Radiosensitizing effects of temozolomide observed in vivo only in a subset of O6-methylguanine-DNA methyltransferase methylated glioblastoma multiforme xenografts.
OBJECTIVE
Concurrent temozolomide (TMZ) and radiation therapy (RT) followed by adjuvant TMZ is standard treatment for patients with glioblastoma multiforme (GBM), although the relative contribution of concurrent versus adjuvant TMZ is unknown. In this study, the efficacy of TMZ/RT was tested with a panel of 20 primary GBM xenografts.


METHODS
Mice with intracranial xenografts were treated with TMZ, RT, TMZ/RT, or placebo. Survival ratio for a given treatment/line was defined as the ratio of median survival for treatment vs. placebo.


RESULTS
The median survival ratio was significantly higher for O6-methylguanine-DNA methyltransferase (MGMT) methylated tumors versus unmethylated tumors following treatment with TMZ (median survival ratio, 3.6 vs. 1.5, respectively; p = 0.008) or TMZ/RT (5.7 vs. 2.3, respectively; p = 0.001) but not RT alone (1.7 vs. 1.6; p = 0.47). In an analysis of variance, MGMT methylation status and p53 mutation status were significantly associated with treatment response. When we analyzed the additional survival benefit conferred specifically by combined therapy, only a subset (5 of 11) of MGMT methylated tumors derived substantial additional benefit from combined therapy, while none of the MGMT unmethylated tumors did. Consistent with a true radiosensitizing effect of TMZ, sequential treatment in which RT (week 1) was followed by TMZ (week 2) proved significantly less effective than TMZ followed by RT or concurrent TMZ/RT (survival ratios of 4.0, 9.6 and 12.9, respectively; p < 0.0001).


CONCLUSIONS
Concurrent treatment with TMZ and RT provides significant survival benefit only in a subset of MGMT methylated tumors and provides superior antitumor activity relative to sequential administration of RT and TMZ.
Carlson
Brett L
BL
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Grogan
Patrick T
PT
Mladek
Ann C
AC
Schroeder
Mark A
MA
Kitange
Gaspar J
GJ
Decker
Paul A
PA
Giannini
Caterina
C
Wu
Wenting
W
Ballman
Karla A
KA
James
C David
CD
Sarkaria
Jann N
JN
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D018773:Genes, erbB-1 / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D008745:Methylation; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D016019:Survival Analysis; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D011838:Radiation-Sensitizing Agents; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000077204:Temozolomide
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