High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors.


METHODS
Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded.


RESULTS
There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34).


CONCLUSIONS
The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.
Yule
S M
SM
The Royal Hospital for Sick Children, Glasgow, United Kingdom.
Foreman
N K
NK
Mitchell
C
C
Gouldon
N
N
May
P
P
McDowell
H P
HP
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011379:Prognosis; D015996:Survival Rate
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide