title: Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.
abstract: 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/m2per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2over 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/m2per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2per 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors: Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
authors: Neyssa M
authors: NM
authors: Marina
authors: Oslo University Hospital, Division of Cancer Medicine and Scandinavian Sarcoma Group, University of Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Norway.
authors: Sigbjørn
authors: S
authors: Smeland
authors: Klinikum Stuttgart-Olgahospital, Cooperative Osteosarcoma Study Group (COSS), Stuttgart, Germany.
authors: Stefan S
authors: SS
authors: Bielack
authors: IWK Health Center, Dalhousie University, Halifax, NS, Canada.
authors: Mark
authors: M
authors: Bernstein
authors: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors: Gordana
authors: G
authors: Jovic
authors: Department of Preventive Medicine, Keck Medical Canter at the University of Southern California, Los Angeles CA, USA; Children's Oncology Group, Arcadia, CA, USA.
authors: Mark D
authors: MD
authors: Krailo
authors: 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.
authors: Jane M
authors: JM
authors: Hook
authors: Division of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
authors: Carola
authors: C
authors: Arndt
authors: Emma Children Hospital/Academic Medical Centre, Amsterdam, Netherlands.
authors: Henk
authors: H
authors: van den Berg
authors: Royal Manchester Children's Hospital, Manchester, UK.
authors: Bernadette
authors: B
authors: Brennan
authors: Department of Pediatric Hematology/Oncology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors: Bénédicte
authors: B
authors: Brichard
authors: Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada.
authors: Ken L B
authors: KLB
authors: Brown
authors: Centre for Clinical Trials, University Hospital Muenster, Muenster, Germany.
authors: Trude
authors: T
authors: Butterfass-Bahloul
authors: Pädiatrische Hämatologie und Onkologie, Universitätsklinikum Bonn, Bonn, Germany.
authors: Gabriele
authors: G
authors: Calaminus
authors: Department of Radiology, Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
authors: Heike E
authors: HE
authors: Daldrup-Link
authors: Skane University Hospital and Lund University, Lund, Sweden.
authors: Mikael
authors: M
authors: Eriksson
authors: Department of Surgery, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Mark C
authors: MC
authors: Gebhardt
authors: Leiden University Medical Center, Leiden, Netherlands.
authors: Hans
authors: H
authors: Gelderblom
authors: Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.
authors: Joachim
authors: J
authors: Gerss
authors: UCSF Medical Center-Mission Bay, Pediatric Oncology, San Francisco, CA, USA.
authors: Robert
authors: R
authors: Goldsby
authors: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Allen
authors: A
authors: Goorin
authors: Division of Pediatric Hematology-Oncology, The Children's Hospital at Montefiore, Bronx, NY, USA.
authors: Richard
authors: R
authors: Gorlick
authors: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Holcombe E
authors: HE
authors: Grier
authors: Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
authors: Juliet P
authors: JP
authors: Hale
authors: Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Scandinavian Sarcoma Group, Oslo, Norway.
authors: Kirsten Sundby
authors: KS
authors: Hall
authors: Klinik für Allgemeine Orthopädie und Tumororthopädie, University of Muenster, Muenster, Germany.
authors: Jendrik
authors: J
authors: Hardes
authors: Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors: Douglas S
authors: DS
authors: Hawkins
authors: Abt Pädiatrische Radiologie, AKK Altonaer Kinderkrankenhaus, Hamburg, Germany.
authors: Knut
authors: K
authors: Helmke
authors: Leiden University Medical Center, Leiden, Netherlands.
authors: Pancras C W
authors: PCW
authors: Hogendoorn
authors: Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.
authors: Michael S
authors: MS
authors: Isakoff
authors: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Katherine A
authors: KA
authors: Janeway
authors: Pädiatrische Hämatologie und Onkologie, University of Muenster, Muenster, Germany.
authors: Heribert
authors: H
authors: Jürgens
authors: Department of Pediatrics, St Anna Children's Hospital, Medical University Vienna, Vienna, Austria.
authors: Leo
authors: L
authors: Kager
authors: University Children's Hospital Basel, Basel, Switzerland.
authors: Thomas
authors: T
authors: Kühne
authors: Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors: Ching C
authors: CC
authors: Lau
authors: Department of Pediatrics, UT Southwestern and Children's Medical Center, Dallas, TX, USA.
authors: Patrick J
authors: PJ
authors: Leavey
authors: Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
authors: Stephen L
authors: SL
authors: Lessnick
authors: 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.
authors: Leo
authors: L
authors: Mascarenhas
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Paul A
authors: PA
authors: Meyers
authors: University Hospital Motol, Pediatric Hematology/Oncology, Prague, Czech Republic.
authors: Hubert
authors: H
authors: Mottl
authors: Clinical Cooperation Group Osteosarcoma, Pediatric Oncology Center, Department of Pediatrics, Technical University Munich, Munich, Germany; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
authors: Michaela
authors: M
authors: Nathrath
authors: National Medical Center, Oncology Department, Budapest, Hungary.
authors: Zsuzsanna
authors: Z
authors: Papai
authors: Primary Childrens Hospital, The University of Utah, Salt Lake City, UT, USA.
authors: R Lor
authors: RL
authors: Randall
authors: HELIOS Klinikum Berlin-Buch, Klinik für Interdisziplinäre Onkologie, Berlin, Germany.
authors: Peter
authors: P
authors: Reichardt
authors: Department of Pediatric Hemato-oncology, University Hospital Leuven, Leuven, Belgium.
authors: Marleen
authors: M
authors: Renard
authors: Aarhus University Hospital, Aarhus C, Denmark.
authors: Akmal Ahmed
authors: AA
authors: Safwat
authors: Division of Pediatrics, The University of Texas M D Anderson Cancer Center, Houston, TX, USA.
authors: Cindy L
authors: CL
authors: Schwartz
authors: Bristol Royal Hospital for Children, Bristol, UK.
authors: Michael C G
authors: MCG
authors: Stevens
authors: Department of Oncology, University College Hospital, London, UK.
authors: Sandra J
authors: SJ
authors: Strauss
authors: Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
authors: Lisa
authors: L
authors: Teot
authors: HELIOS Klinikum Emil von Behring GmbH, Orthopädische Pathologie, Berlin, Germany.
authors: Mathias
authors: M
authors: Werner
authors: Medical Research Council Clinical Trials Unit at University College London, London, UK. Electronic address: mrcctu.euramos@ucl.ac.uk.
authors: Matthew R
authors: MR
authors: Sydes
authors: Department of Oncology, University College Hospital, London, UK.
authors: Jeremy S
authors: JS
authors: Whelan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality