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        Clinical efficacy observation of thermostatic intraperitoneal hyperthermic perfusion chemotherapy in treatment of colorectal cancer accompanied with malignant ascites

        Date:2014年2月26日 16:50

        Xiangcai Zou, Chuyuan Hong *, Guojian Liang

        [Abstract] Objective: To investigate the clinical efficacy of thermostatic intraperitoneal hyperthermic perfusion chemotherapy in treatment of colorectal cancer accompanied with malignant ascites.
        Methods: After tumor resection of 42 colorectal cancer patients with ascites, the BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system was used to perform thermostatic intraperitoneal hyperthermic perfusion chemotherapy. The water temperature was constantly remained at 42±0.5℃, chemotherapy liquid was physiological saline 3000 ml + 5-FU 2.0, and perfusion time was 60 minutes. Results: All of the 42 patients successfully completed hyperthermic perfusion chemotherapy and serious adverse reactions requiring discontinuation of treatment did not occur. Among the 42 patients, the results of 24 patients (57.15%) were complete remission of ascites, 12 (28.57%) were partial remission, 2 (4.76%) were stable disease and 4 (9.52 %) were no response. The total efficiency was 85.71%. Conclusion: The efficacy of thermostatic intraperitoneal hyperthermic perfusion chemotherapy in treatment of colorectal cancer accompanied with malignant ascites is definite and the therapy is economical and practical, therefore, the method is worth clinical popularization.
        [Key words] intraperitoneal hyperthermic perfusion; malignant ascites; colorectal cancer; chemotherapy

        CLC: R735.3 Document ID code: A Article number: 1009-976X (2012) 05-0274-03
        doi:10.3969/j. issn.1009-976X.2012.05.010

        Colorectal cancer is one of the common tumors causing malignant ascites. Statistics show that the median survival time of tumor patients with malignant ascites is approximately 78 days [1]. Malignant ascites is very difficult to clinically treat and the effective rate of diuretics is not ideal enough [2]. Although simple repeated puncture can achieve short-term efficacy, during release of large volume of ascites, protein losses to worsen malnutrition of advanced cancer patients and there are blood pressure decrease and other related complications caused by abdominal pressure drop. Some scholars use intraperitoneal perfusion chemotherapy, intraperitoneal hyperthermic therapy, intraperitoneal perfusion chemotherapy combined with hyperthermic therapy or biologics (interleukins, tumor necrosis factor, etc.) intraperitoneal perfusion and other methods, and all of them exert certain effect, but the overall effect is still unsatisfactory [1, 3]. Our department use BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system to perform thermostatic intraperitoneal hyperthermic perfusion chemotherapy and has achieved better efficacy. Now it is reported as follows.

        1 Clinical Data
        1.1 General Information
        This group included 42 patients who had all been definitely diagnosed by pathology before the perfusion operation. The patients included 26 males and 16 females, aged 49 to 73 years with a median of 67 years. 18 cases had KPS (Karnofsky) functional status score of fewer than 60 points, and 24 cases had the score of more than 60 points. Before the perfusion operation, clinical manifestations were: abdominal palpable mass in 2 cases; liver metastases in 3 cases; no symptoms of intestinal obstruction; cancer cells had been found from ascites in 7 cases; during tumor resection, in most patients the tumors had invaded serosal surface, and on the omentum majus and the peritoneum multiple tumor cancerous nodules could be seen (Figure 1). 42 cases included 19 cases of colon cancer, 23 of rectal cancer; 14 cases of highly differentiated adenocarcinoma, 6 of moderately differentiated adenocarcinoma, 10 of poorly differentiated adenocarcinoma, 8 of mucinous adenocarcinoma and 4 of signet ring cell carcinoma. The amount of ascites was 1000-3000 ml. All patients underwent laparoscopic resection of colorectal cancer.

        1.2 Treatment methods
        1.2.1 Measurement method of ascites First, abdominal circumference (C) was measured, and then the depth (d) of ascites was measured by ultrasound when a patient was in knee-chest position and the patient’s spine was parallel to the bed. The volume of ascites could be calculated according to the formula V = 1/3 [πd2 (3r-d)] (Note: r = C/2π) [4]. Amount of ascites of patients with ascites was measured by B ultrasound 1 day before the perfusion operation, at the time when hyperthermic perfusion chemotherapy ended, and then once a week for follow-up reexamination.
        1.2.2 Method of hyperthermic perfusion chemotherapy 42 colorectal cancer patients with ascites received first perfusion immediately after tumor resection. Under anesthesia, from Trocar holes or open incision, 4 drainage tubes were placed and were cross-fixed in the left, right upper abdominal cavity and pelvic cavity (Figure2). The BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system (Guangzhou Barui Medical Technology Co., Ltd.) was used to perform thermostatic intraperitoneal hyperthermic perfusion chemotherapy. The hyperthermic perfusion chemotherapy machine had precise temperature control system to make water temperature constantly remain at 42±0.5℃, and perfusion chemotherapy liquid was physiological saline 3000 ml + 5-FU 2.0 and perfusion time was 60 minutes. By making use of the 4 indwelled drainage tubes, the second and third perfusion chemotherapies were performed under intravenous anesthesia on postoperative days 1 and 2, respectively.

         

         

         Figure 1  Multiple cancerous nodules of the omentum majus and the peritoneum

         

         

        Figure 2  4 perfusion or drainage tubes

         

        1.3 Evaluation method of efficacy
        According to WHO criteria, complete remission (CR) was: ascites disappeared and the state lasted for more than four weeks; partial remission (PR) was: ascites reduced by more than 50% and the state lasted for more than four weeks; stable disease (SD) was: ascites did not reduce or reduced by less than 50%; progressive disease (PD) was: ascites increased. CR+PR were the effective rate of ascites.

        2 Results
        2.1 Short-term efficacy
        All of 42 colorectal cancer patients with ascites successfully completed intraperitoneal hyperthermic perfusion chemotherapy. Among the patients, results of 24 cases (57.15%) were ascites complete remission, 12(28.57%) were partial remission, 4 (9.52%) were stable disease, 2 (4.76%) were no response, and the effective rate reached 85.71% (Table 1).

        Table 1 Analysis and evaluation of efficacy of malignant ascites

        evaluation of
        efficacy of
        malignant ascites

        number

        Constituent ratio (%)

        Complete remission (CR)

        24

        57.15

        Partial remission (PR)

        12

        28.57

        Stable disease (SD)

        4

        9.52

        Progressive disease (PD)

        2

        4.76

        Total

        42

        100

         

        2.2 Adverse reactions during perfusion
        Compared with KPS score before perfusion, after perfusion it was significantly improved (Table 2), and the patients with more than 60 points were increased to 35 cases. During treatment, the following side effects occurred: 3 cases of fever, 4 of dyspnea, 5 of nausea and vomit, 2 of abdominal distention, 3 of abdominal pain and 3 of anemia. All of above side effects were graded (WHO grading criteria of chemotherapy side effects) Ⅱor fewer thanⅡ, and the symptoms   alleviated spontaneously or alleviated after symptomatic treatment, and no side effects with grade Ⅲ or more than grade Ⅲ occurred. No liver and kidney function, heart and nervous system impairment emerged, and serious adverse reactions requiring discontinuation of treatment did not occur (Table 3).

        Table 2 Comparative analysis of KPS scores before and after perfusion therapy

        KPS score

        Below 60 points
        n (%)

        Above 60 points
        n (%)

        Before
        perfusion therapy

        18(42.86%)

        24(57.14%)

        After
        perfusion therapy

        7(16.77%)

        35(83.23%)

         

        Table 3 Analysis of adverse reactions of hyperthermic perfusion

        Adverse reaction

        Grade I
        n

        Grade II
        n

        Percentage
        %

        Fever

        2

        1

        7.14

        Dyspnea

        2

        2

        9.52

        Nausea, vomit

        3

        2

        11.90

        Abdominal pain

        1

        1

        4.76

        Abdominal distention

        1

        2

        7.14

        Anemia

        1

        2

        7.14

         

        3Discussion
        Colorectal cancer is one of the common malignant tumors with malignant ascites and there are varied treatment methods. Although simple repeated release of ascites can achieve short-term efficacy, during release of large volume of ascites, protein losses to worsen hypoalbuminemia of tumor. Domestic scholars [5, 6] have showed that abdominal puncture and perfusing chemotherapeutic drugs have been performed, and the used drugs are 5-FU, mitomycin, oxaliplatin, etc. This method is easy to operate, but its drawbacks are that chemotherapeutic drugs are usually not uniformly distributed in the abdominal cavity, the tubes are smaller and are easily wrapped and blocked by the omentum majus and other tissues, so that the effective rate of oxaliplatin intraperitoneal perfusion therapy for malignant ascites is approximately 50%. Intraperitoneal hyperthermic therapy to treat malignant ascites has achieved certain efficacy, and hyperthermic therapy is based on the following theory: the tolerance of tumor cells to heat is lower than normal cells; usually at more than 42℃ necrosis and coagulation of tumor cells begin to occur, while normal cells can tolerate higher temperature. Therefore, some scholars [6] have tried to combine intraperitoneal perfusion chemotherapy with hyperthermic therapy to form a method of intraperitoneal hyperthermic perfusion chemotherapy for treating malignant ascites. Common methods include (1) Intraperitoneal hyperthermic perfusion chemotherapy: abdominal puncture