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        Hyperthermic intraperitoneal perfusion chemotherapy in the treatment for 34 cases with malignant ascites

        Date:2014年2月26日 15:38

        Xuehui Fang, Qian Wu, Xuemei Han, Xinyue Ren, Xing Bai, Bing Zhu, Jinyan Li,
        Junping Zhao, Li Chen, Tingting Shen
        (Luoyang Dongfang Hospital, Luoyang city 471003, Henan province)

        Abstract: Objective: To observe clinical treatment effect of circulative hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites. Method: 62 patients with cancerous ascites were divided into experiment group and control group. 34 patients in experiment group were treated with circulative hyperthermic intraperitoneal perfusion chemotherapy and 28 patients in control group were treated with conventional intraperitoneal perfusion chemotherapy, and adverse reactions and treatment effect were observed. Result: The effective rate in experiment group was 76.47% (26/34) and significantly higher than 53.57% (15/28) in control group. The difference was statistically significant (P <0.05). The adverse reactions in the two groups were mild and tolerable. Conclusion: circulative hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites is safe and effective.
        Key words: circulative hyperthermic perfusion, drug therapy, malignant ascites
        CLC: R730.6   Document code: B
        Article ID: 1671-170X (2011) 06-0479-02

        Malignant ascites is a common complication of malignant cancer and is also one of main death causes of patients in late stage of cancer. Clinical staging of most patients with malignant ascites belongs to late stage, and most patients are accompanied with local and (or) distant recurrence and metastasis, therefore, improving life quality of a patient is the primary purpose of treatment. 
        In 1988, based on intraperitoneal chemotherapy (IPC), Fujimoto et al [1] first applied continuous hyperthermic peritoneal perfusion chemotherapy (CHPPC) technique to treat gastrointestinal malignant tumor and the effect was significant, and the therapy has been widely applied at home and abroad [2]. Along with continuous improvement of CHPPC technology and continuous development of related heating equipment, the 5-year survival rate has reached more than 50%. This study was performed to compare CHPPC to treat malignant ascites with conventional intraperitoneal perfusion chemotherapy.

        1 Materials and methods
        1.1 Clinical Data 
        62 patients with malignant ascites in our hospital from April 2008 to April 2010 were selected. Diagnoses of all patients had been confirmed by pathology of cast-off cells found from ascites. Among the 62 patients, 29 suffered from gastric cancer, 22 suffered from colorectal cancer and 11 suffered from ovarian cancer; 36 were males and 26 were females. The 62 patients were 38 to 76 years old with a median age of 62 years old. Before treatment, routine blood test, liver function and kidney function were normal, KPS score of every patient was greater than 50 points and the expected survival period was more than three months. The patients were divided into experiment group and control group. The 34 patients in experiment group were treated with continuous hyperthermic peritoneal perfusion chemotherapy and the group included 16 patients with gastric cancer, 12 with colorectal cancer and 6 with ovarian cancer; the 28 patients in control group were treated routine intraperitoneal chemotherapy and the group included 13 patients with gastric cancer, 10 with colorectal cancer and 5 with ovarian cancer. Age, gender, pathological types, KPS scores etc. between the two groups were balanced (P> 0.05).

