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.

Birmingham Women and Children's Hospital Birmingham United Kingdom

Centre Hospitalier Universitaire Tours France

Centre Léon Bérard Lyon; France

Centre Oscar Lambret Lille France

Centre Oscar Lambret Lille; and Université Paris Saclay Villejuif France

Charles University Prague Czech Republic

Children's Hospital of Philadelphia and University of Pennsylvania Philadelphia PA

Chris O'Brien Lifehouse Camperdown NSW Australia

Cliniques Universitaires Saint Luc Brussels Belgium

Dana Farber Boston Children's Cancer and Blood Disorder Center Boston MA

Emma Children Hospital Amsterdam University Medical Centres Amsterdam the Netherlands

Five Time Therapeutics South San Francisco CA

Gustave Roussy Université Paris Saclay Villejuif France

Gustave Roussy Villejuif France

Hôpital René Huguenin Saint Cloud France

Institut Curie Paris France

Institute of Pediatric Onco Haematology Lyon France

Leiden University Medical Center Leiden the Netherlands

Lund University Lund Sweden

MD Anderson Cancer Center Houston TX

Medical University of Vienna Vienna Austria

Nationwide Children's Hospital and The Ohio State University College of Medicine Columbus OH

Northern Institute for Cancer Research Newcastle Upon Tyne United Kingdom

Royal Manchester Children's Hospital Manchester United Kingdom

Royal Marsden Foundation NHS Trust London United Kingdom

Seattle Children's Hospital Seattle WA

Semmelweis University Budapest Hungary

Universitaetskinderklinik Muenster Muenster Germany

University Children's Hospital Basel Basel Switzerland

University College Hospital London United Kingdom

University Hospital Essen Essen Germany

University of Birmingham Birmingham United Kingdom

University of California Davis Sacramento CA

University of California San Francisco Benioff Children's Hospital San Francisco CA

University of Leeds Liverpool United Kingdom

University of Southern California Los Angeles CA

Westfalian Wilhelms University Muenster Muenster; and Friedrich Loeffler Institute Greifswald Insel Riems Germany

Witten Herdecke University Datteln Germany

J Clin Oncol. 2019 Dec 1;37(34):3173-3175. doi: 10.1200/JCO.19.02522. PubMed

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Biological Sample Collection to Advance Research and Treatment: A Fight Osteosarcoma Through European Research and Euro Ewing Consortium Statement

Factors Influencing the Outcome of Patients with Primary Ewing Sarcoma of the Sacrum

Effect of Radiotherapy Dose on Outcome in Nonmetastatic Ewing Sarcoma

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ClinicalTrials.gov
NCT00020566, NCT00987636