BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

Aarhus University Hospital Aarhus C Denmark

Abt Pädiatrische Radiologie AKK Altonaer Kinderkrankenhaus Hamburg Germany

Bristol Royal Hospital for Children Bristol UK

Center for Cancer and Blood Disorders Connecticut Children's Medical Center Hartford CT USA

Center for Childhood Cancer and Blood Disorders Nationwide Children's Hospital and The Ohio State University Columbus OH USA

Centre for Clinical Trials University Hospital Muenster Muenster Germany

Clinical Cooperation Group Osteosarcoma Pediatric Oncology Center Department of Pediatrics Technical University Munich Munich Germany; Department of Pediatric Oncology Klinikum Kassel Kassel Germany

Dana Farber Boston Children's Cancer and Blood Disorders Center Dana Farber Cancer Institute Boston MA USA

Department of Oncology Oslo University Hospital Norwegian Radium Hospital Scandinavian Sarcoma Group Oslo Norway

Department of Oncology University College Hospital London UK

Department of Orthopaedics University of British Columbia Vancouver BC Canada

Department of Pathology Boston Children's Hospital Boston MA USA

Department of Pediatric Hemato oncology University Hospital Leuven Leuven Belgium

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

Department of Pediatrics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pediatrics St Anna Children's Hospital Medical University Vienna Vienna Austria

Department of Pediatrics UT Southwestern and Children's Medical Center Dallas TX USA

Department of Preventive Medicine Keck Medical Canter at the University of Southern California Los Angeles CA USA; Children's Oncology Group Arcadia CA USA

Department of Radiology Stanford University and Lucile Packard Children's Hospital Palo Alto CA USA

Department of Surgery Dana Farber Cancer Institute Boston MA USA

Division of Hematology Oncology and Blood and Marrow Transplantation Department of Pediatrics Children's Hospital Los Angeles Los Angeles CA USA; Keck School of Medicine University of Southern California Los Angeles CA USA

Division of Pediatric and Adolescent Medicine Mayo Clinic Rochester MN USA

Division of Pediatric Hematology Oncology The Children's Hospital at Montefiore Bronx NY USA

Division of Pediatrics The University of Texas M D Anderson Cancer Center Houston TX USA

Emma Children Hospital Academic Medical Centre Amsterdam Netherlands

HELIOS Klinikum Berlin Buch Klinik für Interdisziplinäre Onkologie Berlin Germany

HELIOS Klinikum Emil von Behring GmbH Orthopädische Pathologie Berlin Germany

Institute of Biostatistics and Clinical Research University of Muenster Muenster Germany

IWK Health Center Dalhousie University Halifax NS Canada

Klinik für Allgemeine Orthopädie und Tumororthopädie University of Muenster Muenster Germany

Klinikum Stuttgart Olgahospital Cooperative Osteosarcoma Study Group Stuttgart Germany

Leiden University Medical Center Leiden Netherlands

Medical Research Council Clinical Trials Unit at University College London London UK

Medical Research Council Clinical Trials Unit at University College London London UK; Clinical Trials Research Unit Institute of Clinical Trials Research University of Leeds Leeds UK; St James' Institute of Oncology Leeds UK

National Medical Center Oncology Department Budapest Hungary

Newcastle upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK

Oslo University Hospital Division of Cancer Medicine and Scandinavian Sarcoma Group University of Oslo Norway; Institute for Clinical Medicine University of Oslo Norway

Pädiatrische Hämatologie und Onkologie Universitätsklinikum Bonn Bonn Germany

Pädiatrische Hämatologie und Onkologie University of Muenster Muenster Germany

Primary Childrens Hospital The University of Utah Salt Lake City UT USA

Royal Manchester Children's Hospital Manchester UK

Seattle Children's Hospital Fred Hutchinson Cancer Research Center University of Washington Seattle WA USA

Skane University Hospital and Lund University Lund Sweden

Stanford University School of Medicine and Lucile Packard Children's Hospital Palo Alto CA USA

Texas Children's Cancer Center Baylor College of Medicine Houston TX USA

UCSF Medical Center Mission Bay Pediatric Oncology San Francisco CA USA

University Children's Hospital Basel Basel Switzerland

University Hospital Motol Pediatric Hematology Oncology Prague Czech Republic

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ClinicalTrials.gov
NCT00134030