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Clinical Application of Constant Temperature Circulating Hot Infusion Chemotherapy in the Prevention and Treatment of Cavity Metastatic Cancer - Zhu Yangguang 2009
In the past two years, the use of constant temperature circulating perfusion for intraperitoneal and venous double-route hyperthermic chemotherapy has achieved satisfactory results in preventing and treating intraperitoneal metastatic cancer, which cannot be achieved by non-circulating hyperthermic perfusion chemotherapy. This article analyzes and compares the mechanisms, feasibility, treatment methods, and efficacy of intraperitoneal circulating and non-circulating hyperthermic perfusion chemotherapy based on clinical observations and literature reports.
Release time:
2022-08-26
Source:
"Modern Oncology" June 2009 Volume 17 Issue 6
Clinical application of constant temperature circulating hyperthermic perfusion chemotherapy in the prevention and treatment of cavity metastasis cancer
Zhu Yan-guang, Liu Wen-chao, Liu Du-hu, Fan Li, Cheng Jie, Sun Juan-hua, Shao Jie
The progress of continued hyperthermia perfusion cycle to prevent and cure metastasis cancer in cavity
ZHU Yan-guang, LIU Wen-chao, LIU Du-hu, FAN Li, CHENG Jie, SUN Juan-hua, SHAO Jie
Department of Tumor, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
[Abstract] Satisfactory effects to prevent and cure metastasis cancer in cavity were obtained by the method of venous double circulation and continued hyperthermia perfusion cycle. The article discussed the mechanism and feasibility of both the methods of cycle and non-cycle therapy in clinical practice.
[Key Word] CHP; coelom metastasis cancer; CCCHP
Modern Oncology 2009, 17(06): 1165-1167
[Indicative Abstract] In the past two years, satisfactory effects that non-circulatory hyperthermic perfusion chemotherapy could not achieve have been obtained in the prevention and treatment of cavity metastasis cancer using constant temperature circulating perfusion and venous double route hyperthermia. This article analyzes and compares the mechanism, feasibility, treatment methods, and efficacy of both circulating and non-circulating hyperthermic perfusion chemotherapy based on clinical observations and literature reports.
[Keywords] Cavity hyperthermic perfusion chemotherapy; cavity metastasis cancer; cavity constant temperature circulating hyperthermic perfusion chemotherapy
[Chinese Classification Number] R73-36; R73-37 [Literature Identification Code] A [Article Number] 1672-4992- (2009) 06-1165-03
[Received Date] 2008-12-24
[Revised Date] 2009-01-20
[Author Affiliation] Department of Tumor, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032
[Author Introduction] Zhu Yan-guang (1948-), from Sichuan, associate chief physician, mainly engaged in oncology.
[Corresponding Author] Liu Wen-chao (1962-), female, from Tianjin, professor, chief physician, doctoral supervisor, mainly engaged in comprehensive diagnosis and treatment of oncology and research in tumor biology.
Malignant tumors invading the serosal surface are prone to shedding cancer cells into the cavity, and surgery can also promote the shedding of cancer cells. The positive rate of cancer cells in the abdominal cavity after surgery can reach 50%. There are still 70% of lung cancer patients and 50%-60% of gastrointestinal cancer and ovarian cancer patients who experience recurrence and implantation metastasis, often leading to pleural, abdominal, and pericardial effusion (referred to as cavity). Intravenous chemotherapy has little effect on free cancer cells and small metastatic foci in the cavity. Despite the unremitting efforts of domestic and foreign oncology experts over the years, the 5-year survival rate remains around 30%. How to improve efficacy has become a difficult and hot topic in comprehensive cancer treatment. Since 1988, Spart et al. proposed intraperitoneal hyperthermic perfusion chemotherapy (HIPEC); due to its significant effects, it has been widely used both domestically and internationally. Continuous improvements in HIPEC and the development of related heating equipment have increased its 5-year survival rate to over 50%. Our department began to carry out abdominal cavity chemotherapy (IPC) (referred to as double-route chemotherapy) alongside intravenous chemotherapy in 1993 and has continuously expanded to the thoracic cavity and pericardial cavity, later improved to cavity hyperthermic perfusion chemotherapy (Coelom Hyperthermia Perfusion, CHP), combined with external high-frequency deep heating treatment, achieving good results. Since May 2006, we have adopted the TRL-type cavity circulating hyperthermia perfusion machine, performing 1,075 cases of constant temperature circulating hyperthermic perfusion chemotherapy (Coelom Continued Circulatory Hyperthermia Perfusion, CCCHP) for 290 patients with thoracic and abdominal cavity metastasis cancer, achieving some gratifying effects that non-circulatory hyperthermic perfusion chemotherapy (Coelom Non-Circulatory Hyperthermia perfusion, CNCHP) could not reach. Now, based on clinical observations and literature reports, we analyze and compare the mechanism, feasibility, treatment methods, and efficacy of CCCHP and CNCHP.
1. Constant temperature circulating hyperthermic perfusion chemotherapy (CCCHP)
Currently, there are several types of circulating hyperthermia perfusion machines in clinical use, and there is no unified standard for the devices. There are differences in key components such as infusion power pumps, heat exchangers, temperature monitors, flow control valves, and pipeline systems, leading to variations in operational circulation methods and effects. The method we adopt can achieve continuous heating and constant temperature circulation treatment, using saline/effusion as the thermal energy carrier, with a pressurized pump as the power source, heated through an induction heating tank, with sensors monitoring the inlet and outlet temperatures. The temperature and flow rate are adjusted through a control knob, with a one-time closed pipeline connecting the inlet and outlet puncture needles, maintaining the cavity temperature at 42℃-43℃ for 50-60 minutes, combined with heat-sensitive chemotherapy drugs, allowing thermal energy and drugs to be evenly distributed in the cavity and between organs, achieving effective treatment of malignant effusion and prevention of intra-cavity metastasis and implantation.
1.1 Treatment methods
For cavities without effusion: First, create artificial pleural/abdominal effusion, use B-ultrasound to avoid adhering intestinal tubes, lungs, and tumors, and determine the puncture point. Routine puncture establishes an access channel (for those with pleural effusion, a drainage tube can be placed first), connect the infusion device to inject 500ml of warm saline, ensuring that the puncture needle has unobstructed flow within the cavity. Connect to the circulation machine pipeline, set the temperature to 45℃-45.5℃, and infuse hot saline. Generally, for the abdominal cavity, 2500ml-3500ml is appropriate until mild abdominal distension is felt; for the thoracic cavity, generally 500ml-1000ml, until slight chest tightness is felt. Then, perform a second puncture to place the output needle and connect it to the circulation machine pipeline, starting the heating circulation treatment. During circulation, adjust the internal body temperature to between 43.5℃-44.5℃, with the output body temperature generally at 39.5℃-40.5℃ for the abdominal cavity and 41℃-42℃ for the thoracic cavity, with a flow rate of 150ml/min-220ml/min, maintaining a constant temperature circulation for 50-60 minutes, keeping the average internal body temperature at 42℃-43℃. Finally, drain some fluid, leaving no less than 1500ml in the abdominal cavity and about 500ml in the thoracic cavity. Inject chemotherapy drugs (administered in cycles during or after). Routine injection of dexamethasone 10mg and furosemide 20mg. To avoid brain damage from temperatures ≥39℃, a cool towel is routinely applied to the head. For cavities with effusion: Different treatments are applied based on the volume and nature of the effusion. If the effusion is viscous, first perform one-way synchronous thermal lavage, infusing while draining, using hot saline to replace most of the malignant effusion, diluting the effusion and toxins, ensuring smooth circulation treatment and improving efficacy. If the patient's condition is poor, direct use of thoracic and abdominal effusion circulation treatment can be employed. If there is a large encapsulated effusion in the thoracic and abdominal cavities, as long as there is 200ml-500ml of fluid in the encapsulated cavity, intraluminal circulation treatment can still be performed. If the effusion is gelatinous and difficult to expel through the puncture needle, a thicker side-hole catheter can be placed for one-way lavage before chemotherapy circulation. We have treated 3 cases of gelatinous effusion with good results. If it is infected effusion, only one-way synchronous thermal lavage is performed to control the infection, and circulation treatment is not advisable.
