Lili Liu,Tao Zhang,Xiang Song,Cheng-gong Liao,Tengyun Xu,Yang Yang,Ming Zeng,Junmei Jia,Haichuan Su,Yang Song,Jie Min,Hongmei Zhang,Wei Li,Hongwei Zhang&Helong Zhang

To cite this article:Lili Liu,Tao Zhang,Xiang Song,Cheng-gong Liao,Tengyun Xu,Yang Yang,Ming Zeng,Junmei Jia,Haichuan Su,Yang Song,Jie Min,Hongmei Zhang,Wei Li,Hongwei Zhang&Helong Zhang(2023)Hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy for the malignant effusion:a multi-center randomized clinical trial,International Journal of Hyperthermia,40:1,2241689,DOI:10.1080/02656736.2023.2241689

To link to this article:https://doi.org/10.1080/02656736.2023.2241689

©2023 The Author(s).Published with

license by Taylor&Francis Group,LLC

Published online:13 Aug 2023.

Submit your article to this journal Article views:2170

View related articles View Crossmark data

Citing articles:1 View citing articles

Hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy for the malignant effusion:a multi-center randomized clinical trial

Lili Liua
,Tao Zhanga
,Xiang Songb,Cheng-gong Liaoa,Tengyun Xuc,Yang Yangd,Ming Zenge,Junmei Jiaf,Haichuan Sua,Yang Songa,Jie Mina,Hongmei Zhangg,Wei Lih,Hongwei Zhangi and Helong Zhanga

Department of Oncology,Tangdu Hospital,Air Force Medical University,Xi’an,China;b

Department of Radiotherapy,The Second Affiliated

Hospital,Shanxi Medical University,Taiyuan,China;c

Department of Oncology,The First Affiliated Hospital,China University of Science and

Technology,Hefei,China;d

The Comprehensive Cancer Center of Drum Tower Hospital,Medical School of Nanjing University and Clinical

Cancer Institute of Nanjing University,Nanjing,China;e

Department of Oncology,The People’s Hospital of Sichuan Province,Chengdu,

China;f

Department of Oncology,The First Affiliated Hospital,Shanxi Medical University,Taiyuan,China;g

Department of Oncology,Xijing

Hospital,Air Force Medical University,Xi’an,China;h

Cancer Center,The First Affiliated Hospital,Jilin University,Changchun,China;i

Digestive Disease Center,Wuxi Mingci Hospital,Wuxi,China

ABSTRACT

Objective:To compare the efficacy and safety of hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy in the treatment of malignant pleural or peritoneal effusion.

Methods:A randomized clinical trial was carried out in 8 cancer centers across China.Patients with malignant pleural or peritoneal effusion were randomly assigned to the study group or control group.

Patients in the study group were treated with cisplatin-based hyperthermic intrathoracic chemotherapy(HITHOC)or hyperthermic intraperitoneal chemotherapy(HIPEC),while the control group was treated with conventional intrapleural or intraperitoneal chemotherapy using same chemotherapeutic regime as the study group.The objective response rate(ORR)was analyzed as primary outcome.

Quality-of-life(QOL)score was recorded as secondary outcome using the questionnaire 30(QLQ-C30)of the European Organization for Research and Treatment of Cancer(EORTC).The efficacy and safety of the two treatments were compared.

Results:Total 135 patients were recruited and randomized in this study,with 67 patients in the study group and 68 patients in the control group.The ORR in the study group(80.70%)was significantly higher than that in the control group(31.03%,p<0.001).However,neither changes of QOL scores,nor incidence rates of adverse events were significantly different between the two groups(p¼0.076 and 0.197,respectively).Conclusion:Efficacy of HITHOC or HIPEC is superior to that of conventional modality for the treatment of malignant effusion with comparable side effects.

Background

It has been reported that nearly 15%of cancer patients have comorbidity of malignant pleural effusion(MPE),and majority(50–60%)of the MPE are developed in the lung or breast cancer patients,followed by lymphoma,gynecologic cancers,and malignant mesothelioma[1].Similarly,approximately 10%of cancer patients suffer from comorbidity of malignant ascites(MA),which is most commonly seen in ovarian cancer(25–37%of all MA cases),followed by hepatobiliary and pancreatic cancer,gastric cancer,and colorectal cancer[2,3].

MPE and MA are known causes attributing to worse prognosis and poor quality of life in advanced cancer patients[4,5].

Patients with MPE and MA generally respond poorly to diuretics and sodium restriction.Repeated thoracentesis or paracentesis only temporarily relieve symptoms and may cause complications such as hypoproteinemia and electrolyte disorders.Effect of systemic chemotherapy in controlling MPE or MA is limited due to the poor blood supply to the pleural and peritoneal cavity.Intrapleural or intraperitoneal chemotherapy have potential advantages in treating underly malignancies and controlling MPE or MA.In this regard,direct injection of chemotherapeutic drugs into the pleural or peritoneal cavity can not only dramatically increase the chemotherapeutic effect with higher local concentrations of chemotherapeutic drugs,but also significantly reduce side effects by avoiding systemic toxicities of the chemotherapeutic drugs.Hyperthermic intrathoracic chemotherapy(HITHOC)and Hyperthermic intraperitoneal chemotherapy(HIPEC)are developed by the combination of conventional intrapleural or intraperitoneal chemotherapy and the biological effect of hyperthermia on cancer cells.Experimental evidence suggested that,omparing to normal cells,malignant cells are more sensitive to the effect of hyperthermia in the range of 41C to 43C,resulting in accelerated cell death.In clinical practice,synergetic effects between heat and chemotherapeutics in the enhancement of cytotoxicity to cancer cells have also been well documented[6–9].Compared to conventional intrapleural or intraperitoneal chemotherapy,HITHOC and HIPEC have been shown significant clinical advantages in the treatment of malignant pleural or peritoneal effusions as well as preventing recurrence of the malignant effusion[10–15].

Since 2007,we have developed a novel bedside device for HITHOC or HIPEC,which has been used in thousands of patients with malignant pleural or peritoneal carcinomatosis in multiple cancer centers across mainland China.The most remarkable advantage of this device is that the procedure of HITHOC or HIPEC is easy to perform and well-tolerated by the patients with late-stage cancer or post-surgery recurrent cancer.In the present study,a randomized and controlled open-label clinical trial of HITHOC and HIPEC in the treatment of patients with malignant pleural or peritoneal effusions was prospectively designed and conducted in multiple cancer centers across mainland China.Here,we reported the clinical outcomes of this study.

Methods

Patients and study design

Patients were recruited into the following 8 cancer centers across mainland China:Tangdu Hospital,Air Force Medical University;The Second Affiliated Hospital,Shanxi Medical University;The First Affiliated Hospital,University of Science and Technology of China;The First Affiliated Hospital,Shanxi Medical University;The People’s Hospital of Sichuan Province;Nanjing Drum Tower Hospital,Medical School of Nanjing University;Xijing Hospital,Air Force Medical University;The First Affiliated Hospital,Jilin University.

Tangdu Hospital,The Second Affiliated Hospital of Air Force Medical University,was the principal institute and in charge of organizing,cooperating,and conducting the trial.The study protocol in each participating institute was approved by the Medical Ethics Committees of each participating hospital(#:201809-08).Written informed consents were obtained from the enrolled patients.

Inclusion criteria:(1)Patients had malignant pleural or peritoneal and/or pelvic effusions confirmed by either biopsy or cytology;or had thoracic or peritoneal cancer(either metastatic or primary)confirmed by imaging examination;(2)Ultrasonic examination estimated that the volume of pleural effusion was over 800 ml or the volume of ascites was over 1500 ml;(3)Patients’Eastern Cooperative Oncology Group(ECOG)score was in the range of 0–2;(4)Patients’age18 years.

Exclusion criteria:(1)Anticipated patient’s survival time was less than 2 months;(2)Uncontrolled metastasis to the central nervous system;(3)Uncontrolled severe infection or intractable bleeding;(4)Pregnancy or lactation;(5)Had participated in other clinical studies within the last 30 days prior to this study;(6)Allergic to the drugs used in this trial;(7)Retraction of consent or not stay in compliance with the study protocol.

Patients were assigned to study or control group by simple randomization at the proportion of 1:1.Each participant was scheduled to receive total 3 times of treatment on day 1,4 and 7,respectively.Clinical outcomes were evaluated 4 weeks after the therapeutic procedure.

Therapeutic procedure

In the study group,HITHOC or HIPEC were performed with an extracorporeal perfusion device that was manufactured by The Xi’an Good Doctor Medical Science and Technology Co,Ltd(Xi’an,China,Model:GDPR-2100T).Briefly,after local anesthesia on chest or abdomen,two drainage tubes were inserted into the pleural or peritoneal cavity by puncture technique under the guidance of ultrasound and designated as Inlet or Outlet ports(Figure 1),respectively.The perfusion

Figure 1.An example image of established inlet and outlet ports on a patient’s back.After local anesthesia,two drainage tubes were inserted into the thoracic cavity through puncture technique under the guidance of ultrasound,which were designated as Inlet and Outlet ports for the hyperthermic perfusion and circulation.

Figure 2.An example of bedside application of the perfusion device in a patient with malignant ascites.A perfusion device was connected to the patient,and hyperthermic perfusion and chemotherapy with cisplatin was performed for one hour.

Figure 3.An example image of lavage fluid changing from bloody effusion fluid into clear saline through the process of effusion replacement.Prior to the initialization of hyperthermic perfusion and circulation with chemotherapeutic drug,lavage was performed using the HIPEC machine and normal saline following the manufacturer’s instruction.Note the color changes of the lavage fluid from bloody to clear water.

device was then connected to the Inlet and Outlet as shown in Figure 2[16,17].Prior to initialization of HITHOC or HIPEC,lavage of the body cavities was performed with saline(1000–2000 ml saline for pleural and 3000–5000 ml saline for peritoneal cavity)until the bloody fluid became clear lavage fluid as shown in Figure 3,a procedure is called as‘effusion replacement’[16].After completing the‘effusion replacement’through the one-way lavage,a sealed circulation of hyperthermic solution between the patient’s body cavity and the machine was then established[18].Five minutes after the initialization of hyperthermic perfusion and circulation,cisplatin(Qilu Pharmaceutical,Jinan,China)was dissolved in 50 ml saline and injected into the perfusion solution through the Inlet port.The flow rate was adjusted to 400 ml/min,and the temperature of the perfusion solution at Inlet and Outlet ports was set at 43C and 41±1C,respectively[19].

Circulation of the hyperthermic solution containing cisplatin lasted for 60 min.Afterwards,approximately 700 ml of the perfusion fluid was drained and the remaining perfusion solution containing cisplatin was retained in the body cavity and allowed to be naturally absorbed.To augment the regional chemotherapeutic effect by evenly distributing the retained perfusion solution,patients’body position was changed every 20–30 min during the first hour immediately after completion of the procedure.No additional fluid was drained during the interval days between the HITHOC or HIPEC procedure on day 1,4 and 7.Meanwhile,routine intravenous hydration and diuretic therapy was given to prevent renal damage,and antiemetic drugs were used as needed.

In the control group,conventional intrapleural or intraperitoneal chemotherapy was performed.Briefly,one drainage tube was inserted into thoracic or abdominal cavity via puncture technique under the guidance of ultrasound.

Approximately,700 ml of pleural fluid or ascites was drained.

Afterwards,cisplatin in 50 ml saline was injected into the thoracic or abdominal cavity through the drainage tube.The patients were instructed to change body position every 20–30 min during the first hour after completing the procedure.

No additional fluid was drained during the interval days between the injection of cisplatin on day 1,4 and 7,and post-procedural treatments were same as that of the study group.

Cisplatin dosage

Total dose of cisplatin for each patient was 100 mg/m²,which was divided into 3 equal dosages and given on day 1,4 and 7,respectively[20].During the one therapeutic course(3 times of HITHOC or HIPEC treatment for the study group,or 3 times of conventional intrapleural or intraperitoneal

chemotherapy with cisplatin for the control group on day 1,4,and 7,respectively),the tubes on the chest or abdominal wall were remained on the patients for one week.However,drainage of pleural or peritoneal fluid was not performed at the intervals of no treatment days.

