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        A clinical study of continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy in treatment of cancerous ascites

        Date:2014年2月26日 10:35

        A clinical study of continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy in treatment of cancerous ascites

        Department of Oncology, Shaanxi Province Xianyang City Second People’s Hospital (Xianyang City 712000)
        Dongmei Jiang, Mingliang Yan, Wei Chang, Yanhong Su, Yanling Wang, Chunli Qiu

        Abstract  Objective: To observe the clinical effects of continued circulatory hyperthermic perfusion chemotherapy for malignant peritoneal effusion. Methods: A total of 57 patients with malignant peritoneal effusion were randomly divided into two groups: 27 cases were treated with continued circulatory hyperthermic perfusion chemotherapy (CCHPC group) and 30 cases were treated with intraperitoneal chemotherapy (The control group) 1 time a week. The efficacy and toxicities were assessed after 3 times. Results: The effective rate of CCHPC group (23/27) was significantly higher than the control group [(17/30) (P = 0.019)], the side- effect of the two groups was no significant difference (P > 0.05 ). Conclusion: continued circulatory hyperthermic perfusion chemotherapy is a safe, effective, simple way for controlling malignant peritoneal effusion.

        Key words: abdominal tumors/complications, ascites/therapy, intraperitoneal perfusion and rinsing, fluorouracil/therapeutic application, hyperthermia
        [CLC] R735 [Document ID code] A [Article number] 1000-7377 (2010) 01-0042-03

        Cancerous ascites is a common complication of abdominal and pelvic malignant tumors [1], is also one of the main causes of death in patients with advanced cancer, and there has still been no effective therapeutic method up to now [2]. Clinical staging of such patients belongs to advanced stage, mostly accompanied with local and (or) distant recurrence and metastasis. Therefore, improving quality of life is the main purpose of treatment and is also the main problem to be solved at present [3]. In 1988, based on intraperitoneal chemotherapy (IPC), Fujimoto, et al. first used continuous hyperthermic intraperitoneal perfusion chemotherapy (CHPPC) technique to treat gastrointestinal malignant tumors. In recent years, CHPPC has achieved certain success in prevention and treatment of postoperative recurrence of colorectal cancer [4]. This study compared continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy with conventional intraperitoneal perfusion chemotherapy in the treatment of malignant ascites, and the efficacy of the former was satisfactory. Now they are analyzed and reported as follows. 

        Materials and Methods
        1 Clinical data From October 2008 to August 2009, our hospital admitted 57 patients with malignant ascites. They were ones in advanced stage who were not suitable for systemic chemotherapy, and all patients were confirmed as malignant ascites by finding exfoliated cells and histological examination from ascites (31 cases of gastric cancer, 18 of colorectal cancer and 8 of ovarian cancer). The patients included 32 males and 25 females, aged 38 to 80 years with a mean age of 62 years. The patients clinically belonged to stage IV according to UICC staging. Before treatment, routine blood test, liver and kidney function were normal, Kamof sky was 50 to 70 points, and there was more than 3 months of expected survival period. Above patients were divided into two groups according to random number method. CCHPC group: It was continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy group, having 27 cases including 15 cases of gastric cancer, 9 of colorectal cancer and 3 of ovarian cancer. Control group: It was intraperitoneal perfusion chemotherapy group, having 30 cases including 16 cases of gastric cancer, 9 of colorectal cancer and 5 of ovarian cancer. Age, gender, weight, and tumor distribution and composition of the two groups of patients were comparable (P> 0. 05).

        2 Therapeutic method CCHPC group: The first step was: B ultrasound positioning was performed to avoid the intestine and the tumor, and the puncture points on both sides of the abdominal cavity were determined by guidance of B ultrasound. The gauge 14 puncture needles were punctured into the abdominal cavity to establish inflow and out flow passages, and it would be better that the position of the inflow needle was higher than that of the outflow needle. The inflow needle was connected to an infusion device and warm physiological saline was infused. The outflow needle was connected to a drainage bag for draining ascites. For a patient with obvious abdominal distension, partial liquid could be first released to relieve symptoms. Then liquid was perfused from one side and liquid was released from another side. Ascites was rinsed and replaced until ascites became basically clear. Releasing liquid was stopped, and liquid continued to be perfused until a patient felt mild abdominal distention, and then perfusing liquid was stopped. The second step was: Cisplatin 40-60mg was intraperitoneally injected and then the puncture needles on both sides of the body were connected to the inlet and outlet of circulatory hyperthermic coelom perfusion chemotherapy system. The inflow and outflow temperatures were controlled at 45.0-45.5℃ and 39.5-41.0℃, respectively. Liquid flow rate was controlled at 180-220ml/min and continuous circulatory hyperthermic perfusion chemotherapy lasted for 1 hour. After above operation, appropriately partial liquid was released until a patient felt no abdominal distention. At last, dexamethasone 10mg and furosemide 20mg were intraperitoneally injected. 
        Control group: Under B ultrasound positioning, conventional abdominal puncture was performed on one side of the abdominal cavity. Ascites was all released as far as possible and then the puncture needle was connected to an infusion device. Physiological saline 1500-2000ml containing cisplatin 40-60mg was rapidly infused. At last, dexamethasone 10mg and furosemide 20mg were intraperitoneally injected. Thereafter, the patient is asked to repeatedly change position in order to facilitate uniform distribution of drugs in the abdominal cavity.
        After above operation, the two groups of patients received antiemetic, transfusion of protein, fluid infusion and other symptomatic and supportive treatments. The above treatment was performed once a week for a total of 3 times and after 4 weeks the efficacy was evaluated.

        3 Efficacy evaluation criteria: After all patients completed 3 times of treatments, efficacy was evaluated. Amount of ascites measured by B ultrasound was as an evaluation index of illness state according to WHO evaluation criteria of unmeasurable lesions of malignant tumors [5]. Adverse reactions grading: myelosuppression and gastrointestinal reaction were divided into grade 0-IV according to 1997 UICC criteria [6].

        4 Statistical analysis: All data was processed by SPSS13.0 statistical software. Chi-square test was used to compare two samples of count data. P <0.05 was considered that difference was statistically significant and P <0.01 was considered that difference was statistically very significant.

        Results
        Comparison of short-term efficacies between two groups: see table 1. After three courses of treatments, the effective rate of CCHPC group [85.19% (23/27)] was significantly higher than control group [56.67% (17/30)] and through statistical treatment, χ2 = 5. 52, P = 0.019.

        Table 1 Comparison of efficacies in two groups of patients

        Group

        CR

        PR

        NC

        PD

        Effective rate

        CCHPC group

        13(48.1)

        10(37.1)

        2(7.4)

        2(7.4)

        23/27*

        Controlgroup

        9(30.0)

        8(26.7)

        8(26.7)

        5(16.6)

        17/30

         

        Note: Compared with control group, *P<0.05

        2 Comparison of adverse effects between two groups after chemotherapy: see table 2. The main side effects were digestive reaction, mainly belonging to grade 0-II but no III-IV. The difference of digestive adverse reaction between two groups was not significant (χ2 = 1.20, P = 0.27); myelosuppression belonged to grade 0-I, and the difference between the two groups was not significant, either (χ2 = 0.004, P = 0.95). Before and after treatment, liver and kidney function did not significantly change. All patients receiving treatment had good tolerance.

        Table 2 Comparison of side effects in two groups of patients

        Group

        Digestive system reaction

        Myelosuppression

        0

        I

        II

        III

        IV

        0

        I

        II

        III

        IV

        CCHPC group
        Control group

        4
        8

        17
        15

        6
        7

        0
        0

        0
        0

        20
        22

        7
        8

        0
        0

        0
        0

        0
        0

         

