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Improved Response in High-Risk Neuroblastoma With Protracted Topotecan Administration Using a Pharmacokinetically Guided Dosing Approach

From the Departments of Hematology-Oncology, Biostatistics, Radiological Sciences, Surgery, Molecular Pharmacology, and Pharmaceutical Sciences, St Jude Children's Research Hospital; and Department of Pediatrics and Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, T

Address reprint requests to Victor M. Santana, MD, Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; email: victor.santana{at}stjude.org

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/m² (range, 0.95 to 3.8 mg/m²). The response rate was 60% (95% CI, 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.

Supported by the US Public Health Service Childhood Solid Tumor Program Project Grant No. CA 23099, by Cancer Center Support Grant No. CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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