Phase II evaluation of topotecan for pediatric central nervous system tumors.
BACKGROUND
Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors.


METHODS
Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity.


RESULTS
There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation.


CONCLUSIONS
Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors.
Blaney
S M
SM
The Pediatric Branch, National Cancer Institute, Bethesda, Maryland, USA.
Phillips
P C
PC
Packer
R J
RJ
Heideman
R L
RL
Berg
S L
SL
Adamson
P C
PC
Allen
J C
JC
Sallan
S E
SE
Jakacki
R I
RI
Lange
B J
BJ
Reaman
G H
GH
Horowitz
M E
ME
Poplack
D G
DG
Balis
F M
FM
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D001933:Brain Stem; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D019772:Topotecan
D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin