Implanted system for intraventricular drug infusion in central nervous system tumors

We have developed a totally implanted drug delivery system capable of maintaining constant cerebrospinal fluid (CSF) drug levels through continuous intraventricular infusion in outpatients. This system was used to infuse methotrexate (MTX) intraventricularly in seven patients with incurable CNS malignancies. One patient with meningeal diffuse histiocytic lymphoma, five patients with grade III--IV astrocytomas, and one patient with melanoma metastatic to the brain were treated with this system for 4--40+ weeks. The system consists of an Infusaid pump (Metal Bellows Corp, Sharon, MA), implanted subcutaneously in the infraclavicular fossa, which delivers a drug-containing solution at a set rate (3--5 mg/day) through a subcutaneous silastic catheter to a Rickham ventriculostomy reservoir and into a lateral ventricle. System placement and maintenance were readily tolerated. Constant MTX infusion at rates of 0.5--10 mg/day generated corresponding constant CSF drug levels in the range of 2--30 microM. Simultaneous serum MTX levels were undetectable (less than 0.01 microM), indicative of a 200- to 3000-fold selective regional concentration advantage for this approach. CNS toxic effects included transient meningism and fever (four patients), transverse myelitis (one), and the development of a diffuse hypodensity of the white matter on computerized tomographic scan which was not associated with any neurologic deficit (two). The usual systemic toxic effects (myelosuppression and mucositis) of MTX were not seen. The patient with meningeal lymphoma has had a complete remission of meningeal disease continuing past 10 months. Computerized tomography showed that three of the five high-grade astrocytomas had 25% size reductions in tumors lasting 2--6 months. This system may provide a means for improved treatment of meningeal tumor although its role in the treatment of intraparenchymal brain tumors is less clear. Of greater consequence, however, is the demonstrated ability of this system to maintain a controlled CSF drug level which should prove useful in many areas of therapeutic research.