D9803

Background

Phase III RCT (IRS/COG D9803). 617 patients with intermediate-risk rhabdomyosarcoma. Compared standard VAC (vincristine + actinomycin + cyclophosphamide) to VAC alternating with VTC (vincristine + topotecan + cyclophosphamide). Evaluated whether topotecan improves outcomes in intermediate-risk RMS. All received local RT.

Interventions and follow up

Arm A: VAC: vincristine + dactinomycin + cyclophosphamide (43 weeks) + local RT per IRS protocol
Arm B: VAC/VTC: VAC alternating with vincristine + topotecan + cyclophosphamide (43 weeks) + local RT
Primary endpoint: FFS
mFollow up: 4.5 year

Results

5-yr FFS (VAC/VTC): 54.4% vs VAC 52.0%, P=.46 — no benefit
5-yr OS: 73.0% (VAC/VTC) vs 77.0% (VAC), P=.30
Local control: Equivalent in both arms with per-protocol RT delivery

Adverse events

Main adverse events: VTC arm: grade ≥3 neutropenia higher (86% vs 75%), increased transfusion requirements. Grade ≥3 infection in VTC: 38% vs 28%. RT toxicity: comparable between arms. Treatment-related mortality: 1.8% (VAC) vs 1.6% (VTC).

Conclusions

Adding topotecan to VAC did not improve outcomes in intermediate-risk rhabdomyosarcoma and increased hematologic toxicity. VAC plus local RT remains the standard, consistent with ARST0331 findings confirming the difficulty of improving on VAC with single-agent additions.

Key Limitations

Key Limitations: Topotecan scheduling may not have been optimal. No biomarker stratification. Heterogeneous intermediate-risk group. Topotecan has single-agent activity in RMS — the optimal combination regimen incorporating topotecan may differ from simple alternation.

Clinical Context

D9803 and ARST0331 together confirmed that VAC + local RT is the standard for intermediate-risk RMS and that single-agent additions (topotecan, irinotecan) do not improve outcomes. Current focus is on novel agents (ALK inhibitors, immunotherapy) in molecularly selected patients, and on RT technique optimization.

References

References: Arndt CA et al, JCO 2009 (D9803); PMID: 19770373