Computational Evaluation of Improved HIPEC Drug Delivery Kinetics via Bevacizumab-Induced Vascular Normalization

Abstract

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy.

Keywords: bevacizumab; computational modeling; hyperthermic intrapertioneal chemotherapy (HIPEC); peritoneal metastasis; vascular normalization.

Figure 1

Schematic overview of the present study, investigating the effect of bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg on oxaliplatin concentration in peritoneal tumor nodules during HIPEC. CFD simulations were performed to solve for perfusate velocity (U), temperature (T), and oxaliplatin concentration (C), followed by detailed modeling of drug penetration incorporating the altered tumor biophysical properties resulting from bevacizumab treatment. The model incorporates the vascular normalization effect of bevacizumab, resulting in reduced microvessel density (MVD), hydraulic conductivity (${\mathrm{L}}_{\mathrm{p}}$), interstitial fluid pressure (IFP), and vascular permeability (${\mathrm{P}}_{\mathrm{c}}$), which collectively decrease drug washout. Oxaliplatin accumulation was assessed by calculating the area under the curve (AUC) of the concentration–time profile, and the effective penetration depth was determined using IC50 value for CMS4 colorectal cancer. This figure was created via BioRender.com.

Figure 2

Distribution of oxaliplatin on the surfaces of abdominal organs due to bulk fluid flow. The data were derived from (A) the first catheter setup, where inflow (indicated by a red circle) and outflow (indicated by a blue circle) occur at maximal transverse distance, and (B) the second catheter setup, where inflow and outflow occur at maximal longitudinal distance. The 3D panels present the velocity contours alongside the oxaliplatin concentration on the surfaces of abdominal organs at the end of HIPEC. The line graphs represent the surface-averaged oxaliplatin concentration throughout the 30 min HIPEC chemoperfusion.

Figure 3

Comparison of bevacizumab’s vascular normalization effects on oxaliplatin availability in tumor nodules, assessed by AUC and effective penetration depth values based on IC50 at specific temperatures using catheter setups one (A,C,E) and two (B,D,F). (A,B) AUC of oxaliplatin in tumor nodules at peritoneal and retroperitoneal surfaces. (C,D) Normalized effective penetration depth (${\widehat{d}}_{\mathrm{eff}}$) values for IPEC and (E,F) for HIPEC, with box plots showing interquartile penetration depth values.

Figure 4

Simulated effect of (A,B) collagen fiber density (4% and 32%) and (C) microvascular permeability (ranging from $0.2P_c$ to $5P_c$) on the availability of oxaliplatin in the tumor interstitium following bevacizumab treatment at two doses (0.5 and 5 mg/kg) and HIPEC. The control case is HIPEC alone. (A) Oxaliplatin concentration profile from the tumor surface to a depth of 3 mm. The region from 0 to 2 mm represents the tumor, while 2 to 3 mm corresponds to normal tissue. Solid lines represent tumors with high collagen fiber (CF) density, and dashed lines represent tumors with low collagen fiber density. The IC50 value corresponds to a temperature of 40.1 °C. (B) Fold increase in effective penetration depth compared to the control case. (C) Fold increase in the AUC of oxaliplatin compared to the control case at various permeability levels.

Figure 5

(A) Time course of oxaliplatin concentration in plasma during 30 min HIPEC at different doses (160 $\mathsf{\mu }$M with bevacizumab; 200 $\mathsf{\mu }$M and 300 $\mathsf{\mu }$M without bevacizumab). (B) Pharmacokinetic advantage (PA) ratio comparison between combination therapy (160 $\mathsf{\mu }$M oxaliplatin + bevacizumab) and HIPEC monotherapy (200 $\mathsf{\mu }$M and 300 $\mathsf{\mu }$M oxaliplatin). The combination of 160 $\mathsf{\mu }$M oxaliplatin-based HIPEC with bevacizumab (0.5 mg/kg and 5 mg/kg) is predicted to provide a greater pharmacokinetic advantage compared to higher doses of oxaliplatin in HIPEC alone.