Combination intraventricular therapy with thiotepa and cytarabine in meningeal carcinomatosis due to breast cancer: in vitro evidence for supra-additive cytotoxicity.

Metastatic spread of tumors to the meninges is a frequent complication of many malignancies and is difficult to treat. We describe the case of a patient who developed carcinomatous involvement of the meninges from a breast adenocarcinoma. Despite intrathecal treatment with conventional and experimental agents, the patient's cerebrospinal fluid (CSF) was not cleared of malignant cells until thiotepa and cytarabine were given in combination. This clinical observation led us to assess the in vitro activity of the combination of thiotepa and cytarabine in clonogenic cell survival assays. The human breast adenocarcinoma cell line MCF-7WT and its doxorubicin-resistant variant MCF-7ADR were exposed to thiotepa and cytarabine either singly or in combination. We have found that the combination of the two drugs resulted in more than additive cytotoxicity than would have been predicted from the cytotoxicity of either drug given alone. We discuss the implications of these findings on the clinical management of patients with carcinomatous spread to the meninges.