Abstract
Limited therapeutic success in the treatment of CNS neoplasia with chemotherapy is generally attributed to two factors: natural or acquired resistance to chemotherapy expressed by tumor cells, and delivery impediment related to the blood-brain barrier. The anatomic and physiological properties of the normal blood-brain barrier prevent passage of ionized water-soluble compounds with a molecular weight greater than 500 Daltons. Although complex, the blood-brain barrier basically functions at the level of the tight junctions of the cerebral vascular endothelial cells. Different approaches have been advocated to improve delivery across the blood-brain barrier. One such approach, transient osmotic permeabilization of the blood-brain barrier, is an invasive procedure offering the potential of global delivery. This strategy involves cerebral intravascular infusion of a hypertonic solution to produce, in a given cerebral distribution (carotid or vertebral), producing a transient increase in blood-brain barrier permeability. Two parameters are paramount in the ability to mediate a hyperosmolar modification of the barrier: the osmolality of the solution, and the infusion time. The procedure has been found to produce a marked increase (10- to 100-fold) in brain and cerebrospinal fluid concentrations of methotrexate and of other markers. Pre-clinical studies are underway to assess the use of this procedure to improve delivery of different molecules, including standard chemotherapy, monoclonal antibodies and gene therapy molecules. This approach has been standardized for clinical use. It has been extensively used in patients. Using a standard protocol of osmotic blood-brain barrier disruption to enhance chemotherapy delivery with three different chemotherapy regimens, more than 3000 procedures have been performed in more than 300 patients across the blood-brain barrier distribution consortium, an entity which includes six university centers coordinated by the Oregon Health Sciences University. The procedure has been found to be safe, with very limited toxicity. As part of this consortium, the Sherbrooke University center has been offering this treatment modality since November 1999. We have performed more than 500 procedures in 122 patients with various histologies (malignant gliomas, primary central nervous system lymphoma and metastasis) with low toxicity. In our view, the median survival rate of 138 weeks obtained with glioblastoma multiforme patients is promising; further research to improve these results is needed.
Published Version
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