Metronomic oral maintenance chemotherapy in patients with localized high-risk rhabdomyosarcoma (RMS) and RMS-like tumors: A report from a randomized, multicenter, phase III trial CWS-2007HR.

10033 Background: Low dose maintenance therapy as consolidation after multimodal standard therapy has been shown to improve survival in patients with sarcoma. It is however unclear which drugs and how long would be optimal. We investigated whether adding oral maintenance chemotherapy after standard multimodal therapy (ST) in patients with localized RMS and RMS-like sarcoma defined as high and very-high risk (HR and VHR), according to CWS stratification, would improve survival. Methods: Patients (pts) age > 6 months < 21 years, with 1. embryonal RMS N0, incompletely resected, (Group II or III), tumor size > 5cm and/or ≥10 years, in unfavorable primary sites and all N1 (HR RMS Group), 2. alveolar RMS N0/N1 (VHR RMS Group) 3.Unidfferentiated sarcoma (UDS), extraskeletal Ewing sarcoma (EES) and primary non resectable (Group III) synovial sarcoma (SS) (HR RMS-like Group) in complete remission after ST including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (S-arm) or receive maintenance chemotherapy (M-arm) with eight 10-days courses consisting of trofosfamide (2x 75mg/m²/day) and idarubicine (1 x 5mg/m²/day 1,4,7,10) alternating with trofosfamide and etoposide (2x 25mg/m²/day). The study was designed with 80% power and a two-sided alpha level of 5% to detect an increase in 3 yr EFS from 60 to 75%. Randomisation was stratified according to risk groups. To reduce possible imbalances in the number of treatment assignments, a permuted block design was used. The initial calculated sample size was 145 pts in each group (recruitment period six years). Due to the lower than planned recruitement rate, the accrual was extended to 10 years and sample size recalculated to 98 pts in each group. Results: Between 1.7.2009 and 30.6.2019, 441 pts were eligible at diagnosis and 337 at the end of ST. 195 pts were randomized: 99 were assigned to the S-arm and 96 to M-arm. The distribution of the following clinical features:age, gender, tumor size, IRS-Group, T-Status, N-Status, histology and localisation showed no significant difference between the treatment groups. In the intent to treat population, with a median follow up of 4.9 years (IQR 3.0-5.7) in surviving pts, 3yr EFS and OS in M-arm vs S-arm were respectively: EFS 66.2% (95% IC 57.1-76.79) vs 75.0% (95% IC 66.8-84.3) (p 0.07) and OS 81.9% (95% IC 74.2-90.4) vs 84.6 (95% IC 77.5-92.4) (p 0.15). Toxicity grade 3 (no grade 4) in the M-arm was: hematological in 51 %, febrile infection 5%, sensory neuropathy in 1% pts. Conclusions: The addition of maintenance therapy with trofosfamide, etoposide and idarubicine after ST does not improve EFS and OS in patients with high risk RMS and RMS-like sarcomas. Clinical trial information: 2007-0001478-10.