2.2. Treatment
2.2.1. EpSSG RMS2005
Patients received intensified induction chemotherapy and additional maintenance chemotherapy with systematic local treatment to primary and nodal sites. Induction chemotherapy comprised four 21-day cycles of IVADo (ifosfamide 3 g/m2 on days 1-2 with MESNA, vincristine 1.5 mg/m2 [max dose 2 mg] on days 1, 8 and 15 in the first 2 cycles and on day 1 in cycles 3 and 4, dactinomycin 1.5 mg/m2 [max dose 2 mg] on day 1, and doxorubicin 30 mg/m2 on days 1-2) followed by five 21-day cycles of IVA and six 28-day cycles of maintenance chemotherapy comprising continuous daily oral cyclophosphamide 25 mg/m² and intravenous vinorelbine 25 mg/m² on days 1, 8 and 15 of each cycle. The total duration of chemotherapy was 50 weeks.
Response was evaluated at weeks 9, 27 and at the end of treatment. If free margins were achievable without organ or functional impairment, local treatment after the initial 4 cycles of IVADo (week 13) included delayed surgical resection. External beam radiotherapy was administered to the primary tumor area and the affected lymph node region, delivered using a daily dose per fraction of 1.8 Gy. Doses varied according to chemotherapy response and surgical results. The total dose to the primary tumor following delayed surgery with complete resection was 41.4 Gy. For IRS Group III with incomplete resection, or when delayed surgery was not feasible, total dose was 50.4 Gy with an optional additional boost of 5.4 Gy in 3 fractions for large tumors with poor response to chemotherapy. Radiotherapy (RT) was recommended for involved lymph nodes at a dose of 41.4 Gy regardless of the extent of surgical resection.
2.2.2. COG ARST531
Patients were randomly assigned to receive either VAC (vincristine 1.5 mg/m2 [max dose 2 mg], dactinomycin 0.045 mg/kg [max dose 2.5 mg], cyclophosphamide 1.2 g/m2 with MESNA) or VAC alternating with VI (vincristine 1.5 mg/m2, irinotecan 50 mg/m2 on 5 consecutive days) intravenously. During the first 12 weeks, the two treatment arms were identical in duration and schedule, with the exception of substituting irinotecan for dactinomycin and cyclophosphamide at week 4 and for cyclophosphamide at week 7 in VAC/VI. During the subsequent 30 weeks of therapy, irinotecan replaced dactinomycin and cyclophosphamide at weeks 16, 19, 25, 31, and 37 in VAC/VI. The schedule of vincristine differed slightly between the two treatment regimens, allowing for its administration during the weeks that followed all courses of irinotecan, but the total number of vincristine doses was the same in both regimens. The total duration of chemotherapy was 42 weeks.
Patients were evaluated for response at weeks 15 and 30 and at the end of therapy. For patients older than 24 months, definitive RT was the planned local control modality. Delayed primary resection was allowed but not encouraged. For patients younger than 24 months, individualized local control approaches, including delayed primary excision and response-adapted RT, were permitted. RT started at week 4, and the dose was determined by clinical group and histology at study entry: IRS Group II ARMS with regional lymph node involvement, 41.4 Gy; IRS Group III ARMS with orbital primary site, 45 Gy; and non-orbital primary sites, 50.4 Gy. RT was delivered using megavoltage photon, proton, and/or electron beams. For tumors with a rapid substantial decrease in tumor size, a volume reduction by cone down after 36 Gy was permitted, particularly for tumors with pushing rather than infiltrating margins.