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Pancreatic Neoplasms: HELP
Articles by Eric Van Cutsem
Based on 29 articles published since 2008
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Between 2008 and 2019, E. Van Cutsem wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018

Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.

ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

2 Guideline European experts consensus statement on cystic tumours of the pancreas. 2013

Del Chiaro, Marco / Verbeke, Caroline / Salvia, Roberto / Klöppel, Gunter / Werner, Jens / McKay, Colin / Friess, Helmut / Manfredi, Riccardo / Van Cutsem, Eric / Löhr, Matthias / Segersvärd, Ralf / Anonymous3140750. ·Division of Surgery, CLINTEC, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden. Electronic address: marco.del-chiaro@karolinska.se. ·Dig Liver Dis · Pubmed #23415799.

ABSTRACT: Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

3 Guideline Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2012

Seufferlein, T / Bachet, J B / Van Cutsem, E / Rougier, P / Anonymous3540737. ·Department of Internal Medicine I, University of Ulm, Ulm, Germany. ·Ann Oncol · Pubmed #22997452.

ABSTRACT: -- No abstract --

4 Review Scleroderma-like cutaneous lesions during treatment with paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. Review of literature. 2018

Verhulst, Lien / Noë, Esther / Morren, Marie-Anne / Verslype, Chris / Van Cutsem, Eric / Van den Oord, Joost J / De Haes, Petra. ·Department of Dermatology, AZ Delta Hospital and private practice, Roeselare, Belgium. · Department of Dermatology, UZ Leuven, Leuven, Belgium. · Department of Digestive Oncology, UZ Leuven and KULeuven, Leuven, Belgium. · Department of Pathology, UZ Leuven, Leuven, Belgium. ·Int J Dermatol · Pubmed #29938783.

ABSTRACT: BACKGROUND: Chemotherapy-induced skin sclerosis is generally not associated with other manifestations of systemic sclerosis. It is featured by skin sclerosis without visceral involvement (i.e., Raynaud's phenomenon, esophageal dysmotility, and pulmonary fibrosis), temporal association with chemotherapy administration, and the absence of detectable autoantibodies. The clinical course of scleroderma-like changes induced by paclitaxel or gemcitabine are refractory to treatment and commonly progressive, even after discontinuation of the triggering drugs. OBJECTIVE: Report a case of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma and determine other published cases of scleroderma-like skin changes following treatment with nab-paclitaxel, paclitaxel, or gemcitabine through the period from 2002 to 2018. METHODS: Literature search from the year 2002 onwards using combinations of "Scleroderma" AND "paclitaxel," AND/OR "gemcitabine." RESULTS: Additional to our case report we reviewed 14 other cases in the literature. Most of these cases share three prominent features: skin sclerosis without systemic involvement, temporal association with chemotherapy administration, and absence of detectable scleroderma-specific autoantibodies. CONCLUSION: To our knowledge, this is the first case report of scleroderma-like cutaneous lesions during combination treatment with nab-paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. However, given the current literature, these scleroderma-like lesions are most likely induced by nab-paclitaxel or paclitaxel, rather than by gemcitabine.

5 Review Pancreatic cancer treatment and research: an international expert panel discussion. 2011

Tempero, M A / Berlin, J / Ducreux, M / Haller, D / Harper, P / Khayat, D / Schmoll, H-J / Sobrero, A / Van Cutsem, E. ·Division of Hematology/Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, USA. mtempero@medicine.ucsf.edu ·Ann Oncol · Pubmed #21199884.

ABSTRACT: BACKGROUND: Pancreatic cancer has proven extremely challenging to treat. A collaborative effort is needed to advance research and improve treatment. An expert conference was conducted to elicit perspectives regarding the current treatment and future research of pancreatic cancer. METHODS: The conference comprised an international panel of experts representing five European countries and the United States. RESULTS: Adjuvant radiotherapy is used more frequently in the United States than in Europe. In locally advanced disease, there is now more emphasis on early chemotherapy in both Europe and the United States. In metastatic disease, combination chemotherapy is commonly used in Europe and the United States. This varies by country. Advancing pancreatic research will require improving biorepositories and developing a roadmap to prioritize therapeutic targets in different models. Small randomized phase II trials of both non-selected and enriched patient populations will help identify activity of new agents. Phase III trials should only be initiated in appropriate patients based on strong clinical and biological signals. Developing drugs in the adjuvant setting may be preferable to eliminate some of the challenges of drug development in the advanced disease setting. CONCLUSION: Progress in research combined with encouraging improvements from the past offer hope for the future of pancreatic cancer patients.

6 Review The potential role of targeted therapies in the management of neuroendocrine tumours. 2009

Verset, G / Borbath, I / Delaunoit, T / Demetter, P / Demolin, G / Hendlisz, A / Pattyn, P / Pauwels, S / Peeters, M / Roeyen, G / Van Cutsem, E / Van Hootegem, Ph / Verslype, C / Van Laethem, J L. ·Department Gastrointestinal Oncology Unit, Erasme University Hospital, Anderlecht. ·Acta Gastroenterol Belg · Pubmed #19402374.

ABSTRACT: The management of gastro-entero-pancreatic neuroendocrine tumours is evolving thanks to new TNM-classification, diagnostic and staging procedures and new therapeutic options. Targeting new pathways, mostly angiogenesis, development of novel agents is under way and opens new perspectives in controlling the evolution of these tumours and possibly changing their management. In parallel, new functional imaging techniques and biomolecular markers will be developed to provide adequate tools for the assessment of tumor response according to therapeutic intervention on angiogenesis, proliferation and apoptosis. This paper reviews the potential role of new investigational targeted agents which will likely become the backbone of future therapy of neuroendocrine tumors.

7 Review The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. 2009

Verslype, C / Carton, S / Borbath, I / Delaunoit, T / Demetter, P / Demolin, G / Hendlisz, A / Pattyn, P / Pauwels, S / Peeters, M / Roeyen, G / Van Hootegem, Ph / Van Laethem, J L / Van Cutsem, E. ·Department of Hepatology and Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium. Chris.Verslype@uzleuven.be ·Acta Gastroenterol Belg · Pubmed #19402373.

ABSTRACT: Somatostatin analogs (SSAs) have an important role in the management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP NETs). These compounds can control the symptoms induced by the production of hormones and peptides. The antiproliferative effects of SSAs and especially tumour shrinkage are less obvious in patients with GEP NETs than in those with acromegaly. However, based upon phase II experience there is a strong suggestion of a disease stabilizing effect of SSAs in selected patients. Those patients with a progressive, non-functional GEP NET, positive octreotide scintigraphy, a low proliferation index and in the absence of surgical options may benefit from a first-line medical therapy with SSAs. The exploration of the mechanisms of this effect are unclear and hampered by the lack of suitable preclinical models. The better understanding of the tumour biology of GEP NETs, together with the development of new SSAs with better affinity on all somatostatin receptors, represent an unmet medical need.

8 Review Role of chemotherapy in gastro-entero-pancreatic neuroendocrine tumors: the end of a story? 2009

Delaunoit, T / Van den Eynde, M / Borbath, I / Demetter, P / Demolin, G / Pattyn, P / Pauwels, S / Peeters, M / Roeyen, G / Van Cutsem, E / Van Hootegem, Ph / Van Laethem, J L / Verslype, C / Hendlisz, A. ·Department of Gastroenterology and Medical Oncology, Jolimont Hospital, Haine-Saint-Paul, Belgium. thierry.delaunoit@entitejolimontoise.be ·Acta Gastroenterol Belg · Pubmed #19402372.

ABSTRACT: Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are heterogeneous and rare malignancies although their prevalence is increasing. Multiple therapeutic approaches are available to date for their management, including surgery, hormonal and immune radionucleide therapies and chemotherapy. The purpose of this review is to collect, examine, and analyze data available regarding contemporary chemotherapeutic management of GEP NET in order to determine whether or not chemotherapy still takes place in the therapeutic arsenal of GEP NET. We therefore performed a systematic search of all the English-spoken literature regarding GEP NET. Anthracyclins, 5-fluorouracil (5-FU), DTIC and streptozotocin are amongst the most commonly used chemotherapeutic agents, usually prescribed in combination. Their efficiency in reducing tumor burden is not always associated with better survival, perhaps due to severe toxicity. Chemotherapy in GEP NET is mainly devoted to poorly differentiated tumours, but also in well differentiated carcinomas either not eligible or resistant to other therapies. Chemotherapy remains therefore useful in specific cases of GEP NET management. However, a new era of antitumoral agents, such as targeted therapies, could eventually replace these old recipes in the near future.

9 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

10 Clinical Trial Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. 2018

Hurwitz, Herbert / Van Cutsem, Eric / Bendell, Johanna / Hidalgo, Manuel / Li, Chung-Pin / Salvo, Marcelo Garrido / Macarulla, Teresa / Sahai, Vaibhav / Sama, Ashwin / Greeno, Edward / Yu, Kenneth H / Verslype, Chris / Dawkins, Fitzroy / Walker, Chris / Clark, Jason / O'Reilly, Eileen M. ·Duke University Medical Center, Campus mail 439 Seeley-mudd Bldg, 10 Bryan Searle Drive, Duke University M, Durham, NC, 27710, USA. · Clinical Digestive Oncology, University Hospitals Leuven and KU Leuven, UZ Herestraat 49, 3000, Leuven, Belgium. · Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Ave N, Nashville, TN, 37203, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 11217, Taiwan. · School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Nong Street, Beitou District, Taipei, 112, Taiwan. · Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins, 340, Santiago, Región Metropolitana, Chile. · Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain. · Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Cancer Center Floor B1 Reception E, 1500 E Medical Center Dr SPC 5912, Ann Arbor, MI, 48109-5912, USA. · Thomas Jefferson University Hospital, 925 Chestnut Street, Suite 320A, Philadelphia, PA, 19107, USA. · Division of Hematology, Oncology and Transplantation, University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA. · Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. · Incyte Corporation, 1801 Augustine Cut-off, Wilmington, DE, 19803, USA. · Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. oreillye@mskcc.org. · Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. oreillye@mskcc.org. ·Invest New Drugs · Pubmed #29508247.

ABSTRACT: Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m

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

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

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

12 Clinical Trial Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. 2017

Evans, T R J / Van Cutsem, E / Moore, M J / Bazin, I S / Rosemurgy, A / Bodoky, G / Deplanque, G / Harrison, M / Melichar, B / Pezet, D / Elekes, A / Rock, E / Lin, C / Strauss, L / O'Dwyer, P J. ·Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK. · Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. · Princess Margaret Cancer, Toronto, Canada. · Federal State Budgetary Institution, Dubna, Russia. · Surgery, Florida Hospital, Tampa, Tampa, USA. · Oncology, St.László Teaching Hospital, Budapest, Hungary. · Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · East and North Hertfordshire NHS Trust, Northwood, Middlesex, UK. · Department of Oncology, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic. · CHU Estaing, Clermont-Ferrand, France. · Otsuka Pharmaceutical Development and Commercialization, Princeton. · Bristol-Myers Squibb Company, Princeton. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA. ·Ann Oncol · Pubmed #27998964.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

13 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.

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

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

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

15 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

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

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

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

17 Clinical Trial Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study. 2014

Van Cutsem, E / Li, C-P / Nowara, E / Aprile, G / Moore, M / Federowicz, I / Van Laethem, J-L / Hsu, C / Tham, C K / Stemmer, S M / Lipp, R / Zeaiter, A / Fittipaldo, A / Csutor, Z / Klughammer, B / Meng, X / Ciuleanu, T. ·Gastroenterology/Digestive Oncology, University Hospitals Leuven and KU Leuven, Herestraat 49, 3000 Leuven, Belgium. · 1] Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei City, Taiwan [2] National Yang-Ming University School of Medicine, No. 155, Sec. 2, Linong Street, Taipei 112, Taiwan. · Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie Oddział w Gliwicach, ul. Wybrzeże Armii Krajowej 15, 44-101 Gliwice, Poland. · Department of Medical Oncology, University Hospital of Udine, 33100 Udine, Italy. · Division of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. · NZOZ Magodent, Fieldorfa 40, 04-0125 Warsaw, Poland. · Department of Gastroenterology-GI Cancer Unit, Erasme University Hospital-ULB-Brussels, Route de Lennik 808, 1070 Brussels, Belgium. · National Taiwan University Hospital, No.1 Changde Street, Zhongzheng District, Taipei City 10048, Taiwan. · Department of Medical Oncology, National Cancer Center Singapore, 11 Hospital Drive, Singapore 169610, Singapore. · Institute of Oncology, Davidoff Center, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva 49100, Israel. · GermanOncology GmbH, Überseeallee 1, D-20457 Hamburg, Germany. · Roche Products Ltd, 6 Falcon Way, Shire Park, Hexagon Place Welwyn Garden City, Hertfordshire AL7 1TW, UK. · F. Hoffmann-La Roche, CH-4070 Basel, Switzerland. · PD Biostatistics, Roche, 720 Cai Lun Road, Building 5, Shanghai 201203, Pudong, China. · Institute of Oncology Ion Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca 400015, Romania. ·Br J Cancer · Pubmed #25247318.

ABSTRACT: BACKGROUND: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. METHODS: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety. RESULTS: Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms. CONCLUSION: The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

18 Clinical Trial Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 2013

Von Hoff, Daniel D / Ervin, Thomas / Arena, Francis P / Chiorean, E Gabriela / Infante, Jeffrey / Moore, Malcolm / Seay, Thomas / Tjulandin, Sergei A / Ma, Wen Wee / Saleh, Mansoor N / Harris, Marion / Reni, Michele / Dowden, Scot / Laheru, Daniel / Bahary, Nathan / Ramanathan, Ramesh K / Tabernero, Josep / Hidalgo, Manuel / Goldstein, David / Van Cutsem, Eric / Wei, Xinyu / Iglesias, Jose / Renschler, Markus F. ·From the Translational Genomics Research Institute, Phoenix, and Virginia G. Piper Cancer Center, Scottsdale - both in Arizona (D.D.V.H., R.K.R.) · Cancer Specialists, Fort Myers, FL (T.E.) · Arena Oncology Associates, Lake Success (F.P.A.), and Roswell Park Cancer Institute, Buffalo (W.W.M.) - both in New York · University of Washington, Seattle (E.G.C.) · Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J. Infante) · Princess Margaret Hospital, Toronto (M.M.) · Atlanta Cancer Care (T.S.) and Georgia Cancer Specialists (M.N.S.) - both in Atlanta · Blokhin Cancer Research Center, Moscow (S.A.T.) · Southern Health, East Bentleigh, VIC (M.H.), Prince of Wales Hospital, Sydney (D.G.), and Bionomics, Thebarton, SA (J. Iglesias) - all in Australia · San Raffaele Scientific Institute, Milan (M.R.) · Tom Baker Cancer Centre, Calgary, AB, Canada (S.D.) · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.L.) · University of Pittsburgh Medical Center, Pittsburgh (N.B.) · Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona (J.T.) · Centro Integral Oncológico Clara Campal, Madrid (M.H.) · University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium (E.V.C.) · and Celgene, Summit, NJ (X.W., M.F.R.). ·N Engl J Med · Pubmed #24131140.

ABSTRACT: BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

19 Clinical Trial Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. 2011

Kindler, Hedy L / Ioka, Tatsuya / Richel, Dirk J / Bennouna, Jaafar / Létourneau, Richard / Okusaka, Takuji / Funakoshi, Akihiro / Furuse, Junji / Park, Young Suk / Ohkawa, Shinichi / Springett, Gregory M / Wasan, Harpreet S / Trask, Peter C / Bycott, Paul / Ricart, Alejandro D / Kim, Sinil / Van Cutsem, Eric. ·University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Lancet Oncol · Pubmed #21306953.

ABSTRACT: BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer.

20 Clinical Trial Everolimus for advanced pancreatic neuroendocrine tumors. 2011

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

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

21 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.).

22 Clinical Trial Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. 2010

Van Laethem, Jean-Luc / Hammel, Pascal / Mornex, Françoise / Azria, David / Van Tienhoven, Geertjan / Vergauwe, Philippe / Peeters, Marc / Polus, Marc / Praet, Michel / Mauer, Murielle / Collette, Laurence / Budach, Volker / Lutz, Manfred / Van Cutsem, Eric / Haustermans, Karin. ·Department of Gastroenterology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. JL.Vanlaethem@erasme.ulb.ac.be ·J Clin Oncol · Pubmed #20837948.

ABSTRACT: PURPOSE: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer. PATIENTS AND METHODS: Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS). RESULTS: Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3-related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%). CONCLUSION: Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial.

23 Clinical Trial Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. 2010

Yao, James C / Lombard-Bohas, Catherine / Baudin, Eric / Kvols, Larry K / Rougier, Philippe / Ruszniewski, Philippe / Hoosen, Sakina / St Peter, Jessica / Haas, Tomas / Lebwohl, David / Van Cutsem, Eric / Kulke, Matthew H / Hobday, Timothy J / O'Dorisio, Thomas M / Shah, Manisha H / Cadiot, Guillaume / Luppi, Gabriele / Posey, James A / Wiedenmann, Bertram. ·Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA. jyao@mdanderson.org ·J Clin Oncol · Pubmed #19933912.

