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Clinical application of thermostatic circulatory hyperthermia perfusion chemotherapy in the prevention and treatment of body cavity metastatic cancer

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Clinical application of thermostatic circulatory hyperthermia perfusion chemotherapy in the prevention and treatment of body cavity metastatic cancer
Yanguang Zhu,Wenchao Liu,Duhu Liu,Li Fan,Jie Cheng,Juanhua Sun,Jie Shao
[Abstract]Satisfactory effects of prevention and cure on cavity metastatic cancer were obtained by double circulation and continued hyperthermia perfusion chemotherapy.This article discussed the mechanism and feasibility of both cycle and non-cycle hyperthermia perfusion chemotherapy according to the result of clinical observation and the literature.
[Key words]CHP,coelom metastasis cancer,CCCHP
[CLC]R73-36;R73-37[Document ID code]A[Article number]1672-4992-(2009)07-1165-03
  Cancer cells of malignant tumors invading serosal surfaces are easy to fall in the cavity,and an operation may also induce cancer cell shedding,so that the positive rate of postoperative intraperitoneal cancer cells is up to 50%[1].70%of lung cancer,and 50%-60%of gastrointestinal cancer and ovarian cancer still recur and have planting metastases[2],often causing effusion in the thoracic,abdominal and pericardial cavity(referred to as the body cavity).Intravenous chemotherapy can exert little effect on free cancer cells and micro-metastases in the cavity[3].Although cancer experts at home and abroad exert tireless efforts over the years,its five-year survival rate still remains at approximately 30%[4];therefore,how to improve treatment effect has become difficult and hot issues of cancer comprehensive treatment.Since in 1988 Sprat et al[5]proposed thermostatic hyperthermic intraperitoneal perfusion chemotherapy(HIPEC),the therapy has been widely used at home and abroad due to its obvious effect,and its five-year survival rate has increased to more than 50%along with continuous improvement of HIPEC and continuous development of related heating equipment[6].Since 1993,our department has carried out intravenous chemotherapy combining with intraperitoneal chemotherapy(IPC)(referred to as dual chemotherapies)and continued to expand it to the thoracic and pericardial cavity,and later improved the therapy to hyperthermic body cavity perfusion chemotherapy(Coelom hyperthermia perfusion,CHP),and body cavity chemotherapy plus external high frequency deep diathermy treatment,etc.,so that good treatment effects have been achieved.From May,2006 when TRL circulatory body cavity perfusion machine began to be used,and 290 patients with thoracic and abdominal cavity metastases have underwent 1075 thermostatic circulatory hyperthermic body cavity perfusion chemotherapy(Coelom Continued Circulatory Hyperthermia Perfusion,CCCHP),and it has achieved good treatment effects which non-circulatory hyperthermic body cavity perfusion chemotherapy(Coelom Non-Circulatory Hyperthermia Perfusion CNCHP)cannot achieve.Now,by combining clinical observation with literature,this paper analyzes and compares mechanism,feasibility,treatment methods and treatment effects of CCCHP and CNCHP.
1 Coelom Continued Circulatory Hyperthermia Perfusion(CCCHP)
  Currently,several types of circulatory hyperthermic perfusion machines are being used,and there has been no uniform standard about the equipment.The perfusion power pumps,heat exchangers,temperature monitors,flow regulating valves,piping systems and other key parts differ slightly[7],thus the operating and circulatory modes,and treatment effects vary to some extent[8].The method applied can achieve continued thermostatic circulatory hyperthermic therapy.Heated saline/effusion is used as basic liquid;and perfusion liquid is heated by the inductive heating tank;and the pressure pump is used as power source;and the inflow and outflow temperatures are monitored by sensors;and the temperature and flow rate are adjusted by the control knob;and the disposable closed pipes are connected to inflow and outflow puncture needles.The whole continued thermostatic circulation lasts for 50-60 minutes with the cavity temperature at 42°C-43°C.Thermal sensitive drugs used as well as thermal energy are uniformly distributed in the body cavities and among visceral organs so as to achieve the propose of effective treatment of malignant effusions and prevention from intracavitary metastases and planting.
1.1 Treatment methods
  Patients with no body cavity effusion:At first,artificial pleural effusion/ascites is made,B ultrasound is performed to make sure that the point of puncture keep away from adhesive intestine,lung and tumor,and to determine the puncture site.Conventional puncture is performed to establish inflow passage(after intubation and drainage if there is pleural effusion),and the infusion device is connected to perfuse 500ml warm saline.No resistance should be ensured when the liquid flows within the puncture needle.The pipe of circulation machine is connected and temperature is set at 45°C-45.5°C,and hyperthermic saline is perfused by one-way.2500ml-3500ml of liquid which is maintained in the abdominal cavity is generally appropriate when a patient fells mild distention;500ml-1500ml of liquid which is maintained in the thoracic cavity is generally appropriate when a patient fells mild chest tightness.Then,another puncture is performed and the outflow puncture needle is connected to the circulation machine pipe,and circulatory hyperthermic therapy begins.During circulation,inflow temperature is set at 43.5°C-44.5°C,and outflow temperatures in the abdominal cavity and the thoracic cavity are usually at 39.5°C-40.5°C and at 41°C-42°C,respectively.Flow rate is between 150ml/min-200ml/min,continued thermostatic circulation lasts for 50-60 minutes,and an average of temperatures in the body is maintained at 42°C-43°C.At last,partial liquid has been drained,and the remaining liquid is not less than 1500ml in the abdominal cavity and approximately 500ml in the thoracic cavity,respectively.Chemotherapeutic drugs are infused(administered in multiple times during or after circulation).Dexamethasone 10mg and furosemide 20mg are conventionally injected.To avoid≥39°C temperature which may harmful to brain,a cool towel is conventionally used.Patients with body cavity effusion:According to the difference of volume and property of effusion,the treatment is different.If the effusion is sticky,at first,one-way synchronization hyperthermic perfusion is performed.The drainage is performed during perfusion.Hyperthermic saline replaces most malignant effusion to dilute effusion and toxins so as to ensure smooth and highly effective circulatory therapy.If a patient’s condition is poor,pleural effusion and ascites can be directly made use of in circulatory therapy.If there is a relatively large amount of encapsulated effusion in the abdominal or thoracic cavity,as long as the encapsulated cavity contains 200ml-500ml liquid,circulatory therapy in the encapsulated cavity still can be performed.If jelly-like effusion is difficult to drain from the puncture needle,circulatory chemotherapy can be performed after a relatively thick catheter with side holes has been placed and one-way perfusion has been performed;we treated 3 cases of jelly-like effusion and achieved better effects.If effusion is infected,only one-way synchronization hyperthermic perfusion can be used to control infection and it is not appropriate to perform circulatory therapy.
1.2 Selection and use of drugs
  The selection of body cavity chemotherapeutic drugs is the same scheme as intravenous chemotherapy and the dual ways are performed at the same time.Due to the body cavity-plasma diffuse barrier action,the clearance rate of a drug with the larger molecular weight is much lower than that if it is intravenously administered,and the drug concentration in the body cavity is dozens or hundreds of times higher than that when it is intravenously administered,while hyperthermic chemotherapy synergic action is even up to 1000 times[9].Therefore,each time 1-2 chemotherapeutic drugs which have heat sensitive effect and have small irritation can be chosen.Each dose once for common used drugs is:cisplatin 50mg-100mg,fluorouracil 1g and paclitaxel 60mg-120mg,topotecan 4mg,etc.;or one of them is combined with interleukin-2 4 million U.Continued hyperthermic therpay allows drug potency and adverse reactions to be more obvious[10].For example,epirubicin causes mild reaction in CHP,but causes significant chemical peritonitis after CCCHP.Therefore,use of drugs with large irritation should be cautious or be avoided to prevent serositis,adhesions and other complications,and only is carried out to treat the patient with intractable pleural effusion or after hyperthermic circulatory perfusion therapy has failed.
