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Cited by 555Sarcoma Diagnosis and TreatmentBone Tumor Diagnosis and TreatmentsOvarian cancer diagnosis and treatment

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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

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Marina, Neyssa M, Smeland, Sigbjørn, Bielack, Stefan S, Bernstein, Mark, Jovic, Gordana, Krailo, Mark D, Hook, Jane M, Arndt, Carola, van den Berg, Henk, Brennan, Bernadette, Brichard, Bénédicte, Brown, Ken L B, Butterfass-Bahloul, Trude, Calaminus, Gabriele, Daldrup-Link, Heike E, Eriksson, Mikael, Gebhardt, Mark C, Gelderblom, Hans, Gerss, Joachim, Goldsby, Robert, Goorin, Allen, Gorlick, Richard, Grier, Holcombe E, Hale, Juliet P, Hall, Kirsten Sundby, Hardes, Jendrik, Hawkins, Douglas S, Helmke, Knut, Hogendoorn, Pancras C W, Isakoff, Michael S, Janeway, Katherine A, Jürgens, Heribert, Kager, Leo, Kühne, Thomas, Lau, Ching C, Leavey, Patrick J, Lessnick, Stephen L, Mascarenhas, Leo, Meyers, Paul A, Mottl, Hubert, Nathrath, Michaela, Papai, Zsuzsanna, Randall, R Lor, Reichardt, Peter, Renard, Marleen, Safwat, Akmal Ahmed, Schwartz, Cindy L, Stevens, Michael C G, Strauss, Sandra J, Teot, Lisa, Werner, Mathias, Sydes, Matthew R, Whelan, Jeremy S·2016·The Lancet Oncology
DOI 10.1016/s1470-2045(16)30214-5PMC PMC5052459
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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/m 2 , doxorubicin 37·5 mg/m 2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m 2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m 2 ) at 2·8 g/m 2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m 2 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.

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Figure 1 Trial profile *We later found out that one patient actually had a good histological response (allocated to MAP group at randomisation and analysed as in the MAP group). †One additional patient completed MAP (as he was not assessed for toxicity, he was excluded previously in this diagram). ‡One patient was lost to follow-up at randomisation.
Figure 1 Trial profile *We later found out that one patient actually had a good histological response (allocated to MAP group at randomisation and analysed as in the MAP group). †One additional patient completed MAP (as he was not assessed for toxicity, he was excluded previously in this diagram). ‡One patient was lost to follow-up at randomisation.CC BY · PubMed Central
Figure 2 Event-free survival (A) Kaplan-Meier curve of event-free survival. (B) Absolute difference in event-free survival by flexible parametric model difference. 95% CI is shown by shading. (C) Kaplan-Meier curve of event-free survival by metastases status at registration.
Figure 2 Event-free survival (A) Kaplan-Meier curve of event-free survival. (B) Absolute difference in event-free survival by flexible parametric model difference. 95% CI is shown by shading. (C) Kaplan-Meier curve of event-free survival by metastases status at registration.CC BY · PubMed Central
Figure 3 Kaplan-Meier curve of overall survival
Figure 3 Kaplan-Meier curve of overall survivalCC BY · PubMed Central

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Authors
Marina, N. M., Smeland, S., Bielack, S. S., Bernstein, M., Jovic, G., Krailo, M. D., Hook, J. M., Arndt, C., van den Berg, H., Brennan, B., Brichard, B., Brown, K. L. B., Butterfass-Bahloul, T., Calaminus, G., Daldrup-Link, H. E., Eriksson, M., Gebhardt, M. C., Gelderblom, H., Gerss, J., Goldsby, R., Goorin, A., Gorlick, R., Grier, H. E., Hale, J. P., Hall, K. S., Hardes, J., Hawkins, D. S., Helmke, K., Hogendoorn, P. C. W., Isakoff, M. S., Janeway, K. A., Jürgens, H., Kager, L., Kühne, T., Lau, C. C., Leavey, P. J., Lessnick, S. L., Mascarenhas, L., Meyers, P. A., Mottl, H., Nathrath, M., Papai, Z., Randall, R. L., Reichardt, P., Renard, M., Safwat, A. A., Schwartz, C. L., Stevens, M. C. G., Strauss, S. J., Teot, L., Werner, M., Sydes, M. R., & Whelan, J. S.
Affiliations
  • Lucile Packard Children's Hospital (US)
  • Oslo University Hospital (NO)
  • Olgahospital (DE)
  • Dalhousie University (CA)
  • MRC Clinical Trials Unit at UCL (GB)
  • University of Southern California (US)
  • University of Leeds (GB)
  • Mayo Clinic (US)
  • Royal Manchester Children's Hospital (GB)
  • Cliniques Universitaires Saint-Luc (BE)
  • University of British Columbia (CA)
  • University Hospital Bonn (DE)
  • Lund University (SE)
  • Dana-Farber Cancer Institute (US)
  • Leiden University Medical Center (NL)
  • University of Münster (DE)
  • University of California San Francisco Medical Center (US)
  • Children's Hospital at Montefiore (US)
  • Seattle Children's Hospital (US)
  • Altonaer Kinderkrankenhaus (DE)
  • Connecticut Children's Medical Center (US)
  • St Anna Children's Hospital (AT)
  • University Children’s Hospital Basel (CH)
  • Baylor College of Medicine (US)
  • Children's Medical Center (US)
  • Nationwide Children's Hospital (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University Hospital in Motol (CZ)
  • Klinikum Kassel (DE)
  • Primary Children's Hospital (US)
  • Helios Hospital Berlin-Buch (DE)
  • Universitair Ziekenhuis Leuven (BE)
  • Aarhus University Hospital (DK)
  • The University of Texas MD Anderson Cancer Center (US)
  • University College Hospital (GB)
  • Boston Children's Hospital (US)
  • Helios Klinikum Emil von Behring (DE)
Corresponding author
Sydes, Matthew R
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2016-10
Volume
17
Issue
10
Pages
1396-1408
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(16)30214-5
PMC
PMC5052459
OpenAlex
W2513951655
Cited by
551
References
41
Citations by year
2026: 53 · 2025: 58 · 2024: 74 · 2023: 48 · 2022: 74 · 2021: 69 · 2020: 67 · 2019: 42 · 2018: 26 · 2017: 30 · 2016: 8
FWCI
31.35
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Digital Access to Libraries (submittedVersion)
  • DIAL (Catholic University of Leuven) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • ZonMw
  • Academy of Finland
  • Bundesministerium für Bildung und Forschung (01KN1105)
  • National Cancer Institute (U10CA098413, U10CA098543, U10CA180886, U10CA180899)
  • European Science Foundation (ERASCT-2003-980409)
  • Deutsche Forschungsgemeinschaft (1-2, GZ BI 1045/1-1, JU 203/2-3)
  • Medical Research Council
  • Deutsche Krebshilfe
  • Cancer Research UK (CRUK/05/013)
  • European Commission (MM/NG/EMRC/0202)
  • Fonds De La Recherche Scientifique - FNRS
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Fonds Wetenschappelijk Onderzoek
  • NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
  • Norges Forskningsråd
Topics
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone Tumor Diagnosis and Treatments
  • Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
Keywords
high-grade osteosarcoma, ifosfamide, etoposide, cisplatin, doxorubicin, methotrexate, postoperative chemotherapy, event-free survival, tumor response assessment, metastasis, proximal femur
MeSH terms
Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Bone Neoplasms, Child, Child, Preschool, Combined Modality Therapy, Female, Humans, Infant, Male, Middle Aged, Osteosarcoma

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