Abstract
Backgroundpressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model.Methodslaparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging.ResultsPIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 μm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 μm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 106 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals.Conclusionswe propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.
Highlights
Selected patients with peritoneal metastases (PM) benefit from cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) [1, 2]
Influence of physical parameters on aerosol formation A maximal upstream injection pressure of 20 bar and a fixed flow rate of 0.5 mL/s were associated with a D(v,0.5) of 47 ± 2 μm (Fig. 2a)
When the maximal upstream injection pressure was further decreased to 5 bar, D(v,0.5) remained 51 ± 2 μm (p = 0.127)
Summary
Selected patients with peritoneal metastases (PM) benefit from cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) [1, 2]. Many patients present with irresectable disease, which has a dismal prognosis. Survival in patients with irresectable PM from colon cancer is 15 months, from gastric cancer 4 months, and from pancreatic cancer only 6 weeks [3,4,5]. Systemic chemotherapy is relatively inefficient in PM due to poor vascularity of peritoneal tumor nodules [6, 7]. Chemotherapy is aerosolized in the abdominal cavity using a high-pressure injector and a nebulizer (Capnopen®). This method allows aerosolized chemotherapy to interact directly with tumor tissue. The elevated intra-abdominal pressure may enhance tumor tissue drug penetration [9]
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