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        A clinical study of continuous thermostatic circulative hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites

        Date:2014年2月26日 16:41

        Zengxiang Hu, Yulei Du, Qi Zhao, Jing Dou, Xinsheng Wang 

        [Abstract] Objective: To investigate the treatment effect of continuous thermostatic (42-43℃) circulative hyperthermic intraperitoneal perfusion chemotherapy to treat malignant ascites. Method: Forty-five patients with malignant ascites were randomly divided into two groups. In observation group including 22 patients, the circulative dual passages were established by the conventional puncture needles; first, the abdominal cavity was rinsed and the perfusion liquid in the abdominal cavity was replaced; at last, 2500-3500ml was maintained in the abdominal cavity; 3-5minutes after thermostatic (42-43℃) circulative intraperitoneal therapy began, DDP 40mg was added into the line; continuous thermostatic circulative hyperthermic perfusion chemotherapy lasted 60minutes; after the therapy ended, therapeutic liquid was drained out and the remaining liquid in the abdominal was 1000-1500ml. In control group including 23 patients, the abdominal drainage catheter was placed; the abdominal cavity was rinsed and then 1000-1500ml liquid including DDP 40mg was perfused; all liquid had been heated to 43℃ before it was perfused into the abdominal cavity. Result: The total effective rate in observation group was 86.3% and significantly higher than control group (P <0.05). Conclusion: Compared with the conventional intubation for extraction and hyperthermic perfusion chemotherapy, continuous thermostatic circulative hyperthermic intraperitoneal perfusion chemotherapy significantly increases the effective rate of treating malignant ascites, and meanwhile significantly improves the resurgence of malignant effusion and improves the quality of life of patients with advanced cancers.
        [Key words] malignant ascites; continuous thermostatic circulative hyperthermic perfusion; chemotherapy 
        [CLC] R730.5 [Document ID code] A [Article number] 1672 -2876 (2009) 06 - 0366 - 02
         
        Malignant body cavity effusion, of which malignant ascites accounts for approximately 60% mainly caused by peritoneal metastasis of gastric cancer, colorectal cancer, liver cancer and ovarian cancer, is a common complication in patients with advanced tumors[1]. Main treatment is local simple ascites extraction plus single drug chemotherapy, which has limited effect and ascites is easy to recur. Although the survival period of patients with advanced tumors is limited, the successful palliative care can reduce ascites formation to alleviate the suffering caused by abdominal pain, and exerts positive effect on patients' quality of life and prognosis. In our hospital, continuous thermostatic circulative hyperthermic intraperitoneal perfusion chemotherapy was used to treat 22 cases with cancerous ascites, and achieved good treatment effect.

        1 Subject and method
        1.1 Subject The selected 45 patients in our department were randomly divided into continuous thermostatic circulative chemotherapy group (observation group) including 22 cases and simple extraction and hyperthermic chemotherapy (control group) including 23 cases. Inclusion criteria: Patients should be 38 to 70 years old; physical grading standard (ECOG) NCI was 0-3; all patients had more than moderate ascites confirmed by B ultrasound; besides extraction of fluid had been performed for diagnosis after cancerous ascites puncture, no drug had been injected into the abdominal cavity before the treatment; the interval between the end of the last treatment of patients’ systemic chemotherapy and the entrance into a group should be> 4 weeks; liver, kidney function and routine blood test should be in the normal range; there was > 3 months expected survival period. Exclusion criteria: patients had severe cardiac insufficiency, hepatocirrhosis decompensation, renal insufficiency. Observation group included 22 cases, aged 39 to 65 years old, of which 8 cases suffered from gastric cancer, 5 suffered from colorectal cancer, 6 suffered from ovarian cancer and 3 suffered from other diseases; control group included 23 cases, aged 38 to 70 years old, of which 6 cases suffered from gastric cancer, 9 suffered from colorectal cancer, 5 suffered from ovarian cancer and 3 suffered from other diseases. Each of age, disease, etc. between the patients of the two groups was comparable.
        1.2 Method Observation group: Before the treatment, B ultrasound positioning was required to determine the puncture site. Two needles, i.e., one for inflow and another one for outflow, were punctured. According to the property of the patient’s ascites, hyperthermic perfusion was performed by one-way. 1500-2500 ml warm physiological saline was perfused. The perfusing process was accompanied with drainage to drain out partial malignant effusion and to dilute effusion and toxins, so that symptoms were relieved. After the hyperthermic perfusion ended, TRL 2000 cardiopulmonary bypass hyperthermic perfusion chemotherapy machine (Harbin Aerospace Science and Technology Co., Ltd.) was connected. heating was set at 45℃, inflow temperature was set at 43.5-44℃, and outflow temperature was set at 41.5-42℃. The chemotherapy drug was added and continuous thermostatic circulation lasted for 60 minutes. After the circulation ended, partial liquid was drained out and amount of the remaining liquid was > 1500 ml. The above operation was performed once every 72 hours for 3 consecutive times. Each patient in control group underwent the conventional abdominal puncture, and a single chamber deep venous catheter was indwelled in the abdominal cavity for continuous drainage. Ascites was drained out as much as possible and then the abdominal cavity was rinsed. Perfusion liquid, which had been heated to 45℃, was perfused into the abdominal cavity for hyperthermic chemotherapy once every 72 hours for 3 consecutive times. During the treatment, the patients of the two groups did not receive systemic chemotherapy and interferon, interleukin 2 and other immunotherapy, and only received systematic treatment. Hyperthermic chemotherapy scheme in observation group was: physiological saline 20 ml + DDP 40 mg passed through the circulation machine for thermostatic circulation. Treatment scheme in control group was: physiological saline 500 ml + DDP 40 mg in the perfusion bag was soaked into the boiled water and after the perfusion liquid was heated to 45℃ it was quickly infused into the abdominal cavity. Volumes of ascites before and after the treatment were measured by B ultrasound as observation index, and Kamofsky score was observed. Treatment effect was evaluated according to WPS criteria. Complete relief: ascites disappeared and the state lasted for more than 4 weeks; partial relief: ascites reduced by more than 1/2 and the state lasted for more than 4 weeks, and symptoms were relieved; stable disease; progressive disease: ascites increased >25%. Effectiveness: complete relief + partial relief. Safety evaluation was judged by anticancer drug toxic reaction criteria.
        1.3 Statistical analysis Based on SPSS 11.0 statistical software, χ2 test was used to compare the rates of the two groups.

