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


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 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.


CONCLUSIONS
Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.
Santana
Victor M
VM
Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105, USA. victor.santana@stjude.org
Furman
Wayne L
WL
Billups
Catherine A
CA
Hoffer
Fredric
F
Davidoff
Andrew M
AM
Houghton
Peter J
PJ
Stewart
Clinton F
CF
D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy*; D011379:Prognosis; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019772:Topotecan