Good Doctor·Hyperthermic Perfusion | Literature Review and Analysis | (5) “An Experimental Study on the Safety of Hyperthermic Perfusion Chemotherapy in Body Cavity Circulation”

Good Doctor·Hyperthermic Perfusion | Literature Review and Analysis | (5) “Experimental Study on the Safety of Intracavitary Hyperthermic Perfusion Chemotherapy”

[Abstract]

Experimental equipment: GDPR-2100S type intracavitary circulation hyperthermic perfusion machine

Objective: To investigate the effects of coelomic continued circulatory hyperthermia perfusion (CCCHP) at different temperatures on the vital signs and intra-abdominal organs of experimental animals, with the aim of identifying the optimal treatment temperature and effective methods for temperature control.

Methods: Dogs were used as experimental animals, and a CCCHP animal model was established using an intracavitary perfusion hyperthermic chemotherapy device. Animals were subjected to intraperitoneal hyperthermia at 41°C (divided into a saline‑only group and a cisplatin group), 42°C (saline group), and 43°C (saline group), with each treatment session lasting 1 hour and administered every other day for a total of three sessions—corresponding to one clinical treatment cycle. Vital signs, thermometer readings, and data from the hyperthermia device’s control panel were recorded. Peripheral blood samples were collected before each CCCHP session and 24 hours after each session for laboratory analysis. Twenty-four hours and two weeks after the third CCCHP session, two dogs from each group were euthanized; laparotomy was performed to assess morphological changes in the visceral organs, and liver, kidneys, and other tissues were excised for histopathological examination.

Results: At an intraperitoneal temperature of 41°C, three sessions of CCCHP had no significant effects on the dogs’ vital signs or hepatic and renal function, with only mild injury to the liver, kidneys, spleen, and intestinal tissues. Similarly, three sessions of CCCHP performed at 41°C in combination with cisplatin did not markedly impair the dogs’ normal physiological functions. In contrast, three sessions of CCCHP at an intraperitoneal temperature of 43°C resulted in varying degrees of impairment in the dogs’ vital signs and hepatic and renal function, accompanied by tissue damage of differing severity in the liver, kidneys, spleen, and intestines.

Conclusion: This study examined the effects of different temperatures during intracavitary hyperthermic perfusion chemotherapy on the vital signs and intra-abdominal organs of experimental dogs, with the aim of determining the optimal temperature for this therapeutic modality in animal models. The results demonstrated that a temperature range of 42°C to 42.5°C is therapeutically appropriate, and that only when the intraperitoneal temperature reaches 42.5°C does hyperthermia exert a meaningful therapeutic effect.

丨Article丨Source丨Core丨Background丨

“An Experimental Study on the Safety of Hyperthermic Intracavitary Perfusion Chemotherapy” – June 2012 – Chinese Journal of Clinical Oncology, Vol. 39, No. 22 (Liu Wenchao, Li Chunbao, Wang Yu, Li Wei)

This research was supported by the National Natural Science Foundation of China (Grant No. 30973437).

Objective: To investigate the effects of different temperatures during cavity circulatory thermal perfusion (CCTP) on the vital signs and intra-abdominal organs of experimental dogs, thereby determining the optimal temperature for CCTP in experimental animals.

[Keywords] Intracavitary hyperthermic perfusion chemotherapy, safety, thermal injury, thermochemotherapy‑induced injury

Academic Commentary and Analysis
 

This study used dogs as experimental animals to comparatively assess the effects of three different intraperitoneal hyperthermic chemotherapy (CCTP) temperatures—41°C, 42°C, and 43°C—on vital signs and intra-abdominal organs, with the aim of determining the optimal temperature for CCTP in this animal model. The research topic precisely addressed a central challenge then prevalent in clinical practice: although intraperitoneal hyperthermic chemotherapy holds promise for treating malignant ascites, there was a lack of studies examining the relationship between sustained circulating constant‑temperature therapy and organ‑tissue damage. This experiment sought to identify the safe temperature range for continuous, constant‑temperature hyperthermia combined with chemotherapeutic agents under a circulating perfusion regimen.

This study was officially published in 2012, at a time when intracavitary hyperthermic perfusion chemotherapy was still in the exploratory and developmental stages. At that time, China lacked a standardized protocol for temperature management. The findings of this experimental study not only provide critical preclinical evidence for selecting a safe temperature range for CCTP combined with chemotherapy, but also offer practical, actionable guidance for setting parameters on domestically produced hyperthermic perfusion devices, establishing clinical operating protocols, and conducting multicenter clinical trials.
 