1.2 Drug selection and use
The selection of chemotherapy drugs and intravenous chemotherapy is conducted in the same scheme through dual routes. Due to the diffusion barrier effect of the cavity-plasma, the clearance rate of larger molecular weight drugs is much lower than that of intravenous administration, with drug concentrations in the cavity being dozens or even hundreds of times higher than those administered intravenously, and the synergistic effect of hyperthermia can even reach 100 times. Therefore, 1-2 chemotherapy drugs with thermal sensitivity and low stimulation can be selected each time. Commonly used drugs and their doses per session: cisplatin 50mg-100mg, fluorouracil 1g, paclitaxel 60mg-120mg, and gold sodium thiomalate 4mg, or in combination with interleukin-2 at 24 million U. Continuous hyperthermia will make the drug's efficacy and adverse reactions more pronounced; for example, doxorubicin has milder reactions during CHP, but can cause significant chemical peritonitis after CCCHP. Therefore, highly irritating drugs should be used cautiously or avoided to prevent complications such as serositis and adhesions, and should only be used in cases of refractory pleural effusion where thermal infusion circulation treatment has failed.
1.3 Indications
Cancerous tissues are sensitive to heat; newly formed blood vessels have poor heat dissipation regulation, causing heat to easily accumulate locally, leading to thrombosis and occlusion in small blood vessels, resulting in tumor ischemic degeneration and necrosis. Chemotherapy drugs can only penetrate tumor tissues to less than 3mm, while high temperatures can promote this penetration to increase up to 5mm. Therefore, the efficacy is significant for free cancer cells in the cavity and subclinical lesions less than 3mm3. The larger the tumor and the thicker the newly formed blood vessels, the less effective the thermal killing power becomes, with the direct killing power of hyperthermia significantly weakened for tumors larger than 5mm3. In cases of malignant effusion, cancer cells are often encapsulated by fibrin, making them difficult to phagocytize and penetrate with drugs. Therefore, circulating hyperthermia is suitable for patients with malignant effusion in the cavity, tumors invading the serosal surface of organs, or those with serosal implants, recurrences, or metastases, as well as patients with free cancer cells that cannot be removed post-surgery or with diffuse cancerous nodules in the serosa or mesentery, and enlarged metastatic lymph nodes. This treatment is often used as a supplementary therapy for preventing and treating cavity metastatic cancer and is also suitable for intra-cavity infections, achieving rapid detoxification and infection control through flushing and drainage.
1.4 Treatment course
Biological tissues, when heated, experience a short-term suppression of intracellular protein synthesis, leading to a significant increase in heat shock protein (HSP) synthesis, which reduces heat sensitivity. This phenomenon is referred to as heat tolerance. It can occur in two forms: continuous heating, which occurs when maintained at 43℃ for more than 2 hours; and intermittent heating, which occurs when the temperature is raised to 43℃, then allowed to drop below 41℃ before reheating. However, there are certain patterns to this, and it can decline. Experiments have shown that heat tolerance generally appears 7-8 hours after hyperthermia, peaks at 12-16 hours, begins to decline at 24 hours, significantly declines at 72 hours, and completely dissipates at 120 hours. Therefore, based on the chemotherapy regimen, heat tolerance requirements, and hospitalization time constraints, it is advisable to have intervals of 1-3 days between each session of thermal circulation treatment, with 2-3 sessions constituting a treatment course, and an average hospitalization duration of about 10 days can be completed. The total drug amount must be sufficient, requiring multiple treatment courses, as it has been found that the rate of tumor marker negativity in serum often occurs earlier than in effusion. Therefore, when the effusion disappears quickly and serum markers just turn negative, treatment should not be stopped immediately; instead, it should be consolidated for 1-2 more courses to ensure effective eradication of residual cancer cells in the cavity and improve the complete remission rate.
1.5 Efficacy and complications
The author has treated 155 cases with malignant effusion, including 127 cases of ascites, with the nature of the ascites being: hemorrhagic 43 cases, yellow 69 cases, chylous 11 cases, gelatinous 3 cases, and infected 1 case; 28 cases of pleural effusion, with the nature of the pleural effusion being: hemorrhagic 22 cases and yellow 6 cases. The number of treatment improvements varies with the nature of the effusion: generally, hemorrhagic ascites improve in 1-3 sessions, yellow ascites in 3-6 sessions, and chylous ascites in 6-9 sessions. After 2 treatment courses, the overall effective rate is 91.2%. The thoracic cavity generally shows better results than the abdominal cavity, with an effective rate of over 94% after 1-3 sessions, prolonged remission periods (6-22 months), significantly improved quality of life, a recurrence rate of 3.6%, and a marked decrease in tumor markers. As long as the procedures are strictly followed, preventive measures are effective, and nursing is meticulous, complications such as intra-cavity webbing, adhesions, encapsulation, and intestinal obstruction can be significantly reduced. Adverse reactions such as abdominal distension, abdominal pain, chest pain, and vomiting (6%) can mostly be prevented. Complications (0.6%): 4 cases of puncture into the intestinal cavity, 1 case of pneumothorax, and 1 case of chemical peritonitis, mostly occurring post-surgery or after repeated regional injections leading to adhesions, encapsulation, or in cases with little or no ascites or pleural effusion. With the accumulation of treatment experience and the support of B-ultrasound, the incidence of complications has become lower. No significant abnormalities were found in liver and kidney function or blood ions after treatment.
2 Differences in mechanisms, feasibility, treatment methods, and efficacy between CCCHP and CNCHP
2.1 Thermal chemotherapy killing
Hyperthermic chemotherapy is based on the different tolerance of cancerous tissue cells and normal tissue cells to temperature and the synergistic effect to kill tumors. Cancer cells have low heat tolerance; extending the heating time can increase the damage to cancer cells and inhibit proliferation. Heat therapy for 50-60 minutes at 40°C can increase the adverse drug reactions by 20%. At 42°C, cancer cells begin to degenerate and undergo apoptosis; at 43°C, cancer cells can coagulate and die. Normal tissue cells can tolerate 45°C-47°C without damage. Due to the peritoneal serosal area being equivalent to the body surface area, it has a strong heat absorption and dissipation function (the area of one side of the pleura is relatively small, so there is less heat dissipation). Therefore, when adjusting the internal body temperature, the dissipation factor should be considered, raising it to between 43.5°C-44.5°C to ensure an effective treatment temperature within the body. The heat source for CHP is mostly from constant temperature heaters or pre-warmed infusion. If the infused hot liquid is not continuously heated, it is impossible to maintain an effective temperature for cancer cell apoptosis/death. To prove this result, we used infusion devices or machine infusion divided into two groups for abdominal infusion temperature testing observation. Both groups infused 2500ml of 45°C liquid, observing significant differences in body cavity temperature after 5 minutes of infusion and after 5 minutes of circulating heating.
Table 1 Comparison of body temperature from two methods of abdominal thermal infusion
Group Infusion Flow Infusion 500ml Infusion 2500ml Temperature difference after infusion Heating Circulation In and Out Body Temperature
ml/min Liquid/Hour Liquid/Time After 5 Minutes
Infusion device infusion group 50ml-60ml 9 minutes 45 minutes <37°C <38°C 6°C-7°C
Machine infusion group 130ml 3 minutes 15 minutes >37°C >38°C 3°C-4°C
Combined with external hyperthermia treatment, the temperature of local and surrounding effusion in deep lesions increases, enhancing the local tumor's thermal killing effect. However, heat energy cannot be evenly distributed in the body cavity and between organs, and its efficacy on malignant effusion in the body cavity is not as good as that on solid tumors. If there are metal stents or metal anastomosis staples implanted in the cavity, the temperature at the metal site is prone to gather and increase, which can cause thermal damage to the surrounding normal tissue.
