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Ann Surg Oncol. 2017 Jun;24(6):1650-1657. doi: 10.1245/s10434-017-5790-x. Epub 2017 Feb 3.

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols.

Author information

1
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.
2
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.
3
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.
4
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
5
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
6
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
7
Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
8
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.
9
Internal Medicine, Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, 72076, Tübingen, Germany.
10
Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.

Abstract

BACKGROUND:

Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce.

METHODS:

In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo.

RESULTS:

Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10-15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min.

CONCLUSIONS:

The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.

PMID:
28160138
DOI:
10.1245/s10434-017-5790-x
[Indexed for MEDLINE]

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