Uta Dirksen1, Bernadette Brennan2, Marie-Cécile Le Deley3, Nathalie Cozic4, Henk van den Berg5, Vivek Bhadri6, Bénédicte Brichard7, Line Claude8, Alan Craft9, Susanne Amler10, Natalie Gaspar4, Hans Gelderblom11, Robert Goldsby12, Richard Gorlick13, Holcombe E Grier14, Jean-Marc Guinbretiere15, Peter Hauser16, Lars Hjorth17, Katherine Janeway14, Heribert Juergens18, Ian Judson19, Mark Krailo20, Jarmila Kruseova21, Thomas Kuehne22, Ruth Ladenstein23, Cyril Lervat24, Stephen L Lessnick25, Ian Lewis26, Claude Linassier27, Perrine Marec-Berard28, Neyssa Marina29, Bruce Morland30, Hélène Pacquement31, Michael Paulussen32, R Lor Randall33, Andreas Ranft34, Gwénaël Le Teuff35, Keith Wheatley36, Jeremy Whelan37, Richard Womer38, Odile Oberlin4, Douglas S Hawkins38. 1. University Hospital Essen, Essen, Germany. 2. Royal Manchester Children's Hospital, Manchester, United Kingdom. 3. Centre Oscar Lambret, Lille; and Université Paris-Saclay, Villejuif, France. 4. Gustave Roussy, Villejuif, France. 5. Emma Children Hospital - Amsterdam University Medical Centres, Amsterdam, the Netherlands. 6. Chris O'Brien Lifehouse, Camperdown, NSW, Australia. 7. Cliniques Universitaires Saint Luc, Brussels, Belgium. 8. Centre Léon Bérard, Lyon; France. 9. Northern Institute for Cancer Research, Newcastle Upon Tyne, United Kingdom. 10. Westfalian Wilhelms University Muenster, Muenster; and Friedrich- Loeffler Institute, Greifswald-Insel Riems, Germany. 11. Leiden University Medical Center, Leiden, the Netherlands. 12. University of California San Francisco Benioff Children's Hospital, San Francisco, CA. 13. MD Anderson Cancer Center, Houston, TX. 14. Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA. 15. Hôpital René-Huguenin, Saint-Cloud, France. 16. Semmelweis University, Budapest, Hungary. 17. Lund University, Lund, Sweden. 18. Universitaetskinderklinik Muenster, Muenster, Germany. 19. Royal Marsden Foundation NHS Trust, London, United Kingdom. 20. University of Southern California, Los Angeles, CA. 21. Charles University Prague, Czech Republic. 22. University Children's Hospital Basel, Basel, Switzerland. 23. Medical University of Vienna, Vienna, Austria. 24. Centre Oscar Lambret, Lille, France. 25. Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH. 26. University of Leeds, Liverpool, United Kingdom. 27. Centre Hospitalier Universitaire, Tours, France. 28. Institute of Pediatric Onco-Haematology, Lyon, France. 29. Five Time Therapeutics, South San Francisco, CA. 30. Birmingham Women and Children's Hospital, Birmingham, United Kingdom. 31. Institut Curie, Paris, France. 32. Witten/Herdecke University, Datteln, Germany. 33. University of California Davis, Sacramento, CA. 34. Gustave Roussy, Université Paris-Saclay, Villejuif, France. 35. University of Birmingham, Birmingham, United Kingdom. 36. University College Hospital, London, United Kingdom. 37. Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA. 38. Seattle Children's Hospital, Seattle, WA.
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.
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.
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