2.2 Tumor Reduction Rate
CCCHP has good drug diffusion, minimal residual dead space, and through thermal drug long killing, washing, effusion replacement, and drainage exclusion treatments, the tumor reduction rate is fast in a short time. Many cases of pleural and abdominal effusion treated with CHP for 6-12 times have not been controlled, but after 2-3 times of CCCHP, significant relief is observed, thus significantly shortening the treatment course.
2.3 Physical Clearance
Circulating infusion treatment can turn stagnant effusion into active effusion, allowing tangible substances such as cellulose and necrotic tissue deposited in intestinal loops, between organs, and on the surface of cancer cells to be mechanically washed away and mobilized. After 1-2 treatments, a considerable amount of cellulose and necrotic tissue, as well as encapsulated membranes, can be seen expelled with the drainage fluid. CHP has a flushing effect; however, due to the slow flow rate, the flushing force is not strong, making it difficult to clear the tangible substances deposited in the intestinal loops and between organs, thus affecting the efficacy. The diffusion of infused drugs is not uniform, and there are still chances of adhesion and encapsulation.
2.4 Biological Repair
The circulation of hot saline effectively cleans the serosal surface, removes cellulose and necrotic tissue, facilitates drug penetration, and the moist heat is beneficial for the repair of the serosal surface, reducing exudation. This changes the traditional view of using drugs to stimulate adhesion to reduce pleural effusion. After treatment, many patients not only effectively controlled malignant effusion, but also significantly reduced complications.
2.5 Establishing Channels
There are methods using puncture needles or catheters to establish channels. Clinical practice has confirmed that routinely placing two 14# needles can meet the requirements for treatment temperature and speed, simplifying and standardizing the operation, and ensuring good repeatability. With the support of ultrasound, there are fewer injuries and complications, and patient compliance is good, with a circulation success rate of 96%. Catheters are only placed when treating the thoracic cavity or special effusions; if routine catheter placement increases the difficulty of operation and patient compliance, it complicates nursing, has a high blockage rate, and is prone to increase the chances of peritoneal adhesion and intestinal obstruction.
2.6 Safety
Constant temperature circulation treatment does not cause local temperature accumulation or damage to normal tissues. We treated 5 patients with implanted metal stents or staples, and no abnormalities were observed. The volume of circulating liquid is large, with minimal stimulation, preventing the occurrence of peritonitis and adhesions. Unidirectional synchronous thermal washing changes the quality of effusion in a short time while keeping the volume unchanged, preventing adverse reactions such as decompression syndrome or mediastinal swing caused by excessive or rapid drainage. During treatment, the lowest KPS score of patients was 50, with the oldest being 80-82 years old, many of whom had pulmonary heart disease, and all successfully completed the treatment, indicating that this treatment is very safe and effective. CCCHP, due to its simple operation, safety, ease of use, lasting constant temperature, reliable efficacy, short treatment course, low recurrence rate, minimal damage, few complications, and no sequelae, has a significantly higher control rate for malignant effusion and metastatic lesions compared to non-circulating intraperitoneal hyperthermia, making it an ideal treatment method worth promoting. However, due to the lack of unified requirements for understanding intraperitoneal hyperthermia and existing hyperthermia equipment and implementation methods, there are many issues in clinical application, and the efficacy varies greatly. Continued research, practice, and communication are needed to gradually standardize and rationalize intraperitoneal circulating infusion hyperthermia, allowing more patients to receive safe and effective treatment.
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(Edited by: Li Pengchao)
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