Chemotherapy with cisplatin was suspended if the number of neutrophils dropped to<1.0109/L,platelets dropped to<80109/L,or creatinine clearance was<50 ml/min.Hematopoietic stimulating factor or rehydration was given to the patients and the patients were closely monitored.Study was aborted if the laboratory parameters were not recovered after 14 days of supporting treatment.

Outcome evaluation

Primary outcome:The primary outcome for this study was objective response rate.The response status was defined following the previously published criteria for the outcome evaluation of HIPEC procedure[17,21]:1)complete response(CR)was defined as:disappearance of pleural or peritoneal effusion for more than 4 weeks;2)partial response(PR)was defined as:50%reduction in pleural or peritoneal effusion for more than 4 weeks;3)stable disease(SD)was defined as:<50%reduction or25%increase in pleural or peritoneal

effusion;4)progressive disease(PD)was defined as:>25%increase in pleural or peritoneal effusion.The objective response rate(ORR)¼(CRþPR)/total number of cases100%.The volume of pleural or peritoneal effusion was measured by ultrasound examination before and 4 weeks after the treatment following the instruction of operating procedures for quantification of pleural or peritoneal effusion amount by ultrasound.

Secondary outcome of the current study was the qualityof-life(QOL)score.QOL was evaluated with the core questionnaire 30(QLQ-C30)of the European Organization for Research and Treatment of Cancer(EORTC).QOL scores were evaluated before and 4 weeks after the treatment,respectively.All questionnaires were completed by the patients independently.Researchers were only allowed to give the necessary explanations if the patient could not understand the questions.Any inducive explanations and questions were prohibited.

Adverse events were recorded in both groups.The severity of the adverse events was assessed according to Common Terminology Criteria for Adverse Events(CTCAE)

5.0[22].And adverse eventsgrade 3 were defined as serious adverse events(SAE).

Statistical analysis

The SPSS software for Windows(version 20.0;SPSS Inc.,Chicago,IL,USA)was used to analyze the data.Continuous variables were described as median and interquartile range(IQR)or mean±standard deviation.Categorical variables were described as absolute numbers and percentages.The differences in age,effusion volume,and QOL score between groups were assessed using the student’s t-test or one-way analysis of variance.Pearson’s Chi-square test or Fisher’s exact test was used to compare the differences in gender ratio,primary tumor type,effusion site,ECOG scores and ORR.The difference was considered statistically significant at p<0.05.

Results

From November 23,2018,to September 23,2020,total 135 patients(median age 59 years[IQR 51–67 years],41 men and 94 women)were recruited and randomized to either the study group(n¼67)or the control group(n¼68).

Demographic characteristics of the patients were listed in Table 1.Patients in the two groups were matched for age,gender ratio,primary tumor type,volume of pleural or peritoneal effusion,and ECOG performance status(Table 1).The most common type of primary cancer was ovarian cancer followed by gastric and lung cancer(Table 1).

Twenty patients were withdrawn from the study,with 10 patients in each group(14.9%in the study group and 14.7%in the control group,p¼0.971).These patients were excluded from the final analysis for efficacy but were included for adverse event analysis.As shown in Figure 4,two of the study group and three of the control group were withdrawn due to serious adverse events;eight of the study group and seven of the control group were withdrawn due to incomplete follow-up or missing critical efficacy data.

Outcome of the primary endpoint:objective response rate(ORR)After 4 weeks of the treatment,28.07%(16/57)patients achieved complete response(CR)and 52.63%(30/57)patients had partial response(PR)in the study group,which were significantly higher than that in the control group(CR:10.34%,6/58,p¼0.019;PR:20.69%,12/58,p<0.001).

Furthermore,objective response rate(ORR)was significantly higher in the study group than that in the control group(80.70%vs.31.03%,p<0.001,Table 2).

Therapeutic response among the subgroups,which was categorized by the types of primary tumors,was further analyzed.As shown in Table 3,in the patients with gastric cancer,lung cancer,or other miscellaneous types of cancers,the

ORR was significantly higher in the study group than that of control group(gastric cancer:88.89%vs 21.95%,p<0.001;lung cancer:69.23%vs 14.29%,p¼0.004;others:100.00% vs 30.00%,p¼0.002).However,there was no significant difference between the two groups of patients with ovarian cancer(77.78%vs 60.00%,p¼0.222).

Among the patients with complete response,5 out of 16(31.25%)in the study group and 1 out of 6(16.67%)in the control group achieved CR after 2 sessions of treatment on day 1 and 4 without the 3rd treatment on day 7.

Outcome of the secondary endpoint:quality-of-life(QOL)scores There was no significant difference in the baseline QOL scores between the study and control group(p¼0.403,Table 4).QOL scores improved slightly in both groups after the 4 weeks treatment but without significant difference between the two groups(p¼0.076,Table 4).Adverse events

There was no statistical difference in the overall incidence of adverse events(p¼0.197),and the incidence of severe adverse events between the two groups were comparable(p¼0.676).The most common adverse events were nausea/-vomiting,anemia,and constipation followed by in the order of leukopenia,fever,fatigue,liver dysfunction,thrombocytopenia,renal toxicity,and intestinal obstruction(Table 5).No puncture failure occurred in the current study.Puncturerelated complications were rare,and the incidence of puncture-related complications was not significantly different between the two groups(p¼0.661,Table 5).Specifically,in the study group,one patient developed subcutaneous emphysema and one patient had severe pain at the puncture site;in the control group,one patient developed pneumothorax,one patient had syncope and one patient had infection at the puncture site.

Two patients in the study group withdrew from the study due to serious adverse events(one was pulmonary embolism and the other one was due to progression of the primary tumor during the treatment).In the control group,3 patients dropped out of the study because of serious adverse events(one had syncope during the puncture procedure and two patients had progression of the primary tumors during the treatment).

Discussion

Malignant pleural or peritoneal effusion is a common complication of advanced malignancies.Symptoms arising from the malignant effusion include pain,dyspnea,palpitation,nausea,vomiting,anorexia,and abdominal distension.Severe complications such as intestinal obstruction,biliary and ureteral obstruction,and intestinal fistula could also develop in the late-stage cancer patients with malignant ascites.These symptoms and severe complications of malignant effusion could not only affect patients’quality of life,but also dramatically reduce overall survival of the patients.Therefore,various methods of managing malignant pleural effusion(MPE)and malignant ascites(MA)in the patients with advanced malignancies have been developed in clinical practice.

Intraperitoneal chemotherapy was firstly introduced by Weissberger in 1955[23].In 1980,Spratt et al.[24]combined intraperitoneal chemotherapy with abdominal thermotherapy,which was the first development of the method of hyperthermic intraperitoneal chemotherapy(HIPEC).This therapeutic strategy was also later used for the treatment of pleural malignancies,referred to as hyperthermic intrathoracic chemotherapy(HITHOC)[25,26].HITHOC or HIPEC are often used in combination with cytoreductive surgery.

HITHOC is commonly used for pleural mesothelioma,thymoma and thymic carcinoma[27,28],while HIPEC is commonly used for ovarian,gastric and colorectal cancers[29,30].Yi et al.[31]retrospectively analyzed 33 patients with pleural dissemination of advanced lung cancer,23 patients received HITHOC after surgical resection and 10 patients received surgical resection only.The overall survival rate at 6 months,1 year,and 3 years were 95.7%,91.3%,and 38.6%in the HITHOC plus surgery group,compared with 80.0%,80.0%,and 37.5%in the surgery only group,respectively,which was statistically different(p¼0.045).Aprile et al.[32]also retrospectively analyzed the outcomes of 40 thymoma patients with pleural recurrence(27 patients underwent surgical resection with HITHOC and 13 patients underwent surgical resection only),and found that local disease-free survival was longer in the combination group(88.0±15 months vs.57±19.5 months in the surgery only group,p¼0.046).Similarly,a retrospective study by Jiao et al.[9]on the 80 malignant ascites reported that the ascites control rate was significantly higher in the HIPEC group(91.11%)than that in the conventional intraperitoneal chemotherapy group(40%,p<0.01).Consistent with these reports,objective response rate to the therapy in the current study was significantly higher in the patients treated with HITHOC or HIPEC compared with the patients treated with conventional thoracentesis or paracentesis plus topical chemotherapy,suggesting HITHOC and HIPEC should be considered as first-line choice in clinical practice for the treatment of malignant effusion.

