Renal and hepatic toxicities after pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Abstract

Background: Both in animal models and in human patients, pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve local bioavailability of chemotherapy in peritoneal nodules, as compared with conventional peritoneal lavage. Pharmacokinetic studies show a low drug concentration in peripheral venous blood. However, hepatic and renal toxicities induced by delivering chemotherapeutic drugs into the abdomen as a pressurized aerosol have not yet been investigated.

Methods: Liver and renal function as well as toxicity parameters were monitored after eight PIPAC applications with doxorubicin (1.5 mg/m(2) body surface) and cisplatin (7.5 mg/m(2) body surface) in three end-stage patients suffering therapy-resistant peritoneal carcinomatosis. PIPAC was repeated at 4-week intervals (three times in two patients, twice in one patient). Peripheral venous blood was collected preoperatively and then daily until the 5th postoperative day, and sent to the hospital's clinical chemistry laboratory. Statistical analysis was performed by analysis of variance (ANOVA).

Results: Gamma-glutamyltransferase was significantly elevated (p < 0.05) in the early postoperative phase. Glutamic oxaloacetic transaminase [aspartate aminotransferase], glutamic pyruvic transaminase [alanine aminotransferase], and bilirubin levels were not influenced by the procedure. Quick-test remained normal. Serum creatinine levels were not altered.

Conclusions: Under the above conditions, PIPAC did not induce clinically relevant liver cytotoxicity. Liver metabolism and function were not altered. Renal function remained within the normal range. No cumulative toxicity was observed after repeated PIPAC. PIPAC appears to be associated with very limited hepatic and renal toxicity, which might be a significant advantage over other administration routes.

Fig. 1

Liver toxicity: discrete liver toxicity was observed after PIPAC, with increase of serum gamma-GT levels (ANOVA, p < 0.05). No liver cytolysis was detected, with GOT (ASAT) and GPT (ALAT) remaining within the normal range. ANOVA: repeated analysis of variance. Normal values: gamma-GT 9–36 U/l; GOT (ASAT) 5–31 U/l; GPT (ALAT) 0–34 U/l. Liver function: Liver metabolism was not significantly impaired after PIPAC application. Liver synthesis function, as monitored by Quick-test, remained within the normal range. ANOVA: repeated analysis of variance. Normal values: alkaline phosphatase 40–150 U/l; total bilirubin <1.2 mg/dl; Quick 70–120 %. Green shaded areas = normal range of measured parameters

Fig. 2

Renal function: serum creatinine levels did not increase significantly (ANOVA) after PIPAC application and remained within the normal range. ANOVA: repeated analysis of variance. Normal value: 0.5–0.9 mg/dl. Cumulative renal toxicity of repeated PIPAC with cisplatin 7.5 mg/m² body surface and doxorubicin 1.5 mg/m² body surface over 2–3 months of observation time. Preoperative serum creatinine value before first PIPAC (three patients), second (three patients), and third PIPAC (two patients). Creatinine levels remain within the normal range. Normal value: 0.5–0.9 mg/dl. Green shaded areas = normal range of measured parameters