Characteristics/Advantages of This Study

Outstanding value exploration

This experimental study was conducted around 2011, when intracavitary hyperthermic perfusion chemotherapy was still in its exploratory phase in China. Although some centers had begun to pilot clinical applications, the perfusion temperatures were largely based on foreign non‑circulatory hyperthermia protocols or ex vivo experimental data—typically 43°C (with a mixed intracavitary temperature of 43°C rather than an actual body‑temperature of 43°C) and a duration of 30 minutes considered relatively safe—leaving a critical gap: there was no systematic safety evaluation for sustained, constant‑temperature hyperthermia (60 minutes) combined with repeated chemotherapy administration (three cycles) under a circulatory perfusion regimen. The research team was the first to implement, in a canine model, clinically relevant flow rates (140 mL/min) and a treatment schedule (once every two days, for a total of three sessions), systematically assessing organ‑specific injury patterns and their reversibility across different temperature gradients. This work represents one of the earliest systematic studies in China on the safety of circulatory hyperthermic perfusion, providing groundbreaking experimental evidence that later informed the establishment of standardized clinical temperature protocols.
 

The experimental design is rigorous, and the temperature gradient is scientifically configured.

The study enrolled 18 healthy adult mixed-breed dogs, which were randomly assigned to three groups—41°C, 42°C, and 43°C—with six dogs in each group. Except for the perfusion temperature, all other experimental conditions were strictly standardized: anesthesia protocol, perfusate volume (2,500 mL of saline), chemotherapeutic agent and its dose (cisplatin at 100 mg/kg), flow rate (140 mL/min), duration of perfusion (60 min per session), and treatment regimen (once every 2 days, for a total of three sessions). This single‑variable design allowed for a direct comparison of the two therapeutic approaches. The temperature gradient was carefully calibrated to encompass the clinically relevant critical range (41–43°C), with a rationale that closely aligns with real‑world clinical scenarios.
 

A comprehensive assessment system and multidimensional injury evaluation.

The study has developed a four-dimensional evaluation framework encompassing “vital signs, dynamic monitoring of hepatic and renal function, gross morphological changes, and pathological alterations,” which features two key highlights:

(1) Dynamic monitoring of hepatic and renal function: Hepatic and renal function parameters (ALT, AST, Cr, UA) were continuously assessed at multiple time points—before perfusion and at 2, 4, 6, and 14 days post‑perfusion—allowing for a dynamic characterization of the temporal patterns of organ dysfunction and recovery under different temperature conditions. The results showed that in groups A and B, all measured parameters exhibited only minor fluctuations (P>0.05) and returned to baseline by 2 weeks; in group C, ALT, AST, Cr, and UA were significantly elevated at day 4 (P<0.05), with ALT and AST remaining abnormal at 2 weeks (P<0.05), while Cr and UA recovered to levels close to baseline (see Table 1 in the original text).

(2) Morphological and pathological examinations: Animals were euthanized at two time points—24 hours and 2 weeks after the final perfusion—and subjected to laparotomy for exploration, allowing assessment of acute injury at 24 hours and monitoring of the reversibility of damage at 2 weeks. The results showed that in groups A and B, no obvious injuries were observed in visceral organs such as the liver, kidneys, spleen, and intestines; by 2 weeks, there was no peritoneal adhesion, and gross examination revealed no significant abnormalities. Histopathologically, only mild congestion and inflammatory cell infiltration were noted, with near‑complete recovery by 2 weeks. In contrast, group C exhibited peritoneal adhesions in certain regions and on the omentum, marked congestion of mesenteric vessels, small areas of hepatic stasis, purplish‑brown hemorrhagic zones and petechiae in the intestinal tract, and kidneys that appeared grossly normal but remained unrecovered at 2 weeks; some segments of the intestine still displayed small areas of stasis, though organ adhesions had partially resolved. Therefore, a temperature of 43°C (with an intracavitary mixed temperature of 43°C, not an internal body temperature of 43°C) is not suitable as the therapeutic temperature for CCTP.
 

Proposes a ternary synergistic injury effect involving hyperthermia, fluid dynamics, and pharmacology.

The theoretical contribution of this study lies in its first-ever demonstration, under a circulating perfusion paradigm, that the “safe” temperature for non‑circulating hyperthermic perfusion cannot be directly extrapolated to circulating hyperthermic chemotherapy. The findings reveal that a regimen combining 43°C (with a mixed intracavitary temperature of 43°C, not the inlet body temperature), a flow rate of 140 mL/min, and a duration of 60 minutes, repeated three times with cisplatin, induces irreversible pathological damage to organs such as the liver, kidneys, spleen, and intestines, with no return to normal function even after two weeks. Yet, at the same temperature (43°C), this range has previously been regarded as “relatively safe” in ex vivo animal studies or in the literature on non‑circulating hyperthermia. This study attributes the exacerbated injury to a tripartite synergistic effect—namely, direct thermal damage, mechanical shear from the circulating fluid, and the cytotoxicity of the chemotherapeutic agent—and emphasizes that fluid‑shear–induced injury intensifies with increasing flow rates, while the drug itself also exerts direct deleterious effects on tissues. These experimental results suggest that, when performing circulating hyperthermic chemotherapy, one should not solely prioritize the direct thermal ablation of tumors at high temperatures (43°C and above); rather, it is essential to consider the safety threshold under the combined influence of the perfusate’s hemodynamic dynamics and the pharmacological agents.
 

The equipment offers precise temperature control, and the temperature measurement scheme is reliable.

The study utilized the GDPR-2100S intracavitary circulation hyperthermia perfusion machine (developed by Xi’an Good Doctor Medical Science and Technology Co., Ltd.). This device employs high-precision PT100 temperature sensors to perform real-time, multi-point temperature measurements at the inlet, outlet, and within the abdominal cavity, complemented by cross‑verification with an AI‑5600 digital thermometer. As a result, both temperature control accuracy and temperature uniformity have been significantly improved compared with earlier hyperthermia devices. In this study, temperature sensors were implanted in the left and right upper quadrants, enabling true multi-point temperature monitoring inside the abdominal cavity rather than relying on a single outlet temperature. This temperature‑measurement approach ensures the reliability of the experimental data.
 

Strong clinical guidance

Through rigorous experimentation, the study clearly delineated the safety boundaries at three critical temperature thresholds: a flow rate of 41°C and 140 mL/min for 60 minutes resulted in no significant tissue damage; at 42°C, mild, reversible injury was observed; and at 43°C—where the intracavitary mixed temperature was 43°C, not the core body temperature—the injury was more severe and irreversible. Accordingly, for canine experimental animals, the safe parameters of CCTP are a temperature of 42°C, a flow rate of 140 mL/min, and three intra‑peritoneal infusions, each lasting 60 minutes. Furthermore, a preliminary experiment at 45°C—conducted on a single dog receiving saline infusion at 140 mL/min, which died on the third day after three sessions—further substantiates the necessity of establishing a high‑temperature safety threshold. The experimental findings at these three temperature points provide clinicians with a clear, intuitive basis for selecting appropriate temperatures. These results suggest that, when performing circulating hyperthermic perfusion chemotherapy, it is essential not only to pursue the direct thermal cytotoxic effects of elevated temperatures (above 43°C) but also to account for the combined deleterious effects of the perfusate’s hemodynamic dynamics and the chemotherapeutic agents.
 

— Overall Evaluation —

This study was conducted during the exploratory and developmental phase of domestic CCTP technology around 2011. In a prospective design, 18 dogs were enrolled and divided into three temperature groups—41°C, 42°C, and 43°C. The safety of repeated treatments involving circulating hyperthermic perfusion chemotherapy combined with chemotherapeutic agents was systematically evaluated across four dimensions: vital signs, dynamic monitoring of hepatic and renal function, gross morphological changes, and histopathological alterations. The results demonstrated that a treatment regimen consisting of 42°C, a flow rate of 140 mL/min, maintained for 60 minutes, repeated three times at 2-day intervals, induced only mild, reversible damage to major canine organs (including congestion in the hepatic portal triads, inflammatory cell infiltration of the intestinal mucosa, and splenic congestion), with near-complete recovery within two weeks, thus proving both safe and feasible. In contrast, under identical conditions, 43°C (with an intracavitary mixed temperature of 43°C, not an internal body temperature of 43°C) resulted in irreversible injury, including widespread hydropic degeneration and punctate necrosis of hepatocytes, shedding of small intestinal villi, nuclear pyknosis and necrosis of splenic cells, and loss of the brush border of renal tubules. This research not only provides critical animal‑experimental evidence for selecting appropriate temperatures in intracavitary circulating hyperthermic perfusion chemotherapy but also theoretically elucidates the mechanism by which the triad of “heat + fluid + drug” synergistically induces tissue injury in a circulating perfusion setting. These findings offer robust baseline data and practical reference parameters for optimizing temperature‑control strategies in domestically developed hyperthermic perfusion devices, establishing clinical safety protocols, and facilitating multi‑center clinical studies. To this day, the results of this study continue to hold significant implications for guiding and cautioning clinical CCTP temperature settings.

Expert Profile

Dr. Liu, M.D., Ph.D.
Professional Society Member:
American Society for Cell Biology (2006–present)
American Heart Association (2006–present)
American Thoracic Society (1997–present)
2023–2025.5 Associate Professor, Department of Cardiology, University of Miami, USA
1999–2023 Assistant/Associate Professor, Division of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, USA
1996–1999 Postdoctoral Fellow, Department of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, USA
1992–1995: Master of Medicine, Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University (under Professor Sun Bin)
1986–1992: Clinical Physician, Department of Respiratory Medicine, General Hospital of the Shenyang Military Region
1981–1986 Bachelor of Medicine, Department of Clinical Medicine, Fourth Military Medical University