / Casanovas, O / Salazar, R / Castellano, D / Segura, A / Fuster, P / Aller, J / García-Carbonero, R / Jimenez-Fonseca, P / Grande, E / Castaño, J P. ·Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron, Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. · ProCURE Research Program, Instituto Catalán de Oncología - IDIBELL, Barcelona, Spain. · Oncology Department, Catalan Institute of Oncology-IDIBELL, Universitat de Barcelona, Barcelona, Spain. · Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. · Oncology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain. · Oncology Department, Hospital Universitari Son Espases, Palma de Mallorca, Spain. · Department of Endocrinology, Puerta de Hierro University Hospital, Madrid, Spain. · Medical Oncology Department, Hospital Universitario Doce de Octubre, Center affiliated to the Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain. · Department of Medical Oncology, Central Asturias University Hospital, Oviedo, Spain. · Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Maimónides Institute of Biomedical Research at Córdoba (IMIBIC); Reina Sofía University Hospital; Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain. ·Oncogene · Pubmed #27641330.

ABSTRACT: Interest in research on neuroendocrine tumors (NETs) has grown in the past 10 years, coinciding with improvements in our understanding of the molecular pathogenesis of NETs. In addition, NETs have become one of the most exciting settings for drug development. Two targeted agents for the management of advanced pancreatic NETs have been approved, but the development of targeted agents for NETs is limited by problems with both patient selection and demonstration of activity. In this review, we analyze these limitations and discuss ways to increase the predictive value of preclinical models for target discovery and drug development. The role of translational research and 'omics' methodologies is emphasized, with the final aim of developing personalized medicine. Because NETs usually grow slowly and metastatic tumors are found at easily accessible locations, and owing to improvements in techniques for liquid biopsies, NETs provide a unique opportunity to obtain tumor samples at all stages of the evolution of the disease and to adapt treatment to changes in tumor biology. Combining clinical and translational research is essential to achieve progress in the NET field. Slow growth and genetic stability limit and challenge both the availability and further development of preclinical models of NETs, one of the most crucial unmet research needs in the field. Finally, we suggest some useful approaches for improving clinical drug development for NETs: moving from classical RECIST-based response end points to survival parameters; searching for different criteria to define response rates (for example, antiangiogenic effects and metabolic responses); implementing randomized phase II studies to avoid single-arm phase II studies that produce limited data on drug efficacy; and using predictive biomarkers for patient selection.

7 Review Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development. 2015

Garcia-Carbonero, Rocio / Garcia-Figueiras, Roberto / Carmona-Bayonas, Alberto / Sevilla, Isabel / Teule, Alex / Quindos, Maria / Grande, Enrique / Capdevila, Jaume / Aller, Javier / Arbizu, Javier / Jimenez-Fonseca, Paula / Anonymous5380844. ·Medical Oncology Department, Hospital Universitario Doce de Octubre, Center affiliated to the Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Av. Cordoba km 5.4, 28041, Madrid, Spain. rgcarbonero@gmail.com. · Radiology Department, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain. · Medical Oncology Department, Hospital Universitario Virgen de la Victoria y Hospital Regional Universitario, Málaga, Spain. · Medical Oncology Department, Instituto Catalán de Oncología (ICO), Center affiliated to the Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Seville, Spain. · Medical Oncology Department, Complejo Hospitalario Universitario, A Coruña, Spain. · Medical Oncology Department, Hospital Ramon y Cajal, Madrid, Spain. · Medical Oncology Department, Hospital Vall d'Hebron, Center affiliated to the Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Barcelona, Spain. · Endocrinology Department, Hospital Puerta de Hierro, Madrid, Spain. · Nuclear Medicine Department, Clinica Universidad de Navarra, Navarra, Spain. · Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain. ·Cancer Metastasis Rev · Pubmed #26433592.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of neoplasms with a complex spectrum of clinical behavior. Although generally more indolent than carcinomas, once they progress beyond surgical resectability, they are essentially incurable. Systemic treatment options have substantially expanded in recent years for the management of advanced disease. Imaging plays a major role in new drug development, as it is the main tool used to objectively evaluate response to novel agents. However, current standard response criteria have proven suboptimal for the assessment of the antiproliferative effect of many targeted agents, particularly in the context of slow-growing tumors such as well-differentiated NETs. The aims of this article are to discuss the advantages and limitations of conventional radiological techniques and standard response assessment criteria and to review novel imaging modalities in development as well as alternative cancer- and therapy-specific criteria to assess drug efficacy in the field of GEP-NETs.

