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

Koch R, Haveman L, Ladenstein R, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Kager L, Renard M, Hauser P, Burdach S, Bovee JV, Hong AM, Reichardt P, Kruseova J, Streitbürger A, Kühne T, Kessler T, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Bonar F, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Hartmann W, Hjorth L, Bhadri VA, Metzler M, Gelderblom H, Dirksen U (2023)

Publication Type: Journal article

Publication year: 2023


Book Volume: 29

Pages Range: 5057-5068

Journal Issue: 24

DOI: 10.1158/1078-0432.CCR-23-1966


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.

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Involved external institutions

Medizinische Universität Wien AT Austria (AT) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) University Hospital Ghent BE Belgium (BE) Universität Duisburg-Essen (UDE) DE Germany (DE) Klinikum Ibbenbüren DE Germany (DE) Universitätsklinikum Münster DE Germany (DE) Lund University / Lunds universitet SE Sweden (SE) Universität Witten/Herdecke DE Germany (DE) Chris O’Brien Lifehouse AU Australia (AU) Royal Prince Alfred Hospital AU Australia (AU) Universitätsklinikum Essen DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Vilnius University / Vilniaus universitetas LT Lithuania (LT) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) FI Finland (FI) Motol University Hospital / Fakultní nemocnice v Motole CZ Czech Republic (CZ) Universitäts-Kinderspital beider Basel (UKBB) CH Switzerland (CH) Semmelweis University / Semmelweis Egyetem HU Hungary (HU) HELIOS Kliniken DE Germany (DE) 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) Universitätsklinikum Heidelberg DE Germany (DE) University of Amsterdam NL Netherlands (NL) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Institute of Mother and Child / Instytut Matki I Dziecka PL Poland (PL) Princess Máxima Center NL Netherlands (NL) Drottning Silvias barnsjukhus SE Sweden (SE) Universitätsspital Basel CH Switzerland (CH) Cliniques universitaires Saint-Luc (CHU St-Luc) BE Belgium (BE)

How to cite


Koch, R., Haveman, L., Ladenstein, R., Brichard, B., Jürgens, H., Cyprova, S.,... Dirksen, U. (2023). Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial. Clinical Cancer Research, 29(24), 5057-5068. https://doi.org/10.1158/1078-0432.CCR-23-1966


Koch, Raphael, et al. "Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial." Clinical Cancer Research 29.24 (2023): 5057-5068.

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