Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

Abstract

Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible.

Modelling drug transport during intraperitoneal chemotherapy

“…The obtained penetration depths were compared to values in literature and a close agreement was found (simulated penetration depth range of 0.36-0.49 mm; experimentally defined range of 0.41-0.56 [9]). Similar agreements were found when vascular normalization therapy was applied in our model and the resulting penetration depths were then compared to the recent experimental data in which IP tumours were pre-treated with several different VEGF (R) inhibitors to normalize the microvasculature before subjecting them to IP chemotherapy [52] (simulated penetration depth range 1.6-2.1 mm; experimentally defined 1.68 mm).…”

Historical perspective: Two decades of progress in treating metastatic colorectal cancer

“…The addition of bevacizumab to HIPEC has been shown in animal models to increase the intraperitoneal concentration of oxaliplatin but without an increase in efficacy. A retrospective study in humans found a higher postoperative complication rate, in particular, a greater chance of intra‐abdominal abscess, in patients who received HIPEC with bevacizumab compared with standard HIPEC . The combination of mitomycin C and hydrogen peroxide has been shown to increase the intraperitoneal concentration, whereas decreasing the serum concentration in a phase I trial, which could potentially lead to increased efficacy and decreased toxicity …”

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

“…Recently, works by Shah et al (2009) and Gremonprez et al (2015) showed similar improvement in drug penetration after vascular normalization therapy for IP chemotherapy. We attempted to mimic vascular normalization to test whether our model would be able to reproduce the results from these works.…”