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Pancreatic Neoplasms: HELP
Articles by Michele Reni
Based on 69 articles published since 2008
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Between 2008 and 2019, M. Reni wrote the following 69 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
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 Editorial Role of taxanes in pancreatic cancer. 2012

Belli, Carmen / Cereda, Stefano / Reni, Michele. · ·World J Gastroenterol · Pubmed #22969215.

ABSTRACT: Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.

3 Editorial Neoadjuvant treatment for resectable pancreatic cancer: time for phase III testing? 2010

Reni, Michele. · ·World J Gastroenterol · Pubmed #20954273.

ABSTRACT: This paper discusses the rationale for phase III testing of neoadjuvant therapy in patients affected by resectable pancreatic adenocarcinoma. The therapeutic management of patients affected by resectable pancreatic cancer is particularly troublesome due to the aggressiveness of the disease and to the limited efficacy and sometimes unfavourable risk-benefit ratio of the available therapeutic tools. Conflicting data on the role of adjuvant chemoradiation have been reported, while adjuvant single-agent chemotherapy significantly improved overall survival (OS) when compared to surgery alone. However, the OS figures for adjuvant chemotherapy remain disappointing. In effect, pancreatic cancer exhibits a prominent tendency to recur after a brief median time interval from surgery and extra-pancreatic dissemination represents the predominant pattern of disease failure. Neoadjuvant treatment has a strong rationale in this disease but limited information on the efficacy of this approach is available from single arm trials with low levels of evidence. Thus, in spite of two decades of investigation there is currently no evidence to support the routine use of pre-surgical therapy in clinical practice. To foster knowledge on the optimal management of this disease, and to produce evidence-based treatment guidelines, there is no alternative to well designed randomized trials. Systemic chemotherapy is a candidate for testing because it is supported by a more robust rationale than chemoradiation. Combination chemotherapy regimens with elevated activity in advanced disease warrant investigation. Caution would suggest the running of an exploratory phase II randomized trial before embarking on a large phase III study.

4 Review Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. 2019

Macchini, Marina / Chiaravalli, Marta / Zanon, Silvia / Peretti, Umberto / Mazza, Elena / Gianni, Luca / Reni, Michele. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Electronic address: reni.michele@hsr.it. ·Cancer Treat Rev · Pubmed #30414985.

ABSTRACT: By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.

5 Review Biomarker-driven and molecularly targeted therapies for pancreatic adenocarcinoma. 2018

Zhen, David B / Coveler, Andrew / Zanon, Silvia / Reni, Michele / Chiorean, E Gabriela. ·Division of Medical Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. · Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Division of Medical Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: gchiorea@uw.edu. ·Semin Oncol · Pubmed #30391013.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.

6 Review Systematic review and meta-analysis of prognostic role of splenic vessels infiltration in resectable pancreatic cancer. 2018

Crippa, Stefano / Cirocchi, Roberto / Maisonneuve, Patrick / Partelli, Stefano / Pergolini, Ilaria / Tamburrino, Domenico / Aleotti, Francesca / Reni, Michele / Falconi, Massimo. ·Division of Pancreatic Surgery, Vita e Salute University, San Raffaele Scientific Institute, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy. · Department of General and Oncologic Surgery, University of Perugia, St. Maria Hospital, Terni, Italy. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · Department of Surgery, Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy. · Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Department of Oncology, San Raffaele Scientific Institute, Milan, Italy. · Division of Pancreatic Surgery, Vita e Salute University, San Raffaele Scientific Institute, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy. Electronic address: falconi.massimo@hsr.it. ·Eur J Surg Oncol · Pubmed #29183639.

ABSTRACT: BACKGROUND: Identification of factors associated with dismal survival after surgery in resectable pancreatic ductal adenocarcinoma is important to select patients for neoadjuvant treatment. The present meta-analysis aimed to compare the results of distal pancreatectomy for resectable adenocarcinoma of the pancreatic body-tail with and without splenic vessels infiltration. METHODS: A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines. The inclusion criteria were studies including patients who underwent distal pancreatectomy for pancreatic cancer with or without splenic vessels infiltration. 5-year overall survival (OS) was the primary outcomes. Meta-analysis was carried out applying time-to-event method. RESULTS: Six articles with 423 patients were analysed. Patients with pathological splenic artery invasion had a worse survival compared with those without infiltration (Hazard ratio 1.76, 95% CI 1.36-2.28; P < 0.0001). A similar results was found when considering pathological splenic vessels infiltration, showing that survival was significantly poorer when splenic vein infiltration was present (Hazard ratio 1.51, 95% CI 1.19-1.93; P = 0.0009). CONCLUSIONS: This meta-analysis showed worse survival for patients with splenic vessels infiltration undergoing distal pancreatectomy for pancreatic cancer. Splenic vessels infiltration represents the stigmata of a more aggressive disease, although resectable.

