Tao Zhang1·Wei Mu2·Cheng-gong Liao1·Yan Hou1·Jie Song1·Wen Hu1·Yun Wang1·Dongxu Chen1·Yu Chen1·Linna Liu2·Lili Liu1

Received:15 May 2024/Accepted:11 October 2024

©The Author(s)2024

Abstract

Objective To compare the pharmacokinetics and adverse effects of cisplatin administered via intravenous infusion for sys-temic chemotherapy(SC)versus injection into the perfusate during hyperthermic intrathoracic chemotherapy(HITHOC)or hyperthermic intraperitoneal chemotherapy(HIPEC).

Methods Total 60 patients who received SC,HITHOC,or HIPEC in the Department of Oncology,Tangdu Hospital,were

enrolled into this study.After administering same dose of cisplatin(40 mg)via either intravenous infusion(SC group)or injection into the perfusate during the HITHOC or HIPEC procedure,concentration of cisplatin in the plasma as well as in the hyperthermic perfusate at various time points was quantified by HPLC analysis.The area under the plasma or perfusate concentration–time curve over the last 24h dosing interval(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 were compared.

Results In the perfusate,the AUC0–24h(64.32±27.12µg/mL·h)and Cmax(21.62±5.88µg/mL)were significantly higher

in the HITHOC group compared to that in the HIPEC group(31.68±13.29µg/mL·h and 16.96±5.54µg/mL,respec-tively,p≤0.01).In contrast,MRT0–∞,t1/2z,and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group(p<0.01).In the plasma,average AUC0–24h and Cmax of the HITHOC group were 2.57±0.55µg/mL·h and 0.26±0.08µg/mL,respectively,which were significantly lower than that of systemic chemotherapy(SC)group(3.26±0.56µg/mL·h and 0.69±0.14µg/mL,respectively,p<0.01),but no difference compared to that of HIPEC group(3.02±0.52µg/mL·h and 0.40±0.15µg/mL,respectively,p>0.05).In contrast,MRT0-24h and Tmax in the plasma of HITHOC group were significantly longer compared to that of SC group(p<0.05),but no significant difference compared to that of HIPEC group(p>0.05,.Absolute bioavailability ofcisplatin in the thoracic(HITHOC group)and abdominal(HIPEC group)cavities was 20 and 10 times higher than that in the blood administered intravenously(SC group),respectively.There was no significant difference in the incidence of adverse events among the three groups(p<0.05).

Conclusion The current study demonstrated that,in the perfusate,AUC0–24h and Cmax of cisplatin was significantly higher

in the group of HITHOC compared to that of HIPEC,and that,in the plasma,AUC0–24h and Cmax of cisplatin was lower in the group of HITHOC compared to that of HIPEC or SC group.This study provided pharmacokinetic evidence to further support the concept that topical application of chemotherapeutic drug through minimally invasive HITHOC or HIPEC may enhance local exposure compared to systemic chemotherapy for the patients with malignant pleural effusion or ascites.

Keywords Hyperthermic intrathoracic chemotherapy(HITHOC)·Hyperthermic intraperitoneal chemotherapy(HIPEC)·Systemic chemotherapy·Cisplatin·Pharmacokinetics

Tao Zhang and Wei Mu contributed equally to this work.

Extended author information available on the last page of the article

published online:26December2024

Background

Malignant pleural effusions and ascites are common com-plications of late-stage cancers that severely impact the quality of life.The symptoms caused by malignant pleural effusions or ascites,including chest tightness,shortness of breath,dyspnea,pain,abdominal distention,and intestinal obstruction,not only seriously affect the quality of life,but also considerably increase mortality[1].For these patients,cytoreductive surgery or radiation therapy is often out of consideration,and traditional treatments such as diuresis,sodium restriction and paracentesis can only relieve symp-toms temporarily in that none of these treatments can effec-tively control the malignant pleural or peritoneal effusions.In addition,repeated or multiple thoracentesis or paracente-sis could result in complications such as electrolyte imbal-ance and hypoproteinemia.While systemic chemotherapy is often applied in the patients with malignant pleural effusion or ascites,due to poor blood supply on the surface of the pleura and peritoneum,bioavailability of the chemothera-peutic drugs in the thoracic or abdominal cavities is limited when they are administered intravenously.

