Evaluating the Effect of Micropump© Position, Internal Pressure and Doxorubicin Dosage on Efficacy of Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC) in an Ex Vivo Model

Background/Aim: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel clinical approach to the treatment of peritoneal carcinomatosis. A well-established, not anatomic ex vivo PIPAC model was used to investigate the influence of changes in internal pressure, distance of the Micropump (c) (MIP) to the distributing surface and the drug concentration on the penetration depth of doxorubicin in the target tissue. Materials and Methods: Doxorubicin was aerosolized in an ex vivo PIPAC model using a hermetic container system mimicking the abdominal cavity. Fresh postmortem swine peritoneum was cut into proportional samples. Tissue specimens were spatially placed at 4 different spots within the box: P-1, on the distributing surface of the box, directly opposite to MIP; P-2, on the side wall of the box; P-3, on the ceiling of the box; P-4, on the distributing surface with a partial cover. Impact of changes in the following parameters were analyzed and compared with clinically established values (CEVs) at our center: pressure (CEV=12 mmHg), distance of the MIP from the distributing surface (CEV=8 cm) and doxorubicin concentration (CEV=3 mg/50 ml). In-tissue doxorubicin penetration depth was measured using fluorescence microscopy on frozen thin sections. Results: Tissue positioning in the box had a significant impact on drug penetration after PIPAC with CEV. Under CEV conditions, the highest drug penetration depth was observed in the tissue placed on the distributing surface directly opposite to the MIP (P-1: 351 mu m, P-2: 77 mu m, P-3: 66 mu m, P-4: 34 mu m). A closer positioning of the MIP lead to a significantly higher mean depth penetration of doxorubicin in the P1 in contrast to other samples in which a reduced drug penetration was observed (1 cm vs. 8 cm distance from MIP to the distributing surface, P-1 at 1 cm: 469 mu m vs. P-1 at 8 cm: 351 mu m, p< 0.0001; P-2 at 1 cm: 25 mu m vs. P-2 at 8 cm: 77 mu m, p< 0.0001; P-3 at 1 cm: 21 mu m vs. P-3 at 8 cm: 66 mu m, p< 0.001; P-4 at 1 cm: 13 mu m vs. P-4 at 8 cm: 39 mu m, p=0.021). Higher doxorubicin concentrations led to a highly significant increase of drug penetration in P1 (1 cm vs. 8 cm, p< 0.0001), but only a little significant increase in other samples. An increase of internal pressure did not show a significant increase in penetration depth of doxorubicin. Conclusion: Our ex vivo data suggest that a higher pressure does not increase the penetration deepness of doxorubicin. Higher drug dosage and a closer positioning of the MIP toward the target lead to a higher penetration of doxorubicin within the samples. A more homogeneous penetration within all targets cannot be achieved by changing drug concentration, position of the nozzle or pressure increase.