Abstract 4477: Safety and efficacy of intracarotid administration of temozolomide in a rat model of intracerebral metastasis.

Abstract

Abstract Purpose: Temozolomide (Temodar; Merck) is an alkylating chemotherapeutic agent used to treat glioblastoma and other brain malignancies. After oral administration, the average brain interstitium to plasma area under the drug concentration-time curve ratio for temozolomide has been reported as approximately 0.2 in animal models and patients. We hypothesized that intra-arterial (IA) drug administration into the internal carotid artery would improve temozolomide delivery to brain tissue, with subsequent increased anti-tumor efficacy. Methods: Athymic nude rats received intracerebral implantation of LX-1 human small cell lung carcinoma cells as a model of chemosensitive brain metastasis, and were studied 10 days after cell implantation when tumors measured 10-30 mm3 in volume. To assess drug delivery, rats received 25 μCi 14C-temozolomide by oral, intravenous (IV), or IA/osmotic blood-brain barrier disruption (BBBD) route of administration (n = 5-7 per group). Radiolabeled drug in tumor and brain was measured 10 min after drug administration by quantitative autoradiography. To assess efficacy, rats received either no treatment or a single treatment with 20 mg/kg temozolomide (∼150 mg/m2) by oral, IV, or IA route of administration (n = 8 per group) and rats were followed for survival. Results: The ratio of drug delivery in tumor compared to normal left hemisphere was equivalent for the oral (2.51 ± 25) and IV (2.56 ± 0.87) routes (P = 0.90). After IA/BBBD, the tumor to brain ratio was 4.11 ± 1.12 and tumor-specific 14C-radioactivity was 85.4 ± 29.9 nCi/gram tissue, compared to 38.1 ± 19.9 nCi/gram tissue after IV administration (P = 0.019 by Student t-test). Median survival in untreated control rats was 17.5 days. A single temozolomide dose was effective at increasing survival when given by oral (median survival 25.5 days), IV (25.5 days), or IA (33 days) route of administration (overall P<0.0001 by the Log Rank test). Survival times in the oral and IV groups were significantly longer than control (P<0.001) but did not differ from each other, while survival time in the IA group was significantly longer than all other groups (P<0.01 for all comparisons). Temozolomide could not be given with BBBD in the efficacy study due to toxicities likely related to the diluent; there was no evidence of neurotoxicity in rats given IA temozolomide. Conclusions: Infusion of temozolomide into the internal carotid artery improved drug delivery and safely increased efficacy in a rat intracerebral tumor model. The improved efficacy suggests that a clinical trial of IA temozolomide is warranted in refractory glioblastoma. Citation Format: Leslie L. Muldoon, Michael A. Pagel, Edward A. Neuwelt. Safety and efficacy of intracarotid administration of temozolomide in a rat model of intracerebral metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2013-4477