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        Clinical Research on Continuous Hyperthermic Perfusion in the Treatment of Perfusion in the Treatment of Peritoneal Effusion Induced by Gastric Carcinoma

        Date:2014年2月26日 10:49

        .Clinical Research.
        Clinical Research on Continuous Hyperthermic Perfusion in the Treatment of Perfusion in the Treatment of Peritoneal Effusion Induced by Gastric Carcinoma
        Guoqing Liao, Yimei Qu, Hongmei Wang, Penghui Liu, Liangliang Li
        Correspongdence to : Liao Guoqing, E-mail: lgq2002881@126.com
        Department of Oncology, No. 309 Hospital of PLA, Beijing 100091, China
        Abstract   Objective: To evaluate the effect and safety of hyperthermic perfusion cycle of abdominal space with chemotherapy in the treatment of malignant peritoneal effusion induced by gastric carcinoma.  Methods: A total of 102 cases of malignant peritoneal effusion were randomly divide into combined (n=52) and single-agent (n=50) groups. Based on the systemic treatment (75mg/m2 docetaxel in day 1 every 3 weeks), the combined group was given coelom hyperthermic perfusion extracorporeal circulatory system combined with cisplatin (40mg/m2) once a week for 3 weeks. The single-agent group was treated with cisplatin hyperthermic peritoneal perfusion. The treatment effect and toxicities were assessed. Results: The response rate was 69.23% in the combined group and 46.00 % in the single-agent group (P<0.05). The improvement rates of the Karnofsky performance score were 63.46% and 40.00%, respectively (P<0.05). The main toxicities in two groups were nausea/vomiting and leucopenia. Conclusion: Continuous hyperthermic perfusion is safe and effective for malignant peritoneal effusion induced by gastric carcinoma. It is suitable for clinical treatment application.

        Key words   Circulatory  hyperthermic perfusion; Chemotherapy; Gastric carcinoma; Peritoneal  effusion; Quality of life; Adverse drug reactions
            Gastric carcinoma is one of the most common malignant tumors, with high incidence and mortality in China [1]. When the disease developed to advanced gastric carcinoma, malignant peritoneal effusion often occurs, which effected by multiple pathophysiologic mechanisms[2], and may often accompanied by low proteinemia. The patients suffered from malignant peritoneal effusion often progress rapidly and with short survival. Therefore, how to improve the therapeutic effect and prolong survival time and improve quality of life is the key point concerned during clinical works.  The traditional way to control the growth of ascites is intraperitoneal injection of cisplatin, Mitomycin, Carboplatin and Fluorouracil [3-5]. Despite a certain effect, but it is not ideal, and difficult to maintain.  In this study, the hyperthermic cycle perfusion of abdominal space combined with systemic chemotherapy was used in the treatment of malignant peritoneal effusion induced by gastric carcinoma, and the results were as following.
        1 Patient and Methods
        1.1 Patients eligibility
            A total of 102 cases of malignant peritoneal effusion induced by gastric carcinoma were enrolled between September 2008 and August 2011 in oncology department of 309 Hospital of PLA. The patients were randomly divided into two groups: hyperthermic perfusion chemotherapy group and single-agent group. There were 52 cases in the hyperthermic perfusion chemotherapy group, including 38 male and 14 female, with the age from 38 to 71 years, and the median of age is 56. 50 cases were in single-agent group, including 33 males and 17 females with the age from 40 to 75 years, and the median age of 55. All the cases were diagnosed as gastric carcinoma by histological or cytological result, and were confirmed as malignant peritoneal effusion by abdominal CT or ultrasound and cytological result. All the patients were with the Karnofsky performance score ≥ 60; the expected survival >3 month; no intestinal obstruction; no abdominal adhesions; no intra-abdominal infection, no any kinds of fistula;  normal results of electrocardiogram, liver function, renal function and routine blood test. All the patients had not received any kinds of therapy such as chemotherapy, radiotherapy and biotherapy.
        1.2Treatment
        1.2.1Treatment plan
        Both the two groups were given docetaxel combined with cisplatin.  75mg/m2 docetaxel were given in the first day every 3 weeks. The patients in single-agent group were treated with 40mg/m2 cisplatin injected into abdominal cavity every week, 3 times as one course of treatment. Treatment would be discontinued when effusion disappeared. In the hyperthermic perfusion chemotherapy group, patients were treated with 40mg/m2 cisplatin though hyperthermic peritoneal perfusion every week, 3 times as a course of treatment. Treatment would be discontinued when effusion disappeared.

