 Recently, there has been renewed interest in systemic chemotherapeutic options in these patients. Incorporation of systemic therapies into standard treatment algorithms has been limited as many agents have not been shown to adequately penetrate the blood brain barrier. High-dose methotrexate HD-MTX, however, is unique in that it does penetrate the blood brain barrier. In fact, evidence suggests that it may target areas of poor cerebrospinal fluid CSF flow, penetrate bulk disease, and provide treatment to systemic disease burden. Methotrexate is a drug known to have activity against breast cancer and has been used in combination with cyclophosphamide and 5-fluorouracil as part of a standard adjuvant treatment regimen. 