Patients, who visited Tangdu Hospital during May 2021 through January 2023 and met the following inclusion criteria, were enrolled into this study.

Inclusion criteria: (1). Age was between 18 and 80 years old. (2). Malignant tumors with or without pleural effusion or ascites that was confirmed by histopathology. (3). Agreed to receive cisplatin treatment through either systemic chemotherapy (intravenous infusion), hyperthermic intrathoracic chemotherapy (HITHOC), or hyperthermic intraperitoneal chemotherapy (HIPEC) in the Department of Oncology, Tangdu Hospital. (4). Eastern Cooperative Oncology Group (ECOG) performance status score was between 0 and 2. (5). Outcome of laboratory tests on the routine blood work panel as well as liver and kidney function panels were normal. (6). Capable of following the study procedures and signed an informed Consent Form.

Exclusion criteria: (1). Hemoglobin < 80 g/L. (2). Anticipated survival time was < 2 months. (3). Severe infection or bleeding. (4). Pregnancy or lactation. (5). Allergic to cisplatin or other medications used in this study. (6). Declined or failed to follow the study protocol.

Patients were given systemic chemotherapy (SC), hyperthermic intrathoracic chemotherapy (HITHOC), or hyperthermic intraperitoneal chemotherapy (HIPEC) based on the type and location of the cancers as well as complication of malignant pleural effusion or ascites. This study was approved by The Medical Ethics Committee of Tangdu Hospital, Air Force Medical University of China (Approval No. 202103-29), and written informed consents were obtained from all participants.

To eliminate bias arises from different cisplatin dose, all patients received 40 mg cisplatin on the first day of the therapy, which was the first dose of total 75 mg/m2 body surface area (BSA) cisplatin given by three separate doses on day 1, 4 and 7. The first dose cisplatin (40 mg) was added and circulated in approximately 1000 mL hyperthermic saline for HITHOC and 3000 mL hyperthermic saline for HIPEC. All patients were routinely given intravenous hydration and diuretic therapy to protect kidney function, and antiemetic drugs if it was necessary.

For the systemic chemotherapy, on day 1, the first dose of 40 mg of cisplatin was dissolved in 250 mL of normal saline and administered through intravenous infusion for approximately 1 h.

For the HITHOC or HIPEC procedure, two puncture points at intercostal spaces (HITHOC) or lower abdomen, where accumulated pleural effusion or ascites were found by the bedside ultrasound, were selected, and marked. After routine disinfection of the skin and local infiltration anesthesia, two drainage tubes were placed using thoracic/abdominal puncture techniques and designated as inflow and outflow ports as shown in Fig. 1A for HITHOC and Fig. 1B for HIPEC. The catheterized body cavities were then connected to a hyperthermic perfusion and circulation machine (Model GDPR-2100T, The Xi’an Good Doctor Medical Science and Technology Co., Ltd, Xi’an, China). Before performing the hyperthermic chemotherapy, bloody and malignant pleural effusion or ascites were flushed out with normal saline till the solution was colorless by selecting a unique function of “Unidirectional Flush” button on the GDPR-2100T machine, a process we called as “effusion replacement” (Fig. 1C). A sealed and hyperthermic perfusion and circulation was then established between the body cavities and the GDPR-2100T machine with the following temperature settings: 43 °C for inflow and 41 ± 1 °C for outflow ports. After 5 min circulation of the hyperthermic normal saline, 40 mg cisplatin (kept on ice before being centrifuged and dissolved in 40 mL normal saline) was injected into the circulation through a designated injection port. The HITHOC or HIPEC procedure was performed for 60 min for each therapy. Afterwards, the GDPR-2100T machine was disconnected and the remined perfusate in the pleural or abdominal cavity was left for spontaneous absorption by instructing the patients to change body position every 20–30 min within 1 h of the procedure completion.

