Hyperthermic Pressurized IntraPeritoneal Aerosol Chemotherapy (hPIPAC) – A pharmacological study ex vivo

Abstract

Peritoneal metastasis is relatively resistant to systemic chemotherapy and has a poor prognosis. The therapy remains palliative with the aim of prolonging life and preserving its quality. There is a need to develop improved new therapeutic approaches. An example for a new drug delivery system that addresses systemically the known limitations of intraperitoneal chemotherapy for treating peritoneal metastasis has been pressurized intraperitoneal aerosol chemotherapy (PIPAC). Preclinical experiments, patient cohorts, and controlled clinical studies suggest that PIPAC might be a significant step forward to improve the efficacy of intraperitoneal chemotherapy. Prior scientific research showed that the addition of hyperthermia to chemotherapy can increase its cytotoxic efficacy. Our research hypothesized that the addition of hyperthermia would further improve the pharmacological properties of PIPAC. In this study, we used a validated prototype for establishing and maintaining tissue temperature within a range of 41 – 43 °C in an ex-vivo organ model. The specific aim was to determine whether hyperthermia can increase drug tissue concentration as well as the depth of tissue penetration, as compared to normothermic PIPAC. The drugs cisplatin and doxorubicin were aerosolized into a test group (hyperthermia) and a control group (normothermia) of fresh inverted bovine urinary bladders (IBUB) obtained from the slaughterhouse. The CO2 filled IBUB has an equivalent volume to the expanded human abdominal cavity, and then its inner surface is overlaid with peritoneum. Altogether, 108 biopsies were taken at standardized locations and prepared for further analysis. Pharmacological measures were performed in a GLP-certified laboratory. There, doxorubicin concentration was measured by high-performance liquid chromatography and cisplatin concentration was quantified by atomic absorption spectroscopy. The depth of tissue penetration of doxorubicin was determined using a fluorescence microscope in our laboratory. All analyses were blinded. Surprisingly, results showed no significant pharmacological advantage of hPIPAC over PIPAC. Neither the tissue concentration of doxorubicin nor cisplatin was enhanced by therapeutic hyperthermia. Doxorubicin did not penetrate the tissue more deeply under hyperthermic conditions. A possible explanation for this negative result is a significant liquid uptake by the target tissue during the warming phase preceding the application of chemotherapy. We confirmed this liquid uptake by histology. As a result, we hypothesize that interstitial fluid pressure increases within the peritoneum and the retroperitoneal tissue, which is an obstacle to drug tissue uptake. The interpretation of these results should be done cautiously. First, we only evaluated the pharmacological effects and not the biological impact of hyperthermia on the target tissue. Second, we used ex-vivo, post-mortem tissue. Finally, although the model used simulated heat loss, there was no blood circulation. Further studies are needed before it is possible to conclude that hPIPAC has no pharmacological or biological advantage over PIPAC. These experiments should include measurements in a living animal model. Possibly, other drug delivery technologies might overcome current limitations and allow physicians to exploit the full potential of hyperthermia in combination with PIPAC.