Background
Phase III RCT (COG AEWS0031). 568 patients with localized Ewing sarcoma. Randomized to standard interval (q3-week cycles) vs interval-compressed (q2-week cycles with G-CSF) alternating VDC/IE chemotherapy. Evaluated whether compressing chemotherapy cycles — rather than escalating dose — improves outcomes. All received local therapy.
Interventions and follow up
Arm A: Standard interval VDC/IE: alternating cycles every 3 weeks × 17 cycles + local surgery/RT
Arm B: Interval-compressed VDC/IE: same doses but cycles every 2 weeks with G-CSF + local surgery/RT
Primary endpoint: EFS
mFollow up: 5.0 year
Arm B: Interval-compressed VDC/IE: same doses but cycles every 2 weeks with G-CSF + local surgery/RT
Primary endpoint: EFS
mFollow up: 5.0 year
Results
5-yr EFS (compressed): 73.0% vs standard 65.0%, P=.048
5-yr OS (compressed): 83.0% vs standard 74.0%, P=.028
Local control: Similar between arms; RT was per institutional protocol
5-yr OS (compressed): 83.0% vs standard 74.0%, P=.028
Local control: Similar between arms; RT was per institutional protocol
Adverse events
Main adverse events: Interval-compressed arm: grade ≥3 neutropenia modestly higher but comparable overall due to G-CSF support. Hospitalization rates similar. No significant difference in secondary malignancies at median follow-up. Grade ≥3 infection slightly higher with compression: 28% vs 22%.
Conclusions
Interval-compressed VDC/IE (q2 weeks) significantly improved both EFS and OS in localized Ewing sarcoma with manageable toxicity using G-CSF support. Interval compression became the new standard of care for localized Ewing sarcoma in North America.
Key Limitations
Key Limitations: Only localized disease studied. RT details not standardized across centers. Long-term cardiotoxicity from doxorubicin dose-dense administration requires monitoring. Secondary malignancy risk from etoposide with dose compression is a theoretical concern requiring long-term follow-up.
Clinical Context
AEWS0031 established interval-compressed VDC/IE (q2 weeks) as standard of care for localized Ewing sarcoma in the COG setting. Local RT (45 Gy for R2/unresectable; 36 Gy for R1; surgery preferred if feasible) with IMRT or proton therapy is concurrent standard of care. Most European centers use EURO-EWING protocol with similar compressed scheduling.
References