Images of bedside HTHOC and HIPEC procedure. A Inflow and Outflow catheters for HITHOC on the right-side chest. B Inflow and Outflow catheters for HIPEC. C Fluids collected from abdominal cavity using the default function of “one-way washing” in the GDPR-2100T machine, showing the color change before and after “effusion replacement” with saline

All samples were collected within 24 h after completion of the first dose cisplatin (40mg) administration. For the patients with systemic chemotherapy, 2 mL of venous blood was collected at 0.5, 1, 1.5, 2, 3, 5, 10, 16, and 24 h after completion of cisplatin administration via intravenous infusion. For the patients treated with HITHOC or HIPEC, 2 mL of venous blood as well as 2 mL perfusate were collected at 0.5, 1, 1.5, 2, 3, 5, 10, 16, and 24 h after completion of injecting into the perfusate. The blood and perfusate were placed in a heparin-treated tube, which was kept on ice, and centrifuged at 4 °C (3000 rpm for 10 min) within 30 min after collection. After centrifugation, the supernatants were harvested and stored in a freezer (−80 °C) and analyzed all together within 2 days.

After thawing the frozen samples at room temperature, cisplatin concentration was quantified by HPLC.

Briefly, 200 μL of perfusion sample or 500 µL plasma sample was mixed with equal amount of methanol by rotating for 5 min followed by centrifuging at 4 °C (12,000 rpm for 5 min). The supernatant was harvested and mixed with 100 μL of 1% sodium diethyldithiocarbamate (DDTC) followed by incubating at 40 °C for 2 h. After cooling to room temperature, the sample was mixed with 1 mL chloroform by rotating for 5 min, and then centrifuged at 25 °C (12,000 rpm for 5 min). The chloroform layer (800 μL) was removed and evaporated with nitrogen. The dried sample was reconstituted with 70 μL of acetonitrile and 10 μL of them was applied for HPLC analysis with the following settings: chromatographic column was Ultimate®XB-C18 (Welch, 250 mm × 4.6 mm, 5 µm); detection wavelength was 254 nm; mobile phase composition was methanol/water (77/23), isocratic elution; flow rate was 1.0 mL/min; column temperature was 25 °C.

The limit of detection and quantification of the HPLC analysis in this study was following: the limit of detection for cisplatin in saline was 0.08 µg/mL and the limit of quantification was 0.28 µg/mL; the limit of detection for cisplatin in plasma was 0.01 µg/mL and the limit of quantification was 0.03 µg/mL. The intra-day precision of cisplatin in saline at low (1 µg/mL), medium (8 µg/mL), and high (60 µg/mL) concentrations was 3.24%, 1.56%, and 1.74%, respectively, and the inter-day precision was 3.20%, 1.85%, and 3.41%, respectively. The intra-day precision of cisplatin in plasma at low (0.05 µg/mL), medium (0.5 µg/mL), and high (4 µg/mL) concentrations was 4.19%, 5.40%, and 3.33%, respectively, and the inter-day precision was 5.40%, 5.93%, and 1.73%, respectively.

All patients were closely monitored by collecting and recording vital signs (body temperature, respiratory rate, blood pressure, and heart rate) and clinical symptoms (fatigue, nausea, vomiting, anorexia, and diarrhea). In addition, physical examination, and laboratory tests (routine blood work panel, routine urinalysis, liver function panel, and kidney function panel) were also conducted according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). A side effect of ≥ Grade III was considered as serious adverse event.

DAS2.0 software was used to perform non-compartmental model analysis of pharmacokinetic parameters. The concentration–time curve of the drug was plotted and the AUC0–24h was calculated using the linear trapezoidal rule. SPSS 26.0 software was used for statistical analysis. Analysis of Variance was used to compare the age, body surface area (BSA), AUC0–24h, mean residence time over the 24 h (MRT0–24h), terminal elimination half-life (t1/2z), time to peak concentration (Tmax), apparent clearance (Clz/F), and peak concentration (Cmax) in the perfusate and plasma among the three groups. Pairwise comparisons between different groups were conducted using the LSD method and the Chi-square test was used to compare the gender, ECOG score, and incidence of adverse effect. The test level was defined as 0.05, and p < 0.05 was considered as significant.