AbstractBackgroundThe authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA‐RMS).Patients and MethodsLocalized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA‐RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event‐free survival (EFS) and overall survival (OS).ResultsFrom October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non–bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5–81.6) and 93.5% (95% CI, 90.1–95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5‐year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/‐ radiotherapy was not significant (p = 0.8003). Adjuvant radiotherapy improved EFS with 5‐year estimates of 84.7% versus 65.2% for nonirradiated (p < .0001), but not OS (p = .9298). Omitting radiotherapy for orbital tumors reduced OS (5‐year was 87.1% vs. 97.3% for irradiated, p = .0257). Following R0 resection (n = 60), radiotherapy did not significantly improve EFS or OS.ConclusionsRadiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS.