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Pancreatic Neoplasms: HELP
Articles by Eric Raymond
Based on 31 articles published since 2008

Between 2008 and 2019, E. Raymond wrote the following 31 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. 2016

Garcia-Carbonero, R / Sorbye, H / Baudin, E / Raymond, E / Wiedenmann, B / Niederle, B / Sedlackova, E / Toumpanakis, C / Anlauf, M / Cwikla, J B / Caplin, M / O'Toole, D / Perren, A / Anonymous6950853. ·Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain. ·Neuroendocrinology · Pubmed #26731334.

ABSTRACT: -- No abstract --

2 Editorial Targeting neuroendocrine tumor: mixing standard options with novel therapies. 2012

Raymond, Eric / Dreyer, Chantal / Faivre, Sandrine. · ·Target Oncol · Pubmed #22918794.

ABSTRACT: -- No abstract --

3 Editorial New treatments of pancreatic neuroendocrine tumors: why using them? How to use them? 2012

Raymond, Eric / Ruszniewski, Philippe. · ·Target Oncol · Pubmed #22669625.

ABSTRACT: -- No abstract --

4 Review Targeting cancer cell metabolism in pancreatic adenocarcinoma. 2015

Cohen, Romain / Neuzillet, Cindy / Tijeras-Raballand, Annemilaï / Faivre, Sandrine / de Gramont, Armand / Raymond, Eric. ·INSERM U728, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy La Garenne, France. · Department of Medical Oncology, Henri Mondor University Hospital, Créteil, France. · AAREC Filia Research, Translational Department, Boulogne-Billancourt, France. · Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. · New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. ·Oncotarget · Pubmed #26164081.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

5 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.

6 Review Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas. 2014

Neuzillet, Cindy / de Gramont, Armand / Tijeras-Raballand, Annemilaï / de Mestier, Louis / Cros, Jérome / Faivre, Sandrine / Raymond, Eric. ·INSERM U728 and U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, Clichy, France. ·Oncotarget · Pubmed #24393789.

ABSTRACT: Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-β (TGF-β) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-β pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-β signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-β pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-β as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-β inhibition therapy.

7 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.

8 Review Stromal expression of SPARC in pancreatic adenocarcinoma. 2013

Neuzillet, Cindy / Tijeras-Raballand, Annemilaï / Cros, Jérôme / Faivre, Sandrine / Hammel, Pascal / Raymond, Eric. ·Department of Medical Oncology (INSERM U728-PRES Paris 7 Diderot), Beaujon University Hospital, Assistance Publique-Hôpitaux de Paris, 100 boulevard du Général Leclerc, 92110, Clichy-La-Garenne, France. ·Cancer Metastasis Rev · Pubmed #23690170.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) stands as the poorest prognostic tumor of the digestive tract, with a 5-year survival rate of less than 5%. Therapeutic options for unresectable PDAC are extremely limited and there is a pressing need for expanded therapeutic approaches to improve current options available with gemcitabine-based regimens. With PDAC displaying one of the most prominent desmoplastic stromal reactions of all carcinomas, recent research has focused on the microenvironment surrounding PDAC cells. Secreted protein acid and rich in cysteine (SPARC), which is overexpressed in PDAC, may display tumor suppressor functions in several cancers (e.g., in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia) but also appears to be overexpressed in other tumor types (e.g., breast cancer, melanoma, and glioblastoma). The apparent contradictory functions of SPARC may yield inhibition of angiogenesis via inhibition of vascular endothelial growth factor, while promoting epithelial-to-mesenchymal transition and invasion through matrix metalloprotease expression. This feature is of particular interest in PDAC where SPARC overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and metastasis. Several therapeutic strategies to deplete stromal tissue have been developed. In this review, we focused on key preclinical and clinical data describing the role of SPARC in PDAC biology, the properties, and mechanisms of delivery of drugs that interact with SPARC and discuss the proof-of-concept clinical trials using nab-paclitaxel.

9 Review Targeting the Ras-ERK pathway in pancreatic adenocarcinoma. 2013

Neuzillet, Cindy / Hammel, Pascal / Tijeras-Raballand, Annemilaï / Couvelard, Anne / Raymond, Eric. ·INSERM U728 and Department of Medical Oncology, Beaujon University Hospital (AP-HP Paris 7 Diderot), Clichy, France. ·Cancer Metastasis Rev · Pubmed #23085856.

ABSTRACT: Pancreatic ductal adenocarcinoma (PAC) stands as the poorest prognostic tumor of the digestive tract with limited therapeutic options. PAC carcinogenesis is associated with the loss of function of tumor suppressor genes such as INK4A, TP53, BRCA2, and DPC4, and only a few activated oncogenes among which K-RAS mutations are the most prevalent. The K-RAS mutation occurs early in PAC carcinogenesis, driving downstream activation of MEK and ERK1/2 which promote survival, invasion, and migration of cancer cells. In PAC models, inhibition of members of the Ras-ERK pathway blocks cellular proliferation and metastasis development. As oncogenic Ras does not appear to be a suitable drug target, inhibitors targeting downstream kinases including Raf and MEK have been developed and are currently under evaluation in clinical trials. In this review, we describe the role of the Ras-ERK pathway in pancreatic carcinogenesis and as a new therapeutic target for the treatment of PAC.

10 Review Resistance to targeted therapies in pancreatic neuroendocrine tumors (PNETs): molecular basis, preclinical data, and counteracting strategies. 2012

Tijeras-Raballand, Annemilaï / Neuzillet, Cindy / Couvelard, Anne / Serova, Maria / de Gramont, Armand / Hammel, Pascal / Raymond, Eric / Faivre, Sandrine. ·Pre Clinical Department, AAREC Filia Research, Boulogne-Billancourt, France. araballand@aarec-filia-research.com ·Target Oncol · Pubmed #22923165.

ABSTRACT: Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies.

11 Review Sunitinib in pancreatic neuroendocrine tumors. 2012

Raymond, Eric / Hammel, Pascal / Dreyer, Chantal / Maatescu, Christian / Hentic, Olivia / Ruszniewski, Philippe / Faivre, Sandrine. ·Department of Medical Oncology (INSERM U728-Paris 7 Diderot University), Beaujon University Hospital, 100 boulevard du Général Leclerc, 92110, Clichy, France. eric.raymond@bjn.aphp.fr ·Target Oncol · Pubmed #22661319.

ABSTRACT: Sunitinib is an oral multitarget tyrosine kinase inhibitor with potent antiangiogenic properties. Preclinical data have demonstrated that pancreatic neuroendocrine tumors depend on vascular endothelial growth factor receptors and platelet growth factor receptors-signaling pathways for tumor angiogenesis. Sunitinib has recently been approved for the treatment of patients with advanced, progressive pancreatic neuroendocrine tumors. Sunitinib has demonstrated clinically meaningful improvements in progression-free survival in a double-blinded randomized trial against placebo, setting progression-free survival as a valid endpoint for the evaluation of novel agents in patients with pancreatic neuroendocrine tumors. Although patients who progressed in this phase III trial were allowed to cross-over, a trend toward improvement in overall survival was also observed. In this trial, side effects reported with sunitinib were those previously reported in other tumor types, including hand-foot syndrome, diarrhea, and hypertension. This trial also investigated patient-reported outcome and showed that treatment with sunitinib did not affect quality of life of patient. Interestingly, this trial showed that sunitinib could be combined with somatostatin analogues without affecting the safety profile of either sunitinib or somatostatin analogues. Since the overall survival of patients with well-differentiated neuroendocrine tumors remains sufficiently long, it is worth considering using alternate sequences of targeted therapy (such as everolimus) and chemotherapy to optimize the care of patients with advanced diseases. The optimal sequence for using chemotherapy, everolimus, and sunitinib will remain to be established in clinical trials.

12 Review Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors. 2010

Faivre, Sandrine / Sablin, Marie-Paule / Dreyer, Chantal / Raymond, Eric. ·Department of Medical Oncology, Beaujon University Hospital (AP-HP, Paris 7 Diderot), Clichy, France. ·Endocrinol Metab Clin North Am · Pubmed #21095547.

ABSTRACT: Neuroendocrine tumors (NETs) are rare malignancies that arise from endocrine cells located in various anatomic locations, with a dramatic increase in incidence during the last 30 years. Limited therapeutic options are currently available for patients with advanced well-differentiated NETs, including carcinoids and pancreatic NETs. Streptozotocin-based chemotherapy and somatostatin analogues are drugs that are currently used for the treatment of progressive metastatic NETs. Recently, sunitinib demonstrating efficacy in pancreatic islet cell carcinomas has opened a new avenue for the treatment of NETs, and further trials shall be considered in NET types such as carcinoids, poorly differentiated neuroendocrine carcinomas, and several other endocrine tumors that depend on vascular endothelial growth factor (VEGF)/VEGF receptor for angiogenesis. In addition, drugs with distinct mechanisms of action, such as mammalian target of rapamycin inhibitors, currently investigated in phase 3 trials, may also supply novel options to control tumor growth and metastasis. Although acknowledged as rare tumors, recent data demonstrated the feasibility of large randomized trials in this disease. Furthermore, data from large trials also showed the importance of selecting an appropriate patient population when designing randomized studies. This review focuses on novel therapeutic approaches in the treatment of well-differentiated NETs. Based on recent data, novel strategies may now be designed using those anticancer agents to optimize the current treatment of patients with NETs.

13 Review Markers involved in resistance to cytotoxics and targeted therapeutics in pancreatic cancer. 2009

El Maalouf, Ghassan / Le Tourneau, Christophe / Batty, Georges Nicolas / Faivre, Sandrine / Raymond, Eric. ·Department of Medical Oncology, Service Inter-Hospitalier de Cancérologie Bichat-Beaujon, Beaujon University Hospital, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France. ghassan_maalouf@hotmail.com ·Cancer Treat Rev · Pubmed #19027240.

ABSTRACT: Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers and remains a challenge in oncology. In 1997, gemcitabine became the standard of care in metastatic setting. In the last decades, despite a number of clinical trials assessing novel cytotoxic agents and cell signaling inhibitors, overall survival has reached a plateau that remains difficult to improve. Development of mechanisms implicated in intrinsic and acquired resistance to chemotherapy are considered to play a key role that could explain the limited benefit of most treatment in pancreatic cancers. Key molecular factors implicated in this process include: deficiencies in drugs uptake, activations of DNA repair pathways, resistance to apoptosis, and tumor microenvironment. Moreover, for cell signaling inhibitors, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target, activation of autocrine/paracrine pathways and/or feed-back amplification of the target represent the most important mechanisms achieving resistance of pancreatic cancer cells.

14 Clinical Trial Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. 2018

Van Cutsem, Eric / Hidalgo, Manuel / Canon, Jean-Luc / Macarulla, Teresa / Bazin, Igor / Poddubskaya, Elena / Manojlovic, Nebojsa / Radenkovic, Dejan / Verslype, Chris / Raymond, Eric / Cubillo, Antonio / Schueler, Armin / Zhao, Charles / Hammel, Pascal. ·Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg/Leuven & KULeuven, Leuven, Belgium. · Centro Nacional Investigaciones Oncologicas, Madrid, Spain and START Madrid, Madrid, Spain. · Service d'Oncologie-Hématologie, Grand Hopital de Charleroi, Charleroi, Belgium. · Gastrointestinal Cancer Unit, Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain. · Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, and I.M. Sechenov First Moscow State Medical University, Moscow, Russia. · Clinic for Gastroenterology and Hepatology, Military Medical Academy of Serbia, Belgrade, Serbia. · First Surgical Clinic, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. · Medical Oncology Département, Saint Joseph Hospital, Paris, France. · HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (HM-CIOCC), and Departamento de Ciencias Médicas Clínicas, Universidad CEU San Pablo, Madrid, Spain. · Biostatistics, Merck KGaA, Darmstadt, Germany. · Clinical Oncology Early Development, EMD Serono, Billerica, MA. · Digestive Oncology Unit, Hôpital Beaujon, Clichy, France. ·Int J Cancer · Pubmed #29756206.

