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.
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Acknowledgements
This work was supported by the German Research Foundation - DFG (CRC 685 “Immunotherapy” project C09 to Alfred Königsrainer, and Stefan Löb, and by a research grant from RanD S.r.l, to Markus W. Löffler, and Alfred Königsrainer. We thank Miriam Petersen and Heinz Bussemas (Labmed Dortmund, Dr. Eberhard & Partner, Dortmund, Germany) for expert analysis of samples by AAS and helpful collaboration. We also thank Anita Hack for productive discussions and expert advice as well as RanD S.r.l for financial support. Ultimately, we express our gratitude to the patients who participated in this study, without whom this project would not have been possible.
Disclosure
Markus W. Löffler and Alfred Königsrainer received grant support by RanD S.r.l for this work, a manufacturer of devices and consumables for HIPEC. The other authors declare no conflicts of interest.
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Löffler, M.W., Schuster, H., Zeck, A. et al. Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. Ann Surg Oncol 24, 1650–1657 (2017). https://doi.org/10.1245/s10434-017-5790-x
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DOI: https://doi.org/10.1245/s10434-017-5790-x