Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial

Research output: Contribution to journalArticlepeer-review

Standard

Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma : results of the randomized noninferiority Euro-EWING99-R1 trial. / Le Deley, Marie-Cécile; Paulussen, Michael; Lewis, Ian; Brennan, Bernadette; Ranft, Andreas; Whelan, Jeremy; Le Teuff, Gwénaël; Michon, Jean; Ladenstein, Ruth; Marec-Bérard, Perrine; van den Berg, Henk; Hjorth, Lars; Wheatley, Keith; Judson, Ian; Juergens, Heribert; Craft, Alan; Oberlin, Odile; Dirksen, Uta.

In: Journal of Clinical Oncology , Vol. 32, No. 23, 10.08.2014, p. 2440-8.

Research output: Contribution to journalArticlepeer-review

Harvard

Le Deley, M-C, Paulussen, M, Lewis, I, Brennan, B, Ranft, A, Whelan, J, Le Teuff, G, Michon, J, Ladenstein, R, Marec-Bérard, P, van den Berg, H, Hjorth, L, Wheatley, K, Judson, I, Juergens, H, Craft, A, Oberlin, O & Dirksen, U 2014, 'Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial', Journal of Clinical Oncology , vol. 32, no. 23, pp. 2440-8. https://doi.org/10.1200/JCO.2013.54.4833

APA

Le Deley, M-C., Paulussen, M., Lewis, I., Brennan, B., Ranft, A., Whelan, J., Le Teuff, G., Michon, J., Ladenstein, R., Marec-Bérard, P., van den Berg, H., Hjorth, L., Wheatley, K., Judson, I., Juergens, H., Craft, A., Oberlin, O., & Dirksen, U. (2014). Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. Journal of Clinical Oncology , 32(23), 2440-8. https://doi.org/10.1200/JCO.2013.54.4833

Vancouver

Author

Le Deley, Marie-Cécile ; Paulussen, Michael ; Lewis, Ian ; Brennan, Bernadette ; Ranft, Andreas ; Whelan, Jeremy ; Le Teuff, Gwénaël ; Michon, Jean ; Ladenstein, Ruth ; Marec-Bérard, Perrine ; van den Berg, Henk ; Hjorth, Lars ; Wheatley, Keith ; Judson, Ian ; Juergens, Heribert ; Craft, Alan ; Oberlin, Odile ; Dirksen, Uta. / Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma : results of the randomized noninferiority Euro-EWING99-R1 trial. In: Journal of Clinical Oncology . 2014 ; Vol. 32, No. 23. pp. 2440-8.

Bibtex

@article{316109069a7d464badf045a7411c018b,
title = "Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial",
abstract = "PURPOSE: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566).METHODS: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event)).RESULTS: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%).CONCLUSION: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients.",
keywords = "Adult, Antineoplastic Combined Chemotherapy Protocols, Bone Neoplasms, Consolidation Chemotherapy, Cyclophosphamide, Dactinomycin, Disease-Free Survival, Doxorubicin, Etoposide, Female, Humans, Ifosfamide, Male, Sarcoma, Ewing, Treatment Outcome, Vincristine, Young Adult",
author = "{Le Deley}, Marie-C{\'e}cile and Michael Paulussen and Ian Lewis and Bernadette Brennan and Andreas Ranft and Jeremy Whelan and {Le Teuff}, Gw{\'e}na{\"e}l and Jean Michon and Ruth Ladenstein and Perrine Marec-B{\'e}rard and {van den Berg}, Henk and Lars Hjorth and Keith Wheatley and Ian Judson and Heribert Juergens and Alan Craft and Odile Oberlin and Uta Dirksen",
note = "{\textcopyright} 2014 by American Society of Clinical Oncology.",
year = "2014",
month = aug,
day = "10",
doi = "10.1200/JCO.2013.54.4833",
language = "English",
volume = "32",
pages = "2440--8",
journal = "Journal of Clinical Oncology ",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "23",

}

RIS

TY - JOUR

T1 - Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma

T2 - results of the randomized noninferiority Euro-EWING99-R1 trial

AU - Le Deley, Marie-Cécile

AU - Paulussen, Michael

AU - Lewis, Ian

AU - Brennan, Bernadette

AU - Ranft, Andreas

AU - Whelan, Jeremy

AU - Le Teuff, Gwénaël

AU - Michon, Jean

AU - Ladenstein, Ruth

AU - Marec-Bérard, Perrine

AU - van den Berg, Henk

AU - Hjorth, Lars

AU - Wheatley, Keith

AU - Judson, Ian

AU - Juergens, Heribert

AU - Craft, Alan

AU - Oberlin, Odile

AU - Dirksen, Uta

N1 - © 2014 by American Society of Clinical Oncology.

PY - 2014/8/10

Y1 - 2014/8/10

N2 - PURPOSE: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566).METHODS: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event)).RESULTS: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%).CONCLUSION: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients.

AB - PURPOSE: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566).METHODS: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event)).RESULTS: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%).CONCLUSION: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients.

KW - Adult

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Bone Neoplasms

KW - Consolidation Chemotherapy

KW - Cyclophosphamide

KW - Dactinomycin

KW - Disease-Free Survival

KW - Doxorubicin

KW - Etoposide

KW - Female

KW - Humans

KW - Ifosfamide

KW - Male

KW - Sarcoma, Ewing

KW - Treatment Outcome

KW - Vincristine

KW - Young Adult

U2 - 10.1200/JCO.2013.54.4833

DO - 10.1200/JCO.2013.54.4833

M3 - Article

C2 - 24982464

VL - 32

SP - 2440

EP - 2448

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 23

ER -