A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.
The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.
Chintagumpala
Murali M
MM
Baylor College of Medicine, 6621 Fannin, CC 1510.00, Houston, TX, USA. mxchinta@txccc.org
Friedman
Henry S
HS
Stewart
Clinton F
CF
Kepner
James
J
McLendon
Roger E
RE
Modrich
Paul L
PL
McCluggage
Charles
C
Burger
Peter
P
Holmes
Emi
E
Thompson
Stephen
S
Rutka
James
J
Michalski
Jeff
J
Woo
Shiao
S
Blaney
Susan M
SM
Kun
Larry E
LE
Horowitz
Marc E
ME
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D018365:Neoplasm, Residual; D009687:Nuclear Proteins / Q000378:metabolism; D011344:Procarbazine / Q000008:administration & dosage; D016019:Survival Analysis; D019772:Topotecan / Q000008:administration & dosage
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011344:Procarbazine; D019772:Topotecan; D019883:Alkyl and Aryl Transferases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein