Reprinted from: [Literature Interpretation] Pharmacokinetic Study of Paclitaxel Combined with Cisplatin Intraperitoneal Hyperthermic Perfusion Chemotherapy

[Abstract]: Intraperitoneal combined hyperthermic chemotherapy with CDDP and PTX results in drug concentrations within the peritoneal cavity that far exceed plasma drug levels. This pharmacokinetic profile enables the maximum antitumor effect on micrometastatic lesions in the peritoneal cavity while minimizing systemic toxicity. HIPEC can effectively reduce the risk of recurrence caused by micrometastatic disease, and elevated temperatures enhance the efficacy of chemotherapeutic agents. Post-CRS, intracavitary hyperthermic perfusion chemotherapy with CDDP and PTX is both safe and feasible, offering significant pharmacokinetic advantages.

Pharmacokinetic Study of Paclitaxel Combined with Cisplatin Intraperitoneal Hyperthermic Perfusion Chemotherapy
 

Research Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for peritoneal metastasis in epithelial ovarian cancer (EOC), and the commonly used regimen involves the combination of cisplatin (CDDP) and paclitaxel (PTX). This study aims to characterize the pharmacokinetic profile of cisplatin (CDDP) and paclitaxel (PTX) when administered concurrently during hyperthermic intraperitoneal therapy.

This study was approved by the Ethics Committee of Bergamo, Italy. From March 2012 to November 2013, we enrolled 13 patients with epithelial ovarian cancer peritoneal metastasis (EOCPC) who were expected to be sensitive to CDDP and PTX and received combined treatment with CRS and HIPEC. Additionally, there was 1 male patient, aged 43, with stage IV gastric adenocarcinoma and a peritoneal cancer index of 6, who was included solely for the IMS study. This patient met the same inclusion criteria as the other patients and also received CRS and HIPEC.

Research Methodology

Peritonectomy is performed only on the peritoneal surfaces involved by the cancer. At the conclusion of CRS, the completeness of tumor resection is assessed; the goal of CRS is to achieve a CC-0 or CC-1 status. Open intra-abdominal hyperthermic perfusion chemotherapy is carried out using the Belmont thermotherapy pump. Two probes are placed in the upper abdomen and pelvis, respectively, to measure intra-abdominal temperatures during HIPEC. The doses of CDDP and PTX are 100 and 175 mg/m², respectively, and both drugs are diluted separately in 500 ml of perfusion fluid. The target inflow temperature ranges from 43°C to 48°C, ensuring that the intra-abdominal temperature reaches 41–43°C. CDDP and PTX are continuously mixed for 90 minutes during HIPEC, and a cooling device is used to monitor and maintain the patient’s core body temperature below 38.5°C. After HIPEC, the perfusion fluid containing the chemotherapeutic agents is removed, and the abdominal cavity is rinsed thoroughly.

Research findings

1. Complication status

2. Pharmacokinetic Results

In the circulating perfusion, both CDDP and PTX achieved high concentrations in the perfusate, at 24.83 ± 10.38 µg/ml and 69.8 ± 14.3 µg/ml, respectively. The ratios of the peak drug concentration in the perfusate (Cmax) to the plasma Cmax were 14 for CDDP and 1196 for PTX. Throughout the perfusion process, the drug concentration in the perfusate remained above the cytotoxic threshold level (0.1 µmol/l) for PTX, whereas the plasma drug levels stayed below the toxicity threshold that could induce neutropenia. For CDDP, the plasma concentration also remained below the cytotoxic threshold (10 µg/ml); however, the drug concentration in the perfusate was very high during the first hour and gradually declined thereafter, yet it still exceeded the concentration required to inhibit the proliferation of 90% of tumor cells in vitro. At the end of the 90-minute perfusion, both CDDP and PTX retained relatively high drug concentrations in the peritoneal tissue, at 23.33 ± 7.97 µg/ml and 30.08 ± 18.31 µg/ml, respectively. The PTX concentration in the tissue was 545 times higher than the plasma Cmax and 362 times higher than the cytotoxic threshold; however, there was considerable interindividual variability (Figure 1B). The CDDP concentration in the tissue was 13 times higher than the plasma Cmax, equivalent to the perfusate Cmax, and 2.5 times higher than the cytotoxic threshold (Figure 1B).

3. Paclitaxel drug permeability results

Figure 2 shows the imaging analysis of a peritoneal tissue section from a patient. The drug, marked in light blue, is clearly visible only in the tissue regions that have been in contact with the intraperitoneal infusion fluid, and is undetectable in deeper layers. This method cannot determine the absolute depth of drug penetration; it merely highlights the presence of PTX ion signals against the background. In patients A and B, PTX penetrated the peritoneal tissue by 0.54 mm and 0.41 mm, respectively, while in patient C, the penetration depth was 0.56 mm.

Discussion

This study shows that the combination of intraperitoneal CDDP plus PTX with hyperthermia results in significantly higher drug levels in the peritoneal cavity compared to plasma concentrations. This pharmacokinetic profile allows the treatment to exert maximal antitumor effects on micrometastatic lesions within the peritoneal cavity while minimizing systemic toxicity. HIPEC can effectively reduce the risk of recurrence caused by micrometastatic disease, and elevated temperatures can enhance the efficacy of chemotherapeutic agents.

However, the number of patients in this study was limited. The high incidence of hematological toxicity observed appears to be attributable to the aggressive surgical procedures rather than to the chemotherapy drugs themselves, as drug concentrations in the blood generally remained below the toxicity threshold. The wide variability in CDDP doses across different studies was not associated with differences in complication rates, further suggesting that the complications were linked to the surgical procedures. In summary, despite the short treatment duration, intracavitary hyperthermic perfusion chemotherapy with CDDP and PTX following CRS is safe and feasible, and it offers significant pharmacokinetic advantages.

Proofreading: Ma Yuan, Tong Yingmu

Editor: Zhao Hongxia

Reviewed by: Zhao Wei

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