CYCLOPHOSPHAMIDE DOSE-ESCALATION COMBINATION WITH VINCRISTINE AND ACTINOMYCIN-D (VAC) IN GROSS RESIDUAL SARCOMA - A PILOT-STUDY WITHOUT HEMATOPOIETIC GROWTH-FACTOR SUPPORT EVALUATING TOXICITY AND RESPONSE

Purpose: The Intergroup Rhabdomyosarcoma Study (IRS) initiated an esca lating-dose cyclophosphamide (Cyc) pilot without hematopoietic growth factor (HGF) support in combination with vincristine (Vcr) and actinom ycin-D (Amd), known as VAC, to establish a Cyc dose with myelotoxicity comparable to an ifosfamide (Ifos), Vcr, and Amd combination regimen (VAI). A Cyc dose equivalent to Ifos was to be determined when compara ble myelotoxicity was achieved. Patients and Methods: Patients with ei ther rhabdomyosarcoma or undifferentiated soft-tissue sarcoma and gros s residual (clinical group III) disease were eligible for the VAC pilo t. Feasibility and toxicity were evaluated in the VAC pilot at each Cy c level before escalating the dose. Starting at CYC 1.2 g/m(2) dose es calation was planned at increments of 20-25% in cohorts of 8-10 patien ts until myelotoxicity at a severe or worse grade was seen in >90% of the patients. Results: One hundred nineteen eligible patients were eva luated for toxicity and response at four Cyc levels: 1.2, 1.5, 1.8, an d 2.2 g/m(2). Eight of 87 (9%) evaluable at 2.2 g/m(2) had a toxic dea th. Six of these were attributable to myelotoxicity. Patients age 1-3 years were most vulnerable. The overall complete response (CR) rate of 68% was poorly predicted by the weeks 8 and 20 CR rates of 20 and 40% , respectively. During the first year and overall, myelotoxicity at 2. 2 g/m(2) 1 with VAC was comparable to Ifos 1.8 g/m(2) 5. Cyc was relat ively more myelotoxic than Ifos in the second year of the VAC pilot. B ased on actual amount of drug given, a standardized Ifos dose of 9.0 g /m(2) was equivalent to 2.1 g/m(2) of Cyc, giving an Ifos/Cyc ratio of 4.3. Conclusion: Myelotoxicity using 2.2 g Cyc/m(2) in a single intra venous infusion was dose limiting in this VAC pilot without HGF. In th e first year and overall, myelotoxicity is comparable to that with VAI using Ifos at 9.0 g/m(2). An ongoing IRS-IV randomized trial of VAC a nd VAI should provide a comparison of the efficacy of Ifos and Cyc in children and adolescents with embryonal or alveolar rhabdomyosarcoma a nd undifferentiated soft-tissue sarcomas.