Dose Intensity of Chemotherapy in Patients With Relapsed Hodgkin’s Lymphoma Andreas Josting, Horst Mu ¨ller, Peter Borchmann, Joke W. Baars, Bernd Metzner, Hartmut Do ¨hner, Igor Aurer, Lenka Smardova, Thomas Fischer, Dietger Niederwieser, Kerstin Scha ¨fer-Eckart, Norbert Schmitz, Anna Sureda, Jan Glossmann, Volker Diehl, Daphne DeJong, Martin-Leo Hansmann, John Raemaekers, and Andreas Engert From the University of Cologne, German Hodgkin Study Group; Univer- sity of Cologne, Ko ¨ ln; Hospital of Oldenburg, Oldenburg; University of Ulm, Ulm; University Hospital Magde- burg, Magdeburg; University Hospital Leipzig, Leipzig; Klinikum Nu ¨ rnberg Nord, Nu ¨ rnberg; Asklepios Klinik St Georg, Hamburg; University Hospital Frankfurt, Frankfurt, Germany; The Netherlands Cancer Institute, Antoni Van Leeuwenhoekziekenhuis, Amster- dam; Radboud University Medical Center Nijmegen, Nijmegen, the Neth- erlands; University Hospital Center Rebro, Zagreb, Croatia; General Teach- ing Hospital, Prague, Czech Republic; and the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Submitted May 20, 2010; accepted August 26, 2010; published online ahead of print at www.jco.org on October 25, 2010. Supported by the German Cancer Aid (Deutsche Krebshilfe). Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Andreas Engert, MD, German Hodgkin Study Group, University Hospital Cologne, Joseph- Stelzmann-Str 9, 50924 Cologne, Germany; e-mail: a.engert@uni- koeln.de. © 2010 by American Society of Clinical Oncology 0732-183X/10/2834-5074/$20.00 DOI: 10.1200/JCO.2010.30.5771 A B S T R A C T Purpose High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin’s lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy. Patients and Methods Patients with histologically confirmed, relapsed HL were treated with two cycles of dexa- methasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etopo- side in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points. Results From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P  .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P  .001). Conclusion Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL. J Clin Oncol 28:5074-5080. © 2010 by American Society of Clinical Oncology INTRODUCTION Combination chemotherapy cures approximately 80% of patients with Hodgkin’s lymphoma (HL), but those experiencing treatment failure have a poorer prognosis. 1 High-dose chemotherapy (HDCT) followed by autologous stem-cell trans- plantation (PBSCT) has become standard of care in these patients as demonstrated in randomized trials. 2,3 Variables affecting outcome in patients with relapsed HL undergoing HDCT include chemotherapy sensitivity to conventional salvage treatment, remission status before HDCT, and duration of first remission. 4-8 Randomized clini- cal studies demonstrated a relationship between intensity of chemotherapy and tumor response in this disease. 3,9 Since sequential HDCT (SHDCT) indicated promising results in a number of clini- cal studies, 10-16 the German Hodgkin Study Group (GHSG) evaluated a SHDCT regimen in a prior phase II study demonstrating that this was safe and effective in patients with relapsed and refractory HL. 17 In this study, we thus sought to compare the efficacy, safety, and adverse event profile of a stan- dard HDCT with that of a combined SHDCT- HDCT program in patients with histologically confirmed relapsed HL. JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28  NUMBER 34  DECEMBER 1 2010 5074 © 2010 by American Society of Clinical Oncology 165.112.216.212 Information downloaded from jco.ascopubs.org and provided by at NIH LIBRARY on December 10, 2010 from Copyright © 2010 American Society of Clinical Oncology. All rights reserved.