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        A comparison of curative effects between circulative hyperthermic perfusion chemotherapy and simple perfusion chemotherapy for malignant ascites due to gastrointestinal tumors

        Date:2014年2月26日 11:05

        CLINICAL PRACTICE

        A comparison of curative effects between circulative hyperthermic  perfusion chemotherapy and simple perfusion chemotherapy for  malignant ascites due to gastrointestinal tumors

        Na Li, Changwen Bo, Changpeng Zou, Wenhua Ma, Zheng Zheng, Yonghui An

        Na Li, Changwen Bo, Changpeng Zou, Wenhua Ma, Zheng Zheng, Yonghui An, Oncology
        department,  First Hospital of Hebei Medical University, Hebei Shijiazhuang 050013

        Na Li associate chief physician mainly engaged in the comprehensive treatment on advanced malignant tumor of digestive system. Author contributions: Na Li is responsible for research designing and thesis writing. Cases collecting, Changwen Bo, Changpeng Zou and Wenhua Ma is responsible for treatment operating and curative effect observation was responsible.  Zheng Zheng is responsible for machine operation and data analysis. Yonghui An is responsible for research and technical guidance.
        Corresponding author:  Yonghui An, Professor, chief physician, 050013, No. 89 Dong Gang Road Hebei, Shijiazhuang, Oncology department, First Hospital of Hebei Medical University, Sjzyhd@vip.sina.com Tel: 0311-85917272
        Received date: 2013-09-26   revision date: 2013-11-05
        Accepted date: 2013-11-15   online publication date: 2013-11-28

        ■ Background Malignant pleural effusion is fluid accumulation in the abdominal cavity induced by malignant tumors, and it is one of the common complications of the tumor with advanced stage. Because Malignant pleural effusion often happened in advanced tumor showing as abdominal distention, abdominal pain, it affect the quality of life seriously. So, it is meaningful to control and eliminate ascites for these patients. Some studies reported that, intraperitoneal hyperthermic perfusion chemotherapy had a better therapeutic effect than simple chemotherapy for malignant peritoneal effusion. In this study, continuous hyperthermic peritoneal perfusion chemotherapy applied in this study achieved good results in the treatment of ascites induced by gastrointestinal malignant

        ■Peer reviewers Jiafu Ji, Professor, Peking University Cancer Hospital; Dengfu Yao, Professor, Hospital Affiliated to Nantong University
        ■ Trends and frontier of the study The key point of continuous hyperthermic peritoneal perfusion chemotherapy relies on the controlling and maintaining of the temperature. The therapy machine we used in this study is composed of a heating device, a perfusion system, and control system, forming an enclosed real-time monitoring and regulating the circulating treatment system, and realizing a real-time control and detection of the temperature of perfusion solution. The temperature of input was controlled as 42~43 ℃, and output with 40 ℃-41 ℃, in order to ensure the treatment effect.    
        ■ Related reports a study performed by Shan Guo et al (oncology department of Tang Du hospital, the fourth military medical university) investigated the effect of cavity circulatory thermal perfusion on the vital signs and important organs of experimental animals at different temperatures. The study likewise aimed to determine the optimal temperature for chemotherapy. It concluded that CCCHP with 1hr combined with cisplatin chemotherapy (three times/60min) was safe and feasible at 41℃. Xiaofei Zhang et al (oncology department of Xi Jing hospital, the fourth military medical university) explored the safety and effective of continuous hyperthermic peritoneal perfusion chemotherapy. It showed that hyperthermic peritoneal perfusion chemotherapy and simple chemotherapy both are effective on gastric therapy. However, hyperthermic peritoneal perfusion chemotherapy more advantages on effective rate, clinical benefit rate, ascites controlling and the median progression-free survival time. And the adverse reactions were no significantly difference.
        ■ Innovation point The therapy machine we used was circulation perfusion machine. The temperature of input was controlled as 42~43 ℃, and output with 40 ℃-41 ℃, in order to ensure the treatment effect. Additionally, compared with simple chemotherapy, hyperthermic peritoneal perfusion chemotherapy did not increase the side reactions and heat related injure.
        ■Peer reviewers The methods of the study is scientific and rational, and the conclusion is worth for clinical use.
        Abstract

        Aim: To compare the curative effect and adverse effects of continuous hyperthermic peritoneal perfusion chemotherapy versus simple intraperitoneal chemotherapy in the management of malignant seroperitoneum secondary to gastrointestinal tumors.

