Role of convective flow in carmustine delivery to a brain tumor.

PURPOSE: This paper presents a three-dimensional patient-specific simulation of carmustine delivery to brain tumor. The simulation investigates several crucial factors, particularly the role of convective flow, affecting drug delivery efficacy. METHODS: The simulation utilizes a complete three-dimensional tissue geometry constructed from magnetic resonance images (MRI) of a brain tumor patient in whom commercially available Gliadel wafers were implanted for sustained delivery of carmustine following excision of the tumor. This method permits an estimation of the convective flow field (in the irregularly shaped anatomical region) which can be used for prediction of drug penetration into the domain of interest, i.e. remnant tumor. A finite volume method is utilized to perform all simulations. RESULTS: Drug exposure exceeds its threshold therapeutic concentration (approximately 15 microM) but for only a limited time (i.e. less than a week) and only in the immediately adjacent tissue (i.e. less than 2 mm). A quasi-steady transport process is established within 1 day following treatment, in which the drug is eliminated rapidly by transcapillary exchange, while its penetration into the tumor is mainly by diffusion. Convection appears to be crucial in influencing the drug distribution in the tumor: the remnant tumor near the ventricle is, by one to two orders of magnitude, less exposed to the drug than is the distal remnant tumor. CONCLUSIONS: Carmustine penetration from Gliadel wafers implanted in brain is limited by rapid elimination via transcapillary exchange. Therefore, it could be useful to consider other therapeutic agents such as paclitaxel. In addition, local convective flow within the cavity appears to be a crucial factor in distributing the drug so that the tumor domain near the ventricle is prone to minimal drug exposure. Thus, complete removal of the tumor from this region is of particular concern.

Chemotherapeutic drug transport to brain tumor.

Implantation of polymeric wafers to deliver a chemotherapeutic drug is the most popular strategy against a brain tumor, but the understanding on local drug transport to influence the treatment efficacy is often overlooked. In this work, we employ a computational fluid dynamics simulation to study the suitability of four chemotherapeutic agents from a transport perspective, which specifically are carmustine, paclitaxel, 5-fluorouracil (5-FU), and methotrexate (MTX). The study is based on the diffusion/reaction/convection model, in which Darcy's law is used to account the convective contribution of the interstitial fluid. A realistic three-dimensional (3D) tissue geometry is extracted from magnetic resonance images (MRI) of a brain tumor. Our analysis explains how the distribution of the drug in the brain tumor is sensitively coupled to its physico-chemical properties. For the postulated conditions, only paclitaxel exhibits minimal degradation within the cavity: its effective cavity concentration is at least two times higher than those of others. It also exhibits the best penetration of the remnant tumor, so that the tumor is exposed to higher effective concentration up to two orders of magnitude as compared to others. It is also found that tumor receives uneven distribution of drug concentration, in which, even paclitaxel fails to provide adequate penetration on that part of the cavity surface nearest to the ventricles. In addition, we consider antiangiogenic treatment, which has been postulated to be a way to avoid drug loss from the treatment region by convection. It is shown that convection is of only marginal importance and that renormalization has little effect.