8 Review Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. 2015

Jiménez-Fonseca, P / Carmona-Bayonas, A / Martín-Pérez, E / Crespo, G / Serrano, R / Llanos, M / Villabona, C / García-Carbonero, R / Aller, J / Capdevila, J / Grande, E / Anonymous5620838. ·Department of Medical Oncology, Central Asturias University Hospital, C/ Avenida de Roma sn, Oviedo, 33011, Asturias, Spain. palucaji@hotmail.com. · Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Murcia, Spain. · Department of General Surgery, La Princesa University Hospital, Madrid, Spain. · Department of Medical Oncology, Burgos University Hospital, Burgos, Spain. · Department of Medical Oncology, Reina Sofia University Hospital, Córdoba, Spain. · Department of Medical Oncology, Canarias University Hospital, Tenerife, Spain. · Department of Endocrinology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain. · Department of Medical Oncology, Virgen del Rocio University Hospital, Instituto de Biomedicina de Sevilla (IBIS) [Universidad de Sevilla, CSIC, HUVR], Center affiliated with the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Sevilla, Spain. · Department of Endocrinology, Puerta de Hierro University Hospital, Madrid, Spain. · Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Center affiliated with the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Barcelona, Spain. · Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain. ·Cancer Metastasis Rev · Pubmed #26245646.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population.

9 Review Expert consensus for the management of advanced or metastatic pancreatic neuroendocrine and carcinoid tumors. 2015

Castellano, Daniel / Grande, Enrique / Valle, Juan / Capdevila, Jaume / Reidy-Lagunes, Diane / O'Connor, Juan Manuel / Raymond, Eric. ·Departamento de Oncología Médica, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain, cdanicas@hotmail.com. ·Cancer Chemother Pharmacol · Pubmed #25480314.

ABSTRACT: Neuroendocrine tumors (NETs) are rare tumors that have been increasing in incidence over the last 30 years with no significant changes in survival. As survival of patients with these tumors depends greatly on stage and histology, early diagnosis, classification and staging of tumors in patients in whom NETs are suspected are of great importance. Surgery, either with curative or palliative intent, is the mainstay of treatment for localized NETs. Therapeutic options for this disease almost invariably include somatostatin analogs to alleviate the symptoms of excessive hormone secretion. Other approaches for advanced disease may include hepatic artery embolization or ablation, peptide receptor radionuclide therapy and systemic chemotherapy. Recent advances regarding the signaling pathways involved in tumor development have allowed the development of novel targeted therapies. However, due to the lack of prognostic molecular markers to identify high-risk patients and the absence of a common pathogenesis in all patients, treatment selection is often empirical. There is therefore a need to establish a consensus for the treatment of this disease and to provide evidence-based clinical recommendations and algorithms to optimize and individualize the treatment and follow-up for these patients.

10 Review [Neuroendocrine tumors: the age of targeted therapies]. 2012

Capdevila, Jaume / Argilés, Guillem / Mulet-Margalef, Nuria / Tabernero, Josep. ·Departamento de Oncología Médica, Hospital Universitario Vall d'Hebron, Barcelona, España. jacapdevila@vhebron.net ·Endocrinol Nutr · Pubmed #22565119.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the second most prevalent group of advanced gastrointestinal tract tumors. Resources invested in research on this patient population have exponentially increased in recent years, and this has become one of the most attractive fields for oncological research. Several proangiogenic proteins have been found to be overexpressed in GEP-NETs, including vascular endothelial growth factor and its receptors and the more closely related intracellular signaling pathways such as the epidermal growth factor pathway, type I insulin-like growth factor receptor, and the PI3K-(PTEN)-AKT-mTOR pathway. The recent results of the three most important Phase III studies in GEP-NETs have allowed for approval of two targeted agents, sunitinib and everolimus, for the treatment of patients with pancreatic neuroendocrine tumors after decades of minimal advances in this population.

