(20c) Three-Dimensional Simulation of Carmustine Delivery to a Patient-Specific Brain Tumor

In 2006, an estimated 19,000 new cases of brain tumors and 13,000 deaths will be reported in the United States alone [1]. The most common strategies against brain tumors include surgical removal, chemotherapy, and radiotherapy. Despite the fact that controlled-release implanted chemotherapeutic drug delivery, i.e. Gliadel® wafers, has shown a distinct increase in patient survivability, neither the transport mechanism nor the optimum dosage forms have been investigated in detail. First-principle transport mechanisms have been studied extensively in recent years as the basis of drug delivery simulation in tissue; however, limitations on obtaining an exact geometric simulation of specific tumors have led to incomplete results for specific tissues, e.g. brain. Furthermore, the size, degree of malignancy, and location of the brain tumor are crucial parameters for optimization of the drug delivery efficacy. Recent advances in patient-specific imaging techniques, e.g. magnetic resonance images (MRI) and computed tomography (CT), allow the extraction of exact brain tissue geometry as well as the tumor size and location. Here, the simulation utilizes a complete three-dimensional geometry constructed from MRI of a brain tumor patient to highlight several crucial factors to improve the drug delivery efficacy.

We discuss two potential delivery strategies. These are Gliadel^® wafer implantation and convection-enhanced delivery (CED). Gliadel^® wafers release the carmustine via polymer degradation in two phases [2]. An initial burst at Day 1, which releases about 70% of the total drug, is followed by a constant release through Day 5. This characteristic release helps maintain exposure of the tumor to carmustine for up to five days. Penetration of carmustine released from Gliadel^® wafers is limited by its elimination due to transcapillary exchange. Drug transport is quasi-steady and is largely by convection. CED is able to increase drug penetration by enhancing interstitial fluid convection, e.g. the drug convection rate can be enhanced ten-fold by an infusate flow rate of 0.15 ml/hr.

[1] A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal, M.J. Thun, Cancer Statistics, 2006, CA: A Cancer Journal for Clinicians 56 (2006) 106-130.

[2] A.B. Fleming and W.M. Saltzman. Pharmacokinetics of the carmustine implant. Clinical Pharmacokinetics 41 (2002) 403-419.