A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma.
OBJECTIVE
Survival rates for paediatric diffuse intrinsic brainstem glioma (DIBSG) are dismal. Metronomic dosing of temozolomide (TMZ) combined with standard radiotherapy may improve survival by increasing the therapeutic index and anti-angiogenic effect of TMZ. This study aimed to evaluate the safety and efficacy of this regimen in paediatric DIBSG patients.


METHODS
Children aged 18 years or younger with newly diagnosed DIBSG were treated with standard radiotherapy and concomitant metronomic TMZ at 85 mg/m(2)/day for 6 weeks, followed by metronomic TMZ monotherapy at the same dose. Treatment was continued until tumour progression or unacceptable toxicity occurred. Primary endpoints included overall survival and toxicities. For patients who consented, plasma and urine samples were collected at diagnosis, post-induction and prior to each course of maintenance therapy for the quantification of angiogenesis markers.


RESULTS
Fifteen eligible patients were enrolled, with a median age of 6.4 years. The most common toxicities were myelosuppression, most notably prolonged lymphopaenia and thrombocytopaenia. The only dose-limiting toxicity was thrombocytopaenia. Intratumoural haemorrhage was confirmed in one patient. Median time to progression was 5.13 months (95% CI = 6.4, 10.8) and median overall survival (OS) was 9.8 months (95% CI = 6.4, 10.8). Six-months OS was 80% ± 10.3%, with a 1-year OS of 20% ± 10.3%. Serum levels of both VEGF and endoglin tended to decrease during the first two cycles of therapy.


CONCLUSIONS
Chemoradiotherapy with metronomic dosing of TMZ showed similar toxicity to previous TMZ regimens, and does not appear to improve survival in paediatric DIBSG.
Sharp
Julia R
JR
Department of Paediatrics Division of Haematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.
Bouffet
Eric
E
Stempak
Diana
D
Gammon
Janet
J
Stephens
Derek
D
Johnston
Donna L
DL
Eisenstat
David
D
Hukin
Juliette
J
Samson
Yvan
Y
Bartels
Ute
U
Tabori
Uri
U
Huang
Annie
A
Baruchel
Sylvain
S
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D002170:Canada; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D010865:Pilot Projects; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000209:etiology; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide