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        Clinical observation on cycle thermo chemotherapy of intraperitoneal perfusion for malignant peritoneal effusion

        Date:2014年2月26日 10:54

        [Abstract] Objective: To evaluate the efficacy of cycle thermochemotherapy of intraperitoneal perfusion for malignant peritoneal effusion.  Methods: Fifty six cases with malignant peritoneal effusion were randomly divided into two groups. After abdominal paracentesis and lavation, 29 cases were treated with cycle thermochemotherapy of intraperitoneal perfusion and 27 cases were treated with thermochemotherapy of intraperitoneal  perfusion as control. Then the treatment effect and toxicities were assessed.  Results:  The response rate was 93.1% in treated group and 6 6.7% in the control group (P < 0. 025). The hyperhidrosis is more frequently happened in therapy group (89.7%) than in control group (29. 6%)  (P < 0.05) Conclusion:  Cycle thermochemotherapy of intraperitoneal perfusion for malignant peritoneal effusion is an effective and well tolerated method for the malignant peritoneal effusion with slight side effect.
        [Key words] malignant pleural effusion; thermotherapy; perfusion; cisplatine
        Modern Oncology 2009, 17(11): 2185 - 2187
        [CLC] R 730.53    [Document ID code] A
         
        [Article number] 1672- 4992- (2009) 11- 2185- 03
                                          
             The application of thermo chemotherapy of intraperitoneal perfusion for malignant peritoneal effusion with pharmacokinetic advantages and warm effect [1] had been wildly reported recently [2-4].  The traditional treatments of thermo chemotherapy using pre-warmed solution for perfusion and then heat the abdomen with microwave or radio frequency. However the constant hyperthermia temperature is hardly to reach, so the effect is hardly to be improved. The advent of cavity extracorporeal circulation perfusion machine may solve these problems, while the application of circulating perfusion thermochemotherapy in treatment of malignant peritoneal effusion had been rarely reported. Malignant ascites patients treated with circulating perfusion thermochemotherapy and simple hyperthermic perfusion chemotherapy were reviewed in this study to evaluate the therapeutic effect of circulating perfusion thermochemotherapy.

        1Patients and Methods
        1.1Patients
             56 patients diagnosed as malignant peritoneal effusion by pathology in our treatment center were collected from January 2007, including 33 males, 23 females, the median age of 55 years (54 ±16), the expected survival>3months. Encapsulated effusion were not formed, Including 17 cases of gastric carcinoma, 12 cases of liver cancer, colorectal cancer in 15 cases, 12 cases of ovarian cancer. All the cases had B ultrasound examination results, by which ascites were classified: 16 cases of grade I, 21 cases of grade II and 19 cases of grade III. (Patients were in supine position when underwent B ultrasound examination, grade I: effusion exist between intestinal; grade II: effusion exist between liver and kidney and paracolic sulci; grade III: effusion exist before liver)
             All of the cases met the inclusion criteria. And stratified randomization method was used. Firstly disease and ascites grade were stratified. Then simple randomized method was used in each layer to further divide the patients into treated group and control group. No heterogeneity of basic information was found between two groups (disease P>0.5;  ascites P>0.75), Table1.

        1.2Methods
        1.2.1Treatment plan All patients underwent bilateral abdominal paracentesis and lavage: abdominal paracentesis was performed in the left and right lower abdomen puncture point under the guided of B ultrasound. After that two needles were left and fixed, and connected with the disposable extracorporeal circulation catheter (one as input way and the other as output way) started the perfusion machine, and flooded abdominal cavity with preheating physiology saline at the temperature of 37~38℃。And the same time, output catheter was opened, and drained ascites and perfusion solution until the solution with lighter color of near to colorless. After drainage of fluid, further treatment was given according to treatment plan of each group.

        Table1 heterogeneity test of two groups

         

        Diseases

        Grade of ascites

         

        Gastric cancer

        Liver cancer

        Colorectal cancer

        Ovarian cancer

        I

        II

        III

        Treated group

        7

        7

        9

        6

        10

        9

        10

        Control group

        10

        5

        6

        6

        6

        12

        9

        X2

        1.68

        1.12

        P

        >0.5

        >0.75

         

        Treated group ① the centrifugal pump infusion hole of extracorporeal circulation perfusion machine (Harbin aerospace Technical Developing Company) was connected with inlet catheter, and centrifugal pump liquid hole is connected with the outlet catheter. So a closed loop of “inlet catheter- Abdominal cavity.-outlet catheter-perfusion machine-inlet catheter” was formed. The perfusion fluid (1500~3000ml saline + cisplatin 40~80mg, with concentration of 26.7%) was heated to 44.0~47.0℃ before intraperitoneal injecting to the closed system. ② Regulation of the perfusion machine to make the perfusion fluid circulating in the abdnominal cavity, and keep a constant temperature by real-time temperature measuring and heating when needed. The perfusion time was 60min. ③ Released amount of liquid after perfusion, then intraperitoneal injected of interleukin- II 3000000 u, 10mg dexamethasone, 200000U gentamicin. Pull out the puncture needles after routine disinfection. Pressure dressed the puncture point, ask patient to change position every fifteen minutes. Patients were in Observation wards until 30min after the treatment.④The treatment was repeated every 3 days. 4 times were considered to be 1 course of treatment.

             Control group had the same treatment plan except perfusion fluid circulating.
        1.2.2 Observation index ① the change of perfusion fluid: the input volume, output volume and temperature; ② Volume of ascites: abdominal ultrasound were performed before and 4 weeks after the fourth courses of treatment. ③ Laboratory examination: routine blood test and serum alanine aminotransferase were tested at the the ninth day and 4 weeks after the first course of treatment.④adverse reactions: record all kinds of adverse reactions during and after treatment.1.2.3 Criterion of therapeutic evaluation
             Therapeutic evaluation was classified according to WHO criteria: Complete remission (CR), ascites disappeared completely, lasting more than 4 weeks; Partial remission (PR), ascites reduced at least 50%, and remission of symptoms continued for more than 4 weeks; No response (NR), the change of ascites with less than 50% decreased or no more than 25% increased; Progressive disease (PD), ascites increased or advanced. Complete remission and partial remission were defined as effective results. Adverse reactions were also concerned. It was classified according to the criteria of WHO.
        1.3 Statistical analysis
        Chi-square test and Fisher exact probability test were used.

        2Results
        2.1The change of perfusion fluid: the input volume, output volume and temperature
        Treated group: The total volume was 1500ml~3000ml (mean of 2750ml) with the temperature of 46℃~47℃(mean of 46.5℃). The output volume was 1000ml~3000ml (mean of 2000ml) with the temperature of 39.4℃~43.4℃(mean of 41.4℃).Perfusion time was 60min.
             Control group: The total volume was 1500ml~3000ml (mean of 2750ml) with the temperature of 46℃~47℃(mean of 46.5℃). The output volume was 1000ml~3000ml (mean of 2000ml) with the temperature of 37.4~39.4℃(mean of 38.4℃).Perfusion time was 60min.
        2.2 Effect of treatment
             The Effective rate of treatment in the treated group was CR 13.8% cases (4/29), PR 79.3% (23/29), NR 6.9% (2/29), with effective rate of 93.1%. In control group, the therapeutic effect was CR 3.7% (1/27), PR 63% (17/27), NR 25.9% (7/27), PD 7.4 %(2/27) with the effective rate of the 66.7%. The effective rate of the treatment group was significantly higher than that in control group (X2=6.191, P<0.025). Table2

        Table2 Comparison of effects between the two groups

        Groups

        Effective
        (CR+PR)

        Non-effective
        (CR+PD)

        Total

        Effective rate(%)

        Treated group

        27

        2

        29

        93.1

        Control group

        18

        9

        27

        66.7

         

        X2-6.191, P<0.025

        2.3 adverse reactions
         There were no significantly difference of adverse reactions between two groups except sweating (p<0.05). The incidence rate of bone marrow suppression ,gastrointestinal reaction,abdominal pain, abnormal liver function etc. And adverse reactions have no significantly difference. See table 3

        Table3 Comparison of adverse reactions between the two groups

        Group

        case

        sweating

        fever

        Nausea vomiting

        Leukop-enia

        aglobu-lia

        Thrombo-cytopenia

        Aminotra-nsferase
        elevation

        Creatinine
        elevation

        I

        II

        I

        II

        I

        II

        I

        II

        I

        II

        I

        II

        Treated

        29

        26

        17

        6

        5

        2

        0

        3

        0

        1

        0

        5

        3

        1

        0

        Control

        27

        8

        14

        6

        7

        2

        0

        2

        1

        2

        0

        7

        2

        1

        0

        P

         

        <0.05

        >0.05

        >0.05

        >0.05

        >0.05

        >0.05

        >0.05

        >0.05

         

        3 Discussions
             Malignant ascites had high incidence in patients with malignant tumor. It affect the quality of life seriously. We applied cyclic heat perfusion chemotherapy for malignant peritoneal effusion, and achieved good effect. Circulation heat perfusion chemotherapy in tumor treatment has the following characteristics [5- 6].① High temperature can kill the tumor cells directly. Malignant cells are 2 times more sensitive to high temperature than the normal cells [7]. The ability of heat to killing tumor cells will increase 2 times with 1℃ increased when the temperature is more than 42℃. Or if prolong the time, the ability still enhanced. Besides that, heat can accelerate the apoptosis of tumor cells, and activate the immune response.② Synergistic effect of hyperthermia and chemotherapy. Heat has the effect of dilating of blood vessels and lymphatic vessels, increasing the cancer cell membrane fluidity, thus increase the concentration of chemotherapeutic agents in cancer cells. Heat can catalyze the reaction between drugs and tumor cells, and enhances the sensitivity of chemotherapy drugs, such as cisplatin.③ Intraperitoneal hyperthermic perfusion can wash away a number of cancer cells, and reduce tumor burden. Perfusion chemotherapy in abdominal cavity prolong the contact time of drug to tumor cells, so as to enhance the local concentration 10 times than the plasma concentration. From the above we know that, keeping the constant temperature of perfusion solution, complete contact of perfusion solution to organs and tissues were the key point to the ensure the effect of perfusion thermotherapy. So we let the perfusion solution circulating, and monitor the temperature in real-time mode in order to keep a constant temperature. Flow and heat carrier characteristics of water were also utilized to make the drug contact with organs completely. In this way, tumor cells can be killed effectively [8]. That is to say, “circulating and temperature control” were the key point.

             According to the Y Ellin [9] study, abdominal perfusion, temperature was equally to the average temperature of the inflow and outflow of perfusion. The proposed temperature in abdominal cavity was 43.9℃ in this study, which ensure the safety and effective of the treatment. This is probably the most important reason for the test group has a good curative effect. While in the control group, traditional method without continued heating cannot make sure a constant temperature of 43℃ in 1h. The traditional method without circulation of perfusion cannot wash away the tumor cells. So there was only 66.7% efficiency.
        The experimental group used the method of cycle perfusion fluid, overcome the defects, to ensure the effective treatment temperature of thermo chemotherapy. The effective rate was 93.1%. Most of the patients in the treated group had the symptom of sweating in the circulation process; it may be due high temperature induced by intraperitoneal perfusion therapy. For those patients, fluid infusion was given during treatment, and sweating symptoms disappear after the end of treatment. In the treatment process, the vital signs of the patients remain stable, no patients who could not tolerate the perfusion. Except for sweating, no grade III/ IV hematologic adverse reactions were found [10]. This study suggests that the circulating perfusion chemotherapy in treatment of malignant peritoneal effusion have the advantages of easy to operation, safety, good curative effect, fewer side effects.

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