11 Review Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist? 2012

Grande, Enrique / Capdevila, Jaume / Barriuso, Jorge / Antón-Aparicio, Luis / Castellano, Daniel. ·Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal de Madrid, Madrid, Spain. egrande@oncologiahrc.com ·Cancer Metastasis Rev · Pubmed #22105614.

ABSTRACT: Neuroendocrine tumors (NETs) comprise a broad range of neoplasms that share biological and embryological origin. A deeper knowledge in the underlying molecular biology that results in the development and spread of NETs has allowed the use of novel-targeted therapies against angiogenesis and intracellular pathways, key checkpoints that govern growth, and proliferation of these tumors. Unfortunately, the possibility of cure is still far for patients with advanced stages. Cancer stem cells (CSCs) are present in most solid tumors. Nevertheless, there is limited evidence for the presence of CSCs in NETs. In this review, we will discuss the embryonic origin and possible existence of a gastroenteropancreatic neuroendocrine cancer stem cell. Here, we summarize the body of evidence supporting the presence of active embryological pathways like Notch, Wnt-β-catenin, Hedgehog, or transforming growth factor-β in NETs. New therapeutic approaches in the field of CSCs seem to have a clear role in the treatment of medulloblastomas and basal cell carcinomas, but their future value in other solid tumor types including NETs remains unclear.

12 Review A shining light in the darkness for the treatment of pancreatic neuroendocrine tumors. 2011

Capdevila, Jaume / Tabernero, Josep. ·Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. ·Cancer Discov · Pubmed #22586573.

ABSTRACT: SUMMARY: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies.

13 Review Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). 2010

Garcia-Carbonero, R / Capdevila, J / Crespo-Herrero, G / Díaz-Pérez, J A / Martínez Del Prado, M P / Alonso Orduña, V / Sevilla-García, I / Villabona-Artero, C / Beguiristain-Gómez, A / Llanos-Muñoz, M / Marazuela, M / Alvarez-Escola, C / Castellano, D / Vilar, E / Jiménez-Fonseca, P / Teulé, A / Sastre-Valera, J / Benavent-Viñuelas, M / Monleon, A / Salazar, R. ·Department of Medical Oncology, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Sevilla. rgcarbonero@hotmail.com ·Ann Oncol · Pubmed #20139156.

ABSTRACT: BACKGROUND: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country. PATIENTS AND METHODS: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers. RESULTS: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival. CONCLUSION: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

14 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.

15 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.

16 Clinical Trial A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. 2016

Fazio, Nicola / Buzzoni, Roberto / Baudin, Eric / Antonuzzo, Lorenzo / Hubner, Richard A / Lahner, Harald / DE Herder, Wouter W / Raderer, Markus / Teulé, Alexandre / Capdevila, Jaume / Libutti, Steven K / Kulke, Matthew H / Shah, Manisha / Dey, Debarshi / Turri, Sabine / Aimone, Paola / Massacesi, Cristian / Verslype, Chris. ·European Institute of Oncology, Milan, Italy nicola.fazio@ieo.it. · IRCCS National Tumor Institute, Milan, Italy. · Institut Gustave Roussy, Villejuif, France. · Careggi University Hospital, Florence, Italy. · The Christie NHS Foundation Trust, Manchester, U.K. · University of Duisburg-Essen, Essen, Germany. · Erasmus MC, Rotterdam, the Netherlands. · University Hospital of Vienna, Vienna, Austria. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. · Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY, U.S.A. · Dana-Farber Cancer Institute, Boston, MA, U.S.A. · The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, U.S.A. · Novartis Healthcare Private Limited, Hyderabad, India. · Novartis Pharma AG, Basel, Switzerland. · Novartis Oncology, Paris, France. · University Hospitals Leuven, Leuven, Belgium. ·Anticancer Res · Pubmed #26851029.

