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Hypoxic Single-Pass Isolated Hepatic Perfusion of Hypotonic Cisplatin: Safety Study in the Pig

  • Translational Research and Biomarkers
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgment

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.

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Authors and Affiliations

  1. INSERM UMR 866, School of Medicine, University of Burgundy, Burgundy, France

    Pablo Ortega-Deballon MD, PhD, Hervé Tixier MD, Patrick Rat MD & Bruno Chauffert MD

  2. Department of Digestive and Thoracic Surgical Oncology, University Hospital, Dijon, France

    Pablo Ortega-Deballon MD, PhD, Olivier Facy MD & Patrick Rat MD

  3. Department of Anesthesiology, University Hospital, Dijon, France

    David Consolo MD & Guy Magnin MD

  4. Veterinary Clinic, Nuits Saint Georges, France

    Michel Simonet Vet Med D

  5. Department of Medical Oncology, GF Leclerc Regional Anticancer Center, Dijon, France

    Bruno Chauffert MD

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  1. Pablo Ortega-Deballon MD, PhD
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  2. Olivier Facy MD
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Correspondence to Pablo Ortega-Deballon MD, PhD.

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Ortega-Deballon, P., Facy, O., Consolo, D. et al. Hypoxic Single-Pass Isolated Hepatic Perfusion of Hypotonic Cisplatin: Safety Study in the Pig. Ann Surg Oncol 17, 898–906 (2010). https://doi.org/10.1245/s10434-009-0775-z

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  • DOI: https://doi.org/10.1245/s10434-009-0775-z

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