        Method: Eighty-four inpatients with malignant seroperitoneum secondary to gastrointestinal tumors treated at our hospital between October 2010 and February 2013 were enrolled in the study. They were randomly and equally divided into either a study group to undergo continuous hyperthermic peritoneal perfusion chemotherapy or a control group to receive intraperitoneal chemotherapy. The differences in curative effect, quality of life and adverse effects were compared between the two groups.

        Results: The rate of ascites control was significantly higher in the study group than in the control group (88.33% vs 59.52%, P < 0.05). The rate of improvement of quality of life was also higher in the study group (88.1% vs 53.76%, P <0.05). Adverse effects included mild nausea and vomiting, temporary abdominal pain, CTCAE gradeⅠ-Ⅱbone marrow depression (BMD), and no grade Ⅲ-Ⅳ BMD was identified. No significant differences in adverse effect were ob- served between the two groups.

        Conclusion: Continuous hyperthermic peritoneal perfusion chemotherapy is superior to simple intraperitoneal chemotherapy in the management of malignant seroperitoneum in terms of ascite control, improvement of quality of life, and adverse effects.

        Key words: Hyperthermic peritoneal perfusion chemotherapy; Peritoneal infusion; Malignant pleural effusion

        © copy right 2013 is belonging to Baishideng publishing group co., limited

        Key point: How to control and eliminate the fast growth of ascites is the key point for advanced tumor. Some studies reported that, intraperitoneal hyperthermic perfusion chemotherapy had a better therapeutic effect than simple chemotherapy for malignant peritoneal effusion.  In ordinary thermo-chemotherapy process, the temperature of solution dissipated through transmission pipeline, so than a constant temperature infusion can be guaranteed. However, continuous hyperthermic peritoneal perfusion chemotherapy applied in this study achieved good results in the treatment of ascites induced by gastrointestinal malignant. In this study, the input temperature was controlled in 42℃~43 ℃ strictly, and the output temperature was 40 ℃~41 ℃. These conditions ensure the effective of the therapy. Additionally, compared with simple chemotherapy, continuous hyperthermic peritoneal perfusion chemotherapy had little side reaction and heat related damage.

        0 Introduction
            Malignant pleural effusion is fluid accumulation in the abdominal cavity induced by malignant tumors, and it is one of the common complications of the tumor with advanced stage. The prognosis of malignant pleural effusion was different due to the different of causes. Malignant pleural effusion induced by gastrointestinal tumor had the worst prognosis with 1 year survival rate <10% [1]. Because Malignant pleural effusion often happened in advanced tumor showing as abdominal distention, abdominal pain, it affect the quality of life seriously. So, it is meaningful to control and eliminate ascites for these patients [2]. Some research and clinical practice proved that intraperitoneal hyperthermic perfusion chemotherapy for malignant peritoneal effusion had better effect than single chemotherapy [3]. Ordinary hyperthermic peritoneal perfusion chemotherapy cannot keep temperature constantly due to the loss of heat in the pipeline. In the past ten years, coelom continued circulatory hyperthermia perfusion, (CCCHP) as a new treatment achieved good effect on peritoneal metastasis of malignant tumor [4-6]. It had been more and more used. In this study, a application of CCCHP on malignant peritoneal effusion treatment induced by gastrointestinal tumor also achieved good effect. It reported as following.
        1 Patient and Methods
        1.1 Patients 84 patients with malignant peritoneal effusion induced by gastrointestinal tumor were reviewed, and divided into hyperthermia perfusion chemotherapy group (treatment group) and single chemotherapy group (control group). 42 cases were in treatment group, including 23 males, 19 females, with the median age of 64 years; 10 cases of gastric cancer, 18 cases with colon cancer, 14 cases with rectal carcinoma, 3 cases with the Karnofsky performance Status (KPS)< 40 points, 8 cases with KRS range from 40 to 60, 31 cases with KRS >60. In the control group,  24 cases were male, 18 females, with the median age of 66 years old, 11 cases of gastric cancer, 19 cases of colon cancer, 12 cases of colorectal cancer, KPS score <40 points in 4 cases, 40~60 points in 7 cases, >32 points in 32 cases. There was no difference of general information in two groups. All patients were confirmed as ascites by dopple ultrasound, and diagnosed as Malignant pleural effusion by cytological detection. All the patients did not receive systemic chemotherapy in 1 month. Thermo chemotherapy perfusion machine was produced by Jilin Maida medical instrument limited company, model: RHL-2000A.
        1.2 Methods
        1.2.1 Treatment Two central venous catheters were placed on the left and right abdominal cavity respectively after B ultrasound localization. Ascites drainage was made as far as possible. Thermo chemotherapy perfusion machine was connected as one-time circulation. The pipes were connected with two central venous catheters. According to the patients’ condition, 1500-3000 mL 0.9% saline + 80mg cisplatin was used as perfusion solution with the input temperature of 42~43 ℃ and output temperature of 40~41 ℃.  The flow rate was 100-150ml/min. The perfusion solution was drained after continued circulation of more than 1h. Control group patients were underwent unilateral abdominal puncture and central venous catheter placed. Drainage was made through catheter, and flooded abdominal cavity with 500~1000ml physiological saline containing 80mg cisplatin. Patients were asked to change the position every 15~20min in order to make the drug distribute throughout the peritoneal cavity evenly. Drainage of ascites was needed 72h after drug treatment.  Intravenous injection of ondansetron was given for preventing vomiting before treatment. Perfusion was made in every week both in treatment group and control group. The treatment would finish when effusion disappeared completely or continuous treatment for 3 weeks. The response to treatment of every patients, as well as routine blood test, B ultrasound results, liver and kidney function were recorded. The therapeutic efficacy and adverse reactions were also analyzed.
        1.2.2 Criterion of short term therapeutic effect 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.
        1.2.3 Life quality evaluation Life quality was evaluated by criterion of KRS score. The score increasing 10 was defined as improve, ranging within 10 was stable, and decreasing more than 10 was progressive.
        1.2.4 Adverse reactions An adverse reaction of the drug was evaluated according to NCI CT 3.0 standard, divided into 0- Ⅳ grade: (1) nausea: grade 0: no nausea; Grade Ⅰ: normally eat; Grade Ⅱ, Oral intake decreased without significant weight loss. Grade Ⅲ: Inadequate oral caloric or fluid intake. (2) Vomiting: Grade 0: no vomiting, Grade Ⅰ:1 episode in 24 hrs; Grade Ⅱ:2 – 5 episodes in 24 hrs; Grade Ⅲ:≥6 episodes in 24 hrs; Grade Ⅳ :> 10 episodes in 24 hrs, fluids are needed. (3) Oral ulcer: Grade 0: No abnormal finding of oral mucosa; Grade Ⅰ: asymptomatic ulcer; Grade Ⅱ:  oral ulcer with the symptoms of pain, edema without altered eating; Grade Ⅲ:  oral ulcer with the symptoms of pain, edema with altered eating; Grade Ⅳ: fluids tube feedings. (4) Blood cellularity: Leukocytes (×109/L), Grade 0: ≥4.0; Grade Ⅰ: 3.0~3.9; Grade Ⅱ:  2.0~2.9; Grade Ⅲ:  1.0~1.9; Grade Ⅳ: <1.0. Hemoglobin (g/L): Grade 0: normal; Grade Ⅰ: 100~normal; Grade Ⅱ:  80.0~99.9; Grade Ⅲ:  65.0~79.9; Grade Ⅳ: <65.0. Platelets (×109/L) Grade 0: normal; Grade Ⅰ: 75.0~normal; Grade Ⅱ:  50.0~74.9; Grade Ⅲ:  25.0~49.9; Grade Ⅳ: <25.0. (5) Peripheral nerve dysfunction: Grade 0: normal; Grade Ⅰ: Symptomatic/ weakness of tendon reflexes; Grade Ⅱ:  serious Sensory disturbance and (or) Mild weakness; Grade Ⅲ: Weakness and (or) sensory loss interfering; Grade Ⅳ: disabling.
        1.2.5 Statistical analysis SPSS 11.0 were used to statistical analysis. The comparison between two groups was assessed with chi-square test and ANOVA. P<0.05 was considered to be significantly different.
        2 Results
        2.1 Effect of treatment
        The Effect of treatment in the treatment group was 12 cases of CR, 23 cases of PR, SD 4 cases of SD, 3 cases of PD, with effective rate of 83.33%. In control group, the therapeutic effect was CR 9 cases, PR 16 cases, SD 10 cases, PD 7 cases with the effective rate of the 59.52%. The effective rate of the treatment group was significantly higher than that in control group (P<0.05). Table1.

        Table 1 Comparison of short term therapeutic effect in two groups (n=42)

        Group

        CR

        PR

        SD

        PD

        RR (%)

        Treatment group

        12

        23

        4

        3

        83.33*

        Control group

        9

        16

        10

        7

        59.52

         

        *P<0.05 VS control group, CR: Complete remission, PR: Partial remission, SD: Stable disease, PD: Progressive disease

        2.2 Life quality evaluation
            The number of cases with the quality of life of improvement, stability, reduce after treatment in the treatment group were 37 (88.1%), 3(7.14%) and 3 (7.14%) respectively. While in the control group, the number were respectively 23 cases (54.76%), 9 cases (21.43%) and 10 cases (23.81%). Significantly difference of quality of life were found between the two groups (p<0.05. Table2).

        Table2 Comparison of Life quality in two groups [n=42, n(%)]

        Group

        improve

        stable

        decline

        Treatment group

        37(88.1)a

        2(4.76)

        3(7.14)

        Control group

        23(54.76)

        9(21.43)

        10(23.81)

         

         

         

         a P <0.05VS control group
        2.3 Adverse reactions
            The treatment was well tolerated by patients. Only mild nausea, vomiting and abdominal pain were found, as well as bone marrow depression in grade I and II. No grade Ⅲ and grade Ⅳ reactions happened, No intestinal adhesion, intestinal obstruction, intestinal necrosis were found. And no treatment-related deaths happened. (Table 3)

        Table3 Comparison of adverse reactions in two groups [n=42, n(%)]

        Group

        Nausea, vomiting

        Leukopenia

        Decreased hemoglobin

        Thrombocytopenia

        Treatment group

        4(9.52)

        6(14.29)

        2(4.76)

        3(7.14)

        Control group

        3(7.14)

        7(16.67)

        2(4.76)

        2(4.76)

         