ABSTRACT: BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

17 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.

18 Clinical Trial Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). 2015

Grande, E / Capdevila, J / Castellano, D / Teulé, A / Durán, I / Fuster, J / Sevilla, I / Escudero, P / Sastre, J / García-Donas, J / Casanovas, O / Earl, J / Ortega, L / Apellaniz-Ruiz, M / Rodriguez-Antona, C / Alonso-Gordoa, T / Díez, J J / Carrato, A / García-Carbonero, R. ·Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid egrande@oncologiahrc.com. · Department of Medical Oncology, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona. · Department of Medical Oncology, I + 12 Research Institute, 12 de Octubre University Hospital, Madrid. · Department of Medical Oncology, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona. · Department of Medical Oncology, Instituto de Biomedicina de Sevilla (IBIS) [HUVR, CSIC, University of Seville], Virgen del Rocío University Hospital, Seville. · Department of Medical Oncology, Son Espases Hospital, Palma de Mallorca. · Department of Medical Oncology, Virgen de la Victoria University Hospital, Malaga. · Department of Medical Oncology, Clínico Lozano Blesa University Hospital, Zaragoza. · Department of Medical Oncology, Clínico San Carlos Hospital, Madrid. · Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid. · Tumor Angiogenesis Group, IDIBELL, Catalan Institute of Oncology L'Hospitalet, Barcelona. · Department of Medical Oncology Research Laboratory, Ramón y Cajal University Hospital, Madrid. · Department of Pathology, Clínico San Carlos Hospital, Madrid. · Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, ISCIII Center for Biomedical Research on Rare Disease (CIBERER) Madrid, Madrid. · Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid. · Department of Endocrinology, Ramón y Cajal University Hospital, Madrid, Spain. ·Ann Oncol · Pubmed #26063633.

ABSTRACT: BACKGROUND: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. METHODS: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. RESULTS: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. CONCLUSIONS: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). CLINICAL TRIAL NUMBER: NCT01280201.

19 Clinical Trial Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. 2015

Lombard-Bohas, Catherine / Yao, James C / Hobday, Timothy / Van Cutsem, Eric / Wolin, Edward M / Panneerselvam, Ashok / Stergiopoulos, Sotirios / Shah, Manisha H / Capdevila, Jaume / Pommier, Rodney. ·From the *Department of Medical Oncology, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; †Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; ‡Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN; §Digestive Oncology, University Hospitals Gasthuisberg/Leuven, Leuven, Belgium; ∥Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA; ¶Department of Oncology Biometrics and Data, and #Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ; **Department of Medical Oncology, The Ohio State University, Columbus, OH; ††Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; and ‡‡Division of Surgical Oncology, Oregon Health & Science University, Portland, OR. ·Pancreas · Pubmed #25479584.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate efficacy and safety of everolimus in patients with pancreatic neuroendocrine tumors (pNET) by prior chemotherapy use in the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3). METHODS: Patients with advanced, progressive, low- or intermediate-grade pNET were prospectively stratified by prior chemotherapy use and World Health Organization performance status and were randomly assigned (1:1) to everolimus 10 mg/d (n = 207) or placebo (n = 203). RESULTS: Of the 410 patients, 204 (50%) were naive to chemotherapy (chemonaive). Baseline characteristics were similar for patients with or without prior chemotherapy. Everolimus significantly prolonged median progression-free survival regardless of prior chemotherapy use (prior chemotherapy: 11.0 vs 3.2 months; hazard ratio, 0.34; 95% confidence interval, 0.25-0.48; P < 0.0001) (chemonaive: 11.4 vs 5.4 months; hazard ratio, 0.42; 95% confidence interval, 0.29-0.60; P < 0.0001). Stable disease was the best overall response in 73% of everolimus-treated patients (151/207). The most common drug-related adverse events included stomatitis (60%-69%), rash (47%-50%), and diarrhea (34%). CONCLUSIONS: As more treatment options become available, it is important to consider the goals of treatment and to identify patients who would potentially benefit from a specific therapy. Findings from this planned subgroup analysis suggest the potential for first-line use of everolimus in patients with advanced pNET.

