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

Journal

Book Volume: 29

Pages Range: 5057-5068

Journal Issue: 24

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

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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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

MLA:

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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