Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: A report from the soft tissue sarcoma committee of the children's oncology group

Purpose: More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome. Experimental Design: This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m(2) on days 0, 7, and 14; actinomycin D (A) 135 mg/m(2) on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m(2)/dose; (b) 1.5 g/m(2)/dose; and (c) 1.8 g/m(2)/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m(2)/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others). Results: Between October 1996 and,August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall, survival estimates for patients treated at the maximumtolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-7.7%), respectively, at a median follow-up of 3 years. Conclusions: A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m(2)/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediaterisk rhabdomyosarcoma.