Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols
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Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. / Löffler, Markus W; Schuster, Heiko; Zeck, Anne; Quilitz, Nicolas; Weinreich, Jürgen; Tolios, Alexander; Haen, Sebastian P; Horvath, Philipp; Löb, Stefan; Rammensee, Hans-Georg; Königsrainer, Ingmar; Königsrainer, Alfred; Beckert, Stefan.
In: ANN SURG ONCOL, Vol. 24, No. 6, 06.2017, p. 1650-1657.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols
AU - Löffler, Markus W
AU - Schuster, Heiko
AU - Zeck, Anne
AU - Quilitz, Nicolas
AU - Weinreich, Jürgen
AU - Tolios, Alexander
AU - Haen, Sebastian P
AU - Horvath, Philipp
AU - Löb, Stefan
AU - Rammensee, Hans-Georg
AU - Königsrainer, Ingmar
AU - Königsrainer, Alfred
AU - Beckert, Stefan
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Antineoplastic Agents/pharmacology
KW - Chemotherapy, Cancer, Regional Perfusion
KW - Clinical Protocols
KW - Combined Modality Therapy
KW - Cytoreduction Surgical Procedures
KW - Female
KW - Follow-Up Studies
KW - Humans
KW - Hyperthermia, Induced
KW - Male
KW - Middle Aged
KW - Organoplatinum Compounds/pharmacology
KW - Oxaliplatin
KW - Peritoneal Neoplasms/drug therapy
KW - Prognosis
KW - Research Design
U2 - 10.1245/s10434-017-5790-x
DO - 10.1245/s10434-017-5790-x
M3 - SCORING: Journal article
C2 - 28160138
VL - 24
SP - 1650
EP - 1657
JO - ANN SURG ONCOL
JF - ANN SURG ONCOL
SN - 1068-9265
IS - 6
ER -