Hyperthermic intrathoracic chemotherapy(HITHOC)and hyperthermic intraperitoneal chemotherapy(HIPEC)is a novel treatment approach in which chemotherapeutic drugs are allowed to circulate in the hyperthermic perfusate at con-stant temperature(43℃),and thus,it could kill the cancer cells more efficiently through rapid and sustained absorption by the tumor cells[2–5].

With the technological advancement in the hyperthermic perfusion equipment,HITHOC and HIPEC have emerged as effective methods and recommended by expert consensus and guidelines for the treatment of malignant intraperito-neal tumors as well as variety kinds of late-stage cancers complicated with malignant pleural effusions and ascites[6–8].However,techniques for the establishment of perfu-sion vary among different medical centers worldwide,lead-ing to different outcomes in therapeutic efficacy and adverse reactions.In this regard,majority of HIPEC centers apply HITHOC or HIPEC as an assistant or preventive strategy following cytoreductive surgery of solid cancers including lung cancer,gastrointestinal cancers,and ovarian cancer.The surgical approach of HITHOC or HIPEC,which is usu-ally performed during or after the cytoreduction procedure,requires general anesthesia and retains thoracic or abdominal drainage tubes during and after the open or laparoscopic surgery[9,10].Moreover,due to the invasive and compli-cated surgical procedure,it is impossible to conduct multiple times of HITHOC or HIPEC in the same patient[10].In contrast,a bedside HITHOC or HIPEC can be performed via non-surgical approach by performing catheterization through thoracocentesis or paracentesis under the guidance of bedside ultrasound and local anesthesia[11–13],which features minimal injury,excellence tolerance by the patients,and allowance of multiple times therapeutic HITHOC or HIPEC procedures.

Cisplatin is widely applied in the perfusion treatment of malignant pleural effusions or ascites caused by vari-ous solid tumors including lung cancer,ovarian cancer,and gastric cancer.Previously reported dosage of cisplatin during the HITHOC or HIPEC ranged from 50~250 mg/m2,with varying treatment durations from 30~120 min[11,14–16].Studies on the pharmacokinetics of cisplatin in HITHOC and HIPEC,including phase I dose-escalation tri-als exploring the optimal administration dosage for cisplatin in HIPEC,have been previously reported[17–19].However,in these studies,the HIPEC was performed through surgical approach,most of which were administered intraperitoneally after intraoperative palliation and tumor reduction,and none of them had been compared with the intravenous administra-tion of cisplatin.Therefore,the current study was designed to study pharmacokinetics of cisplatin in both perfusate and plasma after administering same dose of cisplatin during the bedside HITHOC or HIPEC in comparison with the intrave-nous infusion for systemic chemotherapy.

Materials and methods

Patients

Patients,who visited Tangdu Hospital during May 2021 through January 2023 and met the following inclusion cri-teria,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 chemo-therapy(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).Antici-pated survival time was<2 months.(3).Severe infection or bleeding.(4).Pregnancy or lactation.(5).Allergic to cispl-atin or other medications used in this study.(6).Declined or failed to follow the study protocol.

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

Treatment

To eliminate bias arises from different cisplatin dose,all patients received 40 mg cisplatin on the first day of the ther-apy,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 anesthe-sia,two drainage tubes were placed using thoracic/abdomi-nal puncture techniques and designated as inflow and out-flow 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 circu-lation 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 proce-dure was performed for 60 min for each therapy.Afterwards,the GDPR-2100T machine was disconnected and the rem-ined 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.

