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

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.
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.
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 mg/m(2)). 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.
Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.
AuthorsVictor M Santana, Wayne L Furman, Catherine A Billups, Fredric Hoffer, Andrew M Davidoff, Peter J Houghton, Clinton F Stewart
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 18 Pg. 4039-47 (Jun 20 2005) ISSN: 0732-183X [Print] United States
PMID15961757 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Topotecan
  • Adolescent
  • Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
  • Area Under Curve
  • Child
  • Child, Preschool
  • Disease Progression
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Infusions, Intravenous
  • Male
  • Neuroblastoma (drug therapy)
  • Prognosis
  • Prospective Studies
  • Statistics, Nonparametric
  • Survival Analysis
  • Topotecan (adverse effects, pharmacokinetics, therapeutic use)
  • Treatment Outcome

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