Bisogno G, et al. - Experts evaluated the probable benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma. A significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma was not demonstrated by the addition of dose-intensified doxorubicin to standard IVA chemotherapy. Consequently, for patients with localized rhabdomyosarcoma in Europe, the IVA chemotherapy regimen should remain the standard of care.

Methods

• Authors conducted a multicenter, open-label, randomized controlled, phase 3 trial involving 108 hospitals from 14 countries.
• They included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma.
• Each patient was assigned to a specific subgroup according to the EpSSG stratification system.
• They considered those with embryonal rhabdomyosarcoma incompletely resected and localized at unfavorable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement at high risk of relapse.
• Researchers randomly assigned these high-risk patients (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m²given as a 3-h intravenous infusion on days 1 and 2, vincristine 1.5 mg/m²weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1.5 mg/m²on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m²given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA.
• Three weeks was the interval between cycles.
• Using a web-based system, randomization was done and was stratified (block sizes of four) by enrolling country and risk subgroup.
• They did not mask either investigators nor patients to treatment allocation.
• Three-year event-free survival assessed by the investigator at each center in the intention-to-treat population was the primary endpoint.
• They considered the patients in the safety analysis who received at least one dose of study treatment.
• The study was closed to patient entry on Dec 16, 2013, after futility analysis, in agreement with the independent data monitoring committee.

Results

• Findings suggested that between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group).
• Results suggested that median follow-up was 63.9 months (IQR 44.6–78.9).
• As per data, in the IVA plus doxorubicin group, the 3-year event-free survival was 67.5% (95% CI 61.2–73.1) and 63.3% (56.8–69.0) in the IVA group (hazard ratio 0.87, 95% CI 0.65–1.16; p=0.33).
• Experts noted that grade 3–4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0.0061), anemia (195 [78%] vs 111 [49%]; p < 0.0001), thrombocytopenia (168 [67%] vs 59 [26%]; p < 0.0001), and gastrointestinal adverse events (78 [31%] vs 9 [8%]; p < 0.0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group.
• In the IVA plus doxorubicin group, grade 3–5 infections (198 [79%] vs 128 [56%]; p < 0.0001) were also significantly more common than in the IVA group, in which one patient had grade 5 infection.
• In the IVA plus doxorubicin group, 2 treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures), both occurring after the first cycle of treatment, and none were reported in the IVA group.