title: Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial.
abstract: BACKGROUND
  The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma.
  
  
  METHODS
  In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366.
  
  
  RESULTS
  Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin.
  
  
  CONCLUSIONS
  Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT.
  
  
  BACKGROUND
  Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Behringer
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Goergen
authors.affiliation: Cantonal Hospital of St Gallen, St Gallen, Switzerland and SAKK Swiss Group for Clinical Cancer Research, Bern, Switzerland.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Hitz
authors.affiliation: VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Josée M
authors.initials: JM
authors.lastname: Zijlstra
authors.affiliation: Third Medical Department, Paracelcus Medical University, Salzburg, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Markova
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sasse
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.affiliation: University Hospital Würzburg, Würzburg, Germany.
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.affiliation: University of Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Soekler
authors.affiliation: Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Meissner
authors.affiliation: Klinikum Nürnberg, Nürnberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wilhelm
authors.affiliation: University Hospital Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Koch
authors.affiliation: Katholisches Krankenhaus, Hagen, Germany.
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Lindemann
authors.affiliation: Department of Haematology and Oncology, Medical Centre, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Schalk
authors.affiliation: Department of Radiation Oncology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Semrau
authors.affiliation: University Hospital Münster, Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kriz
authors.affiliation: Medizinische Klinik, Universitätsklinik Schleswig-Holstein, Kiel, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Vieler
authors.affiliation: Medizinische Klinik, Städtisches Klinikum Karlsruhe, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bentz
authors.affiliation: Medizinische Klinik, Hämatologie/Onkologie, Evangelisches Krankenhaus, Hamm, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lange
authors.affiliation: Medizinische Klinik, Krankenanstalt Mutterhaus d. Borromäerinnen, Trier, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mahlberg
authors.affiliation: Zentrum für Innere Medizin, Hämatologie/Onkologie, Charité Campus Mitte, Berlin, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Hassler
authors.affiliation: Medizinische Klinik, Universitätsklinik Regensburg, Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vogelhuber
authors.affiliation: Klinik für Onkologie, Katharinenhospital, Stuttgart, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hahn
authors.affiliation: Medizinische Klinik-Hämatologie, Onkologie, Immunologie, Palliativmedizin, St. Vincentius-Kliniken gAG, Karlsruhe, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mezger
authors.affiliation: Department of Internal Medicine 5, Haematology/Oncology, University of Erlangen, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Krause
authors.affiliation: Cochrane Haematological Malignancies Group, Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Böll
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: von Tresckow
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Diehl
authors.affiliation: Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.affiliation: Berlin Reference Center for Lymphoma and Haematopathology, Berlin, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.affiliation: University Hospital Münster, Münster, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Eich
authors.affiliation: German Hodgkin Study Group (GHSG), Department of Internal Medicine 1, University Hospital of Cologne, Cologne, Germany. Electronic address: a.engert@uni-koeln.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001761:Bleomycin / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage*
chemical_list: D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin