Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial-Reference-Cited by-同舟云学术

Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial

Published:2023-10-16 Issue:24 Volume:29 Page:5057-5068
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Koch Raphael¹^ORCID,Haveman Lianne²^ORCID,Ladenstein Ruth³^ORCID,Brichard Benedicte⁴^ORCID,Jürgens Heribert⁵^ORCID,Cyprova Sona⁶^ORCID,van den Berg Henk⁷^ORCID,Hassenpflug Wolf⁸^ORCID,Raciborska Anna⁹^ORCID,Ek Torben¹⁰^ORCID,Baumhoer Daniel¹¹^ORCID,Egerer Gerlinde¹²^ORCID,Kager Leo¹³^ORCID,Renard Marleen¹⁴^ORCID,Hauser Peter¹⁵¹⁶^ORCID,Burdach Stefan¹⁷^ORCID,Bovee Judith V.M.G.¹⁸^ORCID,Hong Angela M.¹⁹²⁰^ORCID,Reichardt Peter²¹^ORCID,Kruseova Jarmila⁶^ORCID,Streitbürger Arne²²^ORCID,Kühne Thomas²³^ORCID,Kessler Torsten²⁴^ORCID,Bernkopf Marie¹³^ORCID,Butterfaß-Bahloul Trude²⁵^ORCID,Dhooge Catharina²⁶^ORCID,Bauer Sebastian²⁷²⁸^ORCID,Kiss János²⁹^ORCID,Paulussen Michael³⁰^ORCID,Bonar Fiona³¹^ORCID,Ranft Andreas²⁸³²³³^ORCID,Timmermann Beate²⁸³³³⁴^ORCID,Rascon Jelena³⁵³⁶^ORCID,Vieth Volker³⁷^ORCID,Kanerva Jukka³⁸^ORCID,Faldum Andreas¹^ORCID,Hartmann Wolfgang³⁹^ORCID,Hjorth Lars⁴⁰^ORCID,Bhadri Vivek A.⁴¹⁴²^ORCID,Metzler Markus⁴³⁴⁴^ORCID,Gelderblom Hans⁴⁵^ORCID,Dirksen Uta²⁸³²³³^ORCID

Affiliation:

1. 1Institute of Biostatistics and Clinical Research, University of Muenster, Germany.

2. 2Department of Solid tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

3. 3Studies and Statistics for Integrated Research and Projects, St. Anna Children's Hospital, Department of Paediatrics and Children's Cancer Research Institute (CCRI), Medical University of Vienna, Vienna, Austria.

4. 4Cliniques Universitaires Saint Luc, Department of Pediatric Haematology and Oncology, Université Catholique de Louvain, Brussels, Belgium.

5. 5Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Germany.

6. 6Charles University, Motol Children's Hospital, Prague, Czech Republic.

7. 7Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Department of pediatric oncology, Amsterdam, the Netherlands.

8. 8Pediatric Hematology and Oncology, University Hospital Eppendorf, Hamburg, Germany.

9. 9Mother and Child Institute, Department of Oncology and Surgical Oncology for Children and Youth, Warsaw, Poland.

10. 10Childhood Cancer Center, Queen Silvia Children's Hospital, Gothenburg, Sweden.

11. 11Bone Tumor Reference Center at the Institute of Medical Genetics and Pathology, University Hospital Basel and University of Basel, Switzerland.

12. 12Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.

13. 13St Anna Children's Hospital and Children's Cancer Research Institute; Department of Paediatrics, Medical University of Vienna, Vienna, Austria.

14. 14Pediatric Hematology and Oncology, University Hospital Leuven Gasthuisberg, Leuven, Belgium.

15. 15Pediatric Oncology and Transplantation Unit, Velkey László Child's Health Center, Borsod-Abaúj-Zemplén County University Teaching Hospital, Miskolc, Hungary.

16. 162nd Dept of Pediatrics, Semmelweis University, Budapest, Hungary.

17. 17Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany.

18. 18Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

19. 19Department of Radiation Oncology, Chris O'Brien Lifehouse, Camperdown, Australia.

20. 20Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

21. 21Department of Oncology and Palliative Care, Helios Klinikum Berlin-Buch, Berlin, Germany.

22. 22Department of Orthopedic Oncology, University Hospital Essen, Essen, Germany.

23. 23Department of Oncology and Hematology, University Children's Hospital Basel, Basel, Switzerland.

24. 24Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

25. 25Centre for Clinical Trials (ZKS) Muenster, University of Muenster, Muenster, Germany.

26. 26Department of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, Princess Elisabeth Children's Hospital, Ghent University, Ghent, Belgium.

27. 27Department of Medical Oncology, Sarcoma Center, University of Duisburg-Essen, Essen, Germany.

28. 28West German Cancer Centre (WTZ) Network, Essen and Muenster, Germany.

29. 29Department of Orthopaedics, Semmelweis University, Budapest, Hungary.

30. 30General Pediatrics, Oncology and Hematology, Vestische Kinder- und Jugendklinik Datteln, Witten/Herdecke University, Datteln, Germany.

31. 31Douglass Hanly Moir Pathology, Notre Dame Medical School, Royal Prince Alfred Hospital, Sydney, Australia.

32. 32Paediatrics III, University Hospital Essen, Essen, Germany.

33. 33German Consortium for Translational Cancer Research (DKTK), German Cancer Research Centre, Essen, Germany.

34. 34Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), Essen, Germany.

35. 35Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.

36. 36Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.

37. 37Department of Clinical Radiology, Klinikum Ibbenbüren, Ibbenburen, Germany.

38. 38Division of Hematology-Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

39. 39Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Muenster, Germany.

40. 40Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden.

41. 41Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia.

42. 42Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

43. 43Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.

44. 44Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.

45. 45Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

Abstract Purpose: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). Patients and Methods: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse–normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller–Schäfer method. Results: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43–1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%–90.8%) for ZOL vs. 81.7% (95% CI, 75.2%–88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%–97.5%) for ZOL and 94.6% (95% CI, 90.9%–98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). Conclusions: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.

Funder

Deutsche Krebshilfe

Bundesministerium für Bildung und Forschung

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-1966/3372789/ccr-23-1966.pdf

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