PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy

Abstract

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m 2 . The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m 2 with an IPEC duration of 1-2 h and an 1-h duration is favored for doses between 100 and 120 mg/m 2 .

Clinical Efficacy and Safety of Tumor Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy for Ovarian Cancer

“…The median survival time was significantly longer in the experimental group (25 months) than in the observation group (22 months), and the 1-year survival rate was significantly higher in the experimental group (79.55%) than in the observation group (49.56%). This is similar to the results of the study by Xie et al [ 27 , 28 ] who used cisplatin for HIPEC, in which the prognosis and the survival rate of patients treated with HIPEC were better than those without HIPEC, indicating that the HIPEC features manageable safety in the treatment of ovarian cancer.…”

Hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of primary advanced and recurrent ovarian cancer: a systematic review and meta-analysis of randomized trials

“… 27 Five studies were excluded due to not being randomized 28 , 29 and due to researching outcomes unrelated to our analysis. 30 , 31 , 32 The eligible studies were conducted in South Korea, 22 Spain, 23 USA, 24 , 27 the Netherlands, 25 Greece 26 and three of them were multicenter. 22 , 24 , 25 Overall 737 patients were randomized across six trials; among these four studies (519 patients) 22 , 23 , 25 , 27 concerned the experimental use of HIPEC in primary ovarian cancer and two (218 patients) its investigational use in recurrent settings.…”

Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside

“…Chemotherapy combined with hyperthermia has been proposed to eliminate microscopic disease, thus improving the outcome of CRCPM patients [ 34 ], with the added benefit of a direct cytotoxic effect on tumor cells [ 35 ]. Indeed, some studies have clarified that hyperthermia can increase drug concentration in intra-abdominal tissues and the rate of systemic absorption [ 36 , 37 ]. Similarly to in vitro studies showing that hyperthermia increases apoptosis and tumor cell arrest in G1 and G2 phases [ 38 ], we have observed an increased rate of apoptotic cells.…”