ABSTRACT: The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m

15 Clinical Trial Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms. 2018

Pellat, Anna / Dreyer, Chantal / Couffignal, Camille / Walter, Thomas / Lombard-Bohas, Catherine / Niccoli, Patricia / Seitz, Jean François / Hentic, Olivia / André, Thierry / Coriat, Romain / Faivre, Sandrine / Zappa, Magaly / Ruszniewski, Philippe / Pote, Nicolas / Couvelard, Anne / Raymond, Eric. ·Medical Oncology, Hôpital Saint Antoine, AP-HP, Paris, France. · Biostatistics, Hôpital Bichat, AP-HP, Paris, France. · Gastroenterology, Hôpital Edouard Herriot, Lyon, France. · Medical Oncology, Hôpital Edouard Herriot, Lyon, France. · Medical Oncology, Hôpital La Timone, Marseille, France. · Gastroenterology and Digestive Oncology, Hôpital La Timone, Marseille, France. · Gastroenterology, Hôpital Beaujon, AP-HP, Clichy, France. · Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, Sorbonne Paris Cité, Paris, France. · Medical Oncology, Hôpital Beaujon, AP-HP, Paris, France. · Radiology, Hôpital Beaujon, AP-HP, Clichy, France. · Department of Pathology Beaujon-Bichat, AP-HP, DHU UNITY, Clichy, France. · Medical Oncology, Hôpital Saint Joseph, AP-HP, Paris, France. ·Neuroendocrinology · Pubmed #29518779.

ABSTRACT: BACKGROUND/AIMS: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. METHODS: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. RESULTS: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. CONCLUSION: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.

16 Clinical Trial Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. 2017

Faivre, S / Niccoli, P / Castellano, D / Valle, J W / Hammel, P / Raoul, J-L / Vinik, A / Van Cutsem, E / Bang, Y-J / Lee, S-H / Borbath, I / Lombard-Bohas, C / Metrakos, P / Smith, D / Chen, J-S / Ruszniewski, P / Seitz, J-F / Patyna, S / Lu, D R / Ishak, K J / Raymond, E. ·Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy. · Cancer Care, Institut Paoli-Calmettes, and RENATEN Network, Marseille, France. · Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. · Medical Oncology Department, The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · Translational Medicine - Digestive Cancers, Institut Paoli-Calmettes and RENATEN Network, Marseille, France. · Eastern Virginia Medical School Streilitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, USA. · Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium. · Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea. · Hepato-Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Medical Oncology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. · McGill University Hospital Centre, Montreal, Canada. · Oncology Department, University Hospital, Bordeaux, France. · Linkou Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan. · Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, and RENATEN Network, Marseille, France. · Pfizer Oncology, La Jolla, USA. · Department of Evidera, St-Laurent, Canada. ·Ann Oncol · Pubmed #27836885.

ABSTRACT: Background: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. Patients and methods: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. Results: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. Conclusions: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. Trial registration number: NCT00428597.

17 Clinical Trial Patient-Reported Outcomes and Quality of Life with Sunitinib Versus Placebo for Pancreatic Neuroendocrine Tumors: Results From an International Phase III Trial. 2016

Vinik, Aaron / Bottomley, Andrew / Korytowsky, Beata / Bang, Yung-Jue / Raoul, Jean-Luc / Valle, Juan W / Metrakos, Peter / Hörsch, Dieter / Mundayat, Rajiv / Reisman, Arlene / Wang, Zhixiao / Chao, Richard C / Raymond, Eric. ·Strelitz Diabetes Research Center and Neuroendocrine Unit, Eastern Virginia Medical School, Strelitz Diabetes Center, Norfolk, VA, USA. vinikai@evms.edu. · Quality of Life Department, European Organization for Research and Treatment of Cancer, Brussels, Belgium. · Pfizer Inc, New York, NY, USA. · Seoul National University College of Medicine, Seoul, Korea. · Paoli-Calmettes Institute, Marseille, France. · The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · McGill University Hospital Center, Montreal, Canada. · Bad Berka Central Clinic, Bad Berka, Germany. · Pfizer Oncology, La Jolla, CA, USA. · Hôpital Beaujon, Clichy, France. ·Target Oncol · Pubmed #27924459.