7 Review Pancreatic ductal adenocarcinoma: State-of-the-art 2017 and new therapeutic strategies. 2017

Chiaravalli, Marta / Reni, Michele / O'Reilly, Eileen M. ·Medical Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States. · Medical Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy. · Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States; Weill Cornell Medical College, Weill Cornell Medicine, New York, NY 10065, United States. Electronic address: oreillye@mskcc.org. ·Cancer Treat Rev · Pubmed #28869888.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5-year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers.

8 Review What treatment in 2017 for inoperable pancreatic cancers? 2017

Taieb, J / Pointet, A-L / Van Laethem, J L / Laquente, B / Pernot, S / Lordick, F / Reni, M. ·Hepatogastroenterology and GI Oncology Department, Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris, France. · Department of Gastroenterology and Digestive Oncology, Erasme University Hospital, ULB, Brussels, Belgium. · Medical Oncology Department, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain. · University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Leipzig, Germany. · Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy. ·Ann Oncol · Pubmed #28459988.

ABSTRACT: Pancreatic adenocarcinoma is a frequent and severe disease, either diagnosed as metastatic pancreatic adenocarcinoma (MPA) or as locally advanced pancreatic carcinoma (LAPC). Though no improvement in patients outcome have been made between 1996 and 2011, since 5 years new treatment options have become available to treat our patients. New standard first line regimens, such as FOLFIRINOX and gemcitabine combined with nab-paclitaxel, have improved overall survivals and second line treatments have been tested and validated. Other first-line treatments have failed, but research remains active and trials are ongoing with promising new anti-cancer agents. These new effective regimens used for MPA have yielded promising results in LAPC patients in open cohorts or phase II trials and a recent trial have failed to demonstrate the added value of classical external radiotherapy in this setting. Here, we review current standards of care in LAPC and MPA, consider the latest challenges and strategic questions, and examine what we may hope for in the future.

9 Review Multimodal treatment of resectable pancreatic ductal adenocarcinoma. 2017

Silvestris, Nicola / Brunetti, Oronzo / Vasile, Enrico / Cellini, Francesco / Cataldo, Ivana / Pusceddu, Valeria / Cattaneo, Monica / Partelli, Stefano / Scartozzi, Mario / Aprile, Giuseppe / Casadei Gardini, Andrea / Morganti, Alessio Giuseppe / Valentini, Vincenzo / Scarpa, Aldo / Falconi, Massimo / Calabrese, Angela / Lorusso, Vito / Reni, Michele / Cascinu, Stefano. ·Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: dr.oronzo.brunetti@tiscali.it. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. Electronic address: e.vasile@ao.pisa.toscana.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: francesco.cellini@uniroma3.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: cataldo.ivana@gmail.com. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: oncologiamedica2reparto@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy. Electronic address: aprile83@gmail.com. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: partelli.stefano@hsr.it. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: marioscartozzi@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy; Department of Medical Oncology, General Hospital of Vicenza, Vicenza, Italy. Electronic address: aprile.giuseppe@aoud.sanita.fvg.it. · Medical Oncology Unit, IRCCS, Meldola, Italy. Electronic address: casadeigardini@gmail.com. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. Electronic address: alessio.morganti2@unibo.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: vincenzo.valentini@unicatt.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: aldo.scarpa@univr.it. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. · Radiology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: acalabrese22@gmail.com. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: vito.lorusso@oncologico.bari.it. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Modena Cancer Center, Policlinico di Modena Università di Modena e Reggio Emilia, Italy. Electronic address: cascinu@yahoo.com. ·Crit Rev Oncol Hematol · Pubmed #28259290.

ABSTRACT: After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.

10 Review Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma. 2016

Silvestris, Nicola / Longo, Vito / Cellini, Francesco / Reni, Michele / Bittoni, Alessandro / Cataldo, Ivana / Partelli, Stefano / Falconi, Massimo / Scarpa, Aldo / Brunetti, Oronzo / Lorusso, Vito / Santini, Daniele / Morganti, Alessio / Valentini, Vincenzo / Cascinu, Stefano. ·Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, 'Mons R Dimiccoli' Hospital, Barletta, Italy. · Radiation Oncology Department, Policlinico Universitario Campus Bio-Medico, Rome, Italy. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milano, Italy. · Medical Oncology Clinic, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · ARC-NET Research Centre, University of Verona, Italy. · Pancreatic Unit, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. · Medical Oncology Unit, University Campus Biomedico, Roma, Italy. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. ·Crit Rev Oncol Hematol · Pubmed #26653573.

ABSTRACT: Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed.

11 Review MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? 2015

Brunetti, Oronzo / Russo, Antonio / Scarpa, Aldo / Santini, Daniele / Reni, Michele / Bittoni, Alessandro / Azzariti, Amalia / Aprile, Giuseppe / Delcuratolo, Sabina / Signorile, Michele / Gnoni, Antonio / Palermo, Loredana / Lorusso, Vito / Cascinu, Stefano / Silvestris, Nicola. ·Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy. · AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Medical Oncology, University Hospital of Udine, Udine, Italy. · Department of Medical Oncology, Hospital of Taranto, Taranto, Italy. ·Oncotarget · Pubmed #26259238.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.

12 Review Metastatic pancreatic cancer: Is there a light at the end of the tunnel? 2015

Vaccaro, Vanja / Sperduti, Isabella / Vari, Sabrina / Bria, Emilio / Melisi, Davide / Garufi, Carlo / Nuzzo, Carmen / Scarpa, Aldo / Tortora, Giampaolo / Cognetti, Francesco / Reni, Michele / Milella, Michele. ·Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy. ·World J Gastroenterol · Pubmed #25944992.

ABSTRACT: Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.

13 Review Target therapies in pancreatic carcinoma. 2014

Silvestris, Nicola / Gnoni, Antonio / Brunetti, Anna Elisabetta / Vincenti, Leonardo / Santini, Daniele / Tonini, Giuseppe / Merchionne, Francesca / Maiello, Evaristo / Lorusso, Vito / Nardulli, Patrizia / Azzariti, Amalia / Reni, Michele. ·Medical Oncology Unit, National Cancer Research Centre - Istituto Tumori Giovanni Paolo II, Viale Orazio Flacco, 65, 70124 Bari, Italy. n.silvestris@oncologico.bari.it. ·Curr Med Chem · Pubmed #23992319.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early locoregional spread and distant metastases at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapy provides only modest benefit to patients with PDAC. Identification of different molecular pathways, overexpressed in pancreatic cancer cells, has provided the opportunity to develop targeted therapies (monoclonal antibodies and small-molecule inhibitors) and peculiar new class of taxanes with a crucial therapeutic role in this cancer setting. A phase III trial has shown that erlotinib in combination with gemcitabine was clinically irrelevant and skin toxicity can be a positive prognostic factor. Moreover, the combination of cetuximab or erlotinib with radiotherapy in advanced pancreatic cancer has shown to be synergistic and a reversal of radio-resistance has been suggested by inhibition of VEGF/EGFR pathway. To overcome EGFR-inhibition therapy resistance several alternative pathways targets are under investigation (IGF- 1R, MMPs, Hedgehog proteins, m-TOR, MEK, COX-2) and provide the rationale for clinical use in phase II/III studies. Also nab-paclitaxel, a new taxanes class, uses high pancreatic albumin-binding protein SPARC levels to act in cancer cells with a less toxic and more effective dose with respect to classic taxanes. Understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. However, many promising data in preclinic and phase I/II trials did not yield promise in phase III trials, suggesting that identification of predictive biomarkers for these new agents is mandatory. The knowledge of biologic and molecular aspects of pancreatic cancer can be the basis for future therapeutic developments.

14 Review Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. 2014

Heinemann, V / Reni, M / Ychou, M / Richel, D J / Macarulla, T / Ducreux, M. ·Department of Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, Ludwig-Maximilians-Universität München, Germany. ·Cancer Treat Rev · Pubmed #23849556.

ABSTRACT: Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.

15 Review Neoadjuvant therapy in resectable pancreatic cancer: a critical review. 2013

Belli, Carmen / Cereda, Stefano / Anand, Santosh / Reni, Michele. ·Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. belli.carmen@hsr.it ·Cancer Treat Rev · Pubmed #23122322.