20 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.).

21 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.).

22 Article SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018). 2019

González-Flores, E / Serrano, R / Sevilla, I / Viúdez, A / Barriuso, J / Benavent, M / Capdevila, J / Jimenez-Fonseca, P / López, C / Garcia-Carbonero, R. ·Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Department of Medical Oncology, Hospital Reina Sofía, Córdoba, IMIBIC, CIBERONC, Córdoba, Spain. · Department of Medical Oncology, Instituto de Investigaciones Biomédicas de Málaga (IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Málaga, Spain. · Department of Medical Oncology, Complejo Hospitalario de Navarra (CHN), OncobionaTras Unit, Navarrabiomed, IdiSNA, Pamplona, Spain. · Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. · Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina, Seville, Spain. · Department of Medical Oncology, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VIHO), Barcelona, Spain. · Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. · Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Santander, Spain. · Department of Medical Oncology, Hospital Universitario 12 de Octubre, IIS imas12, UCM, CNIO, CIBERONC, Av. de Córdoba, s/n, 28041, Madrid, Spain. rgcarbonero@gmail.com. ·Clin Transl Oncol · Pubmed #30535553.

ABSTRACT: NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

23 Article Detection of pancreatic neuroendocrine tumors: 23 years of experience. 2019

Varas-Lorenzo, M J / Cugat, E / Capdevila, J / Sánchez-Vizcaíno Mengual, E. ·Servicio de Aparato Digestivo, Hospital Sanitas CIMA, Barcelona, España; Unidad de Gastroenterología y Hepatología, Hospital Universitario Teknon Quirón Salud, Barcelona, España; Facultat de Ciencias de la Salud, Universitat Oberta de Catalunya (UOC), Barcelona, España. · Servicio de Cirugía General-Aparato Digestivo, Hospital Universitario Teknon Quirón Salud, Barcelona, España. · Instituto Oncológico, Hospital Universitario Teknon Quirón Salud, Barcelona, España. · Unidad de Investigación Clínica, Hospital CIMA Sanitas, Barcelona, España. Electronic address: elenasnchz020@gmail.com. ·Rev Gastroenterol Mex · Pubmed #29858120.

ABSTRACT: INTRODUCTION AND AIMS: Neuroendocrine tumors are of great scientific interest, given that they are difficult to diagnose and treat. Despite being relatively rare (< 1/100,000 individuals, 1-2% of the gastrointestinal neoplasias) and indolent, their potential malignancy must not be forgotten. An increase in the number of diagnosed tumors has been observed in recent years. The aim of the present study was to update a published case series of 19 patients suspected of presenting with pancreatic neuroendocrine tumor with 51 current cases, to study and compare the new results with those of the previous case series, as well as with other recent publications from Spain, the United States, China, and India. MATERIALS AND METHODS: A retrospective, multicenter case series was conducted on 70 patients (19 cases published in 2011), whose data has been collected over a period of 23 years. The variables analyzed were: age, sex, symptomatology, tumor size, location, metastasis, final diagnosis, and surgery, among others. RESULTS: Mean patient age was 55 years and 60% of the patients were men. Disease location was the pancreatic head in 28.5% of the patients and the tail in 27.1%, mean tumor size was 3.9cm (0.2-10cm), 71.4% of the patients had non-functioning tumors, 32.8% had metastases (100% to the liver), 74.2% of the patients were operated on, and actuarial survival was 75%. CONCLUSIONS: Differences were observed between the previously published case series and the current results. There was an increase in incidentalomas and non-functioning tumors, but no variation in the overall survival rate. The differences with other case series (age, sex, and tumor location) were dependent on the country where the cases were compiled. The increase in tumors could be related to a higher number of diagnoses made through imaging studies and to the greater sensitivity of the devices employed.

