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

Journal

Book Volume: 28

Article Number: JCO.21.01942

DOI: 10.1200/JCO.21.01942

Abstract

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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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

MLA:

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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