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.

2nd Dept of Pediatrics Semmelweis University Budapest Hungary

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

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

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

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

Centre for Clinical Trials Muenster University of Muenster Muenster Germany

Charles University Motol Children's Hospital Prague Czech Republic

Childhood Cancer Center Queen Silvia Children's Hospital Gothenburg Sweden

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

Comprehensive Cancer Center Erlangen EMN Erlangen Germany

Department of Clinical Radiology Klinikum Ibbenbüren Ibbenburen Germany

Department of Internal Medicine 5 Heidelberg University Hospital Heidelberg Germany

Department of Medical Oncology Chris O'Brien Lifehouse Sydney Australia

Department of Medical Oncology Leiden University Medical Center Leiden the Netherlands

Department of Medical Oncology Sarcoma Center University of Duisburg Essen Essen Germany

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

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

Department of Oncology and Palliative Care Helios Klinikum Berlin Buch Berlin Germany

Department of Orthopaedics Semmelweis University Budapest Hungary

Department of Orthopedic Oncology University Hospital Essen Essen Germany

Department of Particle Therapy University Hospital Essen West German Proton Therapy Centre Essen Essen Germany

Department of Pathology Leiden University Medical Center Leiden the Netherlands

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

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

Department of Pediatrics and Children's Cancer Research Center Technische Universität München Munich Germany

Department of Pediatrics University Hospital Erlangen Erlangen Germany

Department of Radiation Oncology Chris O'Brien Lifehouse Camperdown Australia

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

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

Division of Translational Pathology Gerhard Domagk Institute of Pathology University Hospital Muenster Muenster Germany

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

Faculty of Medicine and Health University of Sydney Sydney Australia

General Pediatrics Oncology and Hematology Vestische Kinder und Jugendklinik Datteln Witten Herdecke University Datteln Germany

German Consortium for Translational Cancer Research German Cancer Research Centre Essen Germany

Institute of Biostatistics and Clinical Research University of Muenster Germany

Institute of Clinical Medicine Vilnius University Vilnius Lithuania

Lund University Skane University Hospital Department of Clinical Sciences Lund Neurology Lund Sweden

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

Paediatrics 3 University Hospital Essen Essen Germany

Pediatric Hematology and Oncology University Hospital Eppendorf Hamburg Germany

Pediatric Hematology and Oncology University Hospital Leuven Gasthuisberg Leuven Belgium

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

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

Studies and Statistics for Integrated Research and Projects St Anna Children's Hospital Department of Paediatrics and Children's Cancer Research Institute Medical University of Vienna Vienna Austria

West German Cancer Centre Network Essen and Muenster Germany

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