{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:43:23Z","timestamp":1790894603341,"version":"4.1.0"},"reference-count":34,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"34","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.19.00915","type":"journal-article","created":{"date-parts":[[2019,9,25]],"date-time":"2019-09-25T19:58:18Z","timestamp":1569441498000},"page":"3192-3202","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":139,"title":["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"],"prefix":"10.1200","volume":"37","author":[{"given":"Uta","family":"Dirksen","sequence":"first","affiliation":[{"name":"University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Brennan","sequence":"additional","affiliation":[{"name":"Royal Manchester Children's Hospital, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-C\u00e9cile","family":"Le Deley","sequence":"additional","affiliation":[{"name":"Centre Oscar Lambret, Lille; and Universit\u00e9 Paris-Saclay, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cozic","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Emma Children Hospital \u2013 Amsterdam University Medical Centres, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Bhadri","sequence":"additional","affiliation":[{"name":"Chris O\u2019Brien Lifehouse, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Brichard","sequence":"additional","affiliation":[{"name":"Cliniques Universitaires Saint Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line","family":"Claude","sequence":"additional","affiliation":[{"name":"Centre L\u00e9on B\u00e9rard, Lyon; France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Craft","sequence":"additional","affiliation":[{"name":"Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Amler","sequence":"additional","affiliation":[{"name":"Westfalian Wilhelms University Muenster, Muenster; and Friedrich- Loeffler Institute, Greifswald-Insel Riems, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Gelderblom","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Goldsby","sequence":"additional","affiliation":[{"name":"University of California San Francisco Benioff Children\u2019s Hospital, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gorlick","sequence":"additional","affiliation":[{"name":"MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holcombe E.","family":"Grier","sequence":"additional","affiliation":[{"name":"Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorder Center, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Guinbretiere","sequence":"additional","affiliation":[{"name":"H\u00f4pital Ren\u00e9-Huguenin, Saint-Cloud, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hauser","sequence":"additional","affiliation":[{"name":"Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Hjorth","sequence":"additional","affiliation":[{"name":"Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Janeway","sequence":"additional","affiliation":[{"name":"Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorder Center, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heribert","family":"Juergens","sequence":"additional","affiliation":[{"name":"Universitaetskinderklinik Muenster, Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Judson","sequence":"additional","affiliation":[{"name":"Royal Marsden Foundation NHS Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Krailo","sequence":"additional","affiliation":[{"name":"University of Southern California, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarmila","family":"Kruseova","sequence":"additional","affiliation":[{"name":"Charles University Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kuehne","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Ladenstein","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Lervat","sequence":"additional","affiliation":[{"name":"Centre Oscar Lambret, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Lessnick","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital and The Ohio State University College of Medicine, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Lewis","sequence":"additional","affiliation":[{"name":"University of Leeds, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Linassier","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire, Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrine","family":"Marec-Berard","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Onco-Haematology, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neyssa","family":"Marina","sequence":"additional","affiliation":[{"name":"Five Time Therapeutics, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Morland","sequence":"additional","affiliation":[{"name":"Birmingham Women and Children's Hospital, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Pacquement","sequence":"additional","affiliation":[{"name":"Institut Curie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Paulussen","sequence":"additional","affiliation":[{"name":"Witten\/Herdecke University, Datteln, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Lor","family":"Randall","sequence":"additional","affiliation":[{"name":"University of California Davis, Sacramento, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ranft","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Universit\u00e9 Paris-Saclay, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gw\u00e9na\u00ebl","family":"Le Teuff","sequence":"additional","affiliation":[{"name":"University of Birmingham, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Wheatley","sequence":"additional","affiliation":[{"name":"University College Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Whelan","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Womer","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Hospital, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odile","family":"Oberlin","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas S.","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Hospital, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"B1","unstructured":"Hawkins DS, Brennan B, B\u00f6lling T, et al: Ewing sarcoma, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (ed 7). Philadelphia, PA, Wolters-Kluwer, 2015, pp. 855-872"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.5256"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.54.4833"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.9.3044"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.5720"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.1717"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/591698"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2014.04.036"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00066-008-1810-x"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.22.9864"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.05.7059"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25042"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.20820"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00066-009-1009-9"},{"key":"B17","first-page":"555","volume":"49","author":"Claude L","year":"2006","journal-title":"Pediatr Blood Cancer"},{"key":"B18","unstructured":"Carrie C, Le Deley M, Claude L, et al: The radiosensitization effect and toxicity of busulfan containing chemotherapy before radiotherapy for Ewing\u2019s sarcomas, Strahlentherapie Und Onkologie, Urban & Vogel Neumarkter Strasse 43, D-81673 Munich. Germany 2009, pp 31"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.04.106"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.9.1729"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780010204"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/70.3.659"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1143"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2307\/2530245"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200510190"},{"key":"B26","unstructured":"Lakbfleisch R, Prentics R: The Statistical Analysis of Failure Time Data (ed 2). New York, NY, Wiley, 2002"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1999.10474144"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/80.3.557"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dev060"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.3288"},{"key":"B31","doi-asserted-by":"crossref","first-page":"e75","DOI":"10.1016\/S1470-2045(17)30026-8","volume":"18","author":"Skinner R","year":"2017","journal-title":"Lancet Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.26371"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdq573"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.74.7402"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds117"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0003-x"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.19.00915","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,29]],"date-time":"2022-05-29T08:12:42Z","timestamp":1653811962000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.19.00915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":34,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2019,12,1]]}},"alternative-id":["10.1200\/JCO.19.00915"],"URL":"https:\/\/doi.org\/10.1200\/jco.19.00915","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,1]]},"assertion":[{"value":"2019-08-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}