A phase II trial of high-dose methotrexate in previously untreated children and adolescents with high-risk unresectable or metastatic rhabdomyosarcoma

Purpose: The outcome for children with advanced-stage rhabdomyosarcoma remains poor with contemporary treatment regimens. Evaluation of new drugs is important to improve clinical outcome. Because methotrexate has shown promising activity in the treatment of patients with recurrent rhabdomyosarcoma, we conducted a phase II trial in untreated children with advanced-stage disease to evaluate the efficacy and safety of this agent. Patients and Methods: Fifteen patients received 1 to 4 courses of high-dose methotrexate (HDMTX, 12 g/m²). Patients then received standard multiagent chemotherapy (vincristine, dactinomycin, cyclophosphamide, ifosfamide, mesna) with cytokine support and local radiotherapy. Patients who responded to HDMTX received four additional courses of this drug during continuation therapy. Results: Twelve patients were evaluable for response after 2 or more courses of HDMTX; 4 achieved a partial response (33.3%). After administration of standard chemotherapy and radiation, the estimated 2-year progression-free survival for all patients was 56% (SD 15%). The drug was well-tolerated and the most common side effects included mucositis, transient elevation of transaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity which included mucositis, anemia, and thrombocytopenia. Conclusions: About one- third of children with previously untreated advanced-stage rhabdomyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive candidate for incorporation into front-line treatment regimens for rhabdomyosarcoma.