Simulation of mass transport during intraperitoneal chemotherapy : a parametrical model of single tumor nodules

OBJECTIVES Patients with peritoneal carcinomatosis suffer from a widespread metastatic growth of tumor nodules in the peritoneal cavity. Although Intraperitoneal (IP) chemotherapy allows for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration, actual application of IP chemotherapy is limited due to poor drug penetration (typically a few millimeters) in the tumor tissue. It is thus essential to better understand the drug transport during IP chemotherapy. METHODS A 3D computational fluid dynamics model of a tumor nodule with necrotic core was created in Comsol® (COMSOL, Inc., Burlington, USA) describing the drug transport occurring during IP chemotherapy, including convective/diffusive/reactive drug transport in two tumor geometries (a spherical baseline model with radius rsphere,large=1 cm/rsphere,small=2 mm and rnecrotic,large=5 mm/rnecrotic,large=1 mm). To assess the efficiency of drug administration, a penetration depth (PD) was defined as the percentage of the total radius in which the drug concentration resulted to be over 6.6E-3 mol/m3. These baseline models were subsequently adapted to evaluate the effect of therapy-related parameters (different drugs, vascular properties etc.) on drug penetration. RESULTS A large differences in PD (PD; % of total radius) were found in the baseline cases for the two different scales (PDsphere,large= 4.04%; PDsphere,small=20.82%).Vascular normalization therapy yielded different outcomes (ΔPDsphere,large+2.95%; ΔPDsphere,small +17.95%). Both cases showed less penetration when paclitaxel was used as opposed to cisplatin. This effect was more pronounced in the smaller geometry (ΔPDsphere,large =-1.91%; ΔPDsphere,small =-10.25%). CONCLUSIONS The model is able to predict drug penetration depth for different sets of IP chemotherapy-related parameters, which may lead to optimization of drug transport during IP chemotherapy

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

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

Mass transport during intraperitoneal chemotherapy in tumor nodule: a computational model

The intraperitoneal (IP) administration of chemotherapy is an alternative treatment to conventional chemotherapy for patients with peritoneal carcinomatosis. During IP therapy, the peritoneal membrane and embedded tumor nodules are brought into direct contact with the cytotoxic solution, aiming for a higher intratumor drug concentration. Currently, there is no widespread use of this promising therapy because of the limited drug penetration depth in the tumor tissue. To study the influence of different parameters governing the drug transport during IP chemotherapy, a 3D computational fluid dynamics (CFD) model was created to represent a single tumor nodule (isotropic porous medium) and its simplified vascular network. A parameter study was performed in which the drug diffusivity, tissue permeability and mass fraction of chemo at the tumor edge were varied. The model is able to simulate the response of both local and systemic drug concentration profiles to changes in different drug and tissue properties during IP chemotherapy. This approach leads to more insight in the therapeutic relevance of the different parameters

Modeling the mass transport in a tumor nodule during intraperitoneal chemotherapy

INTRODUCTION The intraperitoneal (IP) administration of chemotherapy is an alternative treatment to conventional chemotherapy for patients with peritoneal carcinomatosis. During IP therapy, the peritoneal membrane and embedded tumor nodules are brought into direct contact with the cytotoxic solution, aiming for a higher intratumor concentration. Currently, there is no widespread use of this promising therapy because of the limited drug penetration depth in the tumor tissue. Therefore, we present a mass transport model of a tumor nodule to analyze and optimize the drug penetration during IP therapy. METHODS To study the influence of different parameters governing the drug transport during IP chemotherapy, a 3D computational fluid dynamics (CFD) model was created representing a single tumor nodule (isotropic porous medium) and its simplified vascular network (Fig. 1). A parameter study was performed in which the drug diffusivity (9•10-9, 9•10-10 and 9•10-11 m2/s), tissue permeability (10-14 and 10-13 m2) and mass fraction of chemo at the tumor edge (10% and 20%) were varied. RESULTS The results of the parameter study showed that increasing the mass fraction (Fig. 2) leads to a large increase in the systemic concentration as measured at the vascular outlet (3•10-4 and 6•10-4 kmol/m3 after 1500 s for a mass fraction of 10% and 20%, respectively). However, a higher systemic concentration should ideally be avoided as it results in a higher systemic toxicity. Furthermore, the concentration along the black line in Fig. 1 (Fig. 2) shows only a very limited increase in penetration depth. Increasing the drug diffusivity resulted in an increase in both local and systemic concentrations Increasing the tissue permeability resulted in higher systemic concentrations of chemo and a minor increase in penetration depth. The response to permeability changes was found to be strongly non-linear and will be the subject of future work as this parameter is likely to be significantly different for healthy and tumor tissue. CONCLUSION The model is able to simulate the response of both local and systemic drug concentration profiles to changes in different drug and tissue properties during IP chemotherapy. Future work will focus on extending the model to more realistic configurations and validation