Background
Phase III RCT (INT-0091/IESS-III). 518 patients with Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone — localized and metastatic. Randomized to standard VAC chemotherapy (vincristine + dactinomycin + cyclophosphamide, also called VACA) vs VAC alternating with ifosfamide + etoposide (IE). All patients received local therapy (surgery and/or RT) after induction. Landmark trial establishing ifosfamide/etoposide in Ewing sarcoma.
Interventions and follow up
Arm A: VAC: vincristine + dactinomycin + cyclophosphamide (standard, 12 cycles)
Arm B: VACIE: VAC alternating with ifosfamide + etoposide (12 cycles total)
Primary endpoint: EFS
mFollow up: 7.7 year
Arm B: VACIE: VAC alternating with ifosfamide + etoposide (12 cycles total)
Primary endpoint: EFS
mFollow up: 7.7 year
Results
5-yr EFS (localized, VACIE): 69% vs VAC 54%, P=.005
5-yr OS (localized, VACIE): 72% vs VAC 61%, P=.01
Metastatic disease: No significant EFS benefit with VACIE (5-yr EFS ~20% both arms)
5-yr OS (localized, VACIE): 72% vs VAC 61%, P=.01
Metastatic disease: No significant EFS benefit with VACIE (5-yr EFS ~20% both arms)
Adverse events
Main adverse events: VACIE: grade ≥3 hematologic toxicity significantly higher — neutropenia 88% vs 72%, thrombocytopenia 66% vs 48%. Ifosfamide: nephrotoxicity (Fanconi syndrome 5%), hemorrhagic cystitis. Etoposide: secondary AML (1.4% actuarial 6-yr risk). No significant difference in treatment-related mortality.
Conclusions
Adding ifosfamide and etoposide (IE) to VAC significantly improved EFS and OS in localized Ewing sarcoma/PNET. The four-drug VACIE regimen (or alternating VDC/IE) became the standard of care for localized Ewing sarcoma. Metastatic disease showed no benefit from VACIE in this trial.
Key Limitations
Key Limitations: Etoposide-related secondary leukemia risk is a long-term concern. No RT dose standardization across institutions. Metastatic disease outcome remains poor regardless of regimen — need for new therapeutic strategies. Surgical resection rates and margin status not reported consistently.
Clinical Context
INT-0091 established alternating VDC/IE as the standard chemotherapy backbone for localized Ewing sarcoma worldwide. Local RT (45–55.4 Gy for unresectable or microscopically positive margins; 45 Gy with IMRT for large tumors) is standard after induction. AEWS0031 further improved outcomes by dose compression.
References