Mathematical modeling of intraperitoneal drug delivery: simulation of drug distribution in a single tumor nodule

Abstract

The intraperitoneal (IP) administration of chemotherapy is an alternative treatment for peritoneal carcinomatosis, allowing for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration. Nevertheless, drug penetration depths are still limited to a few millimeters. It is thus necessary to better understand the limiting factors behind this poor penetration in order to improve IP chemotherapy delivery. By developing a threedimensional computational fluid dynamics (CFD) model for drug penetration in a tumor nodule, we investigated the impact of a number of key parameters on the drug transport and penetration depth during IP chemotherapy. Overall, smaller tumors showed better penetration than larger ones, which could be attributed to the lower IFP in smaller tumors. Furthermore, the model demonstrated large improvements in penetration depth by subjecting the tumor nodules to vascular normalization therapy, and illustrated the importance of the drug that is used for therapy. Explicitly modeling the necrotic core had a limited effect on the simulated penetration. Similarly, the penetration depth remained virtually constant when the Darcy permeability of the tissue changed. Our findings illustrate that the developed parametrical CFD model is a powerful tool providing more insight in the drug transport and penetration during IP chemotherapy.

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

“…Drug penetration into solid tumours is a complex mass transport process that involves multiple parameters not only related to the used cytotoxic agent, but also to the tumour tissue properties and even the therapeutic setup [17]. Besides the drug characteristics and pharmacokinetic variables, their penetration depth is determined by factors such as tumour nodule size, cell density, extracellular matrix, vascularity, interstitial fluid pressure and binding [18,19]. Various mathematical models have been proposed which can provide unique insights into the different transport barriers that occur during intraperitoneal chemotherapy [17,[19][20][21].…”

Simulation analysis for tumor radiotherapy based on three‐component mathematical models

“…In other papers, mathematical model was combined with the technique of medical image processing for evaluation and prediction of tumor multidisciplinary treatment . Although there has not been a comprehensive mathematical model for clinical application until now, some positive improvements have been achieved in serials of fields . It is assured that the tumor mathematical models will reach an excellent level with the rapid development of computers in the near future…”

Modelling drug transport during intraperitoneal chemotherapy

“…Given the strong influence of the high IFP on the drug penetration both in IV and IP chemotherapy models [51,57], models incorporating this convective interstitial fluid (IF) flow might be more suited to determine which transport processes are limiting in different cases. In the context of IV chemotherapy, there have been some reports of the use of spatially varying parameters that were determined on a pixel to pixel basis from imaging data [58,59].…”

“…Based on the groundwork done by Baxter and Jain on the drug transport in solid tumours [48], our group created a parametric single tumour nodule model to study the influence of several different parameters on the penetration depth of various drugs (cisplatin, paclitaxel) [51]. Six different geometries were created to mimic the wide variety in shape and size existing among peritoneal tumour nodules (r min = 1 mm, r max = 4 mm).…”