Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols.
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/m2body 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.
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.|Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany. markus.loeffler@uni-tuebingen.de.
Markus W
MW
Löffler
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
Heiko
H
Schuster
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
Anne
A
Zeck
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
Nicolas
N
Quilitz
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
Jürgen
J
Weinreich
Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
Alexander
A
Tolios
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.|Internal Medicine, Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, 72076, Tübingen, Germany.
Sebastian P
SP
Haen
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
Philipp
P
Horvath
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.|Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
Stefan
S
Löb
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.
Hans-Georg
HG
Rammensee
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
Ingmar
I
Königsrainer
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany.
Alfred
A
Königsrainer
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
Stefan
S
Beckert
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D010478:Chemotherapy, Cancer, Regional Perfusion; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D012107:Research Design
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin