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Pancreatic Neoplasms: HELP
Articles by Juan W. Valle
Based on 36 articles published since 2008
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Between 2008 and 2019, J. Valle wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). 2012

Ramage, John K / Ahmed, A / Ardill, J / Bax, N / Breen, D J / Caplin, M E / Corrie, P / Davar, J / Davies, A H / Lewington, V / Meyer, T / Newell-Price, J / Poston, G / Reed, N / Rockall, A / Steward, W / Thakker, R V / Toubanakis, C / Valle, J / Verbeke, C / Grossman, A B / Anonymous3000709. ·Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke RG24 9NA, UK. john.ramage@bnhft.nhs.uk ·Gut · Pubmed #22052063.

ABSTRACT: These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

2 Review Irreversible Electroporation in pancreatic ductal adenocarcinoma: Is there a role in conjunction with conventional treatment? 2018

de Liguori Carino, Nicola / O'Reilly, Derek A / Siriwardena, Ajith K / Valle, Juan W / Radhakrishna, Ganesh / Pihlak, Rille / McNamara, Mairéad G. ·Regional Hepato-Pancreato-Biliary Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. Electronic address: nicola.deliguoricarino@mft.nhs.uk. · Regional Hepato-Pancreato-Biliary Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK. · Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. ·Eur J Surg Oncol · Pubmed #30146253.

ABSTRACT: BACKGROUND: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC. AIMS AND METHODS: This narrative review aims to explore the potential role and timing for the use of IRE in patients with LAPC. RESULTS: To date, there is limited and inconsistent level I and II evidence available in the literature regarding the use of IRE for the treatment of PDAC. DISCUSSION: Although some of the preliminary experience of the use of IRE in patients with LAPC is encouraging, it should only be used after conventional evidence-based treatments and/or within the research context.

3 Review Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis. 2017

Chiramel, Jaseela / Backen, Alison C / Pihlak, Rille / Lamarca, Angela / Frizziero, Melissa / Tariq, Noor-Ul-Ain / Hubner, Richard A / Valle, Juan W / Amir, Eitan / McNamara, Mairéad G. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Jaseela.chiramel@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Alison.backen@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Rille.Pihlak@christie.nhs.uk. · Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK. Rille.Pihlak@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Angela.Lamarca@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Melissa.Frizziero@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Noorulain.Tariq@christie.nhs.uk. · Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK. Noorulain.Tariq@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Richard.hubner@christie.nhs.uk. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. juan.valle@christie.nhs.uk. · Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK. juan.valle@christie.nhs.uk. · Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Eitan.Amir@uhn.ca. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Mairead.McNamara@christie.nhs.uk. · Division of Molecular & Clinical Cancer Sciences, University of Manchester, Manchester M20 4BX, UK. Mairead.McNamara@christie.nhs.uk. ·Int J Mol Sci · Pubmed #28445400.

ABSTRACT: Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90,

4 Review Pancreatic cancer: Are "liquid biopsies" ready for prime-time? 2016

Lewis, Alexandra R / Valle, Juan W / McNamara, Mairead G. ·Alexandra R Lewis, Juan W Valle, Mairead G McNamara, The Christie NHS Foundation Trust, M20 4BX Manchester, United Kingdom. ·World J Gastroenterol · Pubmed #27621566.

ABSTRACT: Pancreatic cancer is a disease that carries a poor prognosis. Accurate tissue diagnosis is required. Tumours contain a high content of stromal tissue and therefore biopsies may be inconclusive. Circulating tumour cells (CTCs) have been investigated as a potential "liquid biopsy" in several malignancies and have proven to be of prognostic value in breast, prostate and colorectal cancers. They have been detected in patients with localised and metastatic pancreatic cancer with sensitivities ranging from 38%-100% using a variety of platforms. Circulating tumour DNA (ctDNA) has also been detected in pancreas cancer with a sensitivity ranging from 26%-100% in studies across different platforms and using different genetic markers. However, there is no clear consensus on which platform is the most effective for detection, nor which genetic markers are the most useful to use. Potential roles of liquid biopsies include diagnosis, screening, guiding therapies and prognosis. The presence of CTCs or ctDNA has been shown to be of prognostic value both at diagnosis and after treatment in patients with pancreatic cancer. However, more prospective studies are required before this promising technology is ready for adoption into routine clinical practice.