1.3 Indications
  Cancer tissue is sensitive to heat[11]and new blood vessels have poor ability of reflectively regulating of heat dissipation,therefore,heat easily accumulates in the local region to cause thrombosis and occlusion in small blood vessels,leading to ischemia-induced tumor degeneration and necrosis.Chemotherapeutic drugs can only penetrate<3mm tumor tissue,while the hyperthermia can facilitate this penetration to 5mm thus treating free cancer cells and<3mm3 tiny subclinical foci in the cavity is obviously effective[12];the larger size the tumor have,the thicker the new blood vessels are,and the smaller thermal lethality is.When the thickness of tumor tissue is>5mm3,direct lethality of hyperthermic chemotherapy significantly reduces.When malignant effusion exists,most of cancer cells are wrapped by fibrin and it is difficult for cancer cells to be swallowed or penetrated by a drug.Therefore,circulatory hyperthermic chemotherapy is suitable for a patient with malignant effusion in the body cavity,a patient with a tumor invading serosal surface of visceral organs or with serosal plantation,recurrence and metastases,or a patient with free cancer cells or serosal,mesenteric diffuse cancerous nodules,metastatic swollen lymph nodes which cannot be cleared after an operation.Mostly,the therapy is performed to prevent and to treat body cavity metastatic cancer,is regarded as complementary treatment for systemic chemotherapy,and is also used to treat infection in the body cavity.Through rinsing and drainage,replacing infective effusion,and cleaning the body cavity,the purposes of rapidly attenuating toxins and controlling infection can be achieved.
1.4 Treatment courses
  Biological tissue sensitivity to heat decreases in a short time after heating because protein synthesis is inhibited and synthesis of heat shock proteins(HSP)increases obviously.The above phenomenon is called heat tolerance.It is produced by two ways:continuous heating at 43°C for more than 2 hours produces it;it is also produced by heating many times:the tissue is heated to 43°C and then returns to less than 41°C and is reheated.However,there are certain rules to follow.The tolerance can decline.An experiment has found that heat tolerance generally emerges 7-8 hours after hyperthermic therapy,it reaches the maximum 12-16 hours later,begins to decline 24 hours later,significantly declines 72 hours later,and completely declines 120 hours later[13].Therefore,according to chemotherapy scheme,heat tolerance requirements and hospital stay limit,1-3 days of hyperthermic circulatory therapy interval is appropriate,treatment for consecutive 2-3 times is regarded as a course,and during an average of 10 days of hospital stay the course can be completed.The total dose should be enough and multiple courses of treatment are required.Because it has been found that the turning negative rate of tumor markers in serum is often earlier than effusion after treatment,when effusion disappears and serum markers turn to the negative state,the therapy cannot be stopped and should consolidate for 1-2 courses to ensure effective killing of residual cancer cells in the cavity and to improve complete remission rate.
1.5 Treatment effects and complications
  155 patients with malignant effusion were treated,including 127 patients with ascites.The character of ascites were as following:43 cases with bloody ascites,69 with yellow ascites,11 with chylous ascites,3 with jelly-like ascites,1 with infective ascites.There were also 28 patients with pleural effusion.The character of pleural effusion was as following:22 cases with bloody pleural effusion,6 with yellow pleural effusion.Due to different properties of effusion,The number of times for effusion improvement by treatment varied:Usually,bloody ascites needed 1-3 times,yellow one needed 3-6 and chylous one needed 6-9,and after two courses of treatment the total effective rate was 91.2%;the treatment effect of pleural effusion was better than ascites,usually pleural effusion needed 1-3 times,and the total effective rate was more than 94%.The relief period(6-22 months)was prolonged significantly,quality of life was significantly improved,and the recurrence rate(3.6%)and tumor markers were significantly decreased.As long as the treatment was performed according to standard operating procedures,strict prevention measures were effective,and nursing was meticulous,network isolation in the cavity,adhesions,package,intestinal obstruction and other sequelae can significantly reduced;most of abdominal distention,abdominal pain,chest pain,vomiting,and other adverse reactions(6%)were preventable.Complications(0.6%):4 cases had punctured intestines,1 had pneumothorax,1 had chemical peritonitis;complications mostly occurred in patients with adhesions,package or no ascites and less pleural effusion after operations or repeated local injection.With the accumulation of the experience in the treatment and ensurance of B ultrasound,at present complication rate becomes much lower.After the treatment,no obvious abnormalities of hepatic,renal function and blood icons were found.
