Impact of gender on efficacy and acute toxicity in standard risk localized (SR) Ewing sarcomas (ES) in the Euro-Ewing99-R1 trial

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  • Hendrik Van Den Berg
  • Michael Paulussen
  • Nathalie Gaspar
  • Ian Lewis
  • Uta Dirksen
  • Bernadette Brennan
  • Gwenael Le Teuff
  • Jeremy Whelan
  • Andreas Ranft
  • Jean Marie Michon
  • Ruth Lydia Ladenstein
  • Perrine Marec-Berard
  • Lars Hjort
  • Ian Robert Judson
  • Odile Oberlin
  • A. W Craft
  • Herbert Juergens
  • Marie-Cecile Le Deley

Colleges, School and Institutes


Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored.Clinical trial information: NCT00020566.

Bibliographic note

Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts. © 2013 American Society of Clinical Oncology.


Original languageEnglish
Article numberabstr 10031
JournalJournal of Clinical Oncology
Issue numbersuppl 15
Publication statusPublished - 20 May 2013