ABSTRACT: BACKGROUND: Pancreatic cancer is among the deadliest tumors. Due to intrinsic chemo- and radio-resistance, surgical resection remains the only chance for cure. However surgery alone is unable to considerably improve survival and complementary chemotherapy and radiotherapy in a multimodal approach have been tested. Adjuvant chemotherapy yielded a modest outcome improvement, whereas the use of adjuvant chemoradiation is highly controversial. In this scenario, the neoadjuvant approach has a strong theoretical rationale, but limited information on the efficacy of this strategy is available. MATERIALS AND METHODS: This review critically overviews the current knowledge, the rationale, the available data and information on neoadjuvant treatment in resectable pancreatic cancer. RESULTS: The very early systemic dissemination of pancreatic cancer endorses the rationale for an up-front use of systemic therapy. However, evidence collected so far depends on retrospective data, small case series that did not balance the different characteristics of patients suitable for surgery before or after neoadjuvant chemotherapy. CONCLUSION: Currently there is no straightforward evidence to support the routine clinical use of this strategy. Only a properly designed randomized trial testing combination chemotherapy regimens selected on the basis of their efficacy and activity against metastatic disease can address this issue.

16 Review Evidences and opinions for adjuvant therapy in pancreatic cancer. 2012

Reni, Michele. ·Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132-Milan, Italy. reni.michele@hsr.it ·Curr Drug Targets · Pubmed #22458525.

ABSTRACT: Pancreatic adenocarcinoma is a rare tumor with a very poor outcome. Even with surgery, 5-year overall survival is less than 10%, due to the propensity of the disease for local and systemic recurrence. Adjuvant chemoradiotherapy and systemic chemotherapy were assessed in prospective trials in order to improve disease control and patients' prognosis. However, due to the difficulty of performing prospective trials in a rare disease; to the progress in surgical and radiotherapic techniques; and to the availability of novel anti-cancer agents, the existing information on the best possible management of patients with resectable disease is limited and becomes rapidly obsolete. Accordingly and also due to some contradictory findings from randomized trials, the topic of optimal adjuvant therapy for this disease encompasses several areas of controversy. The present review reports the main opinions on the role of adjuvant chemoradiotherapy, adjuvant chemotherapy, best single agent, and combination chemotherapy. Data from randomized trials are presented and critically analyzed to identify the available evidence supporting the different therapeutic choices and the main methodological drawbacks hampering the proper interpretation of results. Single agent chemotherapy yields a clinically significant, albeit modest, improvement in overall survival and may represent a standard option. The role of combination chemotherapy warrants further investigation and the impact of adjuvant chemoradiation both on local control and on the final outcome is uncertain. The need for more active and effective systemic treatments, for a better knowledge of the disease biology, for new therapeutic agents and predictors of pattern of recurrence is evident.

17 Clinical Trial Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. 2018

Reni, Michele / Zanon, Silvia / Peretti, Umberto / Chiaravalli, Marta / Barone, Diletta / Pircher, Chiara / Balzano, Gianpaolo / Macchini, Marina / Romi, Silvia / Gritti, Elena / Mazza, Elena / Nicoletti, Roberto / Doglioni, Claudio / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Radiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. ·Lancet Gastroenterol Hepatol · Pubmed #30220407.

ABSTRACT: BACKGROUND: Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS: This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m FINDINGS: Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION: Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING: Celgene.

18 Clinical Trial A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma. 2018

Reni, Michele / Zanon, Silvia / Balzano, Gianpaolo / Passoni, Paolo / Pircher, Chiara / Chiaravalli, Marta / Fugazza, Clara / Ceraulo, Domenica / Nicoletti, Roberto / Arcidiacono, Paolo Giorgio / Macchini, Marina / Peretti, Umberto / Castoldi, Renato / Doglioni, Claudio / Falconi, Massimo / Partelli, Stefano / Gianni, Luca. ·Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiotherapy, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pathology Unit, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. ·Eur J Cancer · Pubmed #30149366.

ABSTRACT: BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.

