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

Neyssa M. Marina, Sigbjørn Smeland, Stefan S. Bielack, Mark Bernstein, Gordana Jovic, Mark D. Krailo, Jane M. Hook, Carola Arndt, Henk van den Berg, Bernadette Brennan, Bénédicte Brichard, Ken L B Brown, Trude Butterfass-Bahloul, Gabriele Calaminus, Heike E. Daldrup-Link, Mikael Eriksson, Mark C. Gebhardt, Hans Gelderblom, Joachim Gerss, Robert Goldsby & 33 others Allen Goorin, Richard Gorlick, Holcombe E. Grier, Juliet P. Hale, Kirsten Sundby Hall, Jendrik Hardes, Douglas S. Hawkins, Knut Helmke, Pancras C W Hogendoorn, Michael S. Isakoff, Katherine A. Janeway, Heribert Jürgens, Leo Kager, Thomas Kühne, Ching C. Lau, Patrick J. Leavey, Stephen L. Lessnick, Leo Mascarenhas, Paul A. Meyers, Hubert Mottl, Michaela Nathrath, Zsuzsanna Papai, R. Lor Randall, Peter Reichardt, Marleen Renard, Akmal Ahmed Safwat, Cindy L. Schwartz, Michael C G Stevens, Sandra J. Strauss, Lisa Teot, Mathias Werner, Matthew R. Sydes, Jeremy S. Whelan

Research output: Contribution to journalArticle

79 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1396-1408
Number of pages13
JournalThe Lancet Oncology
Volume17
Issue number10
DOIs
StatePublished - Oct 1 2016

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Ifosfamide
Etoposide
Osteosarcoma
Randomized Controlled Trials
Drug Therapy
Disease-Free Survival
Doxorubicin
Biomedical Research
Methotrexate
Cisplatin
Research
Neoplasms
Mesna
Febrile Neutropenia
National Cancer Institute (U.S.)
Humerus
National Institutes of Health (U.S.)
Left Ventricular Dysfunction
Therapeutics
Finland

ASJC Scopus subject areas

  • Oncology

Cite this

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. / 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.

In: The Lancet Oncology, Vol. 17, No. 10, 01.10.2016, p. 1396-1408.

Research output: Contribution to journalArticle

Marina, NM, Smeland, S, Bielack, SS, Bernstein, M, Jovic, G, Krailo, MD, Hook, JM, Arndt, C, van den Berg, H, Brennan, B, Brichard, B, Brown, KLB, Butterfass-Bahloul, T, Calaminus, G, Daldrup-Link, HE, Eriksson, M, Gebhardt, MC, Gelderblom, H, Gerss, J, Goldsby, R, Goorin, A, Gorlick, R, Grier, HE, Hale, JP, Hall, KS, Hardes, J, Hawkins, DS, Helmke, K, Hogendoorn, PCW, Isakoff, MS, Janeway, KA, Jürgens, H, Kager, L, Kühne, T, Lau, CC, Leavey, PJ, Lessnick, SL, Mascarenhas, L, Meyers, PA, Mottl, H, Nathrath, M, Papai, Z, Randall, RL, Reichardt, P, Renard, M, Safwat, AA, Schwartz, CL, Stevens, MCG, Strauss, SJ, Teot, L, Werner, M, Sydes, MR & Whelan, JS 2016, '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', The Lancet Oncology, vol. 17, no. 10, pp. 1396-1408. https://doi.org/10.1016/S1470-2045(16)30214-5
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. / 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. In: The Lancet Oncology. 2016 ; Vol. 17, No. 10. pp. 1396-1408.
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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/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.",
author = "Marina, {Neyssa M.} and Sigbj{\o}rn Smeland and Bielack, {Stefan S.} and Mark Bernstein and Gordana Jovic and Krailo, {Mark D.} and Hook, {Jane M.} and Carola Arndt and {van den Berg}, Henk and Bernadette Brennan and B{\'e}n{\'e}dicte Brichard and Brown, {Ken L B} and Trude Butterfass-Bahloul and Gabriele Calaminus and Daldrup-Link, {Heike E.} and Mikael Eriksson and Gebhardt, {Mark C.} and Hans Gelderblom and Joachim Gerss and Robert Goldsby and Allen Goorin and Richard Gorlick and Grier, {Holcombe E.} and Hale, {Juliet P.} and Hall, {Kirsten Sundby} and Jendrik Hardes and Hawkins, {Douglas S.} and Knut Helmke and Hogendoorn, {Pancras C W} and Isakoff, {Michael S.} and Janeway, {Katherine A.} and Heribert J{\"u}rgens and Leo Kager and Thomas K{\"u}hne and Lau, {Ching C.} and Leavey, {Patrick J.} and Lessnick, {Stephen L.} and Leo Mascarenhas and Meyers, {Paul A.} and Hubert Mottl and Michaela Nathrath and Zsuzsanna Papai and Randall, {R. Lor} and Peter Reichardt and Marleen Renard and Safwat, {Akmal Ahmed} and Schwartz, {Cindy L.} and Stevens, {Michael C G} and Strauss, {Sandra J.} and Lisa Teot and Mathias Werner and Sydes, {Matthew R.} and Whelan, {Jeremy S.}",
year = "2016",
month = "10",
day = "1",
doi = "10.1016/S1470-2045(16)30214-5",
language = "English (US)",
volume = "17",
pages = "1396--1408",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
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}

TY - JOUR

T1 - Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1)

T2 - an open-label, international, randomised controlled trial

AU - Marina, Neyssa M.

AU - Smeland, Sigbjørn

AU - Bielack, Stefan S.

AU - Bernstein, Mark

AU - Jovic, Gordana

AU - Krailo, Mark D.

AU - Hook, Jane M.

AU - Arndt, Carola

AU - van den Berg, Henk

AU - Brennan, Bernadette

AU - Brichard, Bénédicte

AU - Brown, Ken L B

AU - Butterfass-Bahloul, Trude

AU - Calaminus, Gabriele

AU - Daldrup-Link, Heike E.

AU - Eriksson, Mikael

AU - Gebhardt, Mark C.

AU - Gelderblom, Hans

AU - Gerss, Joachim

AU - Goldsby, Robert

AU - Goorin, Allen

AU - Gorlick, Richard

AU - Grier, Holcombe E.

AU - Hale, Juliet P.

AU - Hall, Kirsten Sundby

AU - Hardes, Jendrik

AU - Hawkins, Douglas S.

AU - Helmke, Knut

AU - Hogendoorn, Pancras C W

AU - Isakoff, Michael S.

AU - Janeway, Katherine A.

AU - Jürgens, Heribert

AU - Kager, Leo

AU - Kühne, Thomas

AU - Lau, Ching C.

AU - Leavey, Patrick J.

AU - Lessnick, Stephen L.

AU - Mascarenhas, Leo

AU - Meyers, Paul A.

AU - Mottl, Hubert

AU - Nathrath, Michaela

AU - Papai, Zsuzsanna

AU - Randall, R. Lor

AU - Reichardt, Peter

AU - Renard, Marleen

AU - Safwat, Akmal Ahmed

AU - Schwartz, Cindy L.

AU - Stevens, Michael C G

AU - Strauss, Sandra J.

AU - Teot, Lisa

AU - Werner, Mathias

AU - Sydes, Matthew R.

AU - Whelan, Jeremy S.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

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U2 - 10.1016/S1470-2045(16)30214-5

DO - 10.1016/S1470-2045(16)30214-5

M3 - Article

VL - 17

SP - 1396

EP - 1408

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 10

ER -