ABSTRACT: PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

24 Clinical Trial Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. 2009

Van Cutsem, Eric / Vervenne, Walter L / Bennouna, Jaafar / Humblet, Yves / Gill, Sharlene / Van Laethem, Jean-Luc / Verslype, Chris / Scheithauer, Werner / Shang, Aijing / Cosaert, Jan / Moore, Malcolm J. ·University Hospital Gasthuisberg/Leuven, Digestive Oncology Unit, Herestraat 49, B-3000 Leuven, Belgium. eric.vancutsem@uz.kuleuven.ac.be ·J Clin Oncol · Pubmed #19307500.

ABSTRACT: PURPOSE: Treatment with gemcitabine provides modest benefits in patients with metastatic pancreatic cancer. The addition of erlotinib to gemcitabine shows a small but significant improvement in overall survival (OS) versus gemcitabine alone. Phase II results for bevacizumab plus gemcitabine provided the rationale for a phase III trial of gemcitabine-erlotinib plus bevacizumab or placebo. PATIENTS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine (1,000 mg/m(2)/week), erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks) or gemcitabine, erlotinib, and placebo in this double-blind, phase III trial. Primary end point was OS; secondary end points included progression-free survival (PFS), disease control rate, and safety. RESULTS: A total of 301 patients were randomly assigned to the placebo group and 306 to the bevacizumab group. Median OS was 7.1 and 6.0 months in the bevacizumab and placebo arms, respectively (hazard ratio [HR], 0.89; 95% CI, 0.74 to 1.07; P = .2087); this difference was not statistically significant. Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95% CI, 0.61 to 0.86; P = .0002). Treatment with bevacizumab plus gemcitabine-erlotinib was well tolerated: safety data did not differ from previously described safety profiles for individual drugs. CONCLUSION: The primary objective was not met. The addition of bevacizumab to gemcitabine-erlotinib did not lead to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. PFS, however, was significantly longer in the bevacizumab group compared with placebo. No unexpected safety events were observed from adding bevacizumab to gemcitabine-erlotinib.

25 Clinical Trial A phase I radiation dose-escalation study to determine the maximal dose of radiotherapy in combination with weekly gemcitabine in patients with locally advanced pancreatic adenocarcinoma. 2008

Budiharto, Tom / Haustermans, Karin / Van Cutsem, Eric / Van Steenbergen, Werner / Topal, Baki / Aerts, Raymond / Ectors, Nadine / Bielen, Didier / Vanbeckevoort, Dirk / Goethals, Laurence / Verslype, Chris. ·Department of Radiotherapy, University Hospitals Leuven, Leuven, Belgium. tom.budiharto@uz.kuleuven.ac.be ·Radiat Oncol · Pubmed #18808686.

ABSTRACT: BACKGROUND: The primary objective of this study was to determine the maximum tolerated dose (MTD) of escalating doses of radiotherapy (RT) concomitantly with a fixed dose of gemcitabine (300 mg/m2/week) within the same overall treatment time. METHODS: Thirteen patients were included. Gemcitabine 300 mg/m2/week was administered prior to RT. The initial dose of RT was 45 Gy in 1.8 Gy fractions, escalated by adding 5 fractions of 1.8 Gy (one/week) to a dose of 54 Gy with a total duration kept at 5 weeks. All patients received a dynamic MRI to assess the pancreatic respiratory related movements. Toxicity was scored using the RTOG-EORTC toxicity criteria. RESULTS: Three of six patients experienced an acute dose limiting toxicity (DLT) at the 54 Gy dose level. For these patients a grade III gastro-intestinal toxicity (GI) was noted. Patients treated at the 45 Gy dose level tolerated therapy without DLT. The 54 Gy dose level was designated as the MTD and was deemed not suitable for further investigation. Between both dose levels, there was a significant difference in percentage weight loss (p = 0.006) and also in cumulative GI toxicity (p = 0.027). There was no grade 3 toxicity in the 45 Gy cohort versus 4 grade 3 toxicity events in the 54 Gy cohort. The mean dose to the duodenum was significantly higher in the 54 Gy cohort (38.45 Gy vs. 51.82 Gy; p = 0.001). CONCLUSION: Accelerated dose escalation to a total dose of 54 Gy with 300 mg/m2/week gemcitabine was not feasible. GI toxicity was the DLT. Retrospectively, the dose escalation of 9 Gy by accelerated radiotherapy might have been to large. A dose of 45 Gy is recommended. Considering the good patient outcomes, there might be a role for the investigation of a fixed dose of gemcitabine and concurrent RT with small fractions (1.8 Gy/day) in borderline resectable or unresectable non-metastatic locally advanced pancreatic cancer.

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