        1.2 Methods of treatment
        All patients received drugs by abdominal puncture. First, abdominal cavity was punctured and a tube was indwelled, and ascites was drained as much as possible. Each patient in experiment group was connected to HGG2-102 body cavity hyperthermic perfusion treatment machine (Hejia Medical Equipment Co., Ltd. of Zhuhai City). According to the body constitution and the patient’s condition, we gave the patient physiological saline 2000-3000ml + cisplatin 80-100mg + dexamethasone 10mg + 2% lidocaine 10ml, which was heated to 43℃-45℃ and then was quickly infused into the abdominal cavity at 200ml/min. The liquid in the patient’s abdominal cavity was kept at 41℃-43℃. When the patient felt mild abdominal distention, perfusion was stopped. 5 min later, extraction key was pushed and perfusion liquid was drained back into the perfusion machine. The method was circularly performed three times and approximately 1.5 hours were needed. The volume of the ultimate remaining liquid was appropriate when the patient felt mild abdominal distention, and the volume was approximately 700-1000ml. we gave each patient in control group room temperature physiological saline 1000ml + cisplatin 80-100mg + dexamethasone 10mg + 2% lidocaine 10ml by abdominal infusion. Each patient in the two groups was infused once a week for 3 consecutive weeks. 30min before treatment, all patients received a drug to prevent vomiting, while fluid infusion, hydration and diuretic therapy were performed. After the end of the perfusion, each patient was instructed to regularly change position to facilitate full contact of drug with the wall of the abdominal cavity, and 24h urine volume was recorded. Electrolytes, liver function and kidney function were regularly reexamined.
        1.3 Evaluation Criteria of treatment effect
        Volume of ascites and adverse reactions of treatment before and after treatment were observed in the two groups. Volume of ascites which was measured by B-ultrasound was an index for evaluating disease status, 1981 WHO evaluation criteria of clinical treatment effect was used as evaluation criteria of treatment effect of ascites in this study [3]: complete relief (CR): ascites disappeared and the state lasted for more than 4 weeks; partial relief (PR): ascites reduced by more than 50% and the state lasted for more than 4 weeks; stable disease (SD): ascites reduced by less % or increased less than 25%, and the state lasted for more than 4 weeks; Progressive disease (PD): ascites increased by more than 25%. The total effective rate was CR + PR. Adverse reaction grading: bone marrow suppression, digestive tract reactions, liver toxicity and kidney toxicity were divided into 0-Ⅳaccording to 1997 UICC standards [4]. Before and after treatment, routine blood test and liver function and kidney function were examined once a week.
        1.4 Statistical treatment
        All data was processed by SPSS17.0, χ2 test was used to compare the rates of two samples, and P <0.05 was statistically significant.

        2 Results
        2.1 Short- term treatment effect
        After three courses of treatment, in experiment group, 7 cases belonged to CR, 19 cases belonged to PR, and the effective rate was 76.47% (26/34); in control group, 2 cases belonged to CR, 13 cases belonged to PR, and the effective rate was 53.57% (15/28). The effective rate in experiment group was significantly higher than control group (χ2 = 6.452, P = 0.011).
        2.2 Adverse reactions
        During treatment, gradeⅠ-Ⅱgastrointestinal reactions (there were 5 cases in experiment group and 5 cases in control group)and bone marrow suppression (there were 8 cases in experiment group and 6 cases in control group) emerged in both of the two groups; there was no grade Ⅲ or no more than grade Ⅲ adverse reaction. No patient in the two groups had hepatic and renal function impairment and intestinal obstruction.

