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 h as shown promising activity in the treatment of patients with recurren t rhabdomyosarcoma, we conducted a phase II trial in untreated childre n with advanced-stage disease to evaluate the efficacy and safety of t his agent. Patients and Methods: Fifteen patients received 1 to 4 cour ses of high-dose methotrexate (HDMTX, 12 g/m(2)). Patients then receiv ed standard multiagent chemotherapy (vincristine, dactinomycin, cyclop hosphamide, ifosfamide, mesna) with cytokine support and local radioth erapy. Patients who responded to HDMTX received four additional course s of this drug during continuation therapy. Results: Twelve patients w ere evaluable for response after 2 or more courses of HDMTX; 4 achieve d a partial response (33.3%). After administration of standard chemoth erapy and radiation, the estimated 2-year progression-free survival fo r all patients was 56% (SD 15%). The drug was well-tolerated and the m ost common side effects included mucositis, transient elevation of tra nsaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity whi ch included mucositis, anemia, and thrombocytopenia. Conclusions: Abou t one-third of children with previously untreated advanced-stage rhabd omyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive ca ndidate for incorporation into front-line treatment regimens for rhabd omyosarcoma.