Background
Phase III RCT (INT-0154). 478 patients with non-metastatic Ewing family of tumors. Randomized to standard-dose alternating VDC/IE (vincristine + doxorubicin + cyclophosphamide / ifosfamide + etoposide) vs dose-intensive VDC/IE with G-CSF support. All patients received local therapy (surgery/RT). Evaluated whether dose escalation beyond standard VDC/IE improves outcomes.
Interventions and follow up
Arm A: Standard VDC/IE: alternating cycles at established doses every 3 weeks × 17 cycles + local therapy
Arm B: Dose-intensive VDC/IE: escalated cyclophosphamide + ifosfamide doses + G-CSF × 17 cycles + local therapy
Primary endpoint: EFS
mFollow up: 4.0 year
Arm B: Dose-intensive VDC/IE: escalated cyclophosphamide + ifosfamide doses + G-CSF × 17 cycles + local therapy
Primary endpoint: EFS
mFollow up: 4.0 year
Results
5-yr EFS (dose-intensive): 72% vs standard 70%, P=.56 — no benefit
5-yr OS: 78% (dose-intensive) vs 77% (standard), P=.73
Local control: No significant difference between arms
5-yr OS: 78% (dose-intensive) vs 77% (standard), P=.73
Local control: No significant difference between arms
Adverse events
Main adverse events: Dose-intensive arm: significantly higher rates of grade ≥3 neutropenia (96% vs 82%), thrombocytopenia, anemia, infection, and mucositis. Hospitalization for toxicity: 58% vs 42%. No significant difference in secondary malignancy rate at median follow-up.
Conclusions
Dose intensification of VDC/IE beyond standard doses does not improve EFS or OS in non-metastatic Ewing sarcoma and significantly increases toxicity. Standard-dose alternating VDC/IE is the established regimen. The results argue against further dose escalation in this direction.
Key Limitations
Key Limitations: The dose escalation strategy used (increased cyclophosphamide/ifosfamide doses) may not represent the most effective intensification approach. High-risk subgroups (large tumors, axial location) may require different strategies. RT delivery and surgical resection quality varied across institutions.
Clinical Context
INT-0154 confirmed that dose escalation within the VDC/IE framework does not improve outcomes. Interval compression (q2-week cycles) was subsequently tested in AEWS0031 and did show benefit without increased dosing. High-dose chemotherapy with stem cell rescue is reserved for metastatic/relapsed disease.
References