Background
Phase II single-arm study (COG ARST0431). 109 patients with high-risk rhabdomyosarcoma (metastatic at any age, or regional with unfavorable features). Evaluated intensive dose-compressed multiagent chemotherapy with interval-compressed ifosfamide/etoposide (IE) + vincristine/doxorubicin/cyclophosphamide (VDC) combined with local RT and irinotecan added to VAC maintenance.
Interventions and follow up
Arm A: VDC + IE (dose-compressed, q2-week cycles with G-CSF) × 6 alternating cycles → local RT (concurrent with chemotherapy) → VAC + irinotecan maintenance (26 additional weeks)
Primary endpoint: 3-year EFS
mFollow up: 3.0 year
Primary endpoint: 3-year EFS
mFollow up: 3.0 year
Results
3-yr EFS: 38.0% — compared to historical high-risk RMS EFS of ~10–20%
3-yr OS: 56.0%
Response to induction (VDC/IE): ORR 65% (CR+PR)
RT completion rate: 85% of eligible patients completed per-protocol RT
3-yr OS: 56.0%
Response to induction (VDC/IE): ORR 65% (CR+PR)
RT completion rate: 85% of eligible patients completed per-protocol RT
Adverse events
Main adverse events: Grade ≥3: neutropenia 92%, anemia 55%, thrombocytopenia 72%, febrile neutropenia 38%, infection 25%. Grade ≥3 cardiac toxicity (doxorubicin): 4%. RT-concurrent toxicity: mucositis, radiation recall. Treatment-related mortality: 3.7%.
Conclusions
Dose-compressed VDC/IE with RT and irinotecan maintenance improved EFS in high-risk RMS compared to historical controls, with 38% 3-year EFS — a meaningful improvement for this historically fatal disease. The regimen established a new benchmark for high-risk RMS treatment.
Key Limitations
Key Limitations: Single-arm phase II; no randomized comparison. Historical control comparisons are limited by patient selection differences. Toxicity is substantial. Concurrent RT with dose-compressed chemotherapy adds complexity. Long-term cardiotoxicity from doxorubicin and RT to chest/mediastinum requires monitoring.
Clinical Context
ARST0431 established dose-compressed VDC/IE as the standard induction for high-risk metastatic RMS. Subsequent COG trials (ARST1431) are evaluating the addition of temsirolimus or ganitumab to this backbone. Local RT at standard doses (36–50.4 Gy per site) is incorporated after induction chemotherapy.
References