title: Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.
abstract: OBJECTIVE
  To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2.
  
  
  METHODS
  The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS).
  
  
  RESULTS
  Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B.
  
  
  CONCLUSIONS
  The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.
authors.affiliation: Department of Medical Oncology, Georges Pompidou Hospital, University Paris Descartes, Paris, France. Electronic address: stephane.oudard@egp.aphp.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: Department of Medical Oncology, Saint Louis Hospital, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Culine
authors.affiliation: Department of Medical Oncology, Georges Pompidou Hospital, University Paris Descartes, Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Vano
authors.affiliation: Department of Medical Oncology, Cochin Hospital, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.affiliation: Department of Medical Oncology, Foch Hospital, Suresnes, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Théodore
authors.affiliation: Department of Medical Oncology, Besançon University Hospital, Besançon, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Medical Oncology, Victor Hugo Clinic, Le Mans, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Voog
authors.affiliation: Department of Medical Oncology, Georges Pompidou Hospital, University Paris Descartes, Paris, France.
authors.forename: Eugeniu
authors.initials: E
authors.lastname: Banu
authors.affiliation: Department of Medical Oncology, Cochin Hospital, Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Vieillefond
authors.affiliation: Department of Oncology-Hematology, La Roche-Sur-Yon Hospital, La Roche-Sur-Yon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Priou
authors.affiliation: Department of Medical Oncology, Saint Joseph Foundation, Paris, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Deplanque
authors.affiliation: Department of Medical Oncology, Paoli Calmettes Institute, Marseille, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Department of Oncology, Clinique Hartman, Neuilly-sur-Seine, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Vannetzel
authors.affiliation: Department of Medical Oncology, Saint Luc University Clinics, Catholic University of Leuven (IREC/MIRO, pole ONCO), Brussels, Belgium.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Department of Medical Oncology, La Timone Hospital, Marseille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Muracciole
authors.affiliation: Oncobiology Laboratory, René Huguenin Center, St Cloud, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Pichon
authors.affiliation: Department of Oncology, Saint Perrin Hospital, Clermont Ferrand, France.
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Bay
authors.affiliation: ARTIC Group (Association de Recherche sur les Thérapeutiques innovantes en Cancérologie), France.
authors.forename: Reza
authors.initials: R
authors.lastname: Elaidi
authors.affiliation: ARTIC Group (Association de Recherche sur les Thérapeutiques innovantes en Cancérologie), France.
authors.forename: Corine
authors.initials: C
authors.lastname: Teghom
authors.affiliation: Molecular Oncology, Curie Institute, UMR 144, CNRS, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.affiliation: Department of Medical Oncology, Curie Institute, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beuzeboc
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010984:Platinum / Q000008:administration & dosage / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D010984:Platinum; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine
keywords: Advanced urothelial carcinoma; Gemcitabine; Her2 overexpression; Platinum salts; Trastuzumab