High intra-abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis

Abstract

Objective: To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans.

Summary background data: To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats.

Experimental design: BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs.

Results: The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated.

Conclusions: Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of cisplatin in rats bearing advanced peritoneal carcinomatosis. In preclinical conditions, the tolerance of sustained IAP was manageable in ventilated pigs.

Figures

FIGURE 1. Platinum concentration in peritoneal tumors and diaphragm after IV, IP, or IAP cisplatin treatment. Rats with 21-day-old carcinomatosis (5 per group) were treated with cisplatin by intravenous (IV) or conventional intraperitoneal (IP) injection, or by a 1-hour intraperitoneal infusion with a sustained 22 mm Hg intra-abdominal pressure (IAP). The cisplatin dose was 1 mg/rat (3 mg/kg) for the IV administration (dark bars) and 7.5 mg/rat (22.5 mg/kg; 50 mg/L in 150 mL of isotonic saline) for the IAP treatment (diagonal bars). For the conventional IP treatments, cisplatin was given either to obtain the same concentration (50 mg/L in 20 mL; 1 mg/rat; 3 mg/kg; horizontal bars) or the same total dose (7.5 mg/rat; 22.5 mg/kg; 375 mg/L in 20 mL; clear bars) as for the IAP treatment. Each point is the average of 5 determinations and presented as a mean value; bars = SD. *Statistically significant difference between the IAP group and both the conventionally treated IP groups, either at the same concentration or at the same total dose of cisplatin (P < 0.05, Kruskal-Wallis test).

FIGURE 2. Platinum concentration in blood and extraperitoneal organs after IV, IP, or IAP cisplatin treatment. The experimental conditions are the same as those in Figure 1. No significant difference was seen in each organ with the various treatments (Kruskal-Wallis test).

FIGURE 3. Distribution of platinum into peritoneal tumor nodules after conventional IP or IAP cisplatin treatment. Rats with 21-day-old carcinomatosis (4 per group) were treated with cisplatin through a conventional intraperitoneal injection (IP) or an intraperitoneal infusion with increased intra-abdominal pressure (22 mm Hg for 1 hour; IAP). Local platinum concentration was measured along the radii of peritoneal tumor nodules by the PIXE method. The platinum distribution in 400 × 800 ìm2 analyzed areas was plotted from the periphery to the tumor center. In conventionally treated IP groups, the cisplatin concentration in the peritoneal liquid was either 250 mg/L in 20 mL isotonic saline (5 mg/rat; 15 mg/kg; •), or 1875 mg/L in 20 mL isotonic saline (37.5 mg/rat; 112.5 mg/kg; ▴) to compare groups exposed to the same concentration or the same total dose of cisplatin. Cisplatin concentration was 250 mg/L in 150 mL isotonic saline (37.5 mg/rat; 112.5 mg/kg) for the IAP-treated group (▪). Each point is the mean of 4 determinations ± SD. A significant difference among the 3 IP treatments was detected (P = 0.0125, Kruskal-Wallis test). The Mann-Whitney test indicated that the difference between both of the upper curves was only significant between a depth of 1400 and 1800 ìm (P = 0.0421).

FIGURE 4. Animal survival according to treatment. Rats with 14-day-old carcinomatosis (8 per group) were treated with cisplatin by the intravenous (•) (IV) or the intraperitoneal (IP) route with (IAP, ▪) or without increased intra-abdominal pressure (IP conventional; □). Control animals (○) were left untreated. Cisplatin was given at the maximum tolerated dose for IV administration (1 mg/rat; 3 mg/kg). For conventional IP chemotherapy, rats received 20 mL of the 50 mg/L cisplatin solution (1 mg/rat; 3 mg/kg) as a bolus into the peritoneal cavity. For IP chemotherapy with IAP, cisplatin was administered in 150 mL of isotonic saline solution, 50 mg/L (7.5 mg/rat; 22.5 mg/kg), and continuously infused for 1 hour to maintain a constant 22 mm Hg intra-abdominal pressure. In both IP-treated groups, the peritoneal cavity was emptied and washed with drug-free saline 1 hour after starting the treatment. Animals were kept until spontaneous death or sacrifice at 120 days. *Significantly prolonged survival in the group treated with IP cisplatin with IAP compared with the conventionally treated IP group (log-rank test, P = 0.0157).

FIGURE 5. Relationship between the intra-abdominal pressure and the infused volume. Intra-abdominal pressure (approximately 40 mm Hg) was rapidly generated through the intraperitoneal infusion of isotonic saline and then maintained constant for 120 minutes in anesthetized and ventilated animals. Each point is the average of measurements from 7 animals and presented as a mean value; bars = SD.