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        Clinical observation of circulatory intraperitoneal hyperthermic perfusion chemotherapy in treatment of malignant ascites

        Date:2014年2月26日 10:34

        Clinical observation of circulatory intraperitoneal hyperthermic perfusion chemotherapy in treatment of malignant ascites

        Junqing Zhang1, Tieying Wu1, Yanguo Feng1

        [Abstract] Objective: To observe the efficacy of circulatory intraperitoneal hyperthermic perfusion chemotherapy in treatment of malignant ascites. Methods: The circulatory coelom hyperthermia perfusion chemotherapy machine was used to perfuse chemotherapeutic drugs into the abdominal cavity for treating 58 cases of malignant ascites, and its efficacy and adverse reactions were evaluated. Results: The conditions of 10 patients (17.2%) presented complete remission (CR), 17 (29.3%) presented partial remission (PR), 11(18.9%) presented minor response (MR), 8(13.8%) presented stable disease (SD) and 12(20.7%) presented progressive disease (PD). The total effective rate was equal to CR+PR+MR and was approximately 65.5%. Common adverse reactions were nausea and blood toxicity, and no severe adverse reactions were seen, but there was still long-term chemical peritonitis. Conclusion: The effective rate of circulatory intraperitoneal hyperthermic perfusion chemotherapy to treat malignant ascites is high and patients tolerate it well. 
        [Key words] ascites; hyperthermic therapy; chemotherapy
        doi:10.3969/j.issn.1674-4985.2012.25.057

        Malignant ascites is a common complication of digestive tract tumors, causes patients’ very great suffering and significantly decreases their quality of life. The efficacies of routine intraperitoneal chemotherapy and systemic chemotherapy are poor, the interval between the end of the treatment and ascites regeneration is very short, and it is one of the common clinical treatment problems. What the paper studied is that the circulatory coelom hyperthermia perfusion chemotherapy machine was used to directly heat ascites for performing intraperitoneal chemotherapy to malignant ascites, and achieved better clinical effect. Now it is reported as follows.

        1Materials and Methods
        1.1 General Information: Our department treated 58 patients with malignant ascites from August 2007 to October 2009, including 32 males and 26 females, and they were 36 to 78 years with an average of 60.2 years. All patients were pathologically diagnosed and the property of the effusion was exudant. Among the 58 cases, there were 16 cases of gastric cancer, 12 of colorectal cancer, 14 of ovarian cancer, 4 of primary peritoneal cancer, 10 of liver cancer and 2 of esophageal cancer. Requirements: PS ≥2 points and platelets > 80 × 109/L. Exclusion: patients had cardiac functional insufficiency, bleeding tendency or thermal hypersensitivity; property of ascites was transudate. 
        1.2 Treatment methods: All patients were supine and bedside ultrasound was used to position. McBurney's point and counter-McBurney's point (or both lateral sites with maximum ascites depth) were usually selected as the puncture points. The points were marked on the body surface. The disposable abdominal puncture package and the extracorporeal circulation pipeline were purchased from Xi'an Good Doctor medical and science technology co., ltd. Routine abdominal puncture was performed. A puncture needle was connected to the inlet of the circulatory pipeline and another puncture needle was connected to the outlet of the circulatory pipeline. Ascites entered the TRL coelom hyperthermic perfusion therapy machine (Harbin Aerospace Science and Technology Co., Ltd) via the outlet of the abdominal cavity, and after being heated, re-entered the abdominal cavity to perform extracorporeal circulation. Meanwhile, cisplatin, fluorouracil, paclitaxel, mitomycin and other chemotherapeutic drugs were intraperitoneally perfused. After liquid was heated, the abdominal cavity was kept at 42-45℃ to perform circulatory hyperthermic chemotherapy. The circulatory intraperitoneal hyperthermic chemotherapy lasted for 40-60minutes at a time and 3-4 days later the treatment was repeated. A treatment course consisted of three times of treatment.1.3 Evaluation of efficacy
        1.3.1 The criteria of efficacy evaluation of ascites: According to WHO criteria and Millar criteria, the efficacy evaluations were divided into: Complete remission (CR): ascites completely disappeared and the state lasted for more than one month. Partial remission (PR): ascites reduced by more than half and the state lasted for more than one month. Minor response (MR): ascites reduced within the same order of magnitude and the state lasted for more than one month. Stable disease (SD): ascites maintained at the original level within the same order of magnitude and the state lasted for more than one month. Progressive disease (PD): ascites increased than the original one. The effectiveness was equal to CR+PR+MR.
        1.3.2 According to the criteria of drug adverse reactions (NCI-CTC 3.0), treatment-related adverse reactions and safety were evaluated.

        2 Results
        2.1 All patients received circulatory intraperitoneal perfusion chemotherapy for1-4 times with an average of 2.6 times. The temperature of perfusion liquid from the perfusion machine to the abdominal cavity was 43-46℃ with an average of 45.7℃, and the temperature of perfusion liquid from the abdominal cavity to the perfusion machine was 42-45℃ with an average of 43.2℃.
        2.2 Short-term efficacy: The conditions of 10 patients (17.2%) presented complete remission, 17 (29.3%) presented partial remission, 11 (18.9%) presented minor response, 8 (13.8%) presented stable disease and 12 (20.7%) presented progressive disease. The total effective rate, i.e., CR+PR+MR, was approximately 65.5%.
        2.3 Adverse reactions: Adverse reactions were mainly chemotherapy-related toxicity, especially mainly nausea, vomiting and other digestive tract toxicity, and also included mild and moderate fatigue in some patients, who were relieved 2-3 days later, and hematologic toxicity which was rare. Hematologic toxicity grade Ⅰ-Ⅱ was common and no severe hematologic toxicity occurred. See Table 1.

        Table 1 Common adverse reactions(n)

        Adverse reaction

        Grade

        Grade

        Grade
        Ⅲ-Ⅳ

        Vomiting

        15

        4

        0

        Hypersensitivity

        1

        0

        0

        Leucopenia

        7

        3

        0

        thrombopenia

        12

        4

        0

        Anemia

        3

        2

        0

        Renal toxicity

        2

        0

        0

        Fatigue

        5

        5

        0

        Cardiac toxicity

        0

        0

        0

         

        After treatment, late chemical peritonitis was still common (10.3%), and the incidence rate of late chemical peritonitis after paclitaxel perfusion was 21.4% and was higher than other drugs. The time when intestinal obstruction (excluding possibility of disease progression) emerged was 2.6 to 6.4 months with a median of 4.5 months after the treatment, and only 1 case had complete intestinal obstruction.

        3Discussion
        Ascites is one of the most common complications of digestive tract cancers, and abdominal distention, eating less and other symptoms caused by it are very difficult to relieve. Once ascites emerges, advanced stage of tumor often is heralded. Diffuse peritoneal metastasis is an important factor of abdominal tumor staging, and its prognosis is poor and total survival period is often 4 to 6 months [1]. Intraperitoneal chemotherapy is often a palliative treatment method. Its superiorities are: drugs directly contact with peritoneal cancer, the method improves anticancer effect and has pharmacokinetic advantage. However, because diffusion and penetration of drugs can reach only 1-3 mm [2], ascites is not ideally controlled. From the 1990s, intraperitoneal hyperthermic chemotherapy as an experimental treatment has gradually entered clinical practice [3-4]. Hyperthermia can directly kill cancer cells and also can promote the diffusion of drugs which reaches 3-6 mm [5]. Hyperthermic therapy and chemotherapy exert synergistic effect to kill cancer cells and achieve good efficacy. In recent years, on above basis, domestic circulatory abdominal and thoracic cavity perfusion chemotherapy machines have been improved, and thermostatic intraperitoneal perfusion chemotherapy has been realized, and compared with conventional intraperitoneal hyperthermic chemotherapy, these machines have the following superiorities: (1)   
        They rinse peritoneal cancer cells and exert effect of cleaning the abdominal cavity. (2) High-dose continuous perfusion can overcome the resistance of the abdominal cavity to make drugs diffuse uniformly and make every location of the abdominal cavity be at the same temperature, so that homogeneity of hyperthermia and chemotherapeutic drugs is kept in the abdominal cavity. (3) Due to uniform distribution of chemotherapeutic drugs in the abdominal, the incidence rate of chemical peritonitis decreases. (4) The thermostatic state in the abdominal cavity can keep temperature in the effective range. We applied circulatory intraperitoneal hyperthermic chemotherapy to treat ascties caused by digestive tract tumors and have achieved relatively good efficacy.
        Temperature is often one of the keys for achieving efficacy. Generally, 42-45℃ of hyperthermic therapy is considered effective. Some studies have even thought that up to 48℃ of intraperitoneal hyperthermic chemotherapy is safe [5], but we have observed that when the hyperthermia reached more than 45℃ tolerance of patients often declined and it was often accompanied with palpitations, shortness of breath and other discomforts. The reason was analyzed: the blood circulation takes away the hyperthermia to the whole body to make the whole body enter high metabolic state, resulting in increased cardiac load. Therefore, we kept the temperature in the abdominal cavity at 42-45℃ and the patient tolerated it well. The synergistic effect of cisplatin, fluorouracil, mitomycin and other chemotherapeutic drugs and hyperthermia has been demonstrated in previous studies, thus we used above drugs for intraperitoneal hyperthermic chemotherapy and this study has found that the total effective rate of ascites was approximately 65% while the similar studies reported the total effective rate can often reach more than 85% [6-7]. The reason may be that more second-line treatment patients were included in this study, because in 31 previously untreated patients included in the study the effective rate was approximately 80.6% which is consistent with domestic similar reports. Adverse reactions of chemotherapeutic drugs in the circulatory intraperitoneal perfusion were mild, and often presented vomiting and blood toxicity grade Ⅰ-Ⅱ and no obvious liver and kidney function toxicity. The intestinal adhesions caused by long-term chemotherapy peritonitis were still common. Due to different irritation of different drugs, we observed that the chemical peritonitis caused by paclitaxel was more common, but because of the small number of cases, statistical conclusion still cannot be obtained from the difference of the incidence rates of chemical peritonitis caused by different drugs.
        In short, intraperitoneal hyperthermic perfusion chemotherapy is an effective method to treat malignant ascites. Due to its good safety, mild adverse reactions, easy tolerance, the method is worth further clinical study.

        References
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        (Received Date: March 23, 2012) (Editor of this article: Shengli Lian)

        1No. 264 Hospital of the People’s Liberation Army, Taiyuan City 030001, Shanxi Province
        Corresponding author: Junqing Zhang

        Medical Innovation of China, September, 2012, 9(25, total: 235): 97-98.

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