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J Clin Oncol. 2014 Aug 10;32(23):2440-8. doi: 10.1200/JCO.2013.54.4833. Epub 2014 Jun 30.

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

Author information

1
Odile Oberlin, Gustave Roussy Institute, Villejuif; Marie-Cécile Le Deley, Université Paris-Sud, Le Kremlin-Bicêtre; Jean Michon, Institut Curie, Paris; Perrine Marec-Bérard, Centre Léon-Bérard, Lyon, France; Michael Paulussen, Vestische Kinder-und Jugendklinik Datteln, Witten/Herdecke University, Datteln; Andreas Ranft, Heribert Juergens, and Uta Dirksen, University Hospital Münster, Münster, Germany; Ian Lewis, Alder Hey Children's National Health Service Foundation Trust, Liverpool; Bernadette Brennan, Royal Manchester Children's Hospital, Manchester; Jeremy Whelan, University College London Hospital National Health Service Foundation Trust; Ian Judson, The Royal Marsden Hospital, London; Keith Wheatley, University of Birmingham, Birmingham; Alan Craft, Royal Victoria Infirmary, Newcastle, United Kingdom; Ruth Ladenstein, St Anna Children's Cancer Research Institute, Vienna, Austria; Henk van den Berg, Emma Children Hospital AMC, Amsterdam, the Netherlands; and Lars Hjorth, Skåne University Hospital, Lund University, Lund, Sweden. marie-cecile.ledeley@igr.fr.
2
Odile Oberlin, Gustave Roussy Institute, Villejuif; Marie-Cécile Le Deley, Université Paris-Sud, Le Kremlin-Bicêtre; Jean Michon, Institut Curie, Paris; Perrine Marec-Bérard, Centre Léon-Bérard, Lyon, France; Michael Paulussen, Vestische Kinder-und Jugendklinik Datteln, Witten/Herdecke University, Datteln; Andreas Ranft, Heribert Juergens, and Uta Dirksen, University Hospital Münster, Münster, Germany; Ian Lewis, Alder Hey Children's National Health Service Foundation Trust, Liverpool; Bernadette Brennan, Royal Manchester Children's Hospital, Manchester; Jeremy Whelan, University College London Hospital National Health Service Foundation Trust; Ian Judson, The Royal Marsden Hospital, London; Keith Wheatley, University of Birmingham, Birmingham; Alan Craft, Royal Victoria Infirmary, Newcastle, United Kingdom; Ruth Ladenstein, St Anna Children's Cancer Research Institute, Vienna, Austria; Henk van den Berg, Emma Children Hospital AMC, Amsterdam, the Netherlands; and Lars Hjorth, Skåne University Hospital, Lund University, Lund, Sweden.

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.

PMID:
24982464
DOI:
10.1200/JCO.2013.54.4833
[Indexed for MEDLINE]

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