Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy

Abstract

Background: Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients.

Methods: Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m(2) and cisplatin 7.5 mg/m(2) (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C.

Results: No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2-5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0-6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days.

Conclusions: PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10% of a usual systemic dose.

Fig. 1

Pressurized intraperitoneal aerosol chemotherapy (PIPAC). The procedure is performed in an operating room equipped with laminar air-flow and is remote-controlled. In a first step, a normothermic capnoperitoneum is established with a pressure of 12 mmHg at body temperature. A chemotherapy solution (about 10 % of a normal systemic dose) is nebulized with a micropump into the tightly closed abdominal cavity, and maintained for 30 min. The toxic aerosol is then exhausted through a closed system and released into the external environment

Fig. 2

Macroscopical and histological response after PIPAC. Forty-five year male patient with diffuse peritoneal carcinomatosis (PCI = 16) from a signet-ring cells appendiceal cancer with inaugural small bowel obstruction. Macroscopy before (a1), after 1st (a2) and after 3rd PIPAC (a3) showing regression of small bowel PC nodules. Histology shows vital tumor before PIPAC (b1), inflammatory reaction with nodular sclerosis after 1st PIPAC (b2) and large areas of devitalized tumor after 3rd PIPAC (b3). Scale bar 100 µm

Fig. 3

73-year-old patient (patient 3) with therapy-resistant peritoneal carcinomatosis and malignant ascites of ovarian origin. Shown is the macroscopic (upper fig) and histological (HE staining, lower fig) appearance before (left column), after PIPAC (middle column) and at later stages of follow-up (right column). a, b Show partial and then complete macroscopic and microscopic tumor remission after repeated PIPAC. Scale bar 100 µm

Fig. 4

Local and systemic doxorubicin exposure during PIPAC. Local disposition is high with 1.70 ± 1.45 µg/g. In a fluorescence microscopy shows a nuclear presence of doxorubicin up to 500 µm depth. Red doxorubicin. Green picogreen nuclear counterstaining. Scale bar 100 µm. b Shows a typical pharmacokinetic profile in peripheral venous blood after PIPAC with doxorubicin 1.5 mg/m² body surface for 30 min at an intraabdominal pressure of 12 mmHg. Peak doxorubicin plasma concentrations were low (4.0–6.2 ng/ml). Line predicted profile. Dots experimental values