In the previously reported studies,large-diameter catheters or tubes were used for HITHOC or HIPEC,which were usually placed by thoracoscopic or laparoscopic surgeries under general anesthesia.These procedures are more invasive and require patients to be more tolerable to undergo the procedures.In addition,once the drainage tubes are removed after completion of HITHOC or HIPEC procedure,they are difficult to be re-applied,and thus,it is unlikely to perform multiple sessions of HITHOC or HIPEC for the same patients,especially for those who have recurrent effusion.

Here,we reported a new HITHOC/HIPEC protocol that used 16 G puncture needles under the guidance of ultrasound to establish the Inlet and Outlet ports that directly connected to a hyperthermic perfusion machine manufactured by Xi’an Good Doctor Medical Science Technology.Our pre-clinical experiments as well as clinical practices demonstrated that the desired flow rate and temperature control could be achieved with this method of puncture technique although diameter of the catheters applied in our HIPEC device was smaller compared to the tubes applied in other brands of HIPEC devices.Advantages of using this equipment are as followings:1)Local anesthesia is sufficient for the 16 Gneedle puncture technique;2)It is minimally invasive and thus,it is easily tolerable by the patients;3)Establishment of the Inlet and Outlet ports by puncture technique allows performing multiple sessions of HITHOC or HIPEC in the same patient in a short period of time(we recommend 3 times on day 1,4,and 7 as one therapeutic course);4)Temperatures of the perfusion solution at Inlet and Outlet ports on the patient’s chest or abdomen can be precisely controlled and adjusted;5)Positive pressure is applied in the perfusion and circulation system so that the hyperthermic circulating solution,which contains chemotherapeutic drug,can smoothly flow in and out the patient’s body cavity.These unique features of this equipment assure maximum and uniform distribution of the hyperthermic solution throughout the thoracic or abdominal cavity as well as efficient delivery of the chemotherapeutic drug to each corner of the cavities.We have previously reported on the safety of HITHOC or HIPEC procedures with this novel device in 985 patients(5,759 times procedure),and we found that the incidence of HITHOC or HIPEC-related adverse event was mild and low,only 2.0%in HITHOC and 2.4%in HIPEC,respectively,suggesting that HITHOC and HIPEC are safe and easily tolerable[19].In addition,we also compared this novel method of bedside HIPEC with the method of systemic intravenous chemotherapy in patients with locally advanced gastric cancer after D2 radical surgery,and we found that the bedside HIPEC significantly

reduced peritoneal metastasis and resulted in better median overall survival[16].

In the present study,we prospectively designed to compare this novel bedside HITHOC or HIPEC with conventional intrapleural or intraperitoneal chemotherapy for the treatment of malignant effusion.Patients with malignant pleural effusion or ascites resulting from various types of cancers(ovarian,gastric,and lung cancer)were enrolled and randomized in 8 centers.Since the primary cancer type may have great impact on patients’survival,survival rate was not selected as the endpoint measurement of this study.Instead,objective response rate(ORR)was used to compare the outcomes of the two treatments in the current study.The current study demonstrated that ORR was significantly higher in the group of patients treated with the bedside HITHOC or HIPEC than that of the patients treated with conventional intrapleural or intraperitoneal chemotherapy,and that bedside HITHOC or HIPEC was superior to thoracentesis followed by intrapleural injection of chemotherapeutic drug in lung cancer or paracentesis plus intraperitoneal injection of the drug in gastric cancer although it was not the case in the ovarian cancer patients.In addition,neither quality of life nor incidence of adverse event was significantly different between the two treatment groups of the current study.

Findings of the current study indicated that the minimally invasive and innovative method of hyperthermic intrapleural or intraperitoneal chemotherapy is reliable and safe for the treatment of patients with malignant effusion,and that clinical outcome of HITHOC or HIPEC is superior to that of the conventional thoracentesis or paracentesis plus local chemotherapy.Effects of this novel method on patients’survival,however,remains to be investigated in the future.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Funding

This paper was supported by the grants from National Natural Science Foundation of China(No.81572814).

Data availability statement

The data that support the findings of this study are openly available.

