Background
Phase III RCT (COG ARST0331). 448 patients with intermediate-risk rhabdomyosarcoma (localized, unfavorable site or alveolar histology, or metastatic <10 years). Randomized to vincristine + actinomycin + cyclophosphamide (VAC) alone vs VAC alternating with vincristine + irinotecan (VI). All patients received RT to the primary site (45–50.4 Gy for gross disease, 36–41.4 Gy for microscopic disease); 59.4 Gy for parameningeal with intracranial extension.
Interventions and follow up
Arm A: VAC: vincristine + actinomycin D + cyclophosphamide (45 weeks total) + local RT
Arm B: VAC/VI: VAC alternating with vincristine + irinotecan (45 weeks total) + local RT
Primary endpoint: Failure-free survival (FFS)
mFollow up: 4.0 year
Arm B: VAC/VI: VAC alternating with vincristine + irinotecan (45 weeks total) + local RT
Primary endpoint: Failure-free survival (FFS)
mFollow up: 4.0 year
Results
4-yr FFS (VAC/VI): 52.5% vs VAC 52.9%, P=.98 — no improvement with irinotecan
4-yr OS (VAC/VI): 73.0% vs VAC 72.7%, P=.96
RT compliance: >90% of patients received protocol-specified RT doses and volumes
4-yr OS (VAC/VI): 73.0% vs VAC 72.7%, P=.96
RT compliance: >90% of patients received protocol-specified RT doses and volumes
Adverse events
Main adverse events: VAC: grade ≥3 neutropenia 77%, anemia 25%. VAC/VI: addition of irinotecan — grade ≥3 diarrhea 22% (vs 5% VAC), grade ≥3 nausea/vomiting increased. No significant difference in RT-related toxicities. Secondary malignancy: alkylator-related risk with cyclophosphamide.
Conclusions
Adding vincristine/irinotecan (VI) to VAC did not improve FFS or OS in intermediate-risk rhabdomyosarcoma. VAC plus local RT at 45–50.4 Gy remains the standard of care for intermediate-risk RMS. The outcomes confirm that RT is a critical component of local control in RMS.
Key Limitations
Key Limitations: Heterogeneous intermediate-risk group potentially diluting subgroup effects. No stratification by RT delivery quality. Irinotecan scheduling and cumulative dose varied across institutions. Does not address question of dose or volume of RT optimization.
Clinical Context
ARST0331 confirmed VAC as standard backbone for intermediate-risk RMS. RT dose of 45–50.4 Gy for gross disease and 36 Gy for microscopic disease are now standard. Ongoing efforts focus on molecularly targeted therapy (ALK inhibitors in ALK-positive RMS) and reducing late RT effects with proton therapy or IMRT.
References