Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach

Purpose To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma. Patients and Methods In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL (.) h. Patients subsequently received standard treatment. Results Both cycles were administered to 28 (93 %) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72 %) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m(2) (range, 0.95 to 3.8 m(g)/m(2)). The response rate was 60 % (95 % Cl, 41 % to 77 %); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, -58.2 %; range, -95.1 % to -4.9 %) in the 26 patients with available size data. Homovanillic acid levels in 16 (89 %) of 18 patients and vanillylmandelic acid levels in 14 (78 %) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity. Conclusion Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.