Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study.

Abstract

PURPOSE:

To assess the feasibility of adding dose-intensive topotecan and cyclophosphamide to induction therapy for newly diagnosed high-risk neuroblastoma (HRNB).

PATIENTS AND METHODS:

Enrolled patients received two cycles of topotecan (approximately 1.2 mg/m(2)/d) and cyclophosphamide (400 mg/m(2)/d) for 5 days followed by four cycles of multiagent chemotherapy (Memorial Sloan-Kettering Cancer Center [MSKCC] regimen). Pharmacokinetically guided topotecan dosing (target systemic exposure with area under the curve of 50 to 70 ng/mL/hr) was performed. Peripheral-blood stem cell (PBSC) harvest and surgical resection of residual primary tumor occurred after cycles 2 and 5, respectively. Patients achieving at least a partial response received myeloablative chemotherapy with PBSC rescue and radiation to the presurgical primary tumor volume. Oral 13-cis-retinoic acid maintenance therapy was administered twice daily for 14 days in six 28-day cycles.

RESULTS:

Thirty-one patients were enrolled onto the study. No deaths related to toxicity or dose-limiting toxicities occurred during induction. Mucositis rarely occurred after topotecan cycles (9.7%) in contrast to 30% after MSKCC cycles. Thirty patients underwent PBSC collection with median 31.1 × 10(6) CD34+ cells/kg (range, 1.8 to 541.8 × 10(6) CD34+ cells/kg), all negative for tumor contamination by immunocytochemical analysis. Targeted topotecan systemic exposure was achieved in 26 (84%) of 31 patients. At the end of induction, 26 patients (84%) had tumor response and one patient had progressive disease. In the overall cohort, 3-year event-free and overall survival were 37.8% ± 9.4% and 57.1% ± 9.4%, respectively.

CONCLUSION:

This pilot induction regimen was well tolerated with expected and reversible toxicities. These data support investigation of efficacy in a phase III clinical trial for newly diagnosed HRNB.

• Authors: Julie R Park, Jeffrey R Scott, Clinton F Stewart, Wendy B London, Arlene Naranjo, Victor M Santana, Peter J Shaw, Susan L Cohn, Katherine K Matthay
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 33 Pg. 4351-7 (Nov 20 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 22010014 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Topoisomerase I Inhibitors
• Topotecan

Topics

• Adult
• Brain Neoplasms (drug therapy, mortality)
• Child
• Child, Preschool
• Female
• Humans
• Induction Chemotherapy
• Infant
• Male
• Neuroblastoma (drug therapy, mortality)
• Pilot Projects
• Topoisomerase I Inhibitors (administration & dosage)
• Topotecan (administration & dosage, adverse effects, pharmacokinetics)