Sample collection and quantification of cisplatin by HPLC

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 infu-sion.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,200μL of perfusion sample or 500µL plasma sample was mixed with equal amount of methanol by rotat-ing for 5 min followed by centrifuging at 4°C(12,000 rpm for 5 min).The supernatant was harvested and mixed with 100μL of 1%sodium diethyldithiocarbamate(DDTC)fol-lowed by incubating at 40°C for 2 h.After cooling to room temperature,the sample was mixed with 1 mL chlo-roform by rotating for 5 min,and then centrifuged at 25°C(12,000 rpm for 5 min).The chloroform layer(800μL)

Fig.1 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 cav-ity using the default function of“one-way washing”in the GDPR-2100T machine,show-ing the color change before and after“effusion replacement”with saline was removed and evaporated with nitrogen.The dried sam-ple was reconstituted with 70μL of acetonitrile and 10μL of them was applied for HPLC analysis with the following settings:chromatographic column was Ultimate®XB-C18(Welch,250 mm×4.6 mm,5µm);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 detec-tion for cisplatin in saline was 0.08µg/mL and the limit of quantification was 0.28µg/mL;the limit of detection for cisplatin in plasma was 0.01µg/mL and the limit of quantification was 0.03µg/mL.The intra-day precision of cisplatin in saline at low(1µg/mL),medium(8µg/mL),and high(60µg/mL)concentrations was 3.24%,1.56%,and 1.74%,respectively,and the inter-day preci-sion was 3.20%,1.85%,and 3.41%,respectively.The intra-day precision of cisplatin in plasma at low(0.05µg/mL),medium(0.5µg/mL),and high(4µg/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.

Assessment of adverse events

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(rou-tine 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.

Statistical analysis

DAS2.0 software was used to perform non-compartmental model analysis of pharmacokinetic parameters.The concen-tration–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 Vari-ance 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 concentra-tion(Tmax),apparent clearance(Clz/F),and peak concen-tration(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.

Results

Demographic features of the patients

Total 60 patients were enrolled into the study,and 20 patients were in each treatment group of SC,HITHOC,and HIPEC.By the cell type or location of the primary cancer,they were 23 lung cancers,14 gastric cancers,11 ovarian cancers,two esophageal cancers,two peritoneal mesothelio-mas,two primary peritoneal adenocarcinomas,one thymic carcinoma,one appendiceal adenocarcinoma,one cervical cancer,one nasopharyngeal carcinoma,one parotid gland carcinoma,and one head and neck squamous cell carcinoma.Of them,28 were male and 32 were female,and they were all Han nationality.There were no statistically significant differences among the three groups in terms of median age,gender proportion,body surface area,and ECOG scores(p>0.05,Table 1).

Table 1 Demographic feature of the patients

Comparison of cisplatin pharmacokinetics

Following the administration of cisplatin,concentration of cisplatin in the perfusates of HITHOC group and the HIPEC group at various time points were quantified(Supplement Table S1)and the dynamic change was shown in Fig.2.As shown in Supplement Table S1,mean concentrations of cis-platin in the thoracic cavity were significantly higher than that in the abdominal cavity at various time points(p≤0.01).

Next,cisplatin concentrations in the plasma of the patients treated with SC,HITHOC,or HIPEC at various time points were quantified(Supplement Table S2),and their dynamic changes were shown in Fig.3.As shown in Supplement Table S2,up to 5 h after administration,there were significant differences in plasma cisplatin concentra-tions among the three groups(p≤0.01).As expected,at 30 min and 1h after administration,mean plasma cisplatin concentrations were significantly higher in the patients with systemic chemotherapy(0.33±0.10 and 0.69±0.14µg/mL,respectively)compared to that in the HITHOC group(0.14±0.06 and 0.25±0.9µg/mL,respectively)or HIPEC group(0.19±0.08 and 0.37±0.16µg/mL,respectively,p≤0.01,Supplement Table S2).At 5 h after administration,however,mean plasma cisplatin concentrations in the SC group or HIPEC group rapidly reduced to the same level as it was in the HITHOC group(p>0.05)although there were significant differences at 1.5,2,and 3 h after administration between the groups(p≤0.01,Supplement Table S2).

