EFFECTS OF DRUG EFFLUX ON CONVECTION-ENHANCED PACLITAXEL DELIVERY TO MALIGNANT GLIOMAS

Abstract

Abstract OBJECTIVE Convection-enhanced delivery (CED) is an approach in local brain tumor treatment. The spread of infusate in CED can be thought of as involving three phases: backflow, convection, and diffusion. Uncontrolled backflow may lead to efflux of the infusate outside the cranium. METHODS Based on an interim analysis of a clinical trial, the effects of drug efflux on convection were assessed. In a Phase I/II trial, eight patients with recurrent glioblastomas were treated with CED of paclitaxel. The first group of patients was treated with paclitaxel at a concentration of 0.5 mg/ml according to previously approved protocols. RESULTS These Group 1 patients developed severe skin necrosis due to an efflux of paclitaxel out of the cranium. The average volume of distribution (Vd) in these patients was 12.8 cm3. To prevent paclitaxel efflux, the burr hole was sealed with bone wax during and after CED in Groups 2 and 3. Surprisingly, patients in Group 2 showed a larger Vd (22.9 cm3 per catheter), exceeding the boundaries of the previous tumor, which led to subsequent neurological deficits. To allow a large Vd without severe side effects, the infusion volume was maintained, but the concentration of paclitaxel was reduced (paclitaxel concentration in Group 3, 0.25 mg/ml). CONCLUSION Vd remained high and no adverse effects were seen in Group 3. Sealing the burr hole during CED prevented efflux. The simple measure of sealing seems to increase Vd. These data demonstrate that uncontrolled backflow may have an important impact on CED and must be avoided.