Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Gemcitabine Alone in Advanced Pancreatic Cancer Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Michael Gonnermann, Herbert Schöneka ¨s, Andreas Rost, Horst Neuhaus, Caroline Haag, Michael Clemens, Bernard Heinrich, Ursula Vehling-Kaiser, Martin Fuchs, Doris Fleckenstein, Wolfgang Gesierich, Dirk Uthgenannt, Hermann Einsele, Axel Holstege, Axel Hinke, Andreas Schalhorn, and Ralf Wilkowski A B S T R A C T Purpose To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer. Patients and Methods Patients with advanced adenocarcinoma of the pancreas were randomly assigned to receive either gemcitabine 1,000 mg/m 2 and cisplatin 50 mg/m 2 given on days 1 and 15 of a 4-week cycle (GemCis arm) or gemcitabine alone at a dose of 1,000 mg/m 2 on days 1, 8, and 15 of a 4-week regimen (Gem arm). The primary end point was overall survival; secondary end points were progression-free survival, response rate, safety, and quality of life. Results One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms. Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival (5.3 months v 3.1 months; hazard ratio [HR] = 0.75; P = .053). Also, median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm (7.5 v 6.0 months), an advantage which did not, however, reach statistical significance (HR = 0.80; P = .15). Tumor response rates were comparable between treatment arms (10.2% v 8.2%). The rate of stable disease was, however, greater in the combination arm (60.2% v 40.2%; P  .001). Grade 3 to 4 hematologic toxicity did not exceed 15% in both treatment arms. Conclusion These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin. Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone, although the difference did not attain statistical significance. J Clin Oncol 24:3946-3952. © 2006 by American Society of Clinical Oncology INTRODUCTION Cancer of the exocrine pancreas remains a fatal disease for most patients. Because of its predom- inantly late diagnosis, most patients present with advanced disease. 1,2 Without effective treatment, these patients have a median survival of 3 to 4 months. Systemic chemotherapy with single- agent gemcitabine has evolved as a moderately active standard of care for treatment of locally advanced and metastatic pancreatic cancer. 3,4 Its wide acceptance is based not only on good toler- ability but also on its potential to improve clinical benefit response. 5,6 In patients receiving gemcit- abine, Karnofsky performance status (KPS) and stage of disease have been identified as important prognostic factors for treatment outcome. 7 In an effort to improve therapeutic efficacy, numerous clinical studies have investigated gem- citabine (Gem) -based combination regimens. Some trials showed an improvement of overall response rates (ORR) and progression-free sur- vival (PFS). However, a significant prolongation of overall survival (OS) has not been demon- strated when Gem was combined with platinum analogs, 8,9 antimetabolites, 10-13 or topoisomerase inhibitors. 14,15 This may be explained by the no- tably low chemosensitivity of pancreatic cancer, From the Medizinische Klinik und Poliklinik III, Klinikum Grosshadern; Krankenhaus Bogenhausen; Klinikum Neuperlach München; Krankenhaus München-Harlaching; Klinik für Strahlen- therapie, Klinikum Grosshadern, Munich; Klinikum Chemnitz; Universita ¨- tsklinik Kiel, Kiel; Evangelisches Kran- kenhaus Dinslaken, Dinslaken; Klinikum Nu ¨ rnberg Nord, Nürnberg; Klinikum Darmstadt, Darmstadt; Evangelisches Krankenhaus Du ¨ sseldorf, Du ¨ sseldorf; Medizinische Fakulta ¨ t der TU Dresden, Dresden; Mutterhaus der Borroma ¨ erin- nen Trier, Trier; Onkologische Praxis Augsburg, Augsburg; Onkologische Praxis Landshut; Klinikum Landshut, Landshut; Medizinische Universita ¨t zu Lu ¨ beck, Lu ¨ beck; Medizinische Klinik II, Universita ¨t Wu ¨ rzburg, Wu ¨ rzberg; Wissenchaftlicher Service Pharma (WiSP), Langenfeld, Germany. Submitted January 18, 2006; accepted June 20, 2006. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Volker Heinemann, MD, PhD, Medical Clinic III, Klinikum Grosshadern, Marchioninis- trasse 15, 81377 Munich, Germany; e-mail: Volker.Heinemann@med .uni-muenchen.de. © 2006 by American Society of Clinical Oncology 0732-183X/06/2424-3946/$20.00 DOI: 10.1200/JCO.2005.05.1490 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 24  AUGUST 20 2006 3946 Downloaded from jco.ascopubs.org on February 7, 2016. For personal use only. No other uses without permission. Copyright © 2006 American Society of Clinical Oncology. All rights reserved.