The work is devoted to the study of the pathophysiological mechanisms of platinum toxicity during a chemotherapeutic procedure – hyperthermic (41–44°C) intraoperative intraperitoneal chemoperfusion (HIPEC) with cisplatin. HIPEC is a modern method of treatment of primary and secondary tumors of the peritoneum (peritoneal carcinomatosis (PC)). In the world, conducting cytoreductive operations together with HIPEC has become a recognized standard. The general toxic effects of platinum drugs are a logical continuation of their antitumor activity and are well studied by intravenous administration.
Fifteen patients of the surgical department of the Center for Reconstructive and Restorative Medicine (University Hospital) of ONMedU (mean age of patients (53 ± 16) years) who underwent HIPEC with PC were explored. Cisplatin perfusion was carried out at a temperature of 42°C at a dose of 50 mg/m2 of skin. In the dynamics conducted standard biochemical and general blood and urine tests. Additionally, the concentration of platinum and basic essential and toxic elements was measured in blood and urine. Patients' well-being was assessed by objective and subjective indicators. The results of clinical observations showed that HIPEC with PC is more effective than intravenous chemotherapy However, in the blood, an increase in platinum concentration is determined on average to 7.8 mg/dm3 (from 5.1 to 11.7 mg/dm3) during the HIPEC. Measuring the concentration of Zn and Cu in the blood on the eve of the operation allows predicting the patient's sensitivity to cisplatin therapy. It has been established that systemic exposure to cisplatin and elevated temperature is manifested by a decrease in liver and kidney function, a deterioration in the general well-being of patients (weakness, nausea, vomiting) during the first postoperative day. Trace element homeostasis in patients changes significantly a day after HIPEC. Systemic toxicity of cisplatin depends on the general condition, age, volume of cytoreductive surgery, the presence of intercurrent non-oncological diseases. The data obtained indicate the need for nephro-and hepatoprotective procedures before, during and after HIPEC with platinum preparations.
Experimental studies were carried out on adult laboratory rats of the Wistar line, which prior to the experiment were on a general diet with free access to water and food. A dose of 4 mg/kg (LD50 6.27 mg/kg) has been selected to simulate HIPEC with cisplatin. To take into account the effect of temperature, an experiment was carried out with perfusion of a solution of a Cisplatin of room temperature and elevated temperature. With intraperitoneal perfusion of cold (20°C) and hot (44°C) solutions of cisplatin in a total dose of 4 mg/kg for 60 minutes, an increase in the content of platinum in the blood, liver, kidneys, and spleen occurs. In the liver and kidneys, changes in biochemical parameters and mild morphological changes that depend on the temperature of the solution occur. The presence of platinum in the peritoneum, kidneys and liver indicates the possibility of the delayed effects of the general toxic effect of cisplatin on the secondary redistribution of accumulated platinum. With the introduction of cisplatin, there is a rapid increase in the total content of metallothioneins in the liver and kidneys. It is shown that an increase in temperature during HIPEC enhances not only the therapeutic, but also the toxic effect of cisplatin.
From the standpoint of modern pathophysiology, it has been proved that during chemotherapy with platinum compounds, it is necessary to carry out activities aimed at reducing the side effects of platinum and elevated temperature on the parenchymal organs (primarily the kidneys) during HIPEC.
