title: Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalatedalone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group.
abstract: Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy.
  
  
  
  In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalatedand centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalatedchemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated(BEACOPPescalatedgroup) or BEACOPPescalatedplus rituximab (R-BEACOPPescalatedgroup). PET-2 was assessed using a 5-point scale with18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalatedwas given as previously described; rituximab was given intravenously at a dose of 375 mg/m2(maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated(day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554.
  
  
  
  Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalatedgroup (n=220) or the R-BEACOPPescalatedgroup (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalatedgroup and 93·0% (89·4-96·6) for those in the R-BEACOPPescalatedgroup (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalatedgroup vs 211 [96%] of 220 patients in the R-BEACOPPescalatedgroup), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalatedgroup and ten (5%) of 220 in the R-BEACOPPescalatedgroup died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalatedgroup and three (1%) in the R-BEACOPPescalatedgroup, all of them due to infection.
  
  
  
  The addition of rituximab to BEACOPPescalateddid not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma.
  
  
  
  Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany. Electronic address: peter.borchmann@uni-koeln.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.affiliation: Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Haverkamp
authors.affiliation: Cantonal Hospital Baselland, Liestal, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lohri
authors.affiliation: Cantonal Hospital Graubuenden, Chur, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mey
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group, Cologne, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kreissl
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: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Feuring-Buske
authors.affiliation: University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Meissner
authors.affiliation: Department of Hematology, University Hospital of Essen, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.affiliation: Department of Internal Medicine III, Klinikum Großhadern, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Ostermann
authors.affiliation: Department of Internal Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.affiliation: Department of Internal Medicine, Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Maschmeyer
authors.affiliation: Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kuhnert
authors.affiliation: Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Dietlein
authors.affiliation: Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kobe
authors.affiliation: Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Eich
authors.affiliation: Department of Radiotherapy, University Hospital of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Baues
authors.affiliation: Berlin Reference Center for Lymphoma and Haematopathology, Berlin, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.affiliation: German Hodgkin Study Group, Cologne, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Diehl
authors.affiliation: Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001761:Bleomycin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D006801:Humans; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography / Q000379:methods*; D011241:Prednisone / Q000008:administration & dosage; D011344:Procarbazine / Q000008:administration & dosage; D011379:Prognosis; D000069283:Rituximab / Q000008:administration & dosage; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D001761:Bleomycin; D011344:Procarbazine; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone