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

Affiliation
University Hospital Essen, Essen, Germany.
Dirksen, Uta;
Affiliation
Royal Manchester Children's Hospital, Manchester, United Kingdom.
Brennan, Bernadette;
Affiliation
Centre Oscar Lambret, Lille; and Université Paris-Saclay, Villejuif, France.
Le Deley, Marie-Cécile;
Affiliation
Gustave Roussy, Villejuif, France.
Cozic, Nathalie;
Affiliation
Emma Children Hospital - Amsterdam University Medical Centres, Amsterdam, the Netherlands.
van den Berg, Henk;
Affiliation
Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
Bhadri, Vivek;
Affiliation
Cliniques Universitaires Saint Luc, Brussels, Belgium.
Brichard, Bénédicte;
Affiliation
Centre Léon Bérard, Lyon; France.
Claude, Line;
Affiliation
Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom.
Craft, Alan;
GND
1111120358
Affiliation
Westfalian Wilhelms University Muenster, Muenster; and Friedrich- Loeffler Institute, Greifswald-Insel Riems, Germany.
Amler, Susanne;
Affiliation
Gustave Roussy, Villejuif, France.
Gaspar, Natalie;
Affiliation
Leiden University Medical Center, Leiden, the Netherlands.
Gelderblom, Hans;
Affiliation
University of California San Francisco Benioff Children's Hospital, San Francisco, CA.
Goldsby, Robert;
Affiliation
MD Anderson Cancer Center, Houston, TX.
Gorlick, Richard;
Affiliation
Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA.
Grier, Holcombe E.;
Affiliation
Hôpital René-Huguenin, Saint-Cloud, France.
Guinbretiere, Jean-Marc;
Affiliation
Semmelweis University, Budapest, Hungary.
Hauser, Peter;
Affiliation
Lund University, Lund, Sweden.
Hjorth, Lars;
Affiliation
Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA.
Janeway, Katherine;
Affiliation
Universitaetskinderklinik Muenster, Muenster, Germany.
Juergens, Heribert;
Affiliation
Royal Marsden Foundation NHS Trust, London, United Kingdom.
Judson, Ian;
Affiliation
University of Southern California, Los Angeles, CA.
Krailo, Mark;
Affiliation
Charles University Prague, Czech Republic.
Kruseova, Jarmila;
Affiliation
University Children's Hospital Basel, Basel, Switzerland.
Kuehne, Thomas;
Affiliation
Medical University of Vienna, Vienna, Austria.
Ladenstein, Ruth;
Affiliation
Centre Oscar Lambret, Lille, France.
Lervat, Cyril;
Affiliation
Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH.
Lessnick, Stephen L.;
Affiliation
University of Leeds, Liverpool, United Kingdom.
Lewis, Ian;
Affiliation
Centre Hospitalier Universitaire, Tours, France.
Linassier, Claude;
Affiliation
Institute of Pediatric Onco-Haematology, Lyon, France.
Marec-Berard, Perrine;
Affiliation
Five Time Therapeutics, South San Francisco, CA.
Marina, Neyssa;
Affiliation
Birmingham Women and Children's Hospital, Birmingham, United Kingdom.
Morland, Bruce;
Affiliation
Institut Curie, Paris, France.
Pacquement, Hélène;
Affiliation
Witten/Herdecke University, Datteln, Germany.
Paulussen, Michael;
Affiliation
University of California Davis, Sacramento, CA.
Randall, R. Lor;
Affiliation
Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Ranft, Andreas;
Affiliation
University of Birmingham, Birmingham, United Kingdom.
Le Teuff, Gwénaël;
Affiliation
University College Hospital, London, United Kingdom.
Wheatley, Keith;
Affiliation
Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA.
Whelan, Jeremy;
Affiliation
Seattle Children's Hospital, Seattle, WA.
Womer, Richard;
Affiliation
Gustave Roussy, Villejuif, France.
Oberlin, Odile;
Affiliation
Seattle Children's Hospital, Seattle, WA.
Hawkins, Douglas S.

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. From 2000 to 2015, we enrolled patients older 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. 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. In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

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