High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma

Koch R, Gelderblom H, Haveman L, Brichard B, Jürgens H, Cyprova S, Van Den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kühne T, Kessler T, Collaud S, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U (2022)

Publication Type: Journal article

Publication year: 2022


Book Volume: 28

Article Number: JCO.21.01942

DOI: 10.1200/JCO.21.01942


PURPOSEEwing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS).METHODSPhase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method.RESULTSBetween 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P =.035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P =.016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3.CONCLUSIONIn patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

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Involved external institutions

Universitätsklinikum Münster DE Germany (DE) Institute of Mother and Child / Instytut Matki I Dziecka PL Poland (PL) Universitätsklinikum Heidelberg DE Germany (DE) Universitätsklinikum Essen DE Germany (DE) Universitäts-Kinderspital beider Basel (UKBB) CH Switzerland (CH) Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH DE Germany (DE) Medizinische Universität Wien AT Austria (AT) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Princess Máxima Center NL Netherlands (NL) Cliniques universitaires Saint-Luc (CHU St-Luc) BE Belgium (BE) Motol University Hospital / Fakultní nemocnice v Motole CZ Czech Republic (CZ) University of Amsterdam NL Netherlands (NL) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Borsod-Abaúj-Zemplén County Central Hospital and University Teaching Hospital HU Hungary (HU) Technische Universität München (TUM) DE Germany (DE) Douglass Hanly Moir (DHM) Pathology AU Australia (AU) HELIOS Kliniken DE Germany (DE) University Hospital Ghent BE Belgium (BE) Universität Duisburg-Essen (UDE) DE Germany (DE) Universität Witten/Herdecke DE Germany (DE) Chris O’Brien Lifehouse AU Australia (AU) Vilnius University / Vilniaus universitetas LT Lithuania (LT) Klinikum Ibbenbüren DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Drottning Silvias barnsjukhus SE Sweden (SE) Universitätsspital Basel CH Switzerland (CH) Semmelweis University / Semmelweis Egyetem HU Hungary (HU) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) FI Finland (FI) Skåne University Hospital / Skånes universitetssjukhus SE Sweden (SE)

How to cite


Koch, R., Gelderblom, H., Haveman, L., Brichard, B., Jürgens, H., Cyprova, S.,... Dirksen, U. (2022). High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. Journal of Clinical Oncology, 28. https://doi.org/10.1200/JCO.21.01942


Koch, Raphael, et al. "High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma." Journal of Clinical Oncology 28 (2022).

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