        Discussion
        Malignant ascites is one of the major complications of advanced malignant tumors, seriously impacts quality of life of patients. Patients are often accompanied with local recurrence, peritoneal plantation, metastasis to other organs and other late complications and physical exhaustion, and most of them have missed opportunities for systemic chemotherapy. Therefore, how to effectively relieve ascites is the key to improve quality of life of patients with advanced cancer, and is also difficult problem which needs to be emergently solved in clinical work [7]. Intraperitoneal chemotherapy is still one of the most effective methods to treat malignant ascites at present, whereas the hyperthermic therapy combined with chemotherapy can exert synergistic killing effect on tumor cells [8]. Some literature reported that hyperthermic therapy combined with 5-FU and other chemotherapeutic drugs can obtain additive or synergistic anticancer effect [9]. We applied continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites, and its effective rate was 85.19% and was significantly higher than general intraperitoneal perfusion chemotherapy group (effective rate 56.7%). The fact also has showed that compared with intraperitoneal perfusion chemotherapy, continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy has certain advantages, and is an effective method to treat malignant ascites.
        Because intraperitoneal local chemotherapy has advantages of high concentration of drugs in the abdominal cavity, slow clearance, small systemic side effects, etc., it greatly improves the killing effect of anticancer drugs to tumor cells [10]. In recent years, combining hyperthermic therapy with intraperitoneal perfusion chemotherapy has demonstrated another new mode to treat malignant ascites. Killing tumor of hyperthermic therapy is based on different tolerances of cancer tissue cells and normal tissue cells to temperature, and synergistic effect [11]. Due to lower tolerance of cancer cells to heat, prolonging heating time can aggravate the damage of cancer cells and inhibit their proliferation. Some studies have shown that if the liquid medicine in the abdominal cavity maintains at 43℃ for 1 hour, it can effectively kill cancer cells but is harmless to normal tissues, so that survival rate of cancer patients can be greatly improved. The adjuvant therapy needs to precisely control the temperature of the liquid medicine in the peritoneal cavity of the patient, and can easily adjust the flow rate of liquid medicine perfusion, whereas normal tissue cells can tolerate 45-47℃ without damage [12]. Hyperthermic intraperitoneal perfusion chemotherapy with CCHPC mode improves the efficacy of malignant ascites caused by advanced cancer. Our data also showed that the effective rate of application of CCHPC mode to treat malignant ascites was also significantly higher than greneral intraperitoneal perfusion chemotherapy, and this is also consistent with the results of related studies in our country [13~18]. 
        Like general perfusion chemotherapy, major adverse effects of hyperthermic intraperitoneal perfusion chemotherapy with CCHPC mode are those associated with chemotherapeutic agents, including gastrointestinal reaction, myelosuppression, etc. During the treatment of this study, the adverse effect rate of CCHPC group was similar with control group and the difference was not significant, and the result was consistent with the relevant reports [18], but the finding was also related with fewer cases of this study and researching the bulk of cases are still needed to confirm the finding.
        "Effective rinsing, thermostatic circulation and chemotherapeutic sensitization" are three big characteristics of this therapy. A lot of warm physiological saline is used to rinse and original ascites is replaced, changing quality but not volume of effusion, so that adverse reaction, caused by too quickly releasing liquid too much at a time, is eliminated. Then continuous circulatory perfusion therapy liquid at 180-220ml/min of flow rate can better clean shedding cancer cells, fibrin and necrotic tissue among intestinal loops and visceral organs, and is conducive to absorption and penetration of drugs. After physiological saline containing cisplatin is repeatedly circulated, the drug can be uniformly distributed among intestinal loops and visceral organs to improve the efficacy of intraperitoneal therapy, and to eliminate intestinal adhesions and chemical peritonitis and other complications caused by local high drug concentration. Continuous thermal effect can effectively kill peritoneal metastatic cancer nodules, and synergistically increase effect of cisplatin, thereby further enhance lethality to tumor. However, because the anticancer drug and hyperthermic therapy have limited penetration to tumor, i.e., a chemotherapeutic drug can penetrate only <3mm of tumor tissue and hyperthermia can facilitate this penetration to 5mm, therefore, the efficacy of treating intracavitary free cancer cells and <3mm3 minor subclinical foci was significant [20], whereas the larger tumor is and the thicker the new blood vessels are, the smaller thermal lethality is, and to >5mm3 cancer nodules the direct lethality of hyperthermic chemotherapy is significantly weakened. Accordingly, the choice of indications should be strictly controlled. Patient's physical condition, condition of illness, tumor type and other factors should be considered to comprehensively select other therapeutic methods for combination therapy, and the efficacy may be better and this is also a trend in the treatment of advanced tumors [21].
        In summary, continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy is an effective method to control malignant ascites. Its good safety, small side effects and complications, and simple and convenient operation, are conductive to its application, but its long-term efficacy remains to be further observed, especially to be confirmed by prospective study with the bulk of cases.

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        (Received date: July 20, 2009)

        Journal of Shaanxi Medicine, January, 2010, 39(1): 42-44.

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