LOCAL-DELIVERY OF CHEMOTHERAPY PROLONGS SURVIVAL IN EXPERIMENTAL BRAIN METASTASES FROM BREAST-CARCINOMA

OBJECTIVE: Despite improved systemic control of metastatic breast canc er, the incidence of brain metastases from breast carcinoma continues to rise, in part because most systemically administered agents have po or central nervous system penetration. Therefore, as a method of optim izing drug delivery into the central nervous system, we studied the sa fety and efficacy of chemotherapy delivered locally via biodegradable polymers in a mouse model of breast carcinoma metastases to the brain. METHODS: The chemotherapeutic agents carmustine (BCNU), carboplatin, and camptothecin were incorporated into controlled release polymers an d tested individually against intracranial challenges of EMT-6 breast tumor in BALB/c female mice. For each drug, four groups were tested: G roup 1, empty polymer (no drug); Group 2, external beam radiotherapy ( XRT) alone; Group 3, local chemotherapy from biodegradable polymer alo ne; and Group 4, local chemotherapy and XRT together. Polymers were im planted 5 days after intracranial tumor inoculation; XRT was administe red on Days 7 through 9 (300 cGy/d). RESULTS: BCNU polymer alone (n = 10; median survival time, >200 d; P < 0.0001) and BCNU and XRT togethe r (n = 10; median survival time, 41 d; P = 0.02) significantly improve d survival in mice with intracranial EMT-6 breast cancer in comparison with control animals (n = 20; median survival time, 17 d). Carboplati n and camptothecin, either with or without XRT, and XRT alone did not have any significant effect on survival. CONCLUSION: Local delivery of BCNU with biodegradable polymers can significantly prolong survival i n a murine model of intracranial metastatic breast cancer. Surgical re section and placement of BCNU polymers into the resection cavity may d ecrease the incidence of local recurrence of breast cancer metastases with minimal morbidity.