High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma-Reference-Cited by-同舟云学术

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

Published:2022-07-20 Issue:21 Volume:40 Page:2307-2320
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Koch Raphael¹^ORCID,Gelderblom Hans²^ORCID,Haveman Lianne³^ORCID,Brichard Benedicte⁴^ORCID,Jürgens Heribert⁵,Cyprova Sona⁶,van den Berg Henk⁷,Hassenpflug Wolf⁸,Raciborska Anna⁹^ORCID,Ek Torben¹⁰^ORCID,Baumhoer Daniel¹¹^ORCID,Egerer Gerlinde¹²,Eich Hans Theodor¹³,Renard Marleen¹⁴,Hauser Peter¹⁵¹⁶^ORCID,Burdach Stefan¹⁷¹⁸,Bovee Judith¹⁹,Bonar Fiona²⁰^ORCID,Reichardt Peter²¹,Kruseova Jarmila⁶^ORCID,Hardes Jendrik²²^ORCID,Kühne Thomas²³^ORCID,Kessler Torsten²⁴^ORCID,Collaud Stephane²⁵^ORCID,Bernkopf Marie²⁶,Butterfaß-Bahloul Trude²⁷,Dhooge Catharina²⁸^ORCID,Bauer Sebastian²⁹³⁰^ORCID,Kiss János³¹,Paulussen Michael³²,Hong Angela³³³⁴,Ranft Andreas³⁰³⁵³⁶^ORCID,Timmermann Beate³⁰³⁶³⁷,Rascon Jelena³⁸³⁹^ORCID,Vieth Volker⁴⁰,Kanerva Jukka⁴¹,Faldum Andreas¹,Metzler Markus⁴²^ORCID,Hartmann Wolfgang⁴³^ORCID,Hjorth Lars⁴⁴^ORCID,Bhadri Vivek⁴⁵⁴⁶,Dirksen Uta³⁰³⁵³⁶^ORCID

Affiliation:

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

Abstract

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.21.01942

Reference33 articles.

1. Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial

2. GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

3. Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation

4. 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

5. The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES)

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