ABSTRACT: OBJECTIVE: The objective of this analysis was to compare patient-reported outcomes and health-related quality of life (HRQoL) in a pivotal phase III trial of sunitinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NCT00428597). PATIENTS AND METHODS: Patients received sunitinib 37.5 mg (n = 86) or placebo (n = 85) on a continuous daily-dosing schedule until disease progression, unacceptable adverse events (AEs), or death. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 at baseline, Day 1 of every 4-week cycle, and end of treatment or withdrawal. Changes ≥10 points on each scale or item were deemed clinically meaningful. RESULTS: Sunitinib had anti-tumor effects and improved progression-free survival (PFS) compared with placebo. The study was terminated early for this reason and because of more serious AEs and deaths with placebo. Baseline HRQoL scores were well balanced between study arms, and were generally maintained over time in both groups. In the first 10 cycles, there were no significant differences between groups in global HRQoL, cognitive, emotional, physical, role, and social functioning domains, or symptom scales, except for worsening diarrhea with sunitinib (p < 0.0001 vs. placebo). Insomnia also worsened with sunitinib (p = 0.0372 vs. placebo), but the difference was not clinically meaningful. CONCLUSION: With the exception of diarrhea (a recognized side effect), sunitinib had no impact on global HRQoL, functional domains, or symptom scales during the progression-free period. Hence, in patients with pancreatic neuroendocrine tumors, sunitinib provided a benefit in PFS without adversely affecting HRQoL.

18 Clinical Trial Sunitinib: in advanced, well differentiated pancreatic neuroendocrine tumors. 2011

Deeks, Emma D / Raymond, Eric. ·Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz ·BioDrugs · Pubmed #21942915.

ABSTRACT: Sunitinib inhibits several receptor tyrosine kinases involved in cancer growth, metastasis, and neoangiogenesis, with its active metabolite (SU012662) demonstrating similar potency. In a randomized, double-blind, multinational, phase III trial, continuous treatment with oral sunitinib 37.5 mg/day significantly prolonged median progression-free survival time (primary endpoint) ≈2-fold relative to placebo in adults with locally advanced and/or metastatic, well differentiated pancreatic neuroendocrine tumors (pNETs). Sunitinib was also associated with a significantly greater objective tumor response rate than placebo, although limited data from an updated analysis demonstrated no significant difference between the treatments groups in terms of median overall survival. Continuous treatment with sunitinib generally had no detrimental effect on health-related quality of life and was generally well tolerated in patients with pNETs in this trial, with most adverse events being manageable and of grade 1 or 2 severity.

19 Clinical Trial Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. 2011

Raymond, Eric / Dahan, Laetitia / Raoul, Jean-Luc / Bang, Yung-Jue / Borbath, Ivan / Lombard-Bohas, Catherine / Valle, Juan / Metrakos, Peter / Smith, Denis / Vinik, Aaron / Chen, Jen-Shi / Hörsch, Dieter / Hammel, Pascal / Wiedenmann, Bertram / Van Cutsem, Eric / Patyna, Shem / Lu, Dongrui Ray / Blanckmeister, Carolyn / Chao, Richard / Ruszniewski, Philippe. ·Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France. eric.raymond@bjn.aphp.fr ·N Engl J Med · Pubmed #21306237.

ABSTRACT: BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

20 Clinical Trial Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. 2010

Mitry, Emmanuel / Hammel, Pascal / Deplanque, Gaël / Mornex, Françoise / Levy, Philippe / Seitz, Jean-François / Moussy, Alain / Kinet, Jean-Pierre / Hermine, Olivier / Rougier, Philippe / Raymond, Eric. ·Hépato-gastroentérologie et oncologie digestive, Assistance Publique des Hôpitaux de Paris, Hôpital Ambroise Paré, 92104, Boulogne Billancourt, France. ·Cancer Chemother Pharmacol · Pubmed #20364428.

