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        Clinical application of circulative hyperthermic intraperitoneal perfusion chemotherapy

        Date:2014年2月26日 10:39

        Yiwei Huang, Haifan Xu, Feng Lu, Di Zheng (The First Affiliated Hospital of Nanhua University, Hengyang, Hunan 421000)

        [Abstract] Objective: To evaluate the clinical treatment effect of circulative hyperthermic intraperitoneal perfusion chemotherapy by using the intraperitoneal perfusion machine early after gastric cancer operation. Method: 96 patients receiving gastric cancer operation were divided into treatment group and control group with the random number table method. 48 cases in treatment group received early postoperative hyperthermic intraperitoneal perfusion chemotherapy combined with intravenous chemotherapy, and 48 cases in control group received postoperative intravenous chemotherapy only. The adverse reactions and complications, quality of life, immune function, local recurrence rates, distant metastasis rates, survival rates between the two groups were compared. Result: The postoperative adverse reactions and complications of the two groups were compared, and the difference was not statistically significant (P >0.05); Improvement of the quality of life in treatment group was better than control group (P <0 05.); each of CD3+, CD4+, CD4+ /CD8+ values in treatment group was significantly higher than before the treatment (P <0.01), and that in control group did not change significantly; the local recurrence rate of the abdominal cavity in treatment group was significantly lower than control group (P <0.05). Conclusion: Early after gastric cancer operation, by using the intraperitoneal perfusion machine, circulative hyperthermic intraperitoneal perfusion chemotherapy combined with intravenous chemotherapy can improve the quality of life of patients, enhance the patients' cellular immune function, reduce the local recurrence and metastasis rate, and adverse reactions can be tolerated and the patients have no significant complications, thus clinical samples should continue to be expanded for further observation and research.
        [Key words] gastric cancer; hyperthermic intraperitoneal perfusion; chemotherapy; quality of life; immune function

        Gastric cancer is one of the most common human malignant tumors. Peritoneal dissemination is the important way of gastric cancer metastasis; peritoneal metastasis accounts for approximately 50% of gastric cancer postoperative recurrence, and is the most common cause of gastric cancer postoperative recurrence and related death [1]. Since in 1988 Fujimoto applied hyperthermic intraperitoneal perfusion chemotherapy technology to treat gastrointestinal malignant tumors for the first time [2], in recent years hyperthermic intraperitoneal perfusion chemotherapy to prevent and treat gastrointestinal cancer postoperative recurrence has achieved certain effect. From October 2010 to October 2011, in our hospital high-precision circulative hyperthermic intraperitoneal perfusion chemotherapy project was carried out for one whole year. During the year, early after radical operation for gastric cancer, patients received hyperthermic intraperitoneal perfusion chemotherapy combined with intravenous chemotherapy. At present, the project is still being carried out and has achieved good stage effect.
         
        1 Materials and Methods
        1.1General information: 100 cases were divided into hyperthermic intraperitoneal perfusion combined with intravenous chemotherapy group (treatment group) and simple intravenous chemotherapy group (control group) with the random number table method. In treatment group, 48 cases included 28 males and 20 females, aged 30 to 70 years old, including 36 cases of radical distal subtotal gastrectomy and 12 cases of radical total gastrectomy. In control group, 48 cases included 27 males and 21 females, aged 31 to 68 years, including 32 cases of radical distal subtotal gastrectomy and 16 cases radical total gastrectomy. Other data is shown on Table 1. Before the operation, the diagnoses of the selected patients in the two groups were confirmed by gastroscopy and pathology. They had no recent adjuvant radiotherapy and chemotherapy history, and their liver and kidney function, bone marrow function were normal and they had no chemotherapy contraindications. The abdominal B ultrasound and CT before the operation and evaluation during the operation excluded patients who had had distant metastases or whose cancer could not be removed. Furthermore, after the operation, the diagnoses were confirmed by paraffin pathological slice with reference to TNM staging. Gender, age, pathological types, clinical stages and operation methods of the two groups were comparable.
         

        Table 1 Pathological typing and staging of the patients in the two groups (cases)

        Group

        Case number

        Types of pathology

        staging

        Adenocarcinoma

        Mucinous adenocarcinoma

        Poorly differentiated and undifferentiated carcinoma

        Treatment group

        48

        29

        5

        14

        12

        23

        13

        Control group

        48

        27

        8

        13

        10

        26

        12

         

        1.2 Perfusion instrument and equipment
        1.2.1 TRL hyperthermic chemotherapy perfusion machine (manufactured by Harbin Aerospace Science and Technology Development Co., Ltd.): Liquid flow was adjustable between 100 and 600 ml/min; temperature control accuracy was ±1.5℃. The machine could be used to precisely control temperature, flow volume, time, and other indicators to overcome uneven temperature, unstable flow volume and shortness of time for maintaining effective treatment temperature and other difficulties which had been faced when in the past various intraperitoneal perfusion methods had been performed. In addition, the machine had no special requirements to the working environment.
        1.2.2 TRL disposable medical special circulation line.
        1.3 Methods of treatment
        1.3.1 After any patient in treatment group underwent the removal of the tumor, one silicone perfusion tube was indwelled in the right upper quadrant of the abdomen and another was indwelled in the left lower quadrant, and the abdomen was closed after cleaning the abdominal cavity.
        1.3.2 Early postoperative circulative hyperthermic intraperitoneal perfusion method: In treatment group, on the first day after the operation, any patient began to undergo circulative hyperthermic intraperitoneal perfusion chemotherapy under non-anesthesia in the perfusion treatment room. Before the perfusion, fibrous tissue, blood clot and necrotic and cast-off tissue within the equipment and the drainage tube were cleared. The hyperthermic chemotherapy machine was used to heat chemotherapeutic liquid (physiological saline 3000 ml plus cisplatin 50 mg) to 38 ℃, and to infuse it into the abdominal cavity at flow rate of 100-300 ml/min. After the patient adapted to the temperature, the liquid continued to be heated and by using temperature control system the intraperitoneal temperature was stabilized at 42-43℃ for 60-90 min. According to the tolerance of the patient, the volume of the intraperitoneal chemotherapeutic liquid was controlled at 2000-3000 ml. During the perfusion, the patients underwent ECG monitoring, and according to the patient’s condition, the perfusion machine was regulated and controlled at any time. If the patient was difficult to tolerate, bucinperazine 10-20 mg was intramuscularly injected. After the end of the perfusion, the perfusion fluid was released and approximately 1000 ml perfusion therapeutic fluid retained in the abdominal cavity. A perfusion tube was connected to a drainage bag and the perfusion fluid in the abdominal cavity was slowly released. 7 days later, the perfusion tube was pulled out.
        1.3.3 Intravenous chemotherapy: Two weeks after the operation, intravenous chemotherapy was performed. The scheme was oxaliplatin 200 mg/D1 + 5 - FU 0.5g/D1 – D5 + calcium folinate 0.3 g/D1-D5. 3 to 4 weeks after completion of above chemotherapy, each patient went back to the hospital and received the next course of chemotherapy, and then the patient received the course weekly, with a total of 5 courses. The two groups received the same scheme for intravenous chemotherapy. 1.4 Observed indexes
        1.4.1 Observation of adverse reactions and complications: A variety of adverse reactions and complications of the treatment, which were judged according to World Health Organization (WHO) toxic reaction criteria of chemotherapy, were observed and counted in the two groups.
        1.4.2 Evaluation of quality of life: According to the general condition scoring standard Karnofsky (KPS), before the treatment and at the end of the treatment, the quality of life of a patient was evaluated and was divided into 3 grades including improvement, stabilization and reduction, that is, after the end of the treatment, compared with pre-treatment score, increase by 10 points was improvement, decrease by 10 points was reduction, and increase or decrease by<10 points was stabilization.
        1.4.3 Rating immune function: Changes of indexes of patients’ T cell subsets in the two groups were compared before and after the treatment. Fasting peripheral venous blood of all patients was collected and the flow cytometry was used to examine T cell subsets.
        1.4.4 Follow-up observation of recurrence rate and survival rate: Routine blood test, liver and kidney function were regularly reexamined. Gastroscopy and whole abdominal CT were used to determine if there was intraperitoneal recurrence or distant metastasis in patients.
        1.5 Statistical analysis: SPSS13.0 statistical software package was used to process and analyze data. t test was used to compare the means between the two groups and χ2 test was used to compare the rates between the two groups. The survival rate was calculated by Kaplan-Meier method.

        2 Results
        2.1 Adverse reactions and complications: most of adverse reactions which were clinically observed were grade Ⅰ ~ Ⅱand were all relieved by appropriate symptomatic treatment. The bone marrow suppression and nausea, vomiting reaction rates in treatment group were higher than control group, but the difference was not statistically significant (P> 0.05). The intestinal obstruction rate in treatment group was lower than control group and the fact might be related to flushing out of intraperitoneal fibrous tissue, blood clot and necrotic and cast-off tissue by early postoperative perfusion, but the difference was not statistically significant (P> 0.05). In addition, no obvious heart, liver, kidney toxicity was observed. Patients tolerated the treatment well, thus no patient withdrew from the treatment due to adverse reactions. Routine blood test, electrolytes, liver and kidney function were not significantly abnormal, and there were no incision infections and intraperitoneal infections, chemical peritonitis, anastomotic leakage and other complications. Table 2 is shown.

