A 3D CFD model of the interstitial fluid pressure and drug distribution in heterogeneous tumor nodules during intraperitoneal chemotherapy

Abstract

Although intraperitoneal chemotherapy (IPC) has evolved into an established treatment modality for patients with peritoneal metastasis (PM), drug penetration into tumor nodules remains limited. Drug transport during IPC is a complex process that depends on a large number of different parameters (e.g. drug, dose, tumor size, tumor pressure, tumor vascularization). Mathematical modeling allows for a better understanding of the processes that underlie drug transport and the relative importance of the parameters influencing it. In this work, we expanded our previously developed 3D Computational Fluid Dynamics (CFD) model of the drug mass transport in idealized tumor nodules during IP chemotherapy to include realistic tumor geometries and spatially varying vascular properties. DCE-MRI imaging made it possible to distinguish between tumorous tissues, healthy surrounding tissues and necrotic zones based on differences in the vascular properties. We found that the resulting interstitial pressure profiles within tumors were highly dependent on the irregular geometries and different zones. The tumor-specific cisplatin penetration depths ranged from 0.32 mm to 0.50 mm. In this work, we found that the positive relationship between tumor size and IFP does not longer hold in the presence of zones with different vascular properties, while we did observe a positive relationship between the percentage of viable tumor tissue and the maximal IFP. Our findings highlight the importance of incorporating both the irregular tumor geometries and different vascular zones in CFD models of IPC.

Simulating drug penetration during hyperthermic intraperitoneal chemotherapy

“…Furthermore, the necrotic region could be heterogeneous which could alter the dynamics inside the tumor. A recent computational study investigated pressure distributions in tumor nodule models, based on MRI delineations (Steuperaert et al., 2019 ). The interstitial pressure profiles differed from the interstitial pressure profiles found in the simplified geometries used in this study.…”

A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases

“…Due to the complexity and myriad factors governing chemotherapeutic drug transport and eventual penetration into tumor tissue, mathematical modeling has evolved into a reliable methodology to understand chemotherapy delivery, thereby providing a framework to quantitatively examine the relative importance of competing factors and to guide clinical use [ 44 , 54 , 55 ]. Applying a previously developed model of tumor tissue perfusion, here we describe important parameters driving chemotherapy concentration achieved at the tumor site and response to therapy, with a clinical cohort of patients treated with standard 5-FU-based chemotherapy frontline regimens such as FOLFOX.…”

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review

“…An important limitation of IPDD is the very limited penetration distance in tumor tissue, which is a few millimeters at most, depending on drug, treatment, and tissue properties [26]. This is explained by the elevated pressure characterizing the biophysical TME, and by the very low hydraulic conductivity of tumor tissue, which is typically in the range of 10 −15 -10 −14 m 2 /pa•s in colorectal PM as measured using modified Ussing chambers.…”