        3 Discussion
        Malignant pleural effusion is one of the most common complications of advanced gastrointestinal cancer. The patients suffered from symptoms such as abdominal distension, abdominal pain, anorexia, and difficulty in breathing caused by malignant ascites, often have a poor quality of life [7].  Abdominal drainage of ascites can quickly relieve symptoms, but cannot control ascites growth.  Intraperitoneal perfusion therapy is an important method of effusion local treatment for Malignant pleural effusion [8]. It can increase the local drug concentration; prolong the drug contact time of drug to tumor with mild systemic reaction. Since 1980, Speyer established an anticancer drug intraperitoneal chemotherapy pharmacokinetics mathematical model, laying a theoretical foundation for intraperitoneal chemotherapy. And it gradually widely used in clinical. Intraperitoneal chemotherapy can effectively control ascites growth with adverse reactions of fever, abdominal pain and intestinal adhesion [9]. Hyperthermia is a method for heating for tumor treatment, which based on the accumulation of physical energy in tissues and thermal effect.  The tumor then tissue temperature rises to the effective temperature, and maintain for a period of time to kill cancer cells [10, 11].  And this treatment method does not injure normal cells. Tumor hyperthermia has been widely used in clinical practice, and shows good effect. It becomes a new method in the treatment of malignant tumor with good application [12]. Hyperthermia can enhance the therapeutic effect of chemotherapy drugs; Asaumi [13] found that in the thermal conditions, doxorubicin had the same toxicity to both doxorubicin resistant tumor cells and doxorubicin sensitive tumor cells. Yu Xihao [14] reported a clinical observation of intra-peritoneal chemotherapy combined with abdominal hyperthermia in the treatment of malignant ascites, the remission rate of combined group was 64%. And it was only 46.4%. in single intra-peritoneal chemotherapy group. Atanackovic et al [15] found that whole body hyperthermia in enhancement of antitumor effect of chemotherapy, at the same time, does not increase the bone marrow inhibition caused by chemotherapy. It can inhibit a protective role on bone marrow. The high temperature chemical treatment (40 ℃~43 ℃) is more conducive to drug penetration through tissue. So it had better effect than simple chemical treatment [16]. The drugs which played safety and a synergistic effect with hyperthermia are platinum, topoisomerase inhibitors, disaccharide cytidine, paclitaxel, cyclophosphamide.
             Intraperitoneal hyperthermic perfusion chemotherapy technology (intraperitoneal hyperthermic chemotherapy, IHCP) is a comprehensive treatment of hyperthermia combined with chemotherapy, exerting synergistic effects when combined with chemotherapy on tumor cells. The temperature of 40 ℃ -43 ℃ was usually considered to be the effect temperature to tumor cells [18-20]. Some study reported that if the temperature <40 ℃, it fail to effectively kill cancer cells, even leading to cancer cell spread [21, 22]. When the temperature is higher than 43 ℃, tumor cells begin to disintegration and necrosis, but no reversal effect on drug-resistant. But the experiment results shown the damage effect of high temperature on normal cells also can not be ignored, especially in the small intestine and liver [23-25]. So controlling and keeping intraperitoneal treatment temperature is the key point to ensure the safety and effect of hyperthermia treatment. We used hyperthermic perfusion treatment. The therapy machine we used in this study is composed of a heating device, a perfusion system, and control system, forming an enclosed real-time monitoring and regulating the circulating treatment system, and realizing a real-time control and detection of the temperature of perfusion solution. The temperature of input was controlled as 42~43 ℃, and output with 40 ℃-41 ℃, in order to ensure the treatment effect.
        The study concluded that the effective rate of treatment group was 83.3%, while it was 59.52% in control group. The effective rate in treatment group was significantly higher than that in control group (p<0.05). The life quality improvement rate was 88.1% and 53.76% in treatment group and control group respectively. It was significantly higher in treatment group (p<0.05).These conclusions suggested that cavity heat perfusion chemotherapy compared with intracavitary hyperthermia can control malignant peritoneal effusion effectively, and can significantly improve the life quality of patients with advanced tumors creating good conditions for further treatment of patients. This result is related to those reported at home and abroad [26, 27].
             The study also showed the main adverse reactions of treatment group wereⅠ, Ⅱ ° gastrointestinal reaction, followed by mild bone marrow suppression. It had no significantly difference when compared with that in the control group.  The perfusion temperature was controlled as 43 ℃ strictly, so it is no thermal injury happened. And no complications and treatment-related death happened. The effective rate was remarkable.
             In summary, circulatory hyperthermic perfusion chemotherapy is an ideal way in treatment of Malignant pleural effusion with the advantages of simple operation, high safety, constant temperature, reliable effect, little injury, less complications, significantly higher effective rate in control of malignant effusion than ordinary cavity chemotherapy. However, the limitation of understanding of hyperthermic chemotherapy and no uniform requirements make the use of this treatment still have difficulties. For example, therapeutic effect varied from flow rate, time, period of treatment. So we still need to continue to study, practice, and communicate the body circulation rationalization perfusion thermo chemotherapy specification, so that more patients can receive safe and effective treatment.

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