        1.2.2 Hyperthermic perfusion chemotherapy
            B ultrasound-guided injection was used. Two needles were placed, one for input and one for output. The extracorporeal circulation perfusion machine TRL 2000 was (manufactured by Harbin Aerospace Technology Co., Ltd.) connected with abdominal cavity. The lavage solution was heated to 45℃. The input temperature was 43.5~44℃, and the output temperature was 41.5~42℃. The abdomen was flooded with 20ml saline + DDP 40mg/m2 for 60 min continuously; the solution was partially drained at the end of the treatment.
        1.2.3 Drug
             Docetaxel used in this study was produced by Jiangsu Hengrui Medicine Co., LTD as water injection with 20mg.  Cisplatin was produced by Jiangsu Haosen pharmaceutical Co., LTD as water injection with 30mg.
        1.3 Main outcome measures
             The changes of ascites according to the results of abdominal CT or ultrasound as well as symptoms, signs, untoward effect and quality of life were recorded for all the patients before and after the treatment and 4 weeks and 8 weeks after treatment. The response of treatment was assessed. All the patients were underwent electrocardiogram, liver function, renal function and routine blood test 3 days and 6 days after therapy.
        1.4 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; Stable disease (SD), 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. Side effects of therapy were also concerned. It was classified according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC).(3.0)
             Life quality evaluation:  Life quality was evaluated by comparing the KPS score before and 6 weeks after therapy. The score increasing 10 was defined as improve, ranging within 10 was stable, and decreasing more than 10 was progressive.
        1.5 Statistical analysis
             SPSS 13.0 were used to statistical analysis. The comparison of symptoms and life quality improvement in two groups was assessed with chi-square test. And chi-square test was also used to compare the difference of treatment effect in two groups. P<0.05 was considered to be significantly different.
        2 Results
        2.1 Effect of treatment
             All the patients in the two groups were quality to be evaluated the effect of treatment. In the hyperthermic perfusion chemotherapy group, 36 cases (69.23%) were considered to be effective; while in the single-agent group, 23 cases (46.00%) were considered to be effective. The effective percentage of hyperthermic perfusion chemotherapy group were significantly higher than that in single-agent group (X2=5.641, P=0.027). Table1.
        2.2 Life quality improvement
             All the patients in the two groups were quality to be evaluated the life quality improvement. The cases evaluated as increasing KRS score in hyperthermic perfusion chemotherapy group and single-agent group were 30 and 20 respectively, The different was significantly (X2=5.621, P=0.029). Table2.
        2.3 Side effect
             Main side effects found in both two groups were nausea, vomiting and leucopenia, which can be alleviated after symptomatic treatment. Minority of patients in hyperthermic perfusion chemotherapy group had the feeling of mild bloating and abdominal burning at the day of therapy, while these symptoms disappeared after few hours without any treatment. No case with abdominal infection was found in hyperthermic perfusion chemotherapy group.  The incidence of nausea, vomiting, the decrease of white blood cells, elevated transaminase and impairment of renal function in two groups was no significantly difference. Table3.
        Table1 Comparison of effects between the two groups

        Group

        Cases

        CR

        PR

        SD

        PD

        RR (%)

        Hyperthermic perfusion chemotherapy group

        52

        11

        25

        12

        4

        (69.23)

         single-agent group

        50

        5

        18

        19

        8

        (46.00)

        Table2 Comparison of quality of life between the two groups before and after the treatment

         

        Group

        cases

        improve

        stable

        decline

        Improvement rate (%)

        Hyperthermic perfusion chemotherapy group

        52

        33

        15

        4

        (63.46)

         single-agent group

        50

        20

        14

        16

        (40.00)

        Table3 Comparison of side effect between the two groups

        Side effect

        Hyperthermic perfusion chemotherapy group

         Single-agent group

        Nausea and vomiting

        6

        7

        Decrease of platelet

        4

        3

        Decrease of white blood cells

        7

        8

        elevated transaminase

        2

        3

         Impairment of renal function

        2

        1

        Hair loss

        10

        11

        3 Discussion
             Current chemotherapy of advanced gastric cancer has no uniform standards, although 5-Fu was widely used as basic chemotherapy according to NCCN Guidelines [6]. A phase 3 trials reported the result of advanced gastric cancer therapy using docetaxel combing with DDP and 5-Fu. When compared with DDP and 5-Fu combination groups, the former groups had higher remission rate and 2-year survival rates.  So these chemotherapy regimens were approved by FDA.
             The rationale hyperthermic chemotherapy is based on the difference of tolerance ability between normal cells and tumor cells and thermal sensitivity of chemotherapeutic drugs. It is a therapeutic way which combined chemotherapy and hyperthermia. High temperature can increase the penetration of chemotherapeutic drugs from 3mm to 5mm. Therefore, the concentration of drugs within tumor increased without damage to normal cells. Additionally, combination of chemotherapy and hyperthermia can postpone resistance to chemotherapy, relieve pain symptoms effectively and improve the quality of life with noninvasive or minimally invasive. Other study reported that immunity can be stimulated by hyperthermia, so as to prompt anticancer effect and inhibit tumor metastasis. Even the local hyperthermia had the same effect. Hyperthermia induced Immune stimulation in both primary and metastatic tumor can eliminate local and distant lesions [8]. Hyperthermia can also increase cell activity and immune ability of NK cell, T lymphocytes and macrophage, and promote the synthesis of IL-6, IL-8 and TNF.  So Hyperthermia can change the immunogenicity of tumor cell, Improve the immune surveillance, and induced immune response so as to kill tumor [9-10].
             The treatment of malignant peritoneal effusion included systemic therapy and local therapy. Systemic treatment is often unable to effectively eliminate the effusion. While peritoneal drainage can only temporarily relieve symptoms, however, easy to be relapse. The advantage of intraperitoneal administration are : 1) The pharmacokinetic characteristics is obviously; 2) Can directly act on the peritoneum, or enter the systemic circulation through the peritoneal and arrive at tumor tissue, finally resulting “double path” effect on tumor[12]. The extracorporeal circulation perfusion machine TRL lavage system was performed via the catheter with a heat exchange solution, which was heated autonomically by an external heat exchanger. The whole therapy is under the detection and feedback control by computer. The solution maintains a constant temperature in the course of treatment.  The in-vivo study reported that, the temperature of 43℃ can induce apoptosis of tumor cells, and cytotoxicity mediated by apoptosis is the main mechanism which Hyperthermia can be used in treatment of malignant peritoneal effusion [13-14]. Coelom hyperthermic perfusion extracorporeal circulatory system combined with chemotherapy drugs can let the heat and the drug uniformly distributed between the cavity and the internal organs, so as to inhibition of tumor metastasis [15].
             In this study, hyperthermic perfusion chemotherapy group and single-agent group were both had effect on gastric carcinoma therapy.  However, the effective percentage and life quality improvement in hyperthermic perfusion chemotherapy group were much better than the single-agent group, and no obviously side effect were found. So intraperitoneal hyperthermic perfusion chemotherapy is a safe and effective new treatment method for peritoneal effusion Induced by gastric carcinoma, and It is worthy of clinical application.
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