To compare bioavailability of cisplatin in the pleural and abdominal cavities,area under the concentration–time curve over the 24 h dosing interval(AUC0–24h),mean residence

Fig.2 Cisplatin concentration–time curve in the perfusate.Samples of perfusate in the body cavities were collected from the HITHOC and HIPEC groups at various time points and cisplatin concentration was quantified by HPLC as described in the methods.Vertical axis:cisplatin concentration(µg/mL),horizontal axis:elapsed time(h).

Solid circle:HITHOC group;solid square:HIPEC group

Fig.3 Cisplatin concentration–time curve in the plasma.Venous blood samples were collected from the SC,HITHOC,and HIPEC groups at various time points and cisplatin concentration was quantified by HPLC as described in the methods.Vertical axis:cisplatin concentration(µg/mL),horizontal axis:elapsed time(h).Solid circle:systemic chemotherapy(SC)group;solid square:HITHOC group;

solid triangle:HIPEC grouptime over the 24 h(MRT0–24h),terminal elimination halflife(t1/2z),time to peak concentration(Tmax),apparent clearance(Clz/F),and peak concentration(Cmax)in the perfusate were compared.As shown in Fig.2 and Table 2,the AUC0-24h(64.32±27.12µg/mL·h)and Cmax(21.62±5.88µg/mL)were significantly higher in the perfusate of HITHOC group compared to that in the HIPEC group(31.68±13.29µg/mL·h and 16.96±5.54µg/mL,respectively,p<0.01,Table 2).In contrast,MRT0–∞,t1/2z,and Clz/F were significantly lower in the HITHOC group compared to that in the HIPEC group(MRT0–∞:6.44±2.92 vs 10.24±3.45 h;

Table 2 Pharmacokinetic parameters of cisplatin in the perfusate analyzed by statistical moment principle

HITHOC hyperthermic intrathoracic chemotherapy,HIPEC hyperthermic intraperitoneal chemotherapy,AUC area under the concentration–time curve,MRT mean residence time,t1/2z the terminal elimination half-life,Tmax time to peak concentration,CLz/F apparent clearance,Cmax peak concentrationt1/2z:5.03±3.96 vs 10.05±4.25 h;Clz/F:0.70±0.32 vs

1.20±0.53 L/h/kg,p<0.01,Table 2).

To further compare bioavailability of cisplatin in the plasma among the three different treatment groups,AUC 0–24h,MRT0–24h,t1/2z,Tmax,Clz/F,and Cmax in the plasma were compared.As shown in the Fig.3 and Table 3,aver-age AUC0–24h and Cmax in the plasma of HITHOC group were 2.57±0.55µg/mL·h and 0.26±0.08µg/mL,respec-tively,which were significantly lower than that of sys-temic chemotherapy(SC)group(3.26±0.56µg/mL·h and 0.69±0.14µg/mL,respectively,p<0.01,Table 3),without significant difference compared to that of HIPEC group(3.02±0.52µg/mL·h and 0.40±0.15µg/mL,respectively,p>0.05,Table 3).In contrast,MRT0–24h(9.63±0.77 h)and Tmax(1.38±0.46 h)in the plasma of HITHOC group were significantly longer compared to that of SC group(7.69±1.49 h and 1.00±0.00h,respectively,p<0.01,Table 3),without significant difference compared to that of HIPEC group(8.49±0.71 h and 1.30±0.25 h,respectively,p>0.05,Table 3).In addition,MRT0–∞in the plasma of HITHOC(35.67±15.32 h)was significantly longer com-pared to SC(25.78±21.66 h)or HIPEC(21.18±13.20 h)group(p<0.01,Table 3).

Adverse events

As shown in Table 4,in the current study,the most common adverse effect was gastrointestinal event including nausea,vomiting,constipation,abdominal distension,decreased appetite,and diarrhea.The second common side effect was sign of bone marrow suppression including anemia,neutro-penia,and thrombocytopenia.In addition,other side effects including fever,fatigue,and respiratory system symptoms(cough and dyspnea)were occasionally seen in this study.No severe adverse events(≥Grade III)occurred in any of the patients,and the incidence rates of common adverse events

Table 3 Pharmacokinetic parameters of cisplatin in the plasma analyzed by statistical moment principle

Table 4 Comparison of adverse effects among the three groups[N(%)]

SC systemic chemotherapy,HITHOC hyperthermic intrathoracic chemotherapy,HIPEC hyperthermic intraperitoneal chemotherapy were not significantly different among the three groups(Table 4).