2,Differential points of mechanism,feasibility,treatment methods and treatment effects between CCCHP and CNCHP treatment[14-15]
2.1 Lethality of hyperthermic chemotherapy
  Hyperthermic chemotherapy kills tumor,based on different tolerance of cancer tissue cells and normal tissue cells to temperature and synergic effect[5].Due to low tolerance of cancer cells to heat,prolonged heating can aggravate cancer cell damage and inhibit their proliferation;when heating at 40°C for 50-60 minutes,adverse reactions of tissue cells to drugs can be increased by 20%;at 42°C,degeneration and apoptosis of cancer cells begin to emerge;at 43°C,coagulation and necrosis of cancer cells occur;however,normal cells can tolerate 45°C-47°C without impairment[10].Because peritoneal serosal area is equivalent to body surface area and peritoneal serosa has relatively strong function to absorb heat dissipation(one side pleural area is relatively smaller,thus the ability of heat dissipation is also less),when regulating inflow temperature the heat dissipation factor should be taken into account and the temperature setting should be increased to 43.5°C-44.5°C to ensure that the temperature in the body is effective[16].The CHP heat source is mostly the thermostatic heater or perfusion after preheating[17-18],and perfusion liquid is no longer heated,thus effective temperature at which apoptosis/lethality of cancer cells is ensured cannot be maintained.To prove this result,we used the infusion device or the perfusion machine to divide patients into two groups for intraperitoneal perfusion temperature test observation.2500ml at 45°C was perfused into each patient of the two groups.The outflow temperatures was observed separately in 5 minutes after perfusion group and 5 minutes after circulatory heating group;there was significantly difference between the outflow temperatures with the two groups(Table 1).
  The difference between inflow and outflow temperature is caused by the pipes and body cavity heat dissipations.Usually,only after continuous heating circulatory perfusion lasts 10 minutes,the temperature in the body can reach 42°C-43°C.Because the inactivation of the tumor cells is in a time-dependent manner,the treatment time cannot be less than 50 minutes;if the temperature is≤41°C,prolonging the circulatory time to 90 minutes can improve the hyperthermic lethality.Therefore,CHP can improve the effect of hyperthermic chemotherapy,but it is difficult to achieve action of directly effectively killing cancer cells.Some reports have pointed out that if the temperature is<40°C,effectively killing cancer cells cannot be achieved and cancer cells also may be promoted to spread[11,19].To improve the thermal lethality,mostly,the external diathermy treatment is used as an adjuvant to increase temperature of local deep lesion region and effusion around it for enhancing thermal lethality to local tumor[20-21].However,heat energy cannot be uniformly distributed among the body cavity and visceral organs,thus treatment effect of malignant effusion in the body cavity is not as good as that of a solid tumor.If there are implanted stents or indwelled metal staples the cavity,the temperature of the metal is easily suddenly elevated and the thermal impairment of local normal tissue may be caused[22].
2.2 Cytoreductive speed
  CCCHP has good drug diffusion and less residual dead cavity.In addition,through long killing of hyperthermic drugs,perfusion and rinsing,replacement and drainage of effusion,and other treatments,tumor reduction is fast in a short time.A lot of abdominal and pleural effusions cannot be controlled with 6-12 times CHP treatment but can be significantly relieved with 2-3 times CCCHP.Therefore,the treatment course becomes shorter significantly).
2.3 Physical clearance
  Circulatory perfusion therapy allows effusion to become“active water”from“dead water”along with circulation,and allows the fibrin,necrotic tissue and other tangible materials depositing among the intestinal loops,visceral organs,surface of cancer cells to fall off and swim along with mechanical circulation and rinsing.It is often found that after the therapy 1-2 times,more fibrin,necrotic tissue and even wrapped cyst membrane are discharged along with draining liquid.CHP has rinsing effect[23],however,because flow speed is slow and scouring force is not large,it is difficult to clear tangible materials depositing among the intestinal loops and visceral organs so that the treatment effect is affected and due to difficultly uniform diffusion of the perfusion drug,there is still chance of adhesion and encapsulation.
2.4 Biological repair
  Circulatory perfusion with hyperthermic saline better cleans the serosal surface,clears the fibrin and necrotic tissue,and facilitates penetration of drugs.Wet heat is also conducive to repair of serosal surface and to decrease of exudation.Therefore,the traditional treatment opinion that drug stimulation has been used to generate adhesion so as to reduce pleural effusion is changed.After the new treatment,many patients not only have effectively controlled malignant effusions,but also have significantly decreased complications.
2.5 Establishing passages
  Passages are established by puncture needles or indwelled catheters[6].Clinical practice has confirmed that if two gauge 14 needles are routinely punctured and indwelled the treatment temperature and speed can meet the requirements.The operation is simple,can be routinely used,and has good repeatability.Due to the ensurance of B ultrasound,there are less impairment and fewer complications,patient have better compliance,and the successful circulation rate reaches 96%.Only in the treatment of pleural effusion or of special effusions,catheterization is required.If the catheter is routinely indwelled,difficulty in operation and patient compliance can be increased,nursing becomes troublesome,blockage rate of the catheters increases,the therapy only can be maintained for a shorter time,the chance of adhesions around the catheters and intestinal obstruction easily increases.
2.6 Security
  Thermostatic circulatory therapy cannot cause local temperature accumulation and normal tissue impairment.We treated 5 patients with metallic stents or staples implanted in their bodies,but no abnormalities have been found..Large circulating liquid volume and mild drug irritation can prevent peritonitis and adhesions.One-way synchronization hyperthermic perfusion allows much liquid inflow and outflow in a short time to change quality of effusion but not to change the volume,so as to prevent decompression syndrome/mediastinal swing and other adverse reactions due to too rapidly releasing too much liquid once.During the treatment,patients had a minimum of 50 points of KPS score,the oldest patients were 80 years old-82 years old,and most of patients were accompanied with pulmonary heart disease,but all of the patients could successfully complete the treatment,indicating that this treatment is very safe and effective.CCCHP is an ideal therapeutic method because its control rate of malignant effusion and metastatic foci is significantly higher than non-circulatory hyperthermic body cavity chemotherapy due to its simple operation,safety and feasibility,long lasting and constant temperature,reliable treatment effect,short course,low recurrence rate,less impairment,fewer complications,no sequelae and other obvious advantages.Therefore,the therapy is worth popularization.However,because many problems are faced by clinical applications and treatment effects are largely different due to opinions about body cavity hyperthermic chemotherapy and due to no uniform requirements of the existing equipments and the implementation of the therapy,continuous efforts in study,practice and communication are needed and circulatory hyperthermic body cavity perfusion chemotherapy should be gradually standardized and rationalized so as to allow more patients to receive safe and effective treatment.
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(Editing and proofreading:Pengchao Li)
[Received date]December 24,2008
[Received date after revision]January 20,2009
[Author unit]Department of oncology,Xijing Hospital of the Fourth Military Medical University,Xi’an City 710032,Shaanxi province
[Author introduction]Yanguang Zhu(1948-),female,born in Sichuan province,deputy chief physician,mainly engages in oncological internal medicine work.
[Corresponding author]Wenchao Liu(1962-),female,born in Tianjin city,professor,chief physician,doctoral tutor,mainly engages in comprehensive diagnosis and treatment of oncological interna medicine,and cancer biology research.
Modern Oncology,June,2009,17(6):1165-1167
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