As reported by Bisogno et al in The Lancet Oncology, a phase III trial (EpSSG RMS 2005) has shown no benefit of adding doxorubicin to standard IVA (ifosfamide, vincristine, dactinomycin) in 3-year event-free survival among patients with high-risk rhabdomyosarcoma.
In the open-label trial, 484 patients aged > 3 months to < 21 years from 108 sites in 14 countries were randomly assigned between October 2005 and December 2013 to receive IVA with (n = 242) or without (n = 242) doxorubicin. Patients were considered to be at high risk of relapse on the basis of embryonal rhabdomyosarcoma that was incompletely resected and localized at unfavorable sites with or without nodal involvement or alveolar rhabdomyosarcoma without nodal involvement.
Treatment consisted of 9 cycles of IVA (ifosfamide at 3 g/m² on days 1 and 2; vincristine at 1.5 mg/m² weekly during the first 7 weeks, then only on day 1 of each cycle; and dactinomycin at 1.5 mg/m² on day 1) or 4 cycles of IVA with doxorubicin at 30 mg/m² on days 1 and 2, followed by 5 cycles of IVA. The interval between cycles was 3 weeks.
The primary endpoint was investigator-assessed 3-year event-free survival in the intention-to-treat population. On recommendation of the independent data monitoring committee, the study was closed to patient entry in December 2013 after a futility analysis. Follow up continues.
Median follow-up was 63.9 months. Rates of 3-year event-free survival were 67.5% in the doxorubicin group vs 63.3% in the IVA group (hazard ratio [HR] = 0.87, P = .33). Overall survival at 3 years was 78.3% vs 80.6% (HR = 1.17, P = .37).
The doxorubicin group had higher rates of grade 3 or 4 leukopenia (93% vs 85%, P = .0061), anemia (78% vs 49%, P < .0001), thrombocytopenia (67% vs 26%, P < .0001), and gastrointestinal adverse events (31% vs 8%, P < .0001) and a higher rate of grade ≥ 3 infection (79%, including 1 grade 5 infection, vs 56%, P < .0001). Two treatment-related deaths were reported in the doxorubicin group, due to septic shock and intractable seizures in the setting of Goldenhar syndrome, with both occurring after the first cycle of treatment; no treatment-related deaths were reported in the IVA group.
The investigators concluded, “The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk nonmetastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe.”
The study was funded by Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France. Gianni Bisogno, MD, of the Hematology Oncology Division, Department of Women’s and Children’s Health, University of Padova, is the corresponding author for The Lancet Oncology article.
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