BACKGROUND. Topotecan is a topoisomerase I inhibitor that has good pen
etration across the blood-brain barrier and significant antitumor acti
vity against human brain tumor xenografts. In a Phase I trial in child
ren with refractory cancer, topotecan was well tolerated when administ
ered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m(2)
and the dose-limiting toxicity was myelosuppression. This Phase II st
udy of topotecan was performed to assess the activity of topotecan aga
inst childhood brain tumors. METHODS, Forty-five children with either
a previously treated primary brain tumor that was refractory to standa
rd therapy, or an untreated brain stem glioma or glioblastoma multifor
me, received topotecan administered as a 24-hour intravenous infusion
every 21 days. The initial dose was 5.5 mg/m(2) with escalation to 7.5
mg/m(2) on the second and subsequent doses in patients who did not ex
perience dose-limiting toxicity. RESULTS, There were no complete or pa
rtial responses in the patients with high grade glioma (n = 9), medull
oblastoma (n = 9), or brain stem glioma (n = 14). One of 2 patients wi
th a low grade glioma had a partial response lasting more than 17 mont
hs; 3 patients with a brain stem glioma had stable disease for 12 to 2
8 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 pa
tient with an optic glioma had stable disease for 41 weeks and 22 week
s, respectively. Dose escalation from 5.5 mg/m(2) to 7.5 mg/m(2) was w
ell tolerated in the first 11 patients enrolled on this study who had
not received prior craniospinal radiation therapy. The starting dose w
as subsequently increased to 7.5 mg/m(2) for patients without prior cr
aniospinal radiation. CONCLUSIONS, Topotecan administered as a 24-hour
infusion every 21 days is inactive in high grade gliomas, medulloblas
tomas, and brain stem tumors. (C) 1996 American Cancer Society.