Hypoxic Single-Pass Isolated Hepatic Perfusion of Hypotonic Cisplatin: Safety Study in the Pig
- 110 Downloads
Isolated hepatic perfusion (IHP) of chemotherapy has been proposed to deliver high doses of drug while avoiding systemic toxicity. Hypotonic cisplatin has a high in vitro activity on human colon cancer cells. We studied the safety of a 30-min hypoxic single-pass IHP with hypotonic cisplatin.
A preliminary in vitro assay was performed to compare the cytotoxicity of cisplatin and oxaliplatin, in either a normotonic or hypotonic medium. Cisplatin in hypotonic medium was then chosen for the in vivo IHP. Eleven pigs underwent 30 min of IHP with 0, 50, 75, or 100 mg/L of cisplatin in a hypotonic solution under total vascular exclusion of the liver. Clinical and biological parameters were recorded for 30 days, and liver histology was performed at necropsy. The cytotoxic activity of the effluent against resistant human colon cancer cells was tested in vitro.
No hepatic failure was recorded after IHP with cisplatin, but limited foci of necrosis were found at necropsy in animals receiving 75 or 100 mg/L of cisplatin. No clinical, biological, macroscopic, or microscopic toxicity was observed after IHP with 50 mg/L of hypotonic cisplatin. The liver effluent showed high in vitro cytotoxic activity against colon cancer cells.
A hypoxic single-pass isolated liver perfusion with hypotonic cisplatin is feasible and safe. Effluent from the liver is highly cytotoxic on cancer cells. A clinical study with 50 mg/L of hypotonic cisplatin is warranted in patients with unresectable liver metastases from colon cancer.
KeywordsOxaliplatin Human Colon Cancer Cell Isolate Limb Perfusion Platinum Concentration Hypotonic Medium
Supported in part by grants from the French National League against Cancer (Committees of Côte d’Or, Saône et Loire and Nièvre) and from the Scientific Committee of the School of Medicine of Dijon (University of Burgundy, France). We thank Jean-Luc Beltramo for measuring platinum concentrations, Laurence Duvillard for determining osmolarity, Pierre-Emmanuel Puig for the in vitro assays, Philippe Pointaire and Jean-Mathieu Ricard for their help during the experiments in the pigs, and Philip Bastable for revising the article in manuscript.
- 7.Vahrmeijer AL, van Dierendonck JH, Keizer HJ, et al. Increased local cytostatic drug exposure by isolated hepatic perfusion: a phase I clinical and pharmacologic evaluation of treatment with high dose melphalan in patients with colorectal cancer confined to the liver. Br J Cancer. 2000;82:1539–46.CrossRefPubMedGoogle Scholar
- 8.van Iersel LB, Verlaan MR, Vahrmeijer AL, et al. Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation. Eur J Surg Oncol. 2007;33:874–81.PubMedGoogle Scholar
- 33.Heijnen BHM, Straatsburg ICH, Gouma DJ, van Gulik TM. Decrease in core liver temperature with 10°C by in situ hypothermic perfusion under total hepatic vascular exclusion reduces liver ischemia and reperfusion injury during partial hepatectomy in pigs. Surgery. 2003;134:806–17.CrossRefPubMedGoogle Scholar