        2 Results
        2.1 Clinical treatment effect Table 1 is shown. All of the patients received the treatment more than 3 times. In observation group, the effective rate was 86.3% and the complete relief rate was 31.8%; in control group, the effective rate was 56.5% and the complete relief rate was 17.4%. The difference was statistically significant (P <0.05).
        2.2 Toxic and side reactions Nausea, vomiting, leukopenia and other side reactions in the patients of the two groups were mild, and the patients quickly returned to normal state by symptomatic treatment. We specially noted that compared with control group the appetite and mental condition of the patients in observation group did not weaken but strengthened. No one case had abdominal pain and abdominal infection. All patients had no liver and kidney function impairment.

        Table 1 Comparison of the treatment effect of the two groups

         

        Complete relief

        Partial relief

        Stable
        disease

        progressive disease

        Total

        Observation
        group
        Control
        group

        7(31.8)

        4(17.4)

        12(54.5)

        9(39.1)

        2(9.1)

        7(30.4)

        1(4.5)

        3(13.0)

        22

        23

         

        3 Discussion
        When malignant tumors develop to advanced stage, they can cause cancerous ascites to severely affect the quality of life of patients. In several hours after an intraperitoneal chemotherapeutic drug has been administered, the intraperitoneal drug concentration is 2.5 to 8 times higher than the plasma drug concentration [2] to form constant, long-lasting and high concentration anticancer drug environment in the abdominal cavity, the portal vein and the liver, while amount of the drug into circulation of the body is very small. Compared with traditional intravenous chemotherapy, intraperitoneal administration not only increases concentration of the anticancer drug in the abdominal cavity and prolongs time when cancer cells contact with the drug, but also exerts stronger action of killing cancerous embolism and cancer cells which have been transferred to the liver from the portal vein because the drug in the abdominal cavity is mainly absorbed via the portal vein [3, 4]. Hyperthermic intraperitoneal perfusion chemotherapy is designed according to the anatomic structural characteristics of the abdominal cavity, rationality and effectiveness of local chemotherapeutic pharmacokinetics, and anticancer synergic effect principle of hyperthermic therapy combined with chemotherapy. The tumor tissue is more sensitive to heat than the normal tissue, thus heating can directly hurts cancer cells and more than 42℃ for 50-60 minutes can exert significant inactivating effect on malignant tumors. High temperature can increase local drug concentration of tumor tissue, and high concentration of chemotherapeutic drug can overcome drug resistance of tumor cells, so that the antitumor effect is better exerted. Heating can increase the sensitivity of tumor cells to certain chemotherapeutic drugs, and meanwhile cell permeability is enhanced and tumor cell microenvironment and pharmacokinetics is changed, thus effect of anticancer drug is strengthened. Warm liquid can increase the permeability of anticancer drugs, and direct permeability depth can be up to 5 mm; warm liquid also enhances the toxic effect of chemotherapeutic drugs, induces tumor cell apoptosis and enhances lethality against cancer cells [4, 5]. Continuous thermostatic circulative hyperthermic chemotherapy has been another new method of hyperthermic chemotherapy in recent years [6], and perfusion liquid is heated to 45℃±0.5℃ and dual passages are established by general abdominal puncture needles. The inflow temperature is maintained at 43.5-44℃ and the outflow temperature is maintained at 41.5-42℃, and the temperature in the abdominal cavity is maintained at approximately 43℃ for 60 minutes. By prolonging the heating time, the effect of hyperthermic intraperitoneal chemotherapy is significantly strengthened. The effective rate of continuous thermostatic circulative hyperthermic chemotherapy in observation group to treat cancerous ascites was 83.3% and was significantly higher than simple hyperthermic intraperitoneal chemotherapy in control group but the toxic and side reactions of the two groups were similar, indicating that continuous thermostatic circulative hyperthermic chemotherapy is an relatively effective method to treat cancerous ascites and is worth clinical popularization.  

        References
        1. Yan Sun. Manual of clinical oncological internal medicine. The 2nd Edition. Beijing: People's Medical Publishing House, 1991.23.
        2. Jichang Zhou. Practical oncological internal medicine. Beijing: People's Medical Publishing House, 1998. 131-142.
        3 Topuz E, Basaran M, Saip P, et al. Adjuvant intraperitoneal chemotherapy with cisplatinum, mitoxantrone, 5-fluorouracil, and calcium folinate in patients with gastric cancer: a phase II study. Am J Clin Oncol, 2002, 25(6): 619-624.
        4 Zhidong Zhu, Yongdong Pu. Comparison of pharmacokinetics of fluorouracil chemotherapy via the left gastric artery and a peripheral vein. Journal of Chinese Gastrointestinal Surgery, 2004, 3 (1): 28-30.
        5 Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol, 2002, 43 (1): 33-56.
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        Author unit: No.1 department of internal medicine, People's Liberation Army No.260 Hospital, Shijiazhuang City 050041, Hebei province, China

        Journal of Bethune Military Medical College, December, 2009, Volume 7, No.6

         (Received date: June 23, 2009)

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        TypeInfo: academic articles

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