ABSTRACT: PURPOSE: To evaluate the efficacy and safety of masitinib combined with gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-two non-randomised patients with unresectable, locally advanced (n = 9) or metastatic pancreatic cancer (n = 13) received oral masitinib (9 mg/kg/day) combined with standard gemcitabine. All patients were naive to systemic chemotherapy or radiotherapy. The primary endpoint was time-to-progression (TTP) with efficacy and safety analyses performed on the intent-to-treat population. Secondary endpoints included overall survival (OS), as well as, subgroup analyses according to baseline disease, and performance status. RESULTS: Overall median TTP was 6.4 months (95% CI [2.7-11.7]); 8.3 and 2.7 months, respectively, for locally advanced and metastatic patients; 6.4 and 0.8 months, respectively, for patients with KPS [80-100] or KPS [70]. Median OS was 7.1 months (95% CI [4.8-17.0]); 8.4 and 6.8 months for locally advanced or metastatic patients, respectively; 8.0 and 4.4 months in patients with KPS [80-100] or KPS [70], respectively. The 18-month observed survival rate was similar for locally advanced (22%) and metastatic patients (23%) and reached 28% for KPS [80-100] patients. The most common suspected adverse events were nausea, vomiting, rash, diarrhoea, peripheral oedema, anaemia, lymphopenia, thrombocytopenia, pyrexia, neutropenia, asthenia, leucopenia, and abdominal pain, and most were of grades 1-2 severity. CONCLUSIONS: The efficacy and safety of masitinib combined with gemcitabine are encouraging, with extended survival and median TTP that support initiation of a phase 3 trial.

21 Clinical Trial Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. 2008

Tanaka, Chiaki / O'Reilly, Terence / Kovarik, John M / Shand, Nicholas / Hazell, Katharine / Judson, Ian / Raymond, Eric / Zumstein-Mecker, Sabine / Stephan, Christine / Boulay, Anne / Hattenberger, Marc / Thomas, George / Lane, Heidi A. ·Novartis Pharmaceuticals Corp, East Hanover, NJ, USA. ·J Clin Oncol · Pubmed #18332467.

ABSTRACT: PURPOSE: To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients. PATIENTS AND METHODS: Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats. RESULTS: Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses. CONCLUSION: A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.

22 Article Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours. 2018

Raymond, Eric / Kulke, Matthew H / Qin, Shukui / Yu, Xianjun / Schenker, Michael / Cubillo, Antonio / Lou, Wenhui / Tomasek, Jiri / Thiis-Evensen, Espen / Xu, Jian-Ming / Croitoru, Adina E / Khasraw, Mustafa / Sedlackova, Eva / Borbath, Ivan / Ruff, Paul / Oberstein, Paul E / Ito, Tetsuhide / Jia, Liqun / Hammel, Pascal / Shen, Lin / Shrikhande, Shailesh V / Shen, Yali / Sufliarsky, Jozef / Khan, Gazala N / Morizane, Chigusa / Galdy, Salvatore / Khosravan, Reza / Fernandez, Kathrine C / Rosbrook, Brad / Fazio, Nicola. ·Department of Medical Oncology, Paris Saint-Joseph Hospital Group, Paris, France. · Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China. · Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. · Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania. · Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain. · Zhongshan Hospital, Fudan University, Shanghai, China. · Faculty of Medicine, Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic. · Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · No. 307 Hospital, Academy of Military Medical Sciences, Beijing, China. · Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania. · Andrew Love Cancer Center, Geelong Hospital, Victoria, Victoria, Australia. · Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Prague, Czech Republic. · Hepato-Gastroenterology Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. · Division of Hematology/Oncology, Columbia University Medical Center, New York, New York, USA. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · China-Japan Friendship Hospital, Beijing, China. · Service d'Oncologie Digestive, Hôpital Beaujon, Clichy, France. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University Cancer Hospital and Institute, Beijing, China. · GI and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · West China Hospital of Sichuan University, Chengdu, China. · 2nd Department of Oncology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. · Henry Ford Health System, Detroit, Michigan, USA. · National Cancer Center, Tokyo, Japan. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italy. · Pfizer Oncology, Pfizer Inc., San Diego, California, USA. · Pfizer Oncology, Pfizer Inc., Cambridge, Massachusetts, USA. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italynicola.fazio@ieo.it. ·Neuroendocrinology · Pubmed #29991024.

ABSTRACT: BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

23 Article Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response. 2018

Lamarca, Angela / Barriuso, Jorge / Kulke, Matthew / Borbath, Ivan / Lenz, Heinz-Josef / Raoul, Jean Luc / Meropol, Neal J / Lombard-Bohas, Catherine / Posey, James / Faivre, Sandrine / Raymond, Eric / Valle, Juan W. ·Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester M20 4BX, UK. · Faculty of Medical, Biological and Human Sciences, University of Manchester, Manchester M13 9GB, UK. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles 1200, Belgium. · University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. · Paoli-Calmettes Institute, Marseille 13009, France. · Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. · Flatiron Health, New York, NY 10010, USA. · Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon 69002, France. · Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. · Department of Medical Oncology, Beaujon University Hospital, Paris 92110, France. · Department of Medical Oncology, Groupe Hospitalier Paris Saint-Joseph, Paris 75014, France. · Institute of Cancer Sciences, University of Manchester, Manchester M204BX, UK. ·Br J Cancer · Pubmed #29161241.

ABSTRACT: BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg '4-weeks on/2-weeks off' schedule; n=86 '37.5 mg continuous daily dosing (CDD)')) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P<0.001). A PR was seen in 19 patients (13%) on sunitinib; the median change in the sum of the lesions (vs baseline) was -12.8% (range -100 to +36.4). Month 7 was the most informative time-point (AUC 0.78 (95% CI 0.66-0.9); odds ratio 1.05 (95% CI 1.01-1.08), P=0.002). Reduction of 10% (vs baseline) achieved the highest sensitivity (50%) and specificity (82%), amongst cut-offs tested. A 10% reduction in marker lesions was associated with improved PFS in the whole sunitinib population (HR 0.55 (95 CI 0.3-0.9); P=0.04); mostly in patients on sunitinib CDD (HR 0.33 (95% CI 0.2-0.7); P=0.005). A 10% reduction in marker lesions (P=0.034) and sunitinib treatment (P=0.012) independently impacted on PFS (multivariable analysis). CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design.

24 Article High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis. 2015

Neuzillet, Cindy / Couvelard, Anne / Tijeras-Raballand, Annemilaï / de Mestier, Louis / de Gramont, Armand / Bédossa, Pierre / Paradis, Valérie / Sauvanet, Alain / Bachet, Jean-Baptiste / Ruszniewski, Philippe / Raymond, Eric / Hammel, Pascal / Cros, Jérôme. ·INSERM UMR1149. · Department of Digestive Oncology, Beaujon University Hospital, Clichy, France. · Paris 7 Denis Diderot University, Paris, France. · Department of Pathology, Bichat-Beaujon University Hospital, Paris-Clichy, France. · Department of Translational Research, AAREC Filia Research, Boulogne-Billancourt, France. · Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Department of Biliary and Pancreatic Surgery, Beaujon University Hospital, Clichy, France. · Department of Gastroenterology, Pitié-Salpêtrière University Hospital, Paris, France. · Department of Gastroenterology and Pancreatology, Beaujon University Hospital, Clichy, France. ·Histopathology · Pubmed #25809563.

ABSTRACT: AIMS: c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting. METHODS AND RESULTS: c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.

25 Article Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors. 2014

Valle, Juan W / Faivre, Sandrine / Hubner, Richard A / Grande, Enrique / Raymond, Eric. ·University of Manchester, Manchester Health Sciences Centre and Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Electronic address: Juan.Valle@christie.nhs.uk. · Medical Oncology, Beaujon University Hospital (AP-HP) Paris 7 Diderot, Clichy, France. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. · Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain. ·Cancer Treat Rev · Pubmed #25283354.

ABSTRACT: Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4weeks on/2weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand-foot syndrome, and hypertension.