Discussions

Cisplatin is a first line therapeutic drug for many solid tumors and has been widely used for the treatment of various late-stage cancers complicated with malignant pleural effusions or ascites.While cisplatin has been widely used through intravenous infusion for systemic chemotherapy,in our Oncology Center,cisplatin has long been applied for the treatment of malignant pleural effusion and ascites through injecting into the hyperthermic perfusate during the HITHOC or HIPEC procedure.Here,we have studied the pharmacokinetics of cisplatin in the plasma as well as in the hyperthermic intrathoracic and intraperitoneal perfusate in the patients received HITHOC or HIPEC in comparison with the conventional systemic chemotherapy.

Conventionally,HIPEC is often performed for the treatment of peritoneal carcinoma following cytoreductive surgery[9,10].HIPEC is also performed during or immediately after the open or laparoscopic surgery of gastrointestinal cancers or ovarian cancer to prevent recurrence of the primary cancers[3,11,20].In these treatments,HIPEC is an invasive procedure and requires general anesthesia.Similarly,HITHOC has also been performed under general anesthesia by an invasive procedure[21,22].Since it is an invasive procedure,wound healing takes longer,and it is impossible to perform multi-cycle treatments in the same patient.In contrast to the surgery based HIPEC or HITHOC,the bedside HIPEC and HITHOC procedures performed in our institute have the following unique features.(1).It is a minimally invasive and performed under local anesthe-sia followed by the puncture technique.(2).It is repeatable every other day or every week,and thus,multi-cycle of HIPEC or HITHOC procedure can be conducted in the same patient.(3).It can be performed in an out-patient facility or in-patient ward of Oncology without using the operational room.(4).It is easily tolerated by the patients with minimum side effects.

While previous clinical studies have provided supporting evidence of cisplatin application in the HITHOC and HIPEC[20,23],there are limited studies on the pharmacokinetics of cisplatin administered through intravenous infusion for systemic chemotherapy in comparison to topical applica-tion of cisplatin during the HITHOC or HIPEC procedure.In this regard,Anasloni et al.investigated pharmacokinetics of concomitant cisplatin and paclitaxel(100 and 175 mg/m2 BSA)administered by HIPEC to patients with peritoneal carcinomatosis from epithelial ovarian cancer.They reported that mean maximum concentrations of cisplatin were 24.8±10.4µg/mL in the HIPEC perfusate,1.87±0.4µg/mL in the plasma,and 23.3±8.0µg/g in peritoneum at the end of HIPEC[18].Cashin et al.investigated pharmacoki-netics of cisplatin in a group of ten patients treated with cytoreductive surgery and HIPEC(cisplatin 50 mg/m2 BSA).They found that the mean half-life(t1/2)of cisplatin in the perfusate was 18.4 min,with area under the time concentra-tion curve 0–90 min(AUC0–90 m)of 2.87 mM*min[24].Ried et al.investigated pharmacokinetics of cisplatin(100 or 150 mg/m2)administered via HITHOC following pleu-rectomy/decortication in the patients with malignant pleural mesothelioma or advanced thymoma with pleural spread.They found that the mean AUCs of cisplatin(two different doses)in the perfusate were approximately 58 and 55 times greater than detected in the serum and the mean peak of cis-platin in the serum was reached after 1 h of HITHOC[25].While these studies have compared cisplatin concentrations in the perfusate of HIPEC or HITHOC versus serum,to our knowledge,the current study was the first prospective study to compare the dynamic concentration of cisplatin in the perfusate as well as in the plasma of patients who received cisplatin through intravenous infusion for systemic chemo-therapy versus administration of cisplatin through adding into the perfusate of HITHOC or HIPEC.We found that cisplatin concentration in the HITHOC group was relatively high with a peak of exceeding 20µg/mL,which slowly reached to 1.6µg/mL and stabilized at 10h after injecting into the perfusate,indicating that majority of the cisplatin in the thoracic cavity had been completely absorbed at 10 h after administration.In comparison,cisplatin concentration in the HIPEC group was lower with a peak of 16.96µg/mL,which quickly declined to 1.25µg/mL and stabilized at 3 h after injecting into the perfusate,suggesting a com-plete absorption of cisplatin in the abdominal cavity was faster than that in the thoracic cavity.We believe the fol-lowing factors may contribute to the different absorption rates between HITHOC and HIPEC.First,due to the limited space capacity of the thoracic cavity,which is much smaller than that of the abdominal cavity,the volume of perfusate applied in the HITHOC was less than that in the HIPEC procedure,which could result in a relatively higher cisplatin concentration in the perfusate of HITHOC compared to that of HIPEC.Secondly,due to the much smaller surface area of the pleura compared to the peritoneum,the absorption rate of cisplatin in the HITHOC procedure was slower than that in the HIPEC procedure.

Previous studies have reported that minimally invasive surgery could enhance cisplatin diffusion when the chemo-therapeutic drug was administered via HIPEC following cytoreductive surgery[26,27].In this regard,Petrillo et al.reported that median cisplatin Cmax at 60 min in peritoneal tissue was higher in patients treated with minimally invasive secondary cytoreductive surgery compared to open second-ary cytoreductive surgery(8.262µg/mL vs 4.057µg/mL)as well as in the plasma at 120 min(0.511µg/mL vs 0.254µg/mL)[26].To our knowledge,thus far published pharma-cokinetic studies on cisplatin administered during HITHOC and HIPEC were all performed during or immediately after cytoreductive surgeries,that is,either a less invasive such as laparoscopic approach or open surgical approach were used to perform HITHOC or HIPEC.Here,we reported a bedside HIPEC or HITHOC methods.This novel HIPEC or HITHOC procedure is not only most minimally invasive,but also can be repeated every other day or every week in the same patient.However,whether this novel method of HIPEC or HITHOC could further enhance tissue diffusion of chemotherapeutic drugs compared to the laparoscopic or open surgery based HIPEC or HITHOC remains to be investigated.

As anticipated,when cisplatin was administered through intravenous infusion for systemic chemotherapy,plasma concentration of cisplatin rapidly increased and reached the peak of 0.69µg/mL within 1 h,which was also rap-idly declined to 0.29µg/mL at 2 h and to 0.1µg/mL at 10 h after infusion.Similarly,in the HITHOC or HIPEC groups,plasma concentration of cisplatin was also reached its peak concentration at 1 h after injecting into the per-fusate although it was approximately one third(HITHOC:0.25µg/mL)or half(HIPEC:0.37µg/mL)of the SC group.In addition,plasma cisplatin concentration in the HITHOC and HIPEC groups was gradually declined after reaching the peak and stabilized after 10 h.These findings suggested that,in the HITHOC or HIPEC group,majority of cisplatin was rapidly absorbed from the hyperthermic perfusate into the blood circulation at the first hour followed by sustained absorption from the thoracic and abdominal cavities into blood circulation,which could exert sustained chemothera-peutic effect on tumors.

In the patients treated with HITHOC or HIPEC,the AUC 0–24h of cisplatin in the perfusate was 64.32µg/mL·h and 31.68µg/mL·h,respectively,while the AUC0–24h of cispl-atin in the plasma was 3.26µg/mL·h in the patients treated with systemic chemotherapy,indicating that total exposure of the tumor cells to cisplatin in the thoracic and abdominal cavities for the last 24 h was approximately 20 and 10 times higher,respectively,than that in the blood circulation.These findings suggested that bioavailability of cisplatin in the thoracic or abdominal cavities during HITHOC or HIPEC procedure was 20 or 10 times higher,respectively,compared to the bioavailability of cisplatin given by intravenous infu-sion for systemic chemotherapy,confirming the advantage of HITHOC and HIPEC for the treatment malignant pleural infusion and ascites from the evidence of pharmacokinetics study.