References

[1]Gayen S.Malignant pleural effusion:presentation,diagnosis,and management.Am J Med.2022;135(10):1188–1192.doi:10.1016/j.amjmed.2022.04.017.

[2]Hodge C,Badgwell BD.Palliation of malignant ascites.J Surg Oncol.2019;120(1):67–73.doi:10.1002/jso.25453.

[3]Barni S,Cabiddu M,Ghilardi M,et al.A novel perspective for an orphan problem:old and new drugs for the medical management of malignant ascites.Crit Rev Oncol Hematol.2011;79(2):144–153.doi:10.1016/j.critrevonc.2010.07.016.

[4]Spiliotis J,Halkia E,de Bree E.Treatment of peritoneal surface malignancies with hyperthermic intraperitoneal chemotherapycurrent perspectives.Curr Oncol.2016;23(3):e266-75–e275.doi:10.3747/co.23.2831.

[5]Kulandaisamy PC,et al.Malignant pleural Effusions-A review of current guidelines and practices.J Clin Med.2021;10(23):5535.

[6]Di Leo A,Corvasce A,Weindelmayer J,et al.Cytoreductive surgery(CRS)and hyperthermic intraperitoneal chemotherapy(HIPEC)in pseudomyxoma peritonei of appendiceal origin:result of a single Centre study.Updates Surg.2020;72(4):1207–1212.doi:10.1007/s13304-020-00788-5.

[7]Morris MC,Dhar VK,Stevenson MA,et al.Adjuvant hyperthermic intraperitoneal chemotherapy(HIPEC)for patients at High-Risk of peritoneal metastases.Surg Oncol.2019;31:33–37.doi:10.1016/j.suronc.2019.09.002.

[8]Faviana P,Boldrini L,Musco B,et al.Management of peritoneal carcinomatosis with cytoreductive surgery combined with intraperitoneal chemohyperthermia at a novel italian center.In Vivo.2020;34(4):2061–2066.doi:10.21873/invivo.12008.

[9]Jiao J,Li C,Yu G,et al.Efficacy of hyperthermic intraperitoneal chemotherapy(HIPEC)in the management of malignant ascites.World J Surg Oncol.2020;18(1):180.doi:10.1186/s12957-020-01956-y.

[10]Nikiforchin A,Gushchin V,King MC,et al.Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for patients with intrapleural dissemination of peritoneal surface malignancies.Ann Surg Oncol.2021;28(13):9126–9135.doi:10.1245/s10434-021-10298-2.

[11]Aprile V,et al.Hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma:the forefront of Surgery-Based multimodality treatment.J Clin Med.2021;10(17):3801.

[12]Dawson AG,Kutywayo K,Mohammed SB,et al.Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma:a systematic review.Thorax.2023;78(4):409–417.doi:10.1136/thoraxjnl-2021-218214.

[13]Ried M,Eichhorn M,Winter H,et al.[Expert recommendation for the implementation of hyperthermic intrathoracic chemotherapy(HITOC)in Germany].Zentralbl Chir.2020;145(1):89–98.doi:10.1055/a-0934-7806.

[14]Li Y,Zhou Y-F,Liang H,et al.Chinese expert consensus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies.World J Gastroenterol.2016;22(30):6906–6916.doi:10.3748/wjg.v22.i30.6906.

[15]Turaga K,Levine E,Barone R,et al.Consensus guidelines from the American society of peritoneal surface malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy(HIPEC)in colorectal cancer patients in the United States.Ann Surg Oncol.2014;21(5):1501–1505.doi:10.1245/s10434-013-3061-z.

[16]Liu L,Sun L,Zhang N,et al.A novel method of bedside hyperthermic intraperitoneal chemotherapy as adjuvant therapy for stage-III gastric cancer.Int J Hyperthermia.2022;39(1):239–245.doi:10.1080/02656736.2022.2028018.

[17]Cui S,Ba M,Tang Y,et al.B ultrasound-guided hyperthermic intraperitoneal perfusion chemotherapy for the treatment of malignant ascites.Oncol Rep.2012;28(4):1325–1331.doi:10.3892/or.2012.1913.

[18]Lu C,Li L,Luo Z,et al.Clinical efficacy of type-B ultrasoundguided intraperitoneal hyperthermic chemoperfusion combined with systemic chemotherapy in advanced gastric cancer patients with malignant ascites.Neoplasma.2016;63(2):299–303.doi:10.4149/217_150622N345.

[19]Liu L,Zhang N,Min J,et al.Retrospective analysis on the safety

of 5,759 times of bedside hyperthermic intra-peritoneal or intrapleural chemotherapy(HIPEC).Oncotarget.2016;7(16):21570–21578.doi:10.18632/oncotarget.7622.

[20]Urano M.Kinetics of thermotolerance in normal and tumor tissues:a review.Cancer Res.1986;46(2):474–482.

[21]Ba M-C,Cui S-Z,Lin S-Q,et al.Chemotherapy with laparoscopeassisted continuous circulatory hyperthermic intraperitoneal perfusion for malignant ascites.World J Gastroenterol.2010;16(15):1901–1907.doi:10.3748/wjg.v16.i15.1901.

[22]Badrudin D,Sideris L,Perrault-Mercier C,et al.Comparison of

open and closed abdomen techniques for the delivery of intraperitoneal pemetrexed using a murine model.J Surg Oncol.2018;117(6):1318–1322.doi:10.1002/jso.24960.

[23]Weisberger AS,Levine B,Storaasli JP.Use of nitrogen mustard in treatment of serous offusions of neoplastic origin.J Am Med Assoc.1955;159(18):1704–1707.doi:10.1001/jama.1955.02960350004002.

[24]Spratt JS,Adcock RA,Muskovin M,et al.Clinical delivery system for intraperitoneal hyperthermic chemotherapy.Cancer Res.1980;40(2):256–260.

[25]Yellin A,Simansky DA,Paley M,et al.Hyperthermic pleural perfusion with cisplatin:early clinical experience.Cancer.2001;92(8):2197–2203.doi:10.1002/1097-0142(20011015)92:8<2197::AIDCNCR1563>3.0.CO;2-F.

[26]Matsuzaki Y,Shibata K,Yoshioka M,et al.Intrapleural perfusion hyperthermo-chemotherapy for malignant pleural dissemination and effusion.Ann Thorac Surg.1995;59(1):127–131.doi:10.1016/0003-4975(94)00614-D.

[27]Ishibashi H,Kobayashi M,Takasaki C,et al.Interim results of pleurectomy/decortication and intraoperative intrapleural hyperthermic cisplatin perfusion for patients with malignant pleural mesothelioma intolerable to extrapleural pneumonectomy.Gen Thorac Cardiovasc Surg.2015;63(7):395–400.doi:10.1007/s11748-015-0535-x.

[28]Hofmann HS,Ried M.[Hyperthermic intrathoracic chemotherapy in thoracic surgery].Chirurg.2019;90(8):681–694.doi:10.1007/s00104-019-0989-y.

[29]Yasukawa M,Matsuo K,Matsuzaki S,et al.Management of recurrent granulosa cell tumor of the ovary:contemporary literature review and a proposal of hyperthermic intraperitoneal chemotherapy as novel therapeutic option.J Obstet Gynaecol Res.2021;47(1):44–51.doi:10.1111/jog.14494.

[30]Baratti D,Kusamura S,Niger M,et al.Colorectal peritoneal metastases treated by perioperative systemic chemotherapy and cytoreductive surgery with or without mitomycin C-Based HIPEC:a comparative study using the peritoneal surface disease severity score(PSDSS).Ann Surg Oncol.2021;28(6):3332–3342.doi:10.

1245/s10434-019-07935-2.

[31]Yi E,Kim D,Cho S,et al.Clinical outcomes of cytoreductive surgery combined with intrapleural perfusion of hyperthermic chemotherapy in advanced lung adenocarcinoma with pleural dissemination.J Thorac Dis.2016;8(7):1550–1560.doi:10.21037/jtd.2016.06.04.

[32]Aprile V,Bacchin D,Korasidis S,et al.Surgical treatment of pleural recurrence of thymoma:is hyperthermic intrathoracic chemotherapy worthwhile?Interact Cardiovasc Thorac Surg.2020;30(5):765–772.doi:10.1093/icvts/ivaa019.