A topotecan-containing induction regimen for treatment of high risk neuroblastoma

Abstract

9013 Background: We assessed the toxicity and feasibility of adding dose-intensive topotecan and cyclophosphamide to a multi-agent chemotherapy induction regimen for treatment of newly diagnosed high-risk neuroblastoma. Methods: Patients received 2 cycles of topotecan (starting dose 1.2 mg/m2/day for 5 days) and cyclophosphamide (400 mg/m2/day for 5 days) (T/C) followed by an additional 4 cycles of chemotherapy; cisplatin, etoposide alternating with vincristine, doxorubicin, cyclophosphamide. Pharmacokinetically guided topotecan dosing (target systemic exposure of AUC 50 - 70 ng/ml*hr determined by single day topotecan lactone levels) was performed. Chemotherapy cycles were scheduled every 21 days, PBSC harvest occurred after T/C cycles and surgical resection of residual primary tumor after cycle 5. Results: Thirty-one patients, 3 with INSS Stage 3 and 28 with Stage 4, were enrolled between April 2004 and November 2005. Median age at diagnosis was 2.5 years (range 0.9 - 9.35 years). Ten of 25 patients had tumor cell MYCN amplification and 21 of 22 tumors were classified as unfavorable Shimada histology by central review. Targeted topotecan systemic exposure was achieved in 87% (27/31) of patients during T/C cycle 1 and in 85% (23/27) of patients during T/C cycle 2. PBSC collections occurred as intended in 95% of patients (21/22 patients), median harvest 30.8 × 106 CD34+cells cell/kg (range 2.24 - 542). No dose limiting toxicities occurred. All patients experienced Grade 3 or 4 hematopoietic toxicity. Febrile neutropenia occurred in 79% (19/24) of patients during T/C cycles and 78% (18/23) of patients during subsequent cycles of induction therapy. Documented infection occurred in 12.5% (3/24) patients during T/C cycles and 26% (6/23) during subsequent induction cycles. Dose intensity of all chemotherapy agents was maintained in 95.8% (23/24) of patients. Conclusions: This pilot induction regimen was well tolerated with expected and reversible toxicities. Dose intensity of standard induction chemotherapy agents was not limited by the addition of dose-intensive topotecan. These data support investigation of efficacy in a Phase III clinical trial for newly diagnosed high-risk neuroblastoma. [Table: see text]