24 Article Management of controversial gastroenteropancreatic neuroendocrine tumour clinical situations with somatostatin analogues: results of a Delphi questionnaire panel from the NETPraxis program. 2016

Sevilla, Isabel / Segura, Ángel / Capdevila, Jaume / López, Carlos / García-Carbonero, Rocío / Grande, Enrique / Anonymous1511016. ·Oncology Unit. Hospital Clínico y Regional de Málaga, Colonia Santa Inés s/n, Málaga, 29010, Spain. isevilla02@yahoo.es. · Oncology Unit. Hospital Universitario La Fe, Avda. de Fernando Abril Martorell 106, 46026, Valencia, Spain. · Oncology Unit. Hospital Vall d'Hebron, Pg de la Vall d'Hebron 119-129, 08035, Barcelona, Spain. · Oncology Unit. Hospital Marqués de Valdecilla, Avda. Valdecilla 25, 39008, Santander, Spain. · Oncology Unit. Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain. · Oncology Unit. Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo km. 9.100, 28034, Madrid, Spain. ·BMC Cancer · Pubmed #27821081.

ABSTRACT: BACKGROUND: There are clinical situations (CS) in which the use of somatostatin analogs (SSAs) in patients with neuroendocrine tumors (NET) is controversial due to lack of evidence. A Delphi study was conducted to develop common treatment guidelines for these CS, based on clinical practice and expert opinion of Spanish oncologists. METHODS: A scientific committee identified 5 CS with a common core (c-c) [non-functioning NET, not susceptible of surgery/locoregional therapy, Ki67 < 10 % (except for CS5: >10 %), ECOG ≤ 2], and controversy regarding use of SSAs, and prepared a Delphi questionnaire of 48 treatment statements. Statements were rated on a 1 (completely disagree) to 9 (completely agree) scale. Responses were grouped by tertiles: 1-3: Disagreement, 4-6: Neutral, 7-9: Agreement. Consensus was reached when the responses of ≥2/3 participants were located in the same tertile as the median value of all reported responses for that statement. RESULTS: Sixty five (81.2 %) of 80 invited oncologists with experience in the management of NETs answered a first round of the questionnaire and 57 (87.7 %) of those 65 answered a second round (mean age 43.5 years; 53.8 % women; median time of experience 9 years). Consensus was obtained in 42 (36 agreement and 6 disagreement) of the 48 statements (87.5 %). Regarding CS1 (Enteropancreatic NET, c-c, non-progressive in the last 3-6 months), overall, SSA treatment is recommended (a wait and see approach is anecdotal and reserved for fragile patients or with low tumor load or ki-67 < 2 %); CS2 (Pancreatic NET, c-c), overall, SSA monotherapy is recommended, except when high tumor load or tumor progression exists, where combination therapy would be considered; CS3 [Gastroenteropancreatic (GEP)-NET, c-c, in treatment with anti-proliferative dose of SSA and progressing], overall, SSA maintenance is recommended at the time of progression, with or without adding molecular targeted drugs; CS4 (GEP-NET, c-c, and negative octreoscan®), SSA in monotherapy is only considered in low-risk patients (low tumor load and Ki-67 < 5 %); CS5 [GEP-NET, c-c (ki67 > 10 %), and positive octreoscan®], monotherapy with SSA is mainly considered in patients with comorbidities. CONCLUSION: Several recommendations regarding use of SSAs in controversial NET CS were reached in consensus and might be considered as treatment guideline.

25 Article Continued advances in targeting gastroenteropancreatic neuroendocrine tumors: general discussion. 2014

Capdevila, Jaume / Weber, Matthias / Pape, Ulrich-Frank. ·Vall d'Hebron University Hospital, Barcelona, Spain. · Johannes Gutenberg University Mainz, Mainz, Germany. · Charité University Hospital, Berlin, Germany. ·Clin Adv Hematol Oncol · Pubmed #25768107.

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