Experimental pharmacokinetics evaluation of chemotherapy delivery by PIPAC for colon cancer: first evidence for efficacy

Abstract

Background: Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy devoted to unresectable peritoneal metastasis (PM). The first results obtained with PIPAC in preclinical models of colon cancer are presented here. Methods: In vitro, PIPAC (normotherm oxaliplatin at 0.028 mg/mL for 10 min at 1.6 bars) and HIPEC (hyperthermic oxaliplatin at 0.14 mg/mL for 30 min) were compared using the apoptosis and proliferation assay on two colon cancer cell lines (LS 174 and CT 26); ex vivo tumours from an orthotopic mouse model of PM and non-tumour peritoneum from a patient treated according to the two modalities were assessed, investigating the percentage of penetration of oxaliplatin in the tumour and oxaliplatin concentration below the peritoneum. In vivo, a mouse model of colon (CT 26) PM was used to create a PIPAC model (same modalities) for the comparison of IV oxaliplatin (at 5 mg/mL). Results: In vitro, the rate of apoptotic and proliferative cells as well as the level of oxaliplatin penetration in tumour nodes was higher in PIPAC groups with less systemic passage through the peritoneum. In vivo, in the colon PM mouse model, the peritoneal cancer index (PCI) was decreased to the same level using

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

“…In the swine model, systemic oxaliplatin concentrations were significantly lower during PIPAC application time (in the presence of an intraabdominal pressure of 12-15 mmHg) than in the laparoscopic HIPEC group (p < 0.05) [30]. In vitro, the rate of apoptotic and proliferative cells as well as the level of oxaliplatin penetration in tumor nodes was higher in PIPAC groups with less systemic passage through the peritoneum [86]. In vivo, in a mouse model of colorectal PM, systemic passage was lower in the PIPAC group [86].…”

“…In vitro, the rate of apoptotic and proliferative cells as well as the level of oxaliplatin penetration in tumor nodes was higher in PIPAC groups with less systemic passage through the peritoneum [86]. In vivo, in a mouse model of colorectal PM, systemic passage was lower in the PIPAC group [86].…”

“…Several studies have evaluated drug uptake into the target tissue after PIPAC, and some of them have compared PIPAC with other drug delivery techniques such as HIPEC and/or laparoscopic HIPEC. Therapeutic substances investigated include methylene blue [28,76], DNA [77], RNA [29,78], cisplatin [79][80][81][82], doxorubicin [75,[83][84][85], oxaliplatin [82,[86][87][88] and liposomal doxorubicin [89,90].…”

“…All pharmacological data published so far show a superior therapeutic ratio (tissue concentration/dose applied) of PIPAC vs. systemic administration [29], of PIPAC vs. intraperitoneal liquid chemotherapy [29], of PIPAC vs. HIPEC [86] and of PIPAC vs. laparoscopic HIPEC [30]. In the swine model, tissue delivery of oxaliplatin was compared between laparoscopic HIPEC (with 12-15 mmHg pressure), PIPAC (20% of HIPEC dose applied) and electrostatic precipitation PIPAC (ePIPAC, same dose as PIPAC): overall concentrations in the peritoneum were not different among the three groups, documenting an improvement of the therapeutic index (target tissue dose/dose applied) of PIPAC vs. HIPEC by a factor of five.…”

Pharmacology of chemotherapy treatments for peritoneal metastases: optimizing and augmenting HIPEC

“…PIPAC has generated great interest because it can be used repeatedly and because the access of an aerosol to intraperitoneal spaces will greatly exceed that of a liquid solution. Pocard and colleagues have presented the favorable pharmacokinetics that predicts clinical utility for PIPAC [3]. Morris and colleagues are showing us how to eliminate the mucinous component of mucinous peritoneal metastases [4].…”