Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group

Background. The cure rate for children/adolescents with localized rhabdomyo sarcoma (RMS) has tripled over the past 25 years, but patients with metasta tic disease at presentation have not benefited similarly, and urgently need new therapy. We evaluated a new drug pair, ifosfamide + doxorubicin, for s uch patients. Procedure. We estimated the complete and partial response rat es (i.e., CR and PR) of 152 previously untreated children/adolescents with metastatic RMS entered on the I RS-IV pilot from July 1988 to October 1991 who received an "up-front window" of ifosfamide (1.8 gm/m(2)/day for 5 days ) and doxorubicin (30 mg/m(2)/day for 2 days) given every 3 weeks for 12 we eks. This was followed by combination chemotherapy with vincristine, actino mycin D, and cyclophosphamide (VAC), given every 3 weeks for an additional 36 weeks. Results. Of 115 patients evaluable for early response at 12 weeks , 28 (20%) had CR and 66 (43%) had PR. The ultimate CR rate was 52%. Overal l, about one-third of patients survived. Prognostic factor analysis reveale d that patients < 10 years old (P < 0.001), those with embryonal tumors (P = 0.002), or a GU primary site (P = 0.010), and those who lacked nodal dise ase (P = 0.041), and those who lacked bone or bone marrow metastasis (P < 0 .001) fared better than did others. Conclusions. The 63% CR + PR rate achie ved at 12 weeks and overall 5-year FFS seen with this drug pair is similar to that achieved with previously evaluated drug combinations. We conclude t hat ifosfamide/doxorubicin is highly active in advanced RMS, and should be considered for inclusion in frontline therapy for children with intermediat e or highrisk RMS. (C) 2001 Wiley-Liss, Inc.