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


  • Marie-Cécile Le Deley
  • Michael Paulussen
  • Ian Lewis
  • Bernadette Brennan
  • Andreas Ranft
  • Jeremy Whelan
  • Gwénaël Le Teuff
  • Jean Michon
  • Ruth Ladenstein
  • Perrine Marec-Bérard
  • Henk van den Berg
  • Lars Hjorth
  • Ian Judson
  • Heribert Juergens
  • Alan Craft
  • Odile Oberlin
  • Uta Dirksen

Colleges, School and Institutes


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.

Bibliographic note

© 2014 by American Society of Clinical Oncology.


Original languageEnglish
Pages (from-to)2440-8
Number of pages9
JournalJournal of Clinical Oncology
Issue number23
Publication statusPublished - 10 Aug 2014


  • 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