[Ewing's sarcoma].

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Abstract

[Indexed for MEDLINE] 10. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. doi: 10.1200/JCO.21.01942. Epub 2022 Apr 15. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. Koch R(1), Gelderblom H(2), Haveman L(3), Brichard B(4), Jürgens H(5), Cyprova S(6), van den Berg H(7), Hassenpflug W(8), Raciborska A(9), Ek T(10), Baumhoer D(11), Egerer G(12), Eich HT(13), Renard M(14), Hauser P(15)(16), Burdach S(17)(18), Bovee J(19), Bonar F(20), Reichardt P(21), Kruseova J(6), Hardes J(22), Kühne T(23), Kessler T(24), Collaud S(25), Bernkopf M(26), Butterfaß-Bahloul T(27), Dhooge C(28), Bauer S(29)(30), Kiss J(31), Paulussen M(32), Hong A(33)(34), Ranft A(30)(35)(36), Timmermann B(30)(36)(37), Rascon J(38)(39), Vieth V(40), Kanerva J(41), Faldum A(1), Metzler M(42), Hartmann W(43), Hjorth L(44), Bhadri V(45)(46), Dirksen U(30)(35)(36). Author information: (1)Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany. (2)Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (3)Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. (4)Department of Pediatric Haematology and Oncology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium. (5)Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany. (6)Charles University, Motol Children's Hospital, Prague, Czech Republic. (7)Department of Pediatrics/Oncology, Emma Children's Hospital, University of Amsterdam, Amsterdam, the Netherlands. (8)Pediatric Hematology and Oncology, University Hospital Eppendorf, Hamburg, Germany. (9)Department of Oncology and Surgical Oncology for Children and Youth, Mother and Child Institute, Warsaw, Poland. (10)Childhood Cancer Center, Queen Silvia Children's Hospital, Gothenburg, Sweden. (11)Bone Tumor Reference Center at the Institute of Medical Genetics and Pathology, University Hospital Basel and University of Basel, Basel, Switzerland. (12)Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. (13)Department of Radiation Oncology, University Hospital Muenster, Muenster, Germany. (14)Pediatric Hematology and Oncology, University Hospital Leuven Gasthuisberg, Leuven Belgium. (15)Head of the Pediatric Oncology and Transplantation Unit, Velkey László Child's Health Center, Borsod-Abaúj-Zemplén County University Teaching Hospital, Miskolc, Hungary. (16)2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary. (17)Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany. (18)British Columbia Cancer Research Centre, Vancouver, BC, Canada. (19)Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (20)Douglass Hanly Moir Pathology, Macquarie Park, Australia. (21)Department of Oncology and Palliative Care, Helios Klinikum Berlin-Buch, Berlin, Germany. (22)Clinic of Orthopedics, University Hospital Essen, West German Cancer Centre, Essen, Germany. (23)Department of Oncology and Hematology, University Children's Hospital Basel, Basel, Switzerland. (24)Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. (25)Department of Thoracic Surgery, Ruhrlandklinik, University Hospital Essen, Essen, Germany. (26)Department of Pediatrics, St Anna Children's Hospital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria. (27)Centre for Clinical Trials (ZKS) Muenster, University of Muenster, Muenster, Germany. (28)Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, Princess Elisabeth Children's Hospital, Ghent University, Ghent, Belgium. (29)Department of Medical Oncology, Sarcoma Center, University of Duisburg-Essen, Essen, Germany. (30)West German Cancer Centre (WTZ) Network, Essen and Muenster, Germany. (31)Department of Orthopaedics, Semmelweis University, Budapest, Hungary. (32)General Pediatrics, Oncology and Hematology, Vestische Kinder und Jugendklinik Datteln, Witten/Herdecke University, Datteln, Germany. (33)Chris O'Brien Lifehouse, Camperdown, Australia. (34)Sydney Medical School, University of Sydney, Sydney, Australia. (35)Paediatrics III, University Hospital Essen, Essen, Germany. (36)German Consortium for Translational Cancer Research (DKTK), German Cancer Research Centre, Essen, Germany. (37)Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), Essen, Germany. (38)Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. (39)Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania. (40)Department of Clinical Radiology, Klinikum Ibbenbüren, Ibbenbüren, Germany. (41)Hematology and Stem Cell Transplantation, New Children's Hospital, HUS Helsinki University Hospital, University of Helsinki, Helsinki, Finland. (42)Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany. (43)Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Muenster, Germany. (44)Department of Clinical Sciences, Skåne University Hospital, Lund, Sweden. (45)Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia. (46)Faculty of Medicine and Health, University of Sydney, Sydney, Australia. Comment in J Clin Oncol. 2022 Jul 20;40(21):2288-2290. doi: 10.1200/JCO.22.00449. PURPOSE: Ewing 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). METHODS: Phase 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. RESULTS: Between 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. CONCLUSION: In 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. DOI: 10.1200/JCO.21.01942