Combination of Intracranial Temozolomide With Intracranial Carmustine Improves Survival When Compared With Either Treatment Alone in a Rodent Glioma Model

BACKGROUND: Local delivery of temozolomide (TMZ) through polymers is superior to oral administration in a rodent glioma model. OBJECTIVE: We hypothesized that the observed clinical synergy of orally administered TMZ and carmustine (BCNU) wafers would translate into even greater effectiveness with the local delivery of BCNU and TMZ and the addition of radiotherapy in animal models of malignant glioma. METHODS: TMZ and BCNU were incorporated into biodegradable polymers that were implanted in F344 rats bearing established intracranial tumors. We used 2 different rodent glioma models: the 9L gliosarcoma and the F98 glioma. RESULTS: In the 9L rodent glioma model, groups treated with the combination of local TMZ, local BCNU, and radiation therapy (XRT) had 75% long-term survivors (defined as animals alive 120 days after tumor implantation), which was superior to the combination of local TMZ and local BCNU (median survival, 95 days; long-term survival, 25%) and the combination of oral TMZ, local BCNU, and XRT (median survival, 62 days; long-term survival, 12.5%). To simulate the effect of this treatment in chemoresistant gliomas, a second rodent model was used with the F98 glioma, a cell line relatively resistant to alkylating agents. F98 glioma cells express high levels of alkyltransferase, an enzyme that deactivates alkylating agents and is the major mechanism of resistance of gliomas. The triple therapy showed a significant improvement in survival when compared with controls (P = .0004), BCNU (P = .0043), oral TMZ (P = .0026), local TMZ (P = .0105), and the combinations of either BCNU and XRT (P = .0378) or oral TMZ and BCNU (P = .0154). CONCLUSION: The survival of tumor-bearing animals in the 9L and F98 glioma models was improved with the local delivery of BCNU and TMZ combined with XRT when compared with either treatment alone or oral TMZ, local BCNU, and XRT.