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Pancreatic Neoplasms: HELP
Articles by Uwe Pelzer
Based on 31 articles published since 2008
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Between 2008 and 2019, U. Pelzer wrote the following 31 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 Review [Current standards in the treatment of pancreatic cancer]. 2015

Pelzer, Uwe / Riess, Hanno. ·Charité - Universitätsmedizin Berlin; Med. Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, Augustenburger Platz 1, 13353 Berlin. · Charité - Universitätsmedizin Berlin; Med. Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, Charitéplatz 1, 10117 Berlin. ·Dtsch Med Wochenschr · Pubmed #26625229.

ABSTRACT: The poor prognosis of pancreatic adenocarcinoma on the one hand side is due to the fact that early symptoms are nonspecific, often misdiagnosed and the disease is on the other hand side rapidly progressive, so that at diagnosis in about 80 % of cases already locally advanced inoperable, or metastatic cancer stages are present. In these cases the 1 year survival rate ranged from 20 % to 50 % depending of performance status and the used regimen. Thus, symptomatic supportive treatment is as important as palliative chemotherapy. Today several evidence-based chemotherapies are available - and others are expected soon - resulting in a highly significant overall survival benefit. Individual patient characteristics have to be considered for the selection of treatment. Even after successful surgery with curative intention, the 5-year survival rate is about 10 %. By adjuvant chemotherapy the survival probability as well as cure rate can be more than doubled. Since the preparation of the S3 guidelines for pancreatic cancer additional options in the care of patients with pancreatic cancer have become available to be incorporated in clinical practice.

3 Clinical Trial CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. 2017

Sinn, Marianne / Bahra, Marcus / Liersch, Torsten / Gellert, Klaus / Messmann, Helmut / Bechstein, Wolf / Waldschmidt, Dirk / Jacobasch, Lutz / Wilhelm, Martin / Rau, Bettina M / Grützmann, Robert / Weinmann, Arndt / Maschmeyer, Georg / Pelzer, Uwe / Stieler, Jens M / Striefler, Jana K / Ghadimi, Michael / Bischoff, Sven / Dörken, Bernd / Oettle, Helmut / Riess, Hanno. ·Marianne Sinn, Marcus Bahra, Uwe Pelzer, Jens M. Stieler, Jana K. Striefler, Sven Bischoff, Bernd Dörken, and Hanno Riess, Charité-Universitätsmedizin Berlin · Klaus Gellert, Sana Klinikum Lichtenberg, Berlin · Torsten Liersch and Michael Ghadimi, Universitätsmedizin Göttingen, Göttingen · Helmut Messmann, Klinikum Augsburg, Augsburg · Wolf Bechstein, Universitätsklinikum Frankfurt, Frankfurt · Dirk Waldschmidt, Universitätsklinikum Köln, Köln · Lutz Jacobasch, Clinical Center, Dresden · Martin Wilhelm, Paracelsus Medical University, Nürnberg · Bettina M. Rau, Universitätsmedizin Rostock, and Municipal Hospital of Neumarkt, Rostock · Robert Grützmann, Universitätsklinikum Carl Gustav Carus, Dresden, and Universitätsklinikum Erlangen, Erlangen · Arndt Weinmann, Klinikum der Johannes Gutenberg-Universität, Mainz · Georg Maschmeyer, Ernst von Bergmann Klinikum, Potsdam · and Helmut Oettle, Clinical Center, Friedrichshafen, Germany. ·J Clin Oncol · Pubmed #28817370.

ABSTRACT: Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m

4 Clinical Trial Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. 2017

Pelzer, Uwe / Blanc, Jean-Frédéric / Melisi, Davide / Cubillo, Antonio / Von Hoff, Daniel D / Wang-Gillam, Andrea / Chen, Li-Tzong / Siveke, Jens T / Wan, Yin / Solem, Caitlyn T / Botteman, Marc F / Yang, Yoojung / de Jong, Floris A / Hubner, Richard A. ·Department of Hematology/Oncology/Tumorimmunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. · Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Inserm UMR 1053, Université de Bordeaux, Bordeaux, France. · Digestive Molecular Clinical Oncology Unit, University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy. · Servicio de Oncologia Médica, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario Madrid Sanchinarro, Calle Oña, 10, 28050 Madrid, Spain. · Virginia G. Piper Cancer Center at HonorHealth/TGen, 10460N 92nd St #206, Scottsdale, AZ 85258, USA. · Division of Oncology, Washington University in St Louis, 660 South Euclid Avenue, St Louis, MO 63110, USA. · National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan 70456, Taiwan. · Division of Solid Tumor Translational Oncology, DKTK Partner Site Essen, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Pharmerit International, 4350 East-West Hwy #430, Bethesda, MD 20814, USA. · Shire, Plc, 650 East Kendal St, Cambridge, MA 02142, USA. · Department of Global Medical Affairs Oncology, Shire GmbH, Zählerweg 10, 6300 Zug, Switzerland. · Department of Medical Oncology, Christie Hospital NHS Foundation Trust, 550 Wilmslow Rd, Manchester M20 4BX, UK. ·Br J Cancer · Pubmed #28350787.

ABSTRACT: BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). METHODS: Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

5 Clinical Trial Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial. 2015

Sinn, M / Riess, H / Sinn, B V / Stieler, J M / Pelzer, U / Striefler, J K / Oettle, H / Bahra, M / Denkert, C / Bläker, H / Lohneis, P. ·Charité - Universitätsmedizin Berlin, Department of Medical Oncology and Haematology, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: marianne.sinn@charite.de. · Charité - Universitätsmedizin Berlin, Department of Medical Oncology and Haematology, Augustenburger Platz 1, 13353 Berlin, Germany. · Charité - Universitätsmedizin Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. · Outpatient Department Hematology/Oncology, Friedrichstr. 53, 88045 Friedrichshafen, Germany. · Charité - Universitätsmedizin Berlin, Department of General, Visceral and Transplantation Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. ·Eur J Cancer · Pubmed #26049689.

ABSTRACT: BACKGROUND: High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established. METHODS: CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan-Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013. RESULTS: For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p=0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p=0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p=0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p=0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p=0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p=0.83; median OS Farrell: no hENT1 20.2months, low hENT1 17.7 months, high HENT1 19.1 months, p=0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p=0.65) measured by the Farrell or Poplin Score. CONCLUSIONS: We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer. TRIAL REGISTRATION: ISRCTN34802808.

6 Clinical Trial α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. 2014

Sinn, M / Denkert, C / Striefler, J K / Pelzer, U / Stieler, J M / Bahra, M / Lohneis, P / Dörken, B / Oettle, H / Riess, H / Sinn, B V. ·Charité-Universitätsmedizin Berlin, Department of Medical Oncology and Haematology, Augustenburger Platz 1, 13353 Berlin, Germany. · Charité-Universitätsmedizin Berlin, Institute of Pathology, Chariteplatz 1, 10117 Berlin, Germany. · Charité-Universitätsmedizin Berlin, Department of General, Visceral and Transplantation Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. ·Br J Cancer · Pubmed #25314063.

ABSTRACT: BACKGROUND: Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients. METHODS: CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome. RESULTS: High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival. CONCLUSIONS: Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.

7 Clinical Trial Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. 2014

Oettle, Helmut / Riess, Hanno / Stieler, Jens M / Heil, Gerhard / Schwaner, Ingo / Seraphin, Jörg / Görner, Martin / Mölle, Matthias / Greten, Tim F / Lakner, Volker / Bischoff, Sven / Sinn, Marianne / Dörken, Bernd / Pelzer, Uwe. ·Helmut Oettle, Hanno Riess, Jens M. Stieler, Sven Bischoff, Marianne Sinn, Bernd Dörken, and Uwe Pelzer, Charitě Universitätsmedizin · Ingo Schwaner, Clinical Center, Berlin · Helmut Oettle, Clinical Center, Friedrichschafen · Gerhard Heil, Clinical Center, Lüdenscheid · Jörg Seraphin, Clinical Center, Northeim · Martin Görner, Clinical Center, Bielefeld · Matthias Mölle, Clinical Center, Dresden · Tim F. Greten, Hannover Medical School, Hannover · and Volker Lakner, Clinical Center, Rostock, Germany. ·J Clin Oncol · Pubmed #24982456.

ABSTRACT: PURPOSE: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. PATIENTS AND METHODS: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. RESULTS: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). CONCLUSION: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.

8 Clinical Trial SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. 2014

Sinn, M / Sinn, B V / Striefler, J K / Lindner, J L / Stieler, J M / Lohneis, P / Bischoff, S / Bläker, H / Pelzer, U / Bahra, M / Dietel, M / Dörken, B / Oettle, H / Riess, H / Denkert, C. ·Department of Medical Oncology and Haematology. ·Ann Oncol · Pubmed #24562449.

ABSTRACT: BACKGROUND: Previous investigations in pancreatic cancer suggested a prognostic role for secreted protein acidic and rich in cysteine (SPARC) expression in the peritumoral stroma but not for cytoplasmic SPARC expression. The aim of this study was to evaluate the impact of SPARC expression in pancreatic cancer patients treated with gemcitabine compared with untreated patients. PATIENTS AND METHODS: CONKO-001 was a prospective randomized phase III study investigating the role of adjuvant gemcitabine when compared with observation. Tissue samples of 160 patients were available for SPARC immunohistochemistry on tissue microarrays to evaluate its impact on patient outcome. RESULTS: Strong stromal SPARC expression was associated with worse disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P = 0.005, OS: P = 0.033). Its negative prognostic impact was restricted to patients treated with gemcitabine (DFS: P = 0.007, OS: P = 0.006). High cytoplasmic SPARC expression also was associated with worse patient outcome (DFS: P = 0.041, OS: P = 0.011). Again the effect was restricted to patients treated with gemcitabine (DFS: P = 0.002, OS: P = 0.003). In multivariable analysis, SPARC expression was independently predictive of patient outcome. CONCLUSIONS: Our data confirm the prognostic significance of SPARC expression after curatively intended resection. The negative prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine, suggesting SPARC as a predictive marker for response to gemcitabine.

9 Clinical Trial Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. 2011

Pelzer, Uwe / Schwaner, Ingo / Stieler, Jens / Adler, Mathias / Seraphin, Jörg / Dörken, Bernd / Riess, Hanno / Oettle, Helmut. ·Universitätsmedizin Berlin - Charité, Centrum für Tumormedizin, Augustenburger Platz 1, 13353 Berlin, Germany. ·Eur J Cancer · Pubmed #21565490.

ABSTRACT: BACKGROUND: Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy. METHODS: In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy. RESULTS: After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively. INTERPRETATION: Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.

10 Clinical Trial First-line treatment of pancreatic cancer patients with the combination of 5-fluorouracil/folinic acid plus gemcitabine: a multicenter phase II trial by the CONKO-study group. 2011

Pelzer, Uwe / Arnold, Dirk / Reitzig, Peter / Herrenberger, Julia / Korsten, Friedrich Wilhelm / Kindler, Manfred / Stieler, Jens / Dörken, Bernd / Riess, Hanno / Oettle, Helmut. ·Charité Centrum für Tumormedizin, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. uwe.pelzer@charite.de ·Cancer Chemother Pharmacol · Pubmed #21400239.

ABSTRACT: PURPOSE: This open-label, multi-center phase II study investigated the efficacy and safety of the combination of 5-fluorouracil (5-FU)/folinic acid (FA) plus gemcitabine (GFF) in patients with advanced pancreatic cancer. The study is based on our completed dose finding phase I trial. METHODS: A total of 90 patients (pts) were recruited between 02/2000 and 04/2002 to receive 5-FU 750 mg/m(2) (24 h, i.v.), FA 500 mg/m(2) (2 h, i.v.) and gemcitabine 1,000 mg/m(2) (30 min, i.v.) on days 1, 8, 15, and 22. Treatment was repeated on day 43 until disease progression. The primary objective was the 1-year survival rate. The trial was conducted in compliance with the Declaration of Helsinki. RESULTS: The 1-year survival rate was 25% [95% CI: 16-34], median overall survival was 6.8 months [95% CI: 5.13-8.45], 9 patients showed partial responses (PR) so that the overall response rate was 10.3%. Overall control rate (PR + stable disease for at least 6 months) was 56%. Median time to progression was 4.6 months [95% CI: 3.68-5.52]. In 402 GFF cycles, we observed adverse events grade 3 in up to 10% of patients and grade 4 below 5% of patients. CONCLUSIONS: The GFF combination appears to be effective and well tolerated. This intravenous regimen represents an intensified therapy with low frequency of toxicities and seems to be convenient for patients who are unable to get oral anti-neoplastic medication. After these encouraging results, the German CONKO-002 trial investigated the GFF regimen versus single-agent gemcitabine.

11 Clinical Trial Parenteral nutrition support for patients with pancreatic cancer. Results of a phase II study. 2010

Pelzer, Uwe / Arnold, Dirk / Gövercin, Mehmet / Stieler, Jens / Doerken, Bernd / Riess, Hanno / Oettle, Helmut. ·Universitätsmedizin Berlin, Charité Centrum für Tumormedizin, CONKO - Study Group, Augustenburger Platz 1, Berlin, Germany. uwe.pelzer@charite.de ·BMC Cancer · Pubmed #20214798.

ABSTRACT: BACKGROUND: Cachexia is a common problem in patients (pts) suffering from upper gastrointestinal cancer. In addition, most of these patients suffer from malabsorption and stenosis of the gastrointestinal tract due to their illness. Various methods of supplementary nutrition (enteral, parenteral) are practised. In patients with advanced pancreatic cancer (APC), phase angle, determined by bio-electrical impedance analysis (BIA), seems to be a survival predictor. The positive influence of BIA determinate predictors by additional nutrition is currently under discussion. METHODS: To examine the impact of additional parenteral nutrition (APN) we assessed outpatients suffering from APC and progressive cachexia. The assessment based on the BIA method. Assessment parameters were phase angle, ECM/BCM index (ratio of extracellular mass to body cell mass), and BMI (body mass index). Patients suffering from progressive weight loss in spite of additional enteral nutritional support were eligible for the study. RESULTS: Median treatment duration in 32 pts was 18 [8-35] weeks. Response evaluation showed a benefit in 27 pts (84%) in at least one parameter. 14 pts (43.7%) improved or stabilised in all three parameters. The median ECM/BCM index was 1.7 [1.11-3.14] at start of APN and improved down to 1.5 [1.12-3.36] during therapy. The median BMI increased from 19.7 [14.4-25.9] to 20.5 [15.4-25.0]. The median phase angle improved by 10% from 3.6 [2.3-5.1] to 3.9 [2.2-5.1]. CONCLUSIONS: We demonstrated the positive impact of APN on the assessed parameters, first of all the phase angle, and we observed at least a temporary benefit or stabilisation of the nutritional status in the majority of the investigated patients. Based on these findings we are currently investigating the impact of APN on survival in a larger patient cohort. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00919659.

12 Clinical Trial Second-line therapy in refractory pancreatic cancer. results of a phase II study. 2009

Pelzer, Uwe / Stieler, Jens / Roll, Lars / Hilbig, Andreas / Dörken, Bernd / Riess, Hanno / Oettle, Helmut. ·Universitatsmedizin Berlin, CharitéCentrum fur Tumormedizin, Medizinische Klinik m.S. Hamatologie/Onkologie, Berlin, Germany. uwe.pelzer@charite.de ·Onkologie · Pubmed #19295247.

ABSTRACT: BACKGROUND: This phase II trial investigated the efficacy and safety of oxaliplatin (O), 5-fluorouracil (5-FU), and folinic acid (FA) (OFF) as second-line treatment for patients with metastatic pancreatic adenocarcinoma after failure of first-line gemcitabine treatment. PATIENTS AND METHODS: 37 patients with confirmed progressive disease on gemcitabine therapy were treated with OFF (O 85 mg/m(2) days 8, 22; FA 500 mg/m(2), followed by 5-FU 2,600 mg/m(2) days 1, 8, 15, 22) every 6 weeks. Patients were treated on an outpatient basis and remained on treatment until disease progression. RESULTS: All patients were assessable for toxicity and effectiveness. We observed moderate hematotoxicity, the most common non-hematologic toxicity was neurotoxicity. A total of 12 patients had grade 3 nonhematologic toxicities: nausea and vomiting (4 patients), reversible neurotoxicity (5 patients), and diarrhea (3 patients). No grade 4 toxicities were observed. Median time to progression was 12 (1-125) weeks. Survival in second line was 22 (4-326+) weeks. Overall disease control rate was 49% (complete remission = 3%; partial remission = 3%; stable disease > 12 weeks = 43%). CONCLUSIONS: This regimen is feasible and active with an acceptable toxicity profile; it can be safely administered in an outpatient setting. There is an urgent need for further investigation in phase III trials.

13 Clinical Trial Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy). 2008

Riess, Hanno / Pelzer, Uwe / Hilbig, Andreas / Stieler, Jens / Opitz, Bernhard / Scholten, Theo / Kauschat-Brüning, Dörte / Bramlage, Peter / Dörken, Bernd / Oettle, Helmut. ·Charité Campus Virchow-Clinic, Medical Clinic Hematology/Oncology, Augustenburger Platz 1, 13353 Berlin, Germany. hanno.riess@charite.de ·BMC Cancer · Pubmed #19055847.

ABSTRACT: BACKGROUND: Advanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy. METHODS: The aim of this prospective multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients. Primary endpoint is the incidence of clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and/or pelvic and/or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission at 3, 6, 9 and 12 months, overall survival and bleeding. TRIAL REGISTRATION: isrctn.org identifier CCT-NAPN-16752, controlled-trials.com identifier: ISRCTN02140505. RESULTS: An interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding (5 pts vs. 6 pts, Chi2: 0.763). CONCLUSION: PROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer. Its results will lead to a new understanding of the role of heparins in the prevention of venous thromboembolism and of their effect on survival, remission rates and toxicity of chemotherapeutic regimens.

14 Article The role of hepatectomy for synchronous liver metastases from pancreatic adenocarcinoma. 2018

Andreou, Andreas / Knitter, Sebastian / Klein, Fritz / Malinka, Thomas / Schmelzle, Moritz / Struecker, Benjamin / Schmuck, Rosa B / Noltsch, Alina Roxana / Lee, Daniela / Pelzer, Uwe / Denecke, Timm / Pratschke, Johann / Bahra, Marcus. ·Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum, Germany. Electronic address: andreas.andreou@charite.de. · Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum, Germany; Berlin Institute of Health (BIH), Berlin, Germany. · Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum, Germany. · Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum, Germany. · Department of Radiology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum, Germany. ·Surg Oncol · Pubmed #30449494.

ABSTRACT: BACKGROUND: The role of hepatectomy for patients with liver metastases from ductal adenocarcinoma of the pancreas (PLM) remains controversial. Therefore, the aim of our study was to examine the postoperative morbidity, mortality, and long-term survivals after liver resection for synchronous PLM. METHODS: Clinicopathological data of patients who underwent hepatectomy for PLM between 1993 and 2015 were assessed. Major endpoint of this study was to identify predictors of overall survival (OS). RESULTS: During the study period, 76 patients underwent resection for pancreatic cancer and concomitant hepatectomy for synchronous PLM. Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 67%, 25%, and 8% of the patients, respectively. The median PLM size was 1 (1-13) cm and 36% of patients had multiple PLM. The majority of patients (96%) underwent a minor liver resection. After a median follow-up time of 130 months, 1-, 3-, and 5-year OS rates were 41%, 13%, and 7%, respectively. Postoperative morbidity and mortality rates were 50% and 5%, respectively. Preoperative and postoperative chemotherapy was administered to 5% and 72% of patients, respectively. In univariate analysis, type of pancreatic procedure (P = .020), resection and reconstruction of the superior mesenteric artery (P = .016), T4 stage (P = .086), R1 margin status at liver resection (P = .001), lymph node metastases (P = .016), poorly differentiated cancer (G3) (P = .037), no preoperative chemotherapy (P = .013), and no postoperative chemotherapy (P = .005) were significantly associated with worse OS. In the multivariate analysis, poorly differentiated cancer (G3) (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.08-3.24; P = .026), R1 margin status at liver resection (HR = 4.97; 95% CI = 1.46-16.86; P = .010), no preoperative chemotherapy (HR = 4.07; 95% CI = 1.40-11.83; P = .010), and no postoperative chemotherapy (HR = 1.88; 95% CI = 1.06-3.29; P = .030) independently predicted worse OS. CONCLUSIONS: Liver resection for PLM is feasible and safe and may be recommended within the framework of an individualized cancer therapy. Multimodal treatment strategy including perioperative chemotherapy and hepatectomy may provide prolonged survival in selected patients with metastatic pancreatic cancer.

15 Article Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis. 2018

Pelzer, Uwe / Wislocka, Lilianna / Jühling, Anja / Striefler, Jana / Klein, Fritz / Roemmler-Zehrer, Josefine / Sinn, Marianne / Denecke, Tim / Bahra, Marcus / Riess, Hanno. ·Division of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität - Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. Electronic address: uwe.pelzer@charite.de. · Division of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität - Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. · Division of Surgery, Medical Department Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Celgene GmbH, Munich, Germany. Electronic address: jrzehrer@celgene.com. · Division of Radiology, Medical Department Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. ·Eur J Cancer · Pubmed #30014884.

ABSTRACT: INTRODUCTION: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia. METHODS: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed. RESULTS: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13). CONCLUSION: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting.

16 Article Routine portal vein resection for pancreatic adenocarcinoma shows no benefit in overall survival. 2018

Klein, Fritz / Berresheim, Finja / Felsenstein, Matthäus / Malinka, Thomas / Pelzer, Uwe / Denecke, Timm / Pratschke, Johann / Bahra, Marcus. ·Department of Surgery, Charité - Universitätsmedizin Berlin, Germany. Electronic address: fritz.klein@charite.de. · Department of Surgery, Charité - Universitätsmedizin Berlin, Germany. · Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Germany. · Department of Diagnostic and Interventional Radiology, Charité - Universitätsmedizin Berlin, Germany. ·Eur J Surg Oncol · Pubmed #29778616.

ABSTRACT: BACKGROUND: Extended pancreatic resections including resections of the portal (PV) may nowadays be performed safely. Limitations in distinguishing tumor involvement from inflammatory adhesions however lead to portal vein resections (PVR) without evidence of tumor infiltration in the final histopathological examination. The aim of this study was to analyze the impact of these "false negative" resections on operative outcome and long-term survival. METHODS: 40 patients who underwent pancreatic resection with PVR for pancreatic adenocarcinoma (PA) without tumor infiltration of the PV (PVR-group) were identified. In a 1:3 match these patients were compared to 120 patients after standard pancreatic resection without PVR (SPR-group) with regard to operative outcome and overall survival. RESULTS: Survival analysis revealed that median survival was significantly shorter in the PVR group (311 days) as compared to the SPR group (558 days), (p = 0.0011, hazard ratio 1.98, 95% CI: 1.31-2.98). Also postoperative complications ≥ Clavien III occurred significantly more often in the PVR group (37.5% vs. 20.8%). CONCLUSIONS: Radical resection affords the best chance for long-term survival in patients with PA. Based on the results of this study a routine resection of the PV as recently proposed may however not be recommended.

17 Article Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma. 2018

Lohneis, Philipp / Sinn, Marianne / Klein, Fritz / Bischoff, Sven / Striefler, Jana K / Wislocka, Lilianna / Sinn, Bruno V / Pelzer, Uwe / Oettle, Helmut / Riess, Hanno / Denkert, Carsten / Bläker, Hendrik / Jühling, Anja. ·Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charitéplatz 1, Berlin, 10117, Germany. philipp.lohneis@uk-koeln.de. · University Hospital Cologne, Institute of Pathology, Kerpener Strasse 62, Köln, 50924, Germany. philipp.lohneis@uk-koeln.de. · Department of Medical Oncology, CONKO study group, Haematology and Tumorimmunology, Augustenburger Platz 1, Berlin, 13353, Germany. · Department of Surgery Campus Charité Mitte/ Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany. · Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Charitéplatz 1, Berlin, 10117, Germany. · Outpatient Department Hematology/Oncology, Friedrichstrasse 53, Friedrichshafen, 88045, Germany. ·Br J Cancer · Pubmed #29755112.

ABSTRACT: BACKGROUND: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial. METHODS: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm RESULTS: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well. CONCLUSIONS: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.

18 Article Dose-escalated radiotherapy for unresectable or locally recurrent pancreatic cancer: Dose volume analysis, toxicity and outcome of 28 consecutive patients. 2017

Zschaeck, Sebastian / Blümke, Bibiana / Wust, Peter / Kaul, David / Bahra, Marcus / Riess, Hanno / Klein, Fritz / Sinn, Marianne / Pelzer, Uwe / Budach, Volker / Ghadjar, Pirus. ·Charité Universitätsmedizin Berlin, Department of Radiation Oncology, Berlin, Germany. · Charité Universitätsmedizin Berlin, Department of General, Visceral, and Transplantation Surgery, Berlin, Germany. · Charité Universitätsmedizin Berlin, Department of Hematology/Oncology/Tumorimmunology, Berlin, Germany. ·PLoS One · Pubmed #29023527.

ABSTRACT: PURPOSE: The role of radiotherapy for unresectable pancreatic cancer is controversial. A benefit of additional radiotherapy is supported by some observations. A dose-effect relationship was recently found by dose escalation employing image guided and intensity modulated radiotherapy. METHODS: We retrospectively evaluated 28 consecutive patients, all with history of extensive prior therapies for unresectable locally advanced/ recurrent pancreatic cancer (LAPC/LRPC). Treatment was delivered by helical tomotherapy after daily position verification with computed tomography. Dose to the planned target volume (PTV) was 51 Gy, while the dose to the macroscopic tumor was escalated by a simultaneous integrated boost to a median cumulative dose of 66 Gy (60-66 Gy). Concomitant chemotherapy consisted mainly of capecitabine (n = 23). RESULTS: 10 of 28 patients presented acute toxicities > grade 2, one patient succumbed to gastrointestinal bleeding after treatment. No correlations of toxicities and dose volume histograms (DVH) of retrospectively delineated small bowel loops were observed, although average small bowel volume receiving ≥ 20 Gy was 374 ml. DVH analyses revealed a correlation of splenic parameters and acute toxicity: Vomiting, anorexia, dehydration, hematologic toxicity, fatigue, combined gastro-intestinal toxicity wit R-values between 0.392 and 0.561 (all p-values > 0.05). Only one patient developed late toxicities > grade 2. With an average follow-up time in surviving patients of 14 months median overall survival time was 19 months and median time to local recurrence 13 months. In 8 patients with available imaging of local recurrence: 5 in field recurrences, 2 marginal recurrences and one lymph node recurrence outside the high dose radiation field were observed. In univariate analysis only ΔCA-19-9 during radiotherapy was associated with local control (p = 0.029) and overall survival (p = 0.049). CONCLUSION: Dose escalated normo-fractionated radiotherapy for LAPC/LRPC seems feasible and suitable to prolong local control and in consequence long-term survival. However, in-field local progression is still frequently observed and possibilities to increase the local effectiveness should be evaluated. Exposure of the spleen was predictive for acute toxicity and should be further investigated.

19 Article Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma. 2017

Lohneis, Philipp / Sinn, Marianne / Bischoff, Sven / Jühling, Anja / Pelzer, Uwe / Wislocka, Lilianna / Bahra, Marcus / Sinn, Bruno V / Denkert, Carsten / Oettle, Helmut / Bläker, Hendrik / Riess, Hanno / Jöhrens, Korinna / Striefler, Jana K. ·Universitätsmedizin Charité Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: philipp.lohneis@charite.de. · Universitätsmedizin Charité Berlin, CONKO Study Group, Department of Medical Oncology, Haematology and Tumorimmunology, Augustenburger Platz 1, 13353 Berlin, Germany. · Universitätsmedizin Charité Berlin, Department of General, Visceral and Transplantation Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. · Universitätsmedizin Charité Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. · Outpatient Department Hematology/Oncology, Friedrichstrasse 53, 88045 Friedrichshafen, Germany. ·Eur J Cancer · Pubmed #28772128.

ABSTRACT: BACKGROUND: We studied the prognostic effect of CD3-, CD8- and CD103-positive T lymphocytes in a cohort of 165 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the treatment group (adjuvant gemcitabine) and the untreated control group of the CONKO-001 study. METHODS: Immunohistochemical stainings on tissue microarrays (TMAs) against CD3, CD8 and CD103 were performed according to standard procedures. RESULTS: A high number of CD8-positive lymphocytes were significantly and independently associated with longer disease-free survival (DFS) and overall survival (OS) in the overall study population. Median DFS/OS were 7.4/18.1 months for patients with a low number of CD8-positive intratumoural lymphocytes (≤42 per 1 mm tissue core) and 12.7/25.2 months for patients with high numbers (>42 per 1-mm tissue core; p = 0.008/0.020; HR 0.62/0.65). The ratio of intraepithelial to total CD103-positive lymphocytes, but not total numbers of CD103-positive lymphocytes or CD103-positive intraepithelial lymphocytes, was associated with significantly improved DFS and OS in the overall study population (p = 0.022/0.009). Median DFS/OS was 5.9/15.7 for patients with a ratio of intraepithelial to total CD103-positive intratumoural lymphocytes higher than 0.3 and 11.6/24.7 for patients with a lower ratio. CONCLUSION: T-lymphocyte subpopulations might be prognostic in resectable PDAC but need standardization and verification by further studies.

20 Article P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment. 2016

Striefler, Jana K / Sinn, Marianne / Pelzer, Uwe / Jühling, Anja / Wislocka, Lilianna / Bahra, Marcus / Sinn, Bruno V / Denkert, Carsten / Dörken, Bernd / Oettle, Helmut / Riess, Hanno / Bläker, Hendrik / Lohneis, Philipp. ·Charité - Universitätsmedizin Berlin, Department of Medical Oncology and Haematology, Augustenburger Platz 1, 13353 Berlin, Germany. · Charité - Universitätsmedizin Berlin, Department of General, Visceral and Transplantation Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. · Charité - Universitätsmedizin Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. · Outpatient Department Hematology/Oncology, Friedrichstrasse 53, 88045 Friedrichshafen, Germany. · Charité - Universitätsmedizin Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: philipp.lohneis@charite.de. ·Pathol Res Pract · Pubmed #27461834.

ABSTRACT: In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies.

21 Article Second-Line Treatment in Pancreatic Cancer Patients: Who Profits?--Results From the CONKO Study Group. 2016

Sinn, Marianne / Dälken, Louise / Striefler, Jana Käthe / Bischoff, Sven / Schweitzer, Nora / Pelzer, Uwe / Dörken, Bernd / Riess, Hanno / Stieler, Jens Maria. ·From the *Department of Medical Oncology and Haematology, Charité Universitätsmedizin Berlin, Berlin, Germany; and †Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany. ·Pancreas · Pubmed #26646276.

ABSTRACT: OBJECTIVES: With increasing numbers of therapeutic options in inoperable pancreatic cancer (PAC), patients tend to receive more than just a first line (FL) therapy. METHODS: All patients who started FL for PAC at our institution (1997-2012) were retrospectively studied to identify patient's and treatment characteristics. Significant parameters in regard to second-line (SL) related survival were looked for as the basis for a prognostic model. This score was validated in a patient cohort from the CONKO-003 study. RESULTS: Two hundred eighty of 521 (53.7%) patients received SL therapy, median overall survival (OS) from the beginning of SL (OS2) was 5.1 months. Significant more SL patients had undergone surgery, a higher Karnofsky performance state (KPS) and a duration of FL longer than 4 months.Prognostic factors impacting OS2 were KPS, carbohydrate antigen 19-9 levels at start of SL and the duration of FL. These 3 factors establish a prognostic score--validated in CONKO-003--for SL patients with 3 subgroups: "good" (median OS2, 9.3 months), "intermediate" (median OS2, 7.1 months), "poor" prognosis (median OS2, 3.8 months; P < 0.001). CONCLUSIONS: Among patients with PAC, more than 50% receive SL therapy. Our prognostic model identifies 3 subgroups and can identify patients with a maximum benefit of SL therapy.

22 Article Prognostic significance of DNA cytometry for adjuvant therapy response in pancreatic cancer. 2015

Klein, Fritz / Bahra, Marcus / Schirmeier, Anja / Al-Abadi, Hussein / Pratschke, Johann / Pelzer, Uwe / Oettle, Helmut / Striefler, Jana / Riess, Hanno / Sinn, Marianne. ·Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Department of Medical Oncology and Haematology, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Department of Outpatient, Medical Oncology, Friedrichshafen, Germany. ·J Surg Oncol · Pubmed #26193339.

ABSTRACT: BACKGROUND AND OBJECTIVES: The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re-evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease-free (DFS) and overall survival (OS) was analyzed within the CONKO-001 patient population. METHODS: One hundred forty three fresh-frozen paraffin-embedded tissue samples of the resected tumor specimen of the CONKO-001 patient population were available for DNA index analysis to evaluate its impact on patient outcome. RESULTS: Median DFS (7.3 vs. 14.3 months; P = 0.004) and median OS (16.6 vs. 29.2 months; P = 0.011) were significantly decreased in patients with a high DNA index (>1.4). Multivariate analysis revealed both DNA index (DFS: P = 0.002; OS: P = 0.019) and tumor grading (DFS: P = 0.004; OS: P = 0.004) as individual prognostic markers for DFS and OS. The following prognostic subgroups were identified: good (low DNA Index + G1/2 tumor grading), intermediate (low DNA Index + G3 tumor grading or high DNA Index + G1/2 tumor grading), poor (high DNA Index + G3 tumor grading). CONCLUSION: The DNA index/tumor grading constellation may serve as a helpful guide for personalized treatment recommendations for adjuvant therapy of patients with pancreatic adenocarcinoma.

23 Article Efficacy of Prophylactic Low-Molecular Weight Heparin for Ambulatory Patients With Advanced Pancreatic Cancer: Outcomes From the CONKO-004 Trial. 2015

Pelzer, Uwe / Opitz, Bernhard / Deutschinoff, Gerd / Stauch, Martina / Reitzig, Peter C / Hahnfeld, Sabine / Müller, Lothar / Grunewald, Martina / Stieler, Jens M / Sinn, Marianne / Denecke, Timm / Bischoff, Sven / Oettle, Helmut / Dörken, Bernd / Riess, Hanno. ·Uwe Pelzer, Jens M. Stieler, Marianne Sinn, Timm Denecke, Sven Bischoff, Bernd Dörken, and Hanno Riess, Charité-Universitätsmedizin Berlin · Peter C. Reitzig, Hospital Sana Klinikum Lichtenberg, Berlin · Bernhard Opitz, Hospital St Elisabeth/St Barbara, Halle · Gerd Deutschinoff, Allgemeins Krankenhaus, Hagen · Martina Stauch, Clinical Center, Kronach · Sabine Hahnfeld, Clinical Center, Jena · Lothar Müller, Clinical Center, Leer · Martina Grunewald, Hospital Aschersleben, Aschersleben · and Helmut Oettle, Clinical Center, Friedrichshafen, Germany. ·J Clin Oncol · Pubmed #25987694.

ABSTRACT: PURPOSE: Advanced pancreatic cancer (APC), in addition to its high mortality, accounts for the highest rates of venous thromboembolic events (VTEs). Enoxaparin, a low-molecular weight heparin, is effective in prevention and treatment of VTEs. Some small studies have indicated that this benefit might extend to patients with cancer. PATIENTS AND METHODS: Patients with histologically proven APC were randomly assigned to ambulant first-line chemotherapy and prophylactic use of enoxaparin or chemotherapy alone to investigate the probable reduction in symptomatic VTEs and the impact on survival. RESULTS: A total of 312 patients were recruited as one of the protocol end points was reached. Within the first 3 months, the numbers of symptomatic VTEs were as follows: 15 of 152 patients in the observation group and two of 160 patients in the enoxaparin group (hazard ratio [HR], 0.12; 95% CI, 0.03 to 0.52; χ(2) P = .001). The numbers of major bleeding events were as follows: five of 152 patients in the observation arm and seven of 160 patients in the enoxaparin arm (HR, 1.4; 95% CI, 0.35 to 3.72; χ(2) P = 1.0). Overall cumulative incidence rates of symptomatic VTEs were 15.1% (observation) and 6.4% (enoxaparin; HR, 0.40; 95% CI, 0.19 to 0.83; P = .01). Progression-free (HR, 1.06; 95% CI, 0.84 to 1.32; P = .64) and overall survival (HR, 1.01; 95% CI, 0.87 to 1.38; P = .44) did not differ between groups. CONCLUSION: This study demonstrates the high efficacy and feasibility of primary pharmacologic prevention of symptomatic VTEs in outpatients with APC. Treatment efficacy was not affected by simultaneous treatment with enoxaparin in this trial setting.

24 Article Cytoreductive Surgery for Pancreatic Cancer Improves Overall Outcome of Gemcitabine-Based Chemotherapy. 2015

Bahra, Marcus / Pratschke, Johann / Klein, Fritz / Neuhaus, Peter / Boas-Knoop, Sabine / Puhl, Gero / Denecke, Timm / Pullankavumkal, Joyce R / Sinn, Marianne / Riess, Hanno / Pelzer, Uwe. ·From the *Department of General, Visceral, and Transplantation Surgery; †Department of Diagnostic and Interventional Radiology; and ‡Department of Hematology and Oncology, Charité Campus Virchow, Charité-Universitätsmedizin Berlin, Berlin, Germany. ·Pancreas · Pubmed #25931260.

ABSTRACT: OBJECTIVES: Pancreatoduodenectomy is feasible also in patients with locally advanced pancreatic adenocarcinoma (PA) nowadays. Data on risk and survival analysis of palliative pancreatic resections followed by gemcitabine-based chemotherapy (Cx) are limited. METHODS: Between 2000 and 2009, a total of 45 patients had primary cytoreductive surgery (cS) (pancreaticoduodenectomy or total pancreatectomy) followed by gemcitabine-based Cx (cS + Cx) for advanced PA. We matched 1:1 the cS + Cx group with 45 contemporaneous patients who primarily started palliative gemcitabine-based Cx for age, sex, performance status, and body mass index. Overall, survival was evaluated. RESULTS: Local R0 and R1 resection in metastatic patients was achieved in 27% and 27%, respectively. The R2 resection status without distant metastasis resulted in 33%, whereas 13% showed a local R2 status with additional metastasis (M1). Median overall survival was 10.4 months after cytoreductive pancreatic surgery and consecutive gemcitabine-based Cx versus 7.2 months after upfront gemcitabine-based Cx (P = 0.009). Median survival for R0/M1 patients was 14.4 months and 11.0 months for R2/M0 patients, whereas the median survival for R1/M1 and for R2/M1 patients was 7.3 months and 6.1 months, respectively. CONCLUSIONS: Individual patients with advanced PA had a significantly longer overall survival after palliative pancreaticoduodenectomy followed by Cx than patients in a matched control group who underwent primarily palliative Cx.

25 Article Intensity-modulated and image-guided radiotherapy in patients with locally advanced inoperable pancreatic cancer after preradiation chemotherapy. 2014

Sinn, M / Ganeshan, R / Graf, R / Pelzer, U / Stieler, J M / Striefler, J K / Bahra, M / Wust, P / Riess, H. ·Department of Medical Oncology and Haematology, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. · Department of Radiooncology, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. · Department of General, Visceral and Transplantation Surgery, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. ·ScientificWorldJournal · Pubmed #25401140.

ABSTRACT: BACKGROUND: Radiotherapy (RT) in patients with pancreatic cancer is still a controversial subject and its benefit in inoperable stages of locally advanced pancreatic cancer (LAPC), even after induction chemotherapy, remains unclear. Modern radiation techniques such as image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) may improve effectiveness and reduce radiotherapy-related toxicities. METHODS: Patients with LAPC who underwent radiotherapy after chemotherapy between 09/2004 and 05/2013 were retrospectively analyzed with regard to preradiation chemotherapy (PRCT), modalities of radiotherapy, and toxicities. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves. RESULTS: 15 (68%) women and 7 men (median age 64 years; range 40-77) were identified. Median duration of PRCT was 11.1 months (range 4.3-33.0). Six patients (27%) underwent conventional RT and 16 patients (73%) advanced IMRT and IGRT; median dosage was 50.4 (range 9-54) Gray. No grade III or IV toxicities occurred. Median PFS (estimated from the beginning of RT) was 5.8 months, 2.6 months in the conventional RT group (conv-RT), and 7.1 months in the IMRT/IGRT group (P = 0.029); median OS was 11.0 months, 4.2 months (conv-RT), and 14.0 months (IMRT/IGRT); P = 0.141. Median RT-specific PFS for patients with prolonged PRCT > 9 months was 8.5 months compared to 5.6 months for PRCT < 9 months (P = 0.293). This effect was translated into a significantly better median RT-specific overall survival of patients in the PRCT > 9 months group, with 19.0 months compared to 8.5 months in the PRCT  <  9 months group (P = 0.049). CONCLUSIONS: IGRT and IMRT after PRCT are feasible and effective options for patients with LAPC after prolonged preradiation chemotherapy.

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