Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modificationto enhance delivery, using propofol for general anesthesia, in a rat model

OBJECTIVE: Osmotic blood-brain barrier disruption (BBBD) increases brain an d brain tumor delivery of chemotherapeutic agents, which results in increas ed efficacy against brain tumors. We previously noted that the use of propo fol anesthesia for BBBD increased the percentage of successful disruptions, resulting in delivery of increased amounts of chemotherapeutic drugs. This study evaluated the neurotoxicity of combination chemotherapeutic administ ration with this enhanced delivery system. METHODS: Osmotic BBBD was performed in Long-Evans rats with isoflurane (n = 11) or propofol (n = 90) anesthesia. Carboplatin and/or melphalan, methotr exate, or etoposide phosphate was administered intraarterially (IA) after B BBD using propofol anesthesia. Animals were assessed for systemic and neuro logical toxicity. Animals were killed for neuropathological evaluation 30 d ays after treatment. RESULTS: With propofol or isoflurane anesthesia, BBBD alone produced no sys temic or neurological toxicity. Single agents were relatively non-neurotoxi c when administered IA with BBBD, as were the combinations of carboplatin o r melphalan with methotrexate. Etoposide phosphate in combination with any other agent was observed to be highly neurotoxic if both agents were admini stered after BBBD. Administration of etoposide phosphate before BBBD comple tely eliminated neurotoxicity, although acute pulmonary toxicity occurred w ith any combination of etoposide phosphate and methotrexate, regardless of the timing of administration. CONCLUSION: Neurotoxicity was significantly increased for etoposide phospha te combination groups, particularly when both drugs were administered IA af ter BBBD. This increase in neurotoxicity may reflect on increase in drug de livery observed with propofol anesthesia. The neurotoxicity of IA administe red etoposide phosphate with BBBD and propofol anesthesia could be minimize d by administering etoposide phosphate IA before BBBD and administering car boplatin or melphalan IA after BBBD.