title: A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action.
  
  
  METHODS
  A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR).
  
  
  RESULTS
  The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank).
  
  
  CONCLUSIONS
  The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.
authors.affiliation: Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany. Electronic address: l.bergmann@em.uni-frankfurt.de.
authors.forename: L
authors.initials: L
authors.lastname: Bergmann
authors.affiliation: Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Maute
authors.affiliation: Klinik für Hämatologie und Onkologie, Märkische Kliniken Lüdenscheid, Lüdenscheid, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Heil
authors.affiliation: Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Rüssel
authors.affiliation: Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt/Main, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Weidmann
authors.affiliation: Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Köberle
authors.affiliation: Onkologische Schwerpunktpraxis, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fuxius
authors.affiliation: Medizinische Klinik, Klinikum Nürnberg Nord, Nürnberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Weigang-Köhler
authors.affiliation: Hämatologie, Onkologie, Klinische Immunologie, Robert-Bosch-Krankenhaus, Stuttgart, Germany.
authors.forename: W E
authors.initials: WE
authors.lastname: Aulitzky
authors.affiliation: Medizinisches Versorgungszentrum Onkologie, Charité - Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Wörmann
authors.affiliation: Onkologische Schwerpunktpraxis, Groß-Gerau, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Hartung
authors.affiliation: CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Moritz
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Edler
authors.affiliation: Department of Nursing and Health, University of Applied Sciences of the Saarland, Saarbruecken, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Burkholder
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Scheulen
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Richly
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005060:Europe; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D003841:Deoxycytidine; D000077210:Sunitinib; D000093542:Gemcitabine
keywords: Combination; Gemcitabine; Pancreatic cancer; Sunitinib