        Table 2 Adverse reactions of the patients in the two groups [cases (%)]

        Group

        Case number

        Bone marrow suppression

        Nausea,
        vomiting

        Bellyache

        Diarrhea

        Intestinal obstruction,
        enteroparalysis

        Ⅰ,Ⅱ

        Ⅲ,Ⅳ

        Ⅰ, Ⅱ

        Ⅲ,Ⅳ

        Treatment group

        48

        31
        (64.6)

        16
        (33.3)

        25
        (52.1)

        10
        (20.8)

        7(14.6)

        3(6.3)

        2(4.2)

        Control group

        48

        25
        (52.1)

        12
        (25.0)

        19
        (39.6)

        7
        (14.6)

        3(6.3)

        1(2.1)

        4(8.3)

        P value

         

        >0.05

        >0.05

        >0.05

        >0.05

        >0.05

         

        2.2 Comparison of the quality of life (KPS score) before and after the treatment: The results showed that the difference between the two groups was statistically significant (P <0.05). Table 3 is shown.
        2.3 Comparison of the cellular immune functions in the two groups: In treatment group, CD3+, CD4+, CD4+ /CD8+ after the treatment were higher than before the treatment, CD8+ reduced, and the difference was statistically significant (P <0.01); in control group, compared with each of the values before the treatment, relevant value after the treatment did not change obviously, and the difference was not statistically significant (P> 0.05). Table 4 is shown.
        2.4 Recurrence rate and survival rate: The local recurrence rate in treatment group was 4.2% and that in control group was 16.7%. The difference of the local recurrence rates between the two groups was statistically significant (P <0.05). The distant metastasis rate in treatment group was 6.3% and that in control group was 10.4%. The difference of the distant metastasis rates between groups was not statistically significant (P> 0.05). The postoperative one-year survival rate in treatment group was 95.8% and that in the control group was 93.7%, and the difference between the two groups was not statistically significant (P> 0.05).

        Table 3 Comparison of KPS scoring results of the patients of the two groups after the treatment

        Group

        Case number

        KPS scoring results (cases)

        Total effective rate [cases (%)]

        improvement

        stabilization

        reduction

        Treatment group

        48

        31

        11

        6

        42 (87.5)①

        Control group

        48

        13

        19

        16

        32 (66.7)

         

        Note: Compared with control group, ①P<0.05

        Table 4 Changes of the patients’ cellular immune functions in the two groups before and after the treatment ( ±s)

        Group

        Time

        CD3 +

        CD4 +

        CD8 +

        CD4 + /CD8 +

        Treatment group

        Before the treatment

        44.63 ± 3.03

        33.16 ± 2.52

        38.60 ± 1.54

        0.86 ± 0.10

        After the treatment

        58.43±3.43

        46.24 ±2.48

        29.29 ±1.52

        1.58 ±0.14

        Control
        group

        Before the treatment

        43.47 ± 3.59

        33.20 ± 2.93

        38.30 ± 1.46

        0.87 ± 0.09

        After the treatment

        44.01 ± 4.27

        32.88 ± 2.78

        38.04 ± 1.14

        0.86 ± 0.08

         

        Note: Compared with the group itself before the treatment, ① P<0.05

        3 Discussion
        Intraperitoneal recurrence is a major postoperative death cause of intraperitoneal malignant tumors, especially gastric cancer [3]. The mechanism of postoperative peritoneal recurrence and metastasis of gastric cancer is: the presences of intraperitoneal free cancer cells and residual tiny foci are the main factors of postoperative peritoneal recurrence and metastasis, and sources of free cancer cells include the first one that gastric cancer cells invade the whole gastric wall including serosa and directly fall into the abdominal cavity, and the second one that during the operation the cancer cells at the cutting edge of the specimens fall off or the third one that the cancer cells in the severed blood vessels and lymph vessels on the operative field flow into the abdominal cavity with blood and lymph, especially when there is tumor thrombus formation in the blood vessels and lymph vessels [4]. Therefore, reducing postoperative intraperitoneal recurrence of gastric cancer is a key factor for improving postoperative prognosis and survival rate of gastric cancer patients.
        Early postoperative hyperthermic perfusion chemotherapy has many advantages [5-6]: (1) Plantation recurrence of the cancer cells in the surgical removal site and on the peritoneal surface injured by   operation is easiest to take place. (2) At this time when the tumor had been radically resected, tumor burden in the body is smallest, and cell division and proliferation are fastest, thus cancer cells are sensitive to chemotherapy. (3) Abdominal adhesions have not yet formed, thus all peritoneal surfaces can fully contact with the chemotherapeutic liquid. (4) Intraperitoneal temperature and chemotherapeutic fluid are more uniformly distributed. Large volume of warm liquid containing chemotherapeutic drugs can make tiny cancer metastases in the abdominal cavity more fully contact with chemotherapeutic drugs; during the perfusion, chemotherapeutic liquid can exert mechanical clearing effect to the free cancer cells in the abdominal cavity; after chemotherapeutic drugs are infused into the abdominal cavity, relatively high, constant and long-lasting drug concentration can be formed in the abdominal cavity and only less liquid goes into the systemic circulation resulting in mild systemic adverse reactions, thus compared with simple intraperitoneal chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy has obvious advantages in clinical practice [7-8]. The main anti-tumor mechanism of hyperthermic perfusion chemotherapy is direct killing effect of high temperature to tumor, antitumor synergistic effect of high temperature and chemotherapeutic drugs, and mechanical rinsing effect, thus the effective treatment temperature in the abdominal cavity is the key to obtain satisfactory clinical treatment effect [9]. During the actual clinical application, intraperitoneal perfusion liquid temperature, duration and selection of perfusion fluid chemotherapeutic drugs are key factors affecting the clinical treatment effect and safety of hyperthermic intraperitoneal perfusion chemotherapy; perfusion speed of perfusion fluid is also an important factor for maintaining a precise constant temperature in the abdominal cavity. Therefore, high-precision control of temperature and perfusion speed is the key technology of circulative hyperthermic intraperitoneal perfusion chemotherapy. Only the key technology can meet the requirement of continuous constant temperature circulative perfusion, and ensure the best treatment effect under the premise of stabilization and safety. Therefore, the use of the high-precision control perfusion machine in this study is ideal technical method of current clinical intraperitoneal perfusion chemotherapy.
        Clinical studies have shown that complications and adverse reactions during and early after hyperthermic intraperitoneal perfusion therapy were mainly digestive tract reactions [10], followed by bone marrow suppression, and the complication incidence was related to drug infusion, operative time, operative extent, peritoneal metastasis staging, anastomotic number and others [11], indicating that the strength of a patient’s adverse reactions will directly affect the treatment effect. Through the retrospective analysis of 96 patients in our hospital, 48 patients in treatment group were found to have no wound dehiscence, anastomotic fistula, abdominal cavity infections, adhesive intestinal obstruction and other severe complications, and no treatment related death. The postoperative adverse reactions and complications of the two groups were compared, and the difference was not statistically significant (P> 0. 05). In present society, quality of life has been confirmed to be an independent prognostic factor for tumor and is regarded as an ultimate evaluation method. Evaluation of quality of life is the most sensitive and powerful one among indexes related to disease outcome, thus improving the quality of life of cancer patients is the real challenge which cancer treatment faces [12]. In this study, the evaluation of quality of life in the two groups after the treatment showed that improvement of quality of life in treatment group was better than control group (P <0.05). Another study showed that the peripheral CD3+ and CD4+ cells of patients with malignant tumor significantly reduced, and CD8+ cells significantly increased. Along with increase of the clinical stage, the inhibition degree of peripheral blood T lymphocyte subsets gradually strengthened, showing that the weakening of the immune function of patients with cancer may be the result of tumor progression [13]. In this study, in treatment group each of CD3+, CD4+, CD4+ /CD8+ values after the treatment was significantly higher than before the treatment, and CD8+ value decreased (P < 0.01), showing that immune function is elevated. Under heat stress state the body's normal tissues and systems, especially the immune system has good blood circulation due to blood vessel dilation and blood flow acceleration, thus its good blood circulation is more conducive to enhance the body's immune function to resist damage factor and may be one of the reasons of the result that compared with simple intravenous chemotherapy group hyperthermic perfusion chemotherapy group enhanced immune function in the study. The dual pathway chemotherapy of hyperthermic intraperitoneal perfusion combined with intravenous chemotherapy is an effective method for treating gastric cancer, and is expected to be continuously popularized and applied in clinical practice. 
        In short, according to the stage summary since this clinical study was carried out one year ago, circulative hyperthermic intraperitoneal perfusion chemotherapy early after gastric cancer operation by using the high-precision perfusion machine is safe and feasible, and has caused no significant adverse reactions and complications, and can improve a patient’s quality of life and immune function, and reduce to some extent the postoperative abdominal cavity local recurrence rate of gastric cancer, which is closely related to the fact that intraperitoneal perfusion has cleared tiny residual cancer tissue during early period. Distant metastasis rate is not related to survival rate temporarily. Long-term treatment effect needs to be further observed. The therapy is worth clinical popularization and application, and samples should be enlarged for further research.

        4 References
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        [Received date: November 23, 2011  Editing and proofreading: Li Xiaofei]

        Corresponding author: Xu Haifan

        Jilin Medicine, March, 2012, Volume 33, No.8

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        TypeInfo: academic articles

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