We have previously reported on the safety of HITHOC and HIPEC with findings of mild side effects during and after the procedure[12,13].Consistent with our previous reports,only mild gastrointestinal event including nausea,vomiting,constipation,abdominal distension,decreased appetite,and diarrhea were found in this study,and there was no significant difference in the rate of adverse events among the three groups.This was further supported by the evidence of cisplatin pharmacokinetics of this study.In this regard,the plasma bioavailability of cisplatin in the three groups was every much similar as evidenced by the AUC 0–24h of cisplatin in the plasma(SC:3.26µg/mL·h;HITHOC:2.57µg/mL·h;HIPEC:3.02µg/mL·h),which further sup-ported the novelty and advantage of bedside HITHOC or HIPEC for the treatment of patients with malignant pleural effusion or ascites.

There were some limitations in this study.Firstly,total therapeutic dose of cisplatin was divided and given in three doses,and to ensure the comparability among the three groups,same initial dosage of 40 mg was administered in all patients of the three groups.However,considering that excessive blood sampling might cause poor compliance of patients,cisplatin pharmacokinetics was investigated only following administra-tion of the first dose but not for the subsequent two administra-tions,which might cause a bias of sample collection.Secondly,cell types of the primary tumors and stages ofthe cancers were different among the participants who were assigned into the 3 study groups.In this regard,patients with lung cancer were assigned into the HITHOC group,but not to HIPEC group,and vice versa,patients with gastric or ovarian cancer were assigned for the HIPEC treatment,not for HITHOC.Thirdly,since the cancer cell type as well as strategy and history of the treatment could affect overall survival,objective response rates and overall survival rate was not analyzed in this study.

Taken together,the current study investigated pharmacoki-netics of cisplatin administrated through intravenous infusion in comparison to injection into the hyperthermic perfusate for the treatment of variety kinds of cancers complicated with malignant pleural effusion or ascites.It was found that the AUC0-24h and Cmax of cisplatin in the perfusate of HITHOC group was significantly higher than that of HIPEC group,while the AUC0–24h and Cmax of cisplatin in the plasma of HITHOC group was significantly lower than that ofSC group;and that absolute bioavailability of cisplatin in the thoracic(HITHOC)and abdominal(HIPEC)cavities was 20 and 10 times higher than that in the blood administered via intrave-nous infusion(SC group),respectively.This study provided pharmacokinetic evidence to further support the concept that topical application of chemotherapeutic drugs through minimally invasive HITHOC or HIPEC may enhance local exposure of the affected tissues to the chemotherapeutic drugs compared to systemic chemotherapy for the patients with malignant pleural effusion or ascites.

Supplementary Information The online version contains supplemen-tary material available at https://doi.org/10.1007/s00280-024-04727-8.

Author contributions Data collection and analysis:Yan Hou,Jie Song,Wen Hu,Yun Wang,Dongxu Chen,Yu Chen.Study design:Lili Liu.Manuscript draft:Tao Zhang.Project administration:Tao Zhang,Wei Mu,Linna Liu.PI of the grant:Lili Liu,Cheng-gong Liao.All authors approved the final submission.

Funding This study was supported by the grant from the National Natural Science Foundation of China(81572251,81572814).

Availability of data and materials No datasets were generated or ana-lysed during the current study.

Declarations

Conflict of interest The authors declare no competing interests.

Ethics approval and consent to participate The clinical experiment was approved by the Local Ethical Review Committee(Assigned No.202103–29;Shaanxi,China).

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License,which permits any non-commercial use,sharing,distribution and repro-duction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if you modified the licensed material.You do not have permission under this licence to share adapted material derived from this article or parts of it.The images or other third party material in this article are included in the article’s Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http://crea-tivecommons.org/licenses/by-nc-nd/4.0/.

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