Determination of the Maximum Tolerated Dose of Cyclophosphamide in Conjunction with High-Dose Etoposide and Carboplatin Followed by Autologous CD34+ Hematopoietic Rescue in Pediatric Patients with Recurrent/Refractory Solid Tumors.

Abstract

Cyclophosphamide (Cy) is an alkylating agent utilized in almost all preparative regimens for hematopoietic stem cell transplantation, and in vitro sensitivity has been demonstrated with carboplatin and etoposide. Multiple previous studies have involved this combination of agents; however, they almost exclusively utilized a fixed dose of Cy and/or bolus administration. The potential fatal cardiac toxicity of Cy is likely related to high peak concentrations of active metabolites from bolus dosing. Additionally, some evidence exists that the increased metabolism of Cy with continuous infusion has a therapeutic benefit. The objective of this study was to determine the maximum tolerated dose (MTD) of continuous infusion Cy with fixed dose etoposide (2400 mg/m2) and carboplatin (2175 mg/m2) followed by autologous CD34+ hematopoietic rescue in pediatric patients with recurrent/refractory solid tumors. Twenty patients were enrolled, and fourteen patients completed therapy on study. The MTD of Cy was 60 mg/kg/24 hr by continuous 60 hr infusion on days -4 to -2 for a total dose of 150 mg/kg. Alopecia, stomatitis and nausea were the most common toxicities. The single episode of direct cardiac toxicity was reversible. Two Grade IV toxicities occurred, consisting of diarrhea in one patient and coma in another patient who recovered and remains a long-term survivor. All patients were evaluable for neutrophil engraftment, with a median time to ANC > 200/μl of 11 days (range 7–30 days). Thirteen of the fourteen patients were evaluable for platelet engraftment, with a median time to platelet count of 20,000/μl independent of transfusion of 21 days (range 11–72 days). Six out of the fourteen patients remain alive greater than five years after study completion. The MTD of Cy was lower than expected. These results suggest that autoinduction of Cy metabolism (repeated administration of Cy at 24 hour intervals leads to increased hepatic cytochrome enzymes) could be a primary factor in the determination of the MTD. Future studies should aim to further characterize the pharmacokinetics and effectiveness of continuous infusion Cy in pediatric patients.