5 Review 18F-FLT PET imaging of cellular proliferation in pancreatic cancer. 2016

Lamarca, Angela / Asselin, Marie-Claude / Manoharan, Prakash / McNamara, Mairéad G / Trigonis, Ioannis / Hubner, Richard / Saleem, Azeem / Valle, Juan W. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. Electronic address: angela.lamarca@christie.nhs.uk. · University of Manchester Wolfson Molecular Imaging Centre (WMIC), Manchester, United Kingdom. · Department of Radiology, The Christie NHS Foundation Trust, Manchester, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; University of Manchester, Institute of Cancer Sciences, Manchester Academic Health Science Centre, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. · University of Manchester Wolfson Molecular Imaging Centre (WMIC), Manchester, United Kingdom; Imanova Centre for Imaging Sciences, Imperial College Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; University of Manchester, Institute of Cancer Sciences, Manchester Academic Health Science Centre, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. Electronic address: juan.valle@manchester.ac.uk. ·Crit Rev Oncol Hematol · Pubmed #26778585.

ABSTRACT: Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of computerized tomography, magnetic resonance and endoscopic ultrasound, novel imaging techniques have struggled to get established in the management of patients diagnosed with pancreatic adenocarcinoma for several reasons. Thus, imaging assessment of pancreatic cancer remains a field with scope for further improvement. In contrast to cross-sectional anatomical imaging methods, molecular imaging modalities such as positron emission tomography (PET) can provide information on tumour function. Particularly, tumour proliferation may be assessed by measurement of intracellular thymidine kinase 1 (TK1) activity level using thymidine analogues radiolabelled with a positron emitter for use with PET. This approach, has been widely explored with [(18)F]-fluoro-3'-deoxy-3'-L-fluorothymidine ((18)F-FLT) PET. This manuscript reviews the rationale and physiology behind (18)F-FLT PET imaging, with special focus on pancreatic cancer and other gastrointestinal malignancies. Potential benefit and challenges of this imaging technique for diagnosis, staging and assessment of treatment response in abdominal malignancies are discussed.

6 Review A Systematic Review of the Burden of Pancreatic Cancer in Europe: Real-World Impact on Survival, Quality of Life and Costs. 2015

Carrato, A / Falcone, A / Ducreux, M / Valle, J W / Parnaby, A / Djazouli, K / Alnwick-Allu, K / Hutchings, A / Palaska, C / Parthenaki, I. ·Medical Oncology Department, Ramon y Cajal University Hospital, Ctra. Colmenar Viejo Km. 9,100, Madrid, Spain. ·J Gastrointest Cancer · Pubmed #25972062.

ABSTRACT: PURPOSE: The purpose of this study was to assess the overall burden of pancreatic cancer in Europe, with a focus on survival time in a real-world setting, and the overall healthy life lost to the disease. METHODS: Real-world data were retrieved from peer-reviewed, observational studies identified by an electronic search. We performed two de novo analyses: a proportional shortfall analysis to quantify the proportion of healthy life lost to pancreatic cancer and an estimation of the aggregate life-years lost annually in Europe. RESULTS: Ninety-one studies were included. The median, age-standardised incidence of pancreatic cancer per 100,000 was 7.6 in men and 4.9 in women. Overall median survival from diagnosis was 4.6 months; median survival was 2.8-5.7 months in patients with metastatic disease. The proportional shortfall analysis showed that pancreatic cancer results in a 98 % loss of healthy life, with a life expectancy at diagnosis of 4.6 months compared to 15.1 years for an age-matched healthy population. Annually, 610,000-915,000 quality-adjusted life-years (QALYs) are lost to pancreatic cancer in Europe. Patients had significantly lower scores on validated health-related quality of life instruments versus population norms. CONCLUSIONS: To the best of our knowledge, this is the first study to systematically review real-world overall survival and patient outcomes of pancreatic cancer patients in Europe outside the context of clinical trials. Our findings confirm the poor prognosis and short survival reported by national studies. Pancreatic cancer is a substantial burden in Europe, with nearly a million aggregate life-years lost annually and almost complete loss of healthy life in affected individuals.

7 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.

8 Review A systematic review of non-surgical treatments for pancreatic neuroendocrine tumours. 2014

Valle, Juan W / Eatock, Martin / Clueit, Ben / Gabriel, Zahava / Ferdinand, Roxanne / Mitchell, Stephen. ·Department of Medical Oncology, Christie Hospital NHS Foundation Trust, Manchester, UK. Electronic address: Juan.valle@christie.nhs.uk. · Department of Medical Oncology, Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, UK. Electronic address: MartinEatock@bch.n-i.nhs.uk. · Pfizer UK, Tadworth, Surrey, UK. Electronic address: Benjamin.Clueit@Pfizer.com. · Pfizer UK, Tadworth, Surrey, UK. Electronic address: Zahava.gabriel@pfizer.com. · Pfizer UK, Tadworth, Surrey, UK. Electronic address: roxanne.ferdinand@pfizer.com. · Abacus International, 6 Talisman Business Centre, Talisman Road, Bicester, Oxfordshire OX26 6HR, UK. Electronic address: Stephen.mitchell@abacusint.com. ·Cancer Treat Rev · Pubmed #24296109.

ABSTRACT: INTRODUCTION: Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base. METHODS: Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers. RESULTS: Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies. DISCUSSION: The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm.

9 Review Sunitinib for advanced pancreatic neuroendocrine tumors. 2011

Hubner, Richard A / Valle, Juan W. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. ·Expert Rev Anticancer Ther · Pubmed #22117148.

ABSTRACT: Recent recognition of the high prevalence of neuroendocrine tumors in combination with a sustained failure to improve outcomes for patients with advanced disease has elevated their priority for research and drug development. Sunitinib (SU11248, Sutent; Pfizer Inc. NY, USA) potently inhibits multiple-receptor tyrosine kinases, resulting in antiangiogenic effects. A growing body of evidence indicates angiogenesis is a clinically relevant therapeutic target in pancreatic neuroendocrine tumors, culminating in a Phase III randomized study of sunitinib in patients with advanced progressive pancreatic neuroendocrine tumors. Sunitinib has recently gained regulatory approval as a single agent in this setting, and future studies will investigate most appropriate patient selection, and sequencing and combination with other targeted and cytotoxic agents. Here, we discuss in detail the molecular properties, clinical efficacy and safety of sunitinib in the context of pancreatic neuroendocrine tumors.

10 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.

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

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

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

12 Clinical Trial Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. 2017

Middleton, Gary / Palmer, Daniel H / Greenhalf, William / Ghaneh, Paula / Jackson, Richard / Cox, Trevor / Evans, Anthony / Shaw, Victoria E / Wadsley, Jonathan / Valle, Juan W / Propper, David / Wasan, Harpreet / Falk, Stephen / Cunningham, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Wadd, Nick / Corrie, Pippa / Hickish, Tamas / Costello, Eithne / Campbell, Fiona / Rawcliffe, Charlotte / Neoptolemos, John P. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London, UK. · Hammersmith Hospital, London, UK. · Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · Royal Marsden, Royal Marsden NHS Foundation Trust, London, UK. · Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Poole Hospital NHS Foundation Trust, Bournemouth University, Poole, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #28259610.

ABSTRACT: BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca.

13 Clinical Trial Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 2017

Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Psarelli, Eftychia E / Valle, Juan W / Halloran, Christopher M / Faluyi, Olusola / O'Reilly, Derek A / Cunningham, David / Wadsley, Jonathan / Darby, Suzanne / Meyer, Tim / Gillmore, Roopinder / Anthoney, Alan / Lind, Pehr / Glimelius, Bengt / Falk, Stephen / Izbicki, Jakob R / Middleton, Gary William / Cummins, Sebastian / Ross, Paul J / Wasan, Harpreet / McDonald, Alec / Crosby, Tom / Ma, Yuk Ting / Patel, Kinnari / Sherriff, David / Soomal, Rubin / Borg, David / Sothi, Sharmila / Hammel, Pascal / Hackert, Thilo / Jackson, Richard / Büchler, Markus W / Anonymous8200894. ·University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. · University of Liverpool, Liverpool, UK; The Clatterbridge Cancer Centre, Wirral, UK. · The Royal Liverpool University Hospital, Liverpool, UK. · University of Liverpool, Liverpool, UK. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. · The Clatterbridge Cancer Centre, Wirral, UK. · Manchester Royal Infirmary, Manchester, UK. · Royal Marsden Hospital, London, UK. · Weston Park Hospital, Sheffield, UK. · Royal Free Hospital, London, UK. · St James's University Hospital, Leeds, UK. · Karolinska Institute, Stockholm, Sweden; Clinical Research Sörmland, Eskilstuna, Sweden. · University of Uppsala, Uppsala, Sweden. · Bristol Haematology and Oncology Centre, Bristol, UK. · University of Hamburg Medical institutions UKE, Hamburg, Germany. · Royal Surrey County Hospital, Guildford, UK. · Guy's Hospital, London, UK. · Hammersmith Hospital, London, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Velindre Hospital, Cardiff, UK. · Queen Elizabeth Hospital, Birmingham, UK. · Churchill Hospital, Oxford, UK. · Derriford Hospital, Plymouth, UK. · Ipswich Hospital, Ipswich, UK. · Skåne University Hospital, Lund, Sweden. · University Hospital Coventry, Coventry, UK. · Hôpital Beaujon, Clichy, France. · University of Heidelberg, Germany. ·Lancet · Pubmed #28129987.

ABSTRACT: BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

14 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.

15 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.

16 Clinical Trial Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. 2014

Middleton, Gary / Silcocks, Paul / Cox, Trevor / Valle, Juan / Wadsley, Jonathan / Propper, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Roques, Tom / Cunningham, David / Falk, Stephen / Wadd, Nick / Harrison, Mark / Corrie, Pippa / Iveson, Tim / Robinson, Angus / McAdam, Karen / Eatock, Martin / Evans, Jeff / Archer, Caroline / Hickish, Tamas / Garcia-Alonso, Angel / Nicolson, Marianne / Steward, William / Anthoney, Alan / Greenhalf, William / Shaw, Victoria / Costello, Eithne / Naisbitt, Dean / Rawcliffe, Charlotte / Nanson, Gemma / Neoptolemos, John. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. · Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK. · Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK. · The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK. · Bristol Haematology And Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middleborough, UK. · Mount Vernon Hospital, The Hillingdon Hospitals NHS Foundation Trust, Northwood, UK. · Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, UK. · Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St Leonards-on-Sea, East Sussex, UK. · Peterborough City Hospital, Peterborough and Stamford Hospitals NHS Foundation Trust, Edith, Cavell Campus, Peterborough, UK. · Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK. · University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK. · Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth, UK. · Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK. · Glan Clwyd Hospital, University Health Board, Rhyl, Denbighshire, UK. · Abderdeen Royal Infirmary, NHS Grampian, Aberdeen, UK. · Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK. · St James University Hospital, The Leeds Teaching Hospital Trust, Beckett Street, Leeds, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #24954781.

ABSTRACT: BACKGROUND: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING: Cancer Research UK and KAEL-GemVax.

17 Clinical Trial Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. 2014

Valle, Juan W / Palmer, Daniel / Jackson, Richard / Cox, Trevor / Neoptolemos, John P / Ghaneh, Paula / Rawcliffe, Charlotte L / Bassi, Claudio / Stocken, Deborah D / Cunningham, David / O'Reilly, Derek / Goldstein, David / Robinson, Bridget A / Karapetis, Christos / Scarfe, Andrew / Lacaine, Francois / Sand, Juhani / Izbicki, Jakob R / Mayerle, Julia / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Lind, Pehr A / Middleton, Mark R / Anthoney, Alan / Sumpter, Kate / Carter, Ross / Büchler, Markus W. ·Juan W. Valle, Derek O'Reilly, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester · Richard Jackson, Trevor Cox, John P. Neoptolemos, Paula Ghaneh, Charlotte L. Rawcliffe, Liverpool Cancer Research UK Centre and the National Institute for Health Research Pancreas Biomedical Research Unit, University of Liverpool, Liverpool · Daniel Palmer, the Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust · Deborah D. Stocken, the Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham · David Cunningham, Royal Marsden Hospital Foundation Trust, Sutton · Mark R. Middleton, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford · Alan Anthoney, The Leeds Teaching Hospital Trust, Leeds · Kate Sumpter, Freeman Hospital, Newcastle upon Tyne · Ross Carter, Glasgow Royal Infirmary, Glasgow, United Kingdom · Claudio Bassi, Giovanni Butturini, University of Verona, Verona, Italy · David Goldstein, Bridget A. Robinson, Christos Karapetis, the Australasian Gastro-Intestinal Trials Group, Camperdown, Australia · Andrew Scarfe, University of Alberta, Edmonton, Canada · Francois Lacaine, Hôpital TENON, Assistance Publique Hôpitaux de Paris, Universite Pierre Et Marie Curie, Paris, France · Juhani Sand, Tampere University Hospital, Tampere, Finland · Jakob R. Izbicki, University of Hamburg, Hamburg · Julia Mayerle, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald · Markus W. Büchler, University of Heidelberg, Heidelberg, Germany · Christos Dervenis, the Agia Olga Hospital, Athens, Greece · Attila Oláh, the Petz Aladar Hospital, Gyor, Hungary · Pehr A. Lind, Karolinska-Stockholm Söder Hospital, Stockholm, Sweden. ·J Clin Oncol · Pubmed #24419109.

ABSTRACT: PURPOSE: Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS: Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS: There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION: Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

18 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.).

19 Clinical Trial Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. 2010

Neoptolemos, John P / Stocken, Deborah D / Bassi, Claudio / Ghaneh, Paula / Cunningham, David / Goldstein, David / Padbury, Robert / Moore, Malcolm J / Gallinger, Steven / Mariette, Christophe / Wente, Moritz N / Izbicki, Jakob R / Friess, Helmut / Lerch, Markus M / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Doi, Ryuichiro / Lind, Pehr A / Smith, David / Valle, Juan W / Palmer, Daniel H / Buckels, John A / Thompson, Joyce / McKay, Colin J / Rawcliffe, Charlotte L / Büchler, Markus W / Anonymous9620671. ·Liverpool Cancer Research UK Cancer Trials Unit, Cancer Research UK Centre, University of Liverpool, Fifth Floor, UCD Bldg, Daulby Street, Liverpool, L69 3GA, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #20823433.

ABSTRACT: CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

20 Clinical Trial A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer. 2010

Meyer, T / Caplin, M E / Palmer, D H / Valle, J W / Larvin, M / Waters, J S / Coxon, F / Borbath, I / Peeters, M / Nagano, E / Kato, H. ·UCL, London, UK. t.meyer@ucl.ac.uk ·Eur J Cancer · Pubmed #20006921.

ABSTRACT: AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

21 Clinical Trial Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. 2009

Cunningham, David / Chau, Ian / Stocken, Deborah D / Valle, Juan W / Smith, David / Steward, William / Harper, Peter G / Dunn, Janet / Tudur-Smith, Catrin / West, Julia / Falk, Stephen / Crellin, Adrian / Adab, Fawzi / Thompson, Joyce / Leonard, Pauline / Ostrowski, Joe / Eatock, Martin / Scheithauer, Werner / Herrmann, Richard / Neoptolemos, John P. ·Royal Marsden National HealthService (NHS) Foundation Trust, London and Surrey, United Kingdom. david.cunningham@rmh.nhs.uk ·J Clin Oncol · Pubmed #19858379.

ABSTRACT: PURPOSE: Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP). PATIENTS AND METHODS: Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status On the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.

22 Article Adjuvant chemotherapy and outcomes in patients with nodal and resection margin-negative pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. 2019

Flaum, Nicola / Hubner, Richard A / Valle, Juan W / Amir, Eitan / McNamara, Mairéad G. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. · Division of Cancer Sciences, University of Manchester, Manchester, UK. · Department of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada. ·J Surg Oncol · Pubmed #30838647.

ABSTRACT: Adjuvant chemotherapy (AC) following pancreatic carcinoma (PC) resection improves overall survival (OS). A systematic review identified 10 phase-2/3 studies investigating AC in 3644 patients looking at the influence of nodal and resection status. AC significantly improved disease free survival, OS and 5-year odds of death risk. There was greater survival benefit in patients PS 0 and with body/tail tumors. There was a nonsignificant effect in N

23 Article Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe. 2019

Javed, Muhammad Ahsan / Beyer, Georg / Le, Nha / Vinci, Alessio / Wong, Helen / Palmer, Daniel / Morgan, Robert D / Lamarca, Angela / Hubner, Richard A / Valle, Juan W / Alam, Salma / Chowdhury, Sumsur / Ma, Yuk Ting / Archibugi, Livia / Capurso, Gabriele / Maisonneuve, Patrick / Neesse, Albrecht / Sund, Malin / Schober, Marvin / Krug, Sebastian. ·NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, Royal Liverpool University Hospital, United Kingdom. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Medical Department II, University Hospital, LMU, Munich, Germany. · Gastroenterology Division, Second Internal Medicine Department, Semmelweis University, Budapest, Hungary. · University of Pavia, Department of Surgery, S. Matteo University Hospital Foundation, Pavia, Italy. · Department of Quality and Information Intelligence, The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom. · Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom. · Department of Hepatobiliary Oncology, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. · Digestive and Liver Disease Unit, S. Andrea Hospital, University Sapienza, Rome, Italy. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · University Medical Centre Göttingen, Department of Gastroenterology and Gastrointestinal Oncology, Göttingen, Germany. · University of Umea, Department of Surgical and Perioperative Sciences, Umea, Sweden. Electronic address: malin.sund@surgery.umu.se. · Department of Gastroenterology and Hepatology, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Pancreatology · Pubmed #30529068.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe. METHODS: A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors. RESULTS: Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis. CONCLUSION: Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.

24 Article Health-related quality of life, anxiety, depression and impulsivity in patients with advanced gastroenteropancreatic neuroendocrine tumours. 2018

Lewis, Alexandra R / Wang, Xin / Magdalani, Laurice / D'Arienzo, Paolo / Bashir, Colsom / Mansoor, Was / Hubner, Richard / Valle, Juan W / McNamara, Mairéad G. ·Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Biostatistics, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Division of Medical Sciences, Scuola Superiore Sant'Anna, Pisa 56127, Italy. · Department of Clinical Psychology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom. mairead.mcnamara@christie.nhs.uk. ·World J Gastroenterol · Pubmed #29456406.

ABSTRACT: AIM: To compare health-related quality of life (HRQoL), anxiety, depression, and impulsivity scores in patients with and without carcinoid syndrome (CS), and correlated them with serum 5-hydroxyindoleacetic acid (5-HIAA) levels. METHODS: Patients with advanced gastroenteropancreatic neuroendocrine tumours (GEPNET), with and without CS completed HRQoL QLQ-C30 and QLQ-GI.NET21, Hospital Anxiety and Depression Scale (HADS) and Barratt Impulsivity Scale (BIS) questionnaires. Two-sample Wilcoxon test was applied to assess differences in serum 5-HIAA levels, two-sample Mann-Whitney RESULTS: Fifty patients were included; 25 each with and without CS. Median 5-HIAA in patients with and without CS was 367nmol/L and 86nmol/L, respectively ( CONCLUSION: Excepting endocrine symptoms, there were no significant differences in HRQoL, anxiety, depression or impulsivity between patients with advanced GEPNET, with or without CS. Over one quarter of patients had high anxiety scores, unrelated to peripheral serotonin metabolism.

25 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.

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