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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

¹ St. Jude Children’s Research Hospital and University of Tennessee College of Medicine, Memphis, Tennessee; ² University of Nebraska Medical Center, Omaha, Nebraska; ³ Ohio State University Medical Center, Columbus, Ohio; ⁴ Stanford University Medical Center, Stanford California; ⁵ Mayo Eugenio Litta Children’s Hospital, Rochester, Minnesota; and ⁶ University of Missouri–Columbia Medical Center, Columbia, Missouri

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/m² on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m² 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/m²/dose; (b) 1.5 g/m²/dose; and (c) 1.8 g/m²/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m²/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 maximum-tolerated dose were 52% (95% confidence interval, 41–64%) and 67% (95% confidence interval, 56–77%), respectively, at a median follow-up of 3 years.

Conclusions: A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m²/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

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