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Lancet Oncol. 2016 Oct;17(10):1396-1408. doi: 10.1016/S1470-2045(16)30214-5. Epub 2016 Aug 25.

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.

Author information

1
Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
2
Oslo University Hospital, Division of Cancer Medicine and Scandinavian Sarcoma Group, University of Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Norway.
3
Klinikum Stuttgart-Olgahospital, Cooperative Osteosarcoma Study Group (COSS), Stuttgart, Germany.
4
IWK Health Center, Dalhousie University, Halifax, NS, Canada.
5
Medical Research Council Clinical Trials Unit at University College London, London, UK.
6
Department of Preventive Medicine, Keck Medical Canter at the University of Southern California, Los Angeles CA, USA; Children's Oncology Group, Arcadia, CA, USA.
7
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.
8
Division of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
9
Emma Children Hospital/Academic Medical Centre, Amsterdam, Netherlands.
10
Royal Manchester Children's Hospital, Manchester, UK.
11
Department of Pediatric Hematology/Oncology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
12
Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada.
13
Centre for Clinical Trials, University Hospital Muenster, Muenster, Germany.
14
Pädiatrische Hämatologie und Onkologie, Universitätsklinikum Bonn, Bonn, Germany.
15
Department of Radiology, Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA, USA.
16
Skane University Hospital and Lund University, Lund, Sweden.
17
Department of Surgery, Dana-Farber Cancer Institute, Boston, MA, USA.
18
Leiden University Medical Center, Leiden, Netherlands.
19
Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.
20
UCSF Medical Center-Mission Bay, Pediatric Oncology, San Francisco, CA, USA.
21
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.
22
Division of Pediatric Hematology-Oncology, The Children's Hospital at Montefiore, Bronx, NY, USA.
23
Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
24
Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Scandinavian Sarcoma Group, Oslo, Norway.
25
Klinik für Allgemeine Orthopädie und Tumororthopädie, University of Muenster, Muenster, Germany.
26
Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
27
Abt Pädiatrische Radiologie, AKK Altonaer Kinderkrankenhaus, Hamburg, Germany.
28
Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.
29
Pädiatrische Hämatologie und Onkologie, University of Muenster, Muenster, Germany.
30
Department of Pediatrics, St Anna Children's Hospital, Medical University Vienna, Vienna, Austria.
31
University Children's Hospital Basel, Basel, Switzerland.
32
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
33
Department of Pediatrics, UT Southwestern and Children's Medical Center, Dallas, TX, USA.
34
Center for Childhood Cancer and Blood Disorders, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.
35
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.
36
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
37
University Hospital Motol, Pediatric Hematology/Oncology, Prague, Czech Republic.
38
Clinical Cooperation Group Osteosarcoma, Pediatric Oncology Center, Department of Pediatrics, Technical University Munich, Munich, Germany; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
39
National Medical Center, Oncology Department, Budapest, Hungary.
40
Primary Childrens Hospital, The University of Utah, Salt Lake City, UT, USA.
41
HELIOS Klinikum Berlin-Buch, Klinik für Interdisziplinäre Onkologie, Berlin, Germany.
42
Department of Pediatric Hemato-oncology, University Hospital Leuven, Leuven, Belgium.
43
Aarhus University Hospital, Aarhus C, Denmark.
44
Division of Pediatrics, The University of Texas M D Anderson Cancer Center, Houston, TX, USA.
45
Bristol Royal Hospital for Children, Bristol, UK.
46
Department of Oncology, University College Hospital, London, UK.
47
Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
48
HELIOS Klinikum Emil von Behring GmbH, Orthopädische Pathologie, Berlin, Germany.
49
Medical Research Council Clinical Trials Unit at University College London, London, UK. Electronic address: mrcctu.euramos@ucl.ac.uk.

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/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.

PMID:
27569442
PMCID:
PMC5052459
DOI:
10.1016/S1470-2045(16)30214-5
[Indexed for MEDLINE]
Free PMC Article

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