Abstract 5453: Drug transport in peritoneal tumors during intraperitoneal therapy – evaluation by computational model

Abstract

Abstract Clinical studies have established that the efficacy of intraperitoneal paclitaxel therapy is dependent on the tumor size, producing survival advantage in patients with small tumors (<1 cm diameter) but not in patients with larger tumors. This study was to investigate the mechanisms of this observation. We developed computational models to examine the effects of tumor size, drug binding (to extracellular proteins), tumor heterogeneity, and drug absorption on drug interstitial transport. The required model parameters were obtained from the literature. The models were used to simulate the drug penetration in small (0.3 cm) and larger (1 cm) tumors. Model performance was evaluated by comparing the simulated results to lab-generated experimental data using paclitaxel in mice bearing peritoneal metastases of ovarian tumors. The experiments measured drug concentration vs tumor penetration depth using autoradiography. The validated models were then used to generate penetration kinetic data for tumors of different sizes. The simulated penetration kinetics was subsequently compared to the pharmacodynamic data obtained from the literature (i.e., the C×T50 that produced 50% inhibition of tumor growth). The penetration kinetic models described the interstitial paclitaxel transport by both diffusion and convection, and the drug absorption into tumor vasculature by diffusion. The model-predicted concentration-penetration depth profiles were in general agreement with the experimental profiles (average deviation of 13.7%), indicating good model performance. The simulated drug C×T exceeded the C×T50 value at depth of up to 3 mm (from all sides of the outer tumor perimeter), indicating that for a spherical tumor of 1 cm diameter, 6.4% of the tumor (volume) would receive less than the therapeutic exposure, C×T50. Additionally, doubling the tumor diameter to 2 cm increased the subtherapeutic tumor volume fraction by nearly 5-times (34.3%). We have developed computational models to depict interstitial drug transport in peritoneal tumors during intraperitoneal therapy. These models provide quantitative measures of the effect of tumor size on local drug exposure for the tumor, and have the potential of predicting the tumor pharmacokinetics-pharmacodynamics for a given treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5453. doi:10.1158/1538-7445.AM2011-5453