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Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors.
Background: Neoplastic meningitis is a devastating complication of extra-CNS malignancies and primary brain tumors with few available treatments and none of outstanding efficacy. Trastuzumab, a large molecule monoclonal antibody directed against the HER-2/neu receptor (overexpressed on some breast cancers, glioblastomas, and medulloblastomas), has negligible access to the CSF after intravenous administration. Intra-CSF administration could circumvent this barrier. Methods: Sixteen patients with neoplastic meningitis (11 GBM, 4 breast cancer, 1 medulloblastoma) and progressive neurologic deterioration were treated with intra-CSF trastuzumab (20-60 mg per dose, either weekly or every other week) for four treatments. Age ranged from 35 to 74 (median 51) years; KPS ranged from 60 to 90 (median 70). Patients who were neurologically and radiographically stable or improved after four treatments were continued on every other week therapy until neurologic progression. CSF cytology, neurologic status, and KPS were assessed at each treatment. MRI scanning of sites of previously demonstrated leptomeningeal tumor was performed after four treatments and then at 8 week intervals. HER-2/neu status of the primary tumors was also evaluated. Results: Two of the four patients with breast cancer (both HER-2/neu+) are responding clinically and cytologically 4 and 14 weeks after initiating treatment. The patient with medulloblastoma (also HER-2/neu+) continues to respond clinically and cytologically after 6 weeks. Seven of 11 patients with GBM have responded (two cytologically, two radiographically, all seven clinically), with response durations ranging from 4 to 12+ weeks. HER-2/neu status is being assessed. There were no adverse events related to the trastuzumab. Conclusions: Trastuzumab can be safely administered into the CSF in patients with solid tumor neoplastic meningitis. Sustained clinical and cytologic responses may occur in patients with breast cancer and primary brain tumors. HER-2/neu status may predict response. Further study to establish the biologically optimum dose and efficacy of this agent may be warranted.