P13.07 Phase II study of systemic high-dose methotrexate and intrathecal liposomal cytarabine for treatment of breast cancer with leptomeningeal metastases

Abstract

BACKGROUND: Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebro‐spinal fluid (CSF) involvement occurs the prognosis is poor with median survival between 3‐7 months. There are limited treatment options available, but none offer significant survival benefit. Methotrexate, given systemically at high doses (HD‐MTX 3.5‐8 gm/m2), achieves cytotoxic concentrations in the CSF and has been shown to prolong survival in patients with LC. Intrathecal (IT) liposomal cytarabine has been shown to increase time to neurologic progression in patients with breast cancer and LC. The combination of these two agents in LC has not been studied extensively but our preliminary data indicated that this approach is feasible and may offer therapeutic benefit. METHODS: A single arm, phase II study was designed to include patients with LC from breast cancer (planned accrual, N=22). Patients had to have MRI imaging and/or CSF confirmation of LC and were allowed to have parenchymal (brain) metastatic disease, but controlled systemic disease. Eligible patients who gave informed consent underwent re‐staging and CSF flow study. Patients were treated with systemic HD‐MTX (8 gm/m2) every two weeks and with intrathecal liposomal cytarabine at 50 mg per injection every two weeks (on HD‐MTX off weeks). Response was assessed clinically, and with MRI of the brain and spine, and CSF cytology. Adverse events were monitored and recorded. RESULTS: The study was closed 3.5 years after the first patient was enrolled due to low accrual. Three patients have been enrolled and treated (13.6% of planned accrual). All patients were female with median age of 50 (range 46‐60). The median Karnofsky Performance Status (KPS) at the time of enrollment was 70%. Mean interval between the diagnosis and initiation of therapy was 1.2 months. Median progression free survival (PFS) was 1.4 months (range 1.3‐8.2) and overall survival (OS) was 8.2 months (range 5.5 ‐ 11.3). The median number of HD‐MTX and IT liposomal cytarabine doses administered per patient was 3 for each drug. The regimen was well tolerated, with no significant hematologic toxicity. Transient grade 3 transaminitis was noted in all three patients. CONCLUSIONS: Breast cancer with leptomeningeal metastases presents a therapeutic challenge. Radiotherapy and standard chemotherapy provide limited benefit. Maximizing cytotoxic concentrations of chemotherapeutics in the CSF is desirable and may offer a therapeutic advantage. Preliminary results from this prospective single‐institution study demonstrate the feasibility of this approach on a limited number of patients with encouraging survival data. Our accrual limitations highlight the challenges of conducting studies in «orphan diseases» such as LC and underscore the importance of multi‐center collaboration.