19 Clinical Trial Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. 2018

Reni, Michele / Balzano, Gianpaolo / Zanon, Silvia / Zerbi, Alessandro / Rimassa, Lorenza / Castoldi, Renato / Pinelli, Domenico / Mosconi, Stefania / Doglioni, Claudio / Chiaravalli, Marta / Pircher, Chiara / Arcidiacono, Paolo Giorgio / Torri, Valter / Maggiora, Paola / Ceraulo, Domenica / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy. · Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy. · Department of Surgery, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Onco-Hematology Department, Oncology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pathology Unit, Vita-Salute San Raffaele University, Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS San Raffaele Scientific Institute, Milan, Italy. · IRCCS Mario Negri Institute for Pharmacological Research, Milan, Italy. · Department of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pancreatic Surgery, Vita-Salute San Raffaele University, Milan, Italy. ·Lancet Gastroenterol Hepatol · Pubmed #29625841.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. METHODS: We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m FINDINGS: Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. INTERPRETATION: Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. FUNDING: PERLAVITA ONLUS and MyEverest ONLUS.

20 Clinical Trial Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma. 2016

Reni, Michele / Balzano, Gianpaolo / Zanon, Silvia / Passoni, Paolo / Nicoletti, Roberto / Arcidiacono, Paolo Giorgio / Pepe, Gino / Doglioni, Claudio / Fugazza, Clara / Ceraulo, Domenica / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Surgery, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Radiotherapy, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Radiology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Department of Gastroenterology, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Nuclear Medicine Unit, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. · Pathology Unit, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy. ·Br J Cancer · Pubmed #27404453.

ABSTRACT: BACKGROUND: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). METHODS: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. RESULTS: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by ⩾49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. CONCLUSIONS: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration.

21 Clinical Trial Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer. 2016

Chiorean, E Gabriela / Von Hoff, Daniel D / Tabernero, Josep / El-Maraghi, Robert / Ma, Wen Wee / Reni, Michele / Harris, Marion / Whorf, Robert / Liu, Helen / Li, Jack Shiansong / Manax, Victoria / Romano, Alfredo / Lu, Brian / Goldstein, David. ·Division Oncology, Department of Medicine, University of Washington, 825 Eastlake Avenue E, G4-833, Seattle, WA 98109-1023, USA. · Translational Genomics Research Institute and HonorHealth, 445 North Fifth Street, Suite 600, Phoenix, AZ 85004, USA. · Vall d'Hebron Institute of Oncology (VHIO), P Vall d'Hebron 119-129, Barcelona 08035, Spain. · Royal Victoria Hospital Barrie Canada, 201 Georgian Drive, Barrie, Ontario, Canada L4M 6M2. · Roswell Park Cancer Institute, 665 Elm Street, Buffalo, NY 14203, USA. · San Raffaele Scientific Institute, Via Olgetina 60, 20132 Milan, Italy. · Monash Health, 246 Clayton Road, Melbourne VIC 3168, Australia. · Florida Cancer Specialists, 2401 60th Street Ct W, Bradenton, FL 34209-5500, USA. · Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. · Department of Medical Oncology, Prince of Wales Hospital, South Sydney Illawarra, Barker Street, Sydney NSW 2031, Australia. ·Br J Cancer · Pubmed #27351217.

ABSTRACT: BACKGROUND: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). METHODS: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. RESULTS: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. CONCLUSIONS: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.

22 Clinical Trial CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. 2016

Chiorean, E G / Von Hoff, D D / Reni, M / Arena, F P / Infante, J R / Bathini, V G / Wood, T E / Mainwaring, P N / Muldoon, R T / Clingan, P R / Kunzmann, V / Ramanathan, R K / Tabernero, J / Goldstein, D / McGovern, D / Lu, B / Ko, A. ·Department of Medicine/Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle gchiorea@uw.edu. · HonorHealth and The Translational Genomics Research Institute (TGen), Scottsdale, USA. · Department of Radiation Oncology, San Raffaele Scientific Institute, Milan, Italy. · Department of Oncology, NYU Langone Arena Oncology, Lake Success. · Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville. · Cancer Center of Excellence, University of Massachusetts Medical School, Worcester. · UAB Comprehensive Cancer Center, Birmingham, USA. · Mater Private Centre for Haematology & Oncology, South Brisbane, Australia. · Department of Oncology, Genesis Cancer Center, Hot Springs, USA. · Southern Medical Day Care Centre, Wollongong, Australia. · Medizinische Klinik und Poliklinik II, University of Wuerzburg, Wuerzburg, Germany. · Medical of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. · Department of Oncology, Prince of Wales Hospital, Sydney, Australia. · Celgene Corporation, Summit, USA. ·Ann Oncol · Pubmed #26802160.

ABSTRACT: BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

23 Clinical Trial Phase II trial of salvage therapy with trabectedin in metastatic pancreatic adenocarcinoma. 2016

Belli, Carmen / Piemonti, Lorenzo / D'Incalci, Maurizio / Zucchetti, Massimo / Porcu, Luca / Cappio, Stefano / Doglioni, Claudio / Allavena, Paola / Ceraulo, Domenica / Maggiora, Paola / Dugnani, Erica / Cangi, Maria Giulia / Garassini, Greta / Reni, Michele. ·Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. · Diabetes Research Institute, San Raffaele Scientific Institute, 20132, Milan, Italy. · Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, 20156, Milan, Italy. · Department of Radiology, San Raffaele Scientific Institute, 20132, Milan, Italy. · Pathology Unit, San Raffaele Scientific Institute, 20132, Milan, Italy. · Department Immunology and Inflammation, IRCCS Clinical and Research Institute Humanitas, 20089, Rozzano, Milan, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. reni.michele@hsr.it. ·Cancer Chemother Pharmacol · Pubmed #26666646.

ABSTRACT: PURPOSE: No standard salvage chemotherapy has been identified for metastatic pancreatic adenocarcinoma (mPA), and there is an urgent need for active agents against this disease. This phase II trial explored the activity of trabectedin in mPA progressing after gemcitabine-based first-line chemotherapy. METHODS: Patients with gemcitabine-resistant disease received trabectedin 1.3 mg/m(2) as a 3-h intravenous continuous infusion every 3 weeks until disease progression or unacceptable toxicity or for a maximum of 6 months. The primary endpoint was progression-free survival rate at 6 months (PFS-6). Since trabectedin modulates the production of selected inflammatory mediators, this study also aimed to identify inflammatory biomarkers predictive for response to trabectedin. RESULTS: Between February 2011 and February 2012, 25 patients received trabectedin. PFS-6 was 4%, median PFS 1.9 months (range 0.8-7.4), and median overall survival 5.2 months (range 1.1-24.3). Grade >2 toxicity consisted of neutropenia in 44% of patients, febrile neutropenia and thrombocytopenia both in 12%, anemia in 8%, fatigue in 12%, and AST and ALT increase in 8 and 4%, respectively. Trabectedin was shown to modulate the production of inflammatory mediators, and at disease progression, levels of a subgroup of cytokines/chemokines were modified. Furthermore, tissue analysis identified 30 genes associated with better prognosis. CONCLUSIONS: Although it has shown some ability to modulate inflammatory process, single-agent trabectedin had no activity as salvage therapy for mPA.

24 Clinical Trial (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial. 2016

Reni, Michele / Dugnani, Erica / Cereda, Stefano / Belli, Carmen / Balzano, Gianpaolo / Nicoletti, Roberto / Liberati, Daniela / Pasquale, Valentina / Scavini, Marina / Maggiora, Paola / Sordi, Valeria / Lampasona, Vito / Ceraulo, Domenica / Di Terlizzi, Gaetano / Doglioni, Claudio / Falconi, Massimo / Piemonti, Lorenzo. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it. · Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. · Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. piemonti.lorenzo@hsr.it reni.michele@hsr.it. ·Clin Cancer Res · Pubmed #26459175.

ABSTRACT: PURPOSE: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. EXPERIMENTAL DESIGN: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. RESULTS: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. CONCLUSIONS: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.

25 Clinical Trial Hypofractionated image-guided IMRT in advanced pancreatic cancer with simultaneous integrated boost to infiltrated vessels concomitant with capecitabine: a phase I study. 2013

Passoni, Paolo / Reni, Michele / Cattaneo, Giovanni M / Slim, Najla / Cereda, Stefano / Balzano, Gianpaolo / Castoldi, Renato / Longobardi, Barbara / Bettinardi, Valentino / Gianolli, Luigi / Gusmini, Simone / Staudacher, Carlo / Calandrino, Riccardo / Di Muzio, Nadia. ·Department of Radiation Oncology, San Raffaele Scientific Institute, Milan, Italy. Electronic address: passoni.paolo@hsr.it. ·Int J Radiat Oncol Biol Phys · Pubmed #24267968.

ABSTRACT: PURPOSE: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. METHODS AND MATERIALS: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. RESULTS: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. CONCLUSIONS: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.

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