Cyclophosphamide Compared With Ifosfamide in Consolidation Treatment of Standard-Risk Ewing Sarcoma: Results of the Randomized Noninferiority Euro-EWING99-R1 Trial
Mené sur 856 patients atteints d'un sarcome d'Ewing localisé à risque standard de rechute, cet essai européen compare l'efficacité et la toxicité du cyclophosphamide et de l'ifosfamide dans un traitement de consolidation après une chimiothérapie d'induction (durée médiane de suivi : 5,9 ans)
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/m2 of cyclophosphamide or seven VAI-courses with 6 g/m2 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 (HRevent).
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 HRevent was 1.12 (91.4% CI, 0.89 to 1.41), and the HRdeath was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HRevent 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.
Journal of Clinical Oncology , résumé, 2014