High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008

Research output: Contribution to journalArticle

Abstract

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Details

Authors
  • Uta Dirksen
  • Bernadette Brennan
  • Marie Cécile Le Deley
  • Nathalie Cozic
  • Henk van den Berg
  • Vivek Bhadri
  • Bénédicte Brichard
  • Line Claude
  • Alan Craft
  • Susanne Amler
  • Natalie Gaspar
  • Hans Gelderblom
  • Robert Goldsby
  • Richard Gorlick
  • Holcombe E. Grier
  • Jean Marc Guinbretiere
  • Peter Hauser
  • Lars Hjorth
  • Katherine Janeway
  • Heribert Juergens
  • Ian Judson
  • Mark Krailo
  • Jarmila Kruseova
  • Thomas Kuehne
  • Ruth Ladenstein
  • Cyril Lervat
  • Stephen L. Lessnick
  • Ian Lewis
  • Claude Linassier
  • Perrine Marec-Berard
  • Neyssa Marina
  • Bruce Morland
  • Hélène Pacquement
  • Michael Paulussen
  • R. Lor Randall
  • Andreas Ranft
  • Gwénaël Le Teuff
  • Keith Wheatley
  • Jeremy Whelan
  • Richard Womer
  • Odile Oberlin
  • Douglas S. Hawkins
  • Euro-E.W.I.N.G. 99 Investigators
  • Ewing 2008 Investigators
Organisations
External organisations
  • University Hospital Essen
  • University of Paris-Saclay
  • Academic Medical Center of University of Amsterdam (AMC)
  • Cancer Institute of New South Wales
  • Saint-Luc University Hospital
  • Centre Léon Bérard
  • University of Newcastle upon Tyne
  • University of Münster
  • Leiden University Medical Centre
  • UCSF Benioff Children‘s Hospital
  • University of Texas
  • Hôpital René-Huguenin
  • Semmelweis University
  • Royal Marsden NHS Foundation Trust
  • University of Southern California
  • Charles University in Prague
  • University Children's Hospital, Basel
  • Medical University of Vienna
  • Centre Oscar Lambret
  • Ohio State University
  • University of Leeds
  • University Hospital of Tours
  • Five Prime Therapeutics Inc
  • Birmingham Children's Hospital
  • Curie Institute, Paris
  • Witten/Herdecke University
  • University of California, Davis
  • University of Birmingham
  • The Children's Hospital of Philadelphia
  • Royal Manchester Children's Hospital
  • Institut Gustave Roussy
  • Emma Children’s Hospital
  • Friedrich Loeffler Institute
  • University of California, San Francisco
  • Boston Children's Hospital
  • University Hospital Münster
  • Pediatric Hematology and Oncology Institute (IHOPE)
  • University College London Hospital
  • University of Pennsylvania
  • Seattle Children’s Hospital
  • Children's Hospital and Regional Medical Center, Seattle
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
  • Pediatrics
Original languageEnglish
Pages (from-to)3192-3202
Number of pages11
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume37
Issue number34
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes