Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomized controlled trial

Stefan S. Bielack, Mathias Werner, Per Ulf Tunn, Knut Helmke, Heribert Jürgens, Gabriele Calaminus, Joachim Gerss, Trude Butterfass-Bahloul, Peter Reichardt, Sigbjørn Smeland, Kirsten Sundby Hall, Jeremy S. Whelan, Gordana Jovic, Jane M. Hook, Matthew R. Sydes, Beatrice Seddon, Maria Michelagnoli, Bernadette Brennan, Susan Picton, Neyssa MarinaClaudia Deffenbaugh, Mark D. Krailo, Mark Gebhardt, Allen Goorin, Lisa A. Teot, Zsuzsanna Pápai, James Meyer, Helen Nadel, Mark Bernstein, R. Lor Randall, Rajaram Nagarajan, G. Douglas Letson, Daniel Baumhoer, Thomas Kühne, Leo Kager, Reinhard Windhager, Ching C. Lau, Hans Gelderblom, Pancras C W Hogendoorn, Peter M. Hoogerbrugge, Henk Van Den Berg, Paul Meyers, Carol Morris, Richard Gorlick, Mikael Eriksson, Paula Schomberg, Tom Böhling, Marleen Renard, Catharina Dhooge

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, <10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues. J Clin Oncol

Original languageEnglish (US)
Pages (from-to)2279-2287
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number20
DOIs
StatePublished - Jul 10 2015

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interferon alfa-2b
Osteosarcoma
Methotrexate
Doxorubicin
Cisplatin
Randomized Controlled Trials
Maintenance
peginterferon alfa-2b
Induction Chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP : First results of the EURAMOS-1 good response randomized controlled trial. / Bielack, Stefan S.; Werner, Mathias; Tunn, Per Ulf; Helmke, Knut; Jürgens, Heribert; Calaminus, Gabriele; Gerss, Joachim; Butterfass-Bahloul, Trude; Reichardt, Peter; Smeland, Sigbjørn; Hall, Kirsten Sundby; Whelan, Jeremy S.; Jovic, Gordana; Hook, Jane M.; Sydes, Matthew R.; Seddon, Beatrice; Michelagnoli, Maria; Brennan, Bernadette; Picton, Susan; Marina, Neyssa; Deffenbaugh, Claudia; Krailo, Mark D.; Gebhardt, Mark; Goorin, Allen; Teot, Lisa A.; Pápai, Zsuzsanna; Meyer, James; Nadel, Helen; Bernstein, Mark; Randall, R. Lor; Nagarajan, Rajaram; Letson, G. Douglas; Baumhoer, Daniel; Kühne, Thomas; Kager, Leo; Windhager, Reinhard; Lau, Ching C.; Gelderblom, Hans; Hogendoorn, Pancras C W; Hoogerbrugge, Peter M.; Van Den Berg, Henk; Meyers, Paul; Morris, Carol; Gorlick, Richard; Eriksson, Mikael; Schomberg, Paula; Böhling, Tom; Renard, Marleen; Dhooge, Catharina.

In: Journal of Clinical Oncology, Vol. 33, No. 20, 10.07.2015, p. 2279-2287.

Research output: Contribution to journalArticle

Bielack, SS, Werner, M, Tunn, PU, Helmke, K, Jürgens, H, Calaminus, G, Gerss, J, Butterfass-Bahloul, T, Reichardt, P, Smeland, S, Hall, KS, Whelan, JS, Jovic, G, Hook, JM, Sydes, MR, Seddon, B, Michelagnoli, M, Brennan, B, Picton, S, Marina, N, Deffenbaugh, C, Krailo, MD, Gebhardt, M, Goorin, A, Teot, LA, Pápai, Z, Meyer, J, Nadel, H, Bernstein, M, Randall, RL, Nagarajan, R, Letson, GD, Baumhoer, D, Kühne, T, Kager, L, Windhager, R, Lau, CC, Gelderblom, H, Hogendoorn, PCW, Hoogerbrugge, PM, Van Den Berg, H, Meyers, P, Morris, C, Gorlick, R, Eriksson, M, Schomberg, P, Böhling, T, Renard, M & Dhooge, C 2015, 'Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomized controlled trial', Journal of Clinical Oncology, vol. 33, no. 20, pp. 2279-2287. https://doi.org/10.1200/JCO.2014.60.0734
Bielack, Stefan S. ; Werner, Mathias ; Tunn, Per Ulf ; Helmke, Knut ; Jürgens, Heribert ; Calaminus, Gabriele ; Gerss, Joachim ; Butterfass-Bahloul, Trude ; Reichardt, Peter ; Smeland, Sigbjørn ; Hall, Kirsten Sundby ; Whelan, Jeremy S. ; Jovic, Gordana ; Hook, Jane M. ; Sydes, Matthew R. ; Seddon, Beatrice ; Michelagnoli, Maria ; Brennan, Bernadette ; Picton, Susan ; Marina, Neyssa ; Deffenbaugh, Claudia ; Krailo, Mark D. ; Gebhardt, Mark ; Goorin, Allen ; Teot, Lisa A. ; Pápai, Zsuzsanna ; Meyer, James ; Nadel, Helen ; Bernstein, Mark ; Randall, R. Lor ; Nagarajan, Rajaram ; Letson, G. Douglas ; Baumhoer, Daniel ; Kühne, Thomas ; Kager, Leo ; Windhager, Reinhard ; Lau, Ching C. ; Gelderblom, Hans ; Hogendoorn, Pancras C W ; Hoogerbrugge, Peter M. ; Van Den Berg, Henk ; Meyers, Paul ; Morris, Carol ; Gorlick, Richard ; Eriksson, Mikael ; Schomberg, Paula ; Böhling, Tom ; Renard, Marleen ; Dhooge, Catharina. / Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP : First results of the EURAMOS-1 good response randomized controlled trial. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 20. pp. 2279-2287.
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title = "Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomized controlled trial",
abstract = "Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, <10{\%} viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76{\%} (95{\%} CI, 72{\%} to 79{\%}); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95{\%} CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues. J Clin Oncol",
author = "Bielack, {Stefan S.} and Mathias Werner and Tunn, {Per Ulf} and Knut Helmke and Heribert J{\"u}rgens and Gabriele Calaminus and Joachim Gerss and Trude Butterfass-Bahloul and Peter Reichardt and Sigbj{\o}rn Smeland and Hall, {Kirsten Sundby} and Whelan, {Jeremy S.} and Gordana Jovic and Hook, {Jane M.} and Sydes, {Matthew R.} and Beatrice Seddon and Maria Michelagnoli and Bernadette Brennan and Susan Picton and Neyssa Marina and Claudia Deffenbaugh and Krailo, {Mark D.} and Mark Gebhardt and Allen Goorin and Teot, {Lisa A.} and Zsuzsanna P{\'a}pai and James Meyer and Helen Nadel and Mark Bernstein and Randall, {R. Lor} and Rajaram Nagarajan and Letson, {G. Douglas} and Daniel Baumhoer and Thomas K{\"u}hne and Leo Kager and Reinhard Windhager and Lau, {Ching C.} and Hans Gelderblom and Hogendoorn, {Pancras C W} and Hoogerbrugge, {Peter M.} and {Van Den Berg}, Henk and Paul Meyers and Carol Morris and Richard Gorlick and Mikael Eriksson and Paula Schomberg and Tom B{\"o}hling and Marleen Renard and Catharina Dhooge",
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TY - JOUR

T1 - Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP

T2 - First results of the EURAMOS-1 good response randomized controlled trial

AU - Bielack, Stefan S.

AU - Werner, Mathias

AU - Tunn, Per Ulf

AU - Helmke, Knut

AU - Jürgens, Heribert

AU - Calaminus, Gabriele

AU - Gerss, Joachim

AU - Butterfass-Bahloul, Trude

AU - Reichardt, Peter

AU - Smeland, Sigbjørn

AU - Hall, Kirsten Sundby

AU - Whelan, Jeremy S.

AU - Jovic, Gordana

AU - Hook, Jane M.

AU - Sydes, Matthew R.

AU - Seddon, Beatrice

AU - Michelagnoli, Maria

AU - Brennan, Bernadette

AU - Picton, Susan

AU - Marina, Neyssa

AU - Deffenbaugh, Claudia

AU - Krailo, Mark D.

AU - Gebhardt, Mark

AU - Goorin, Allen

AU - Teot, Lisa A.

AU - Pápai, Zsuzsanna

AU - Meyer, James

AU - Nadel, Helen

AU - Bernstein, Mark

AU - Randall, R. Lor

AU - Nagarajan, Rajaram

AU - Letson, G. Douglas

AU - Baumhoer, Daniel

AU - Kühne, Thomas

AU - Kager, Leo

AU - Windhager, Reinhard

AU - Lau, Ching C.

AU - Gelderblom, Hans

AU - Hogendoorn, Pancras C W

AU - Hoogerbrugge, Peter M.

AU - Van Den Berg, Henk

AU - Meyers, Paul

AU - Morris, Carol

AU - Gorlick, Richard

AU - Eriksson, Mikael

AU - Schomberg, Paula

AU - Böhling, Tom

AU - Renard, Marleen

AU - Dhooge, Catharina

PY - 2015/7/10

Y1 - 2015/7/10

N2 - Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, <10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues. J Clin Oncol

AB - Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, <10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues. J Clin Oncol

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