        3 Discussion
         

        Malignant ascites is caused by a variety of malignant tumors, and original diseases causing malignant ascites may be intraperitoneal tumors (ovarian cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, etc.), and malignant tumors outside the abdominal cavity such as breast cancer, lung cancer and lymphoma can also cause malignant ascites. The prognosis of patients with malignant ascites is poor; the main purpose of the treatment is often to relieve symptoms caused by ascites, thus the quality of life of patients is improved and survival period is prolonged.
        Intraperitoneal perfusion chemotherapy is a common effective treatment for malignant ascites in the past. Studies have shown that the strength of the antitumor effects is proportional to the concentration of the antitumor drug around a tumor focus. Due to the action of "abdominal cavity - plasma barrier", the intraperitoneal chemotherapeutic drug concentration by intraperitoneal administration can be several times to dozens of times higher than by intravascular administration, so that effect of antitumor drug was strengthened. Local administration presents significantly superior pharmacokinetics: (1) drugs can directly exert effect on the peritoneum; (2) by absorption of peritoneum, a drug goes into the systemic circulation and reaches the tumor tissue again with the blood flow. The antitumor effect is generated from the above two ways to achieve the purpose of controlling ascites. Hyperthermic effects can inhibit DNA, RNA and protein synthesis of tumor cells, make tumor cell skeleton become scattered, harm many important functions of cells and directly destruct tumor cells to induce apoptosis, while hyperthermic effect enhances membrane permeability, is conducive to absorption and penetration of a chemotherapeutic drug, and enhances the cytotoxic effect of a chemotherapeutic drug; to a micrometastasis, hyperthermic effect makes use of poor reflex regulation heat radiation of tumor tissue to make spasm of tumor blood vessels emerge, leading to irreversible damage of microcirculation.
        Hyperthermic therapy combining with chemotherapy exerts synergistic killing effect on tumor cells [5]. Hyperthermic chemotherapy kills cancer cells by making use of the different tolerance of cancer tissue cells and normal tissue cells to heat and by synergistic effect. Tumor cell tolerance to heat is low, therefore, prolonging heating time can increase the impairment of cancerous cells and suppress their reproduction. If heat treatment lasts for 50-60minutes, at 42℃ cancer cells begin to degenerate and their apoptosis appears, at 43℃ coagulation and necrosis of carcinogenic cells emerge; normal tissue cells can tolerate 45℃-47℃ and cannot be harmed [6].
        Cisplatin is a common perfusion chemotherapeutic drug to treat malignant ascites, it belongs to the first generation of platinum-based anticancer drugs and is a cell cycle non-specific drug. Its main site of action is in purine and pyrimidine bases of DNA, and it can cause cross linking within a DNA chain or between DNA chains to damage function of DNA, to prevent DNA replication and to inhibit DNA synthesis. When concentration of cisplatin is high, it also inhibits synthesis of RNA and protein. After entering the abdominal cavity, cisplatin is not easy to go through the peritoneal barrier, thus its intraperitoneal concentration is higher than its plasma concentration. It can maintain effective concentration in the body for a relatively long time, and is an ideal intracavitary perfusion anticancer drug. The literature reported that hyperthermic therapy combining with chemotherapeutic drugs including cisplatin etc. can exert additive or synergistic anticancer effect [7]. We applied continuous circulative hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites, and its effective rate was 76.47% and significantly higher than 53.57% of conventional intraperitoneal perfusion chemotherapy group, indicating that compared with intraperitoneal perfusion chemotherapy, continuous circulative hyperthermic intraperitoneal perfusion chemotherapy has certain advantages and is an effective method for treating malignant ascites. This result is consistent with those of the domestic and foreign relevant reports [8, 9].
        Hyperthermic intraperitoneal perfusion chemotherapy can significantly improve the treatment effect of chemotherapy, its adverse reasons are small and patients tolerate it well, so that the therapy is worthy clinical popularization, but its long-term treatment effect remains to be further observed.

        References:
        [1] Fujimoto S, Shrestha RD, Kokubun M, et al. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding [J]. Ann Surg, 1988, 208(1):36-41.
        [2] Zhao Keyu, Liu FuLian, Wang Zhenxing, et al. Clinical observation of hot intraperitoneal perfusion chemotherapy combined with immune treatment machine to treat malignant ascites [J]. Southwest Military Medicine, 2010,12 (1) :9 -10.
        [3] de Bree E, Romanos J, Michalakis J, et al. Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel as second-line treatment for peritoneal carcinomatosis of gynaecological origin[J]. Anticancer Res, 2003, 23 (3C):3019-3027.
        [4] Zhou Jichang. Practical tumor medicine[M]. Beijing: People's Health Publishing House, 1999.23-24.
        [5] Miller PC, Riehards M, Baid C, et al. Interaction of hyperthermia and chemothermia agents:cell lethality and oncogenic potential [J]. Int J Hyperthermia, 1994, 10(2):89-91.
        [6] Fujunote S, Takahashi M, Mutou T, et al. Improved mortality rate of gastric carcinoma patients with peritoneal carcinomatoesis treated with intraperitoneal hyperthermic chemoperfusion combined with surgery[J].Cancer, 1997, 79 (5):884-891.
        [7] Chou Jinrong, Lu Kaihua, Liu Lianke, et al. Clinical observation of high-dose cisplatin intraperitoneal perfusion to treat malignant ascites [J]. Journal of Clinical and Experimental Medicine, 2006, 5 (12):1964 -1965.
        [8] Liu Zhimin, Kang Lin, Liu Yibing, et al. Clinical observation of cisplatin hot intraperitoneal perfusion to treat malignant ascites [J]. Tumor, 2007, 27 (6): 508 -510.
        [9] Tsiftsis D, de Bree E, Romanos J, et al. Peritoneal expansion by artificially produced ascites during perfusion chemotherapy[J]. Arch Surg, 1999,134 (5):545-549.

        Journal of Chinese Oncology, 2011, 17(6)
        Received date: January 13, 2011; received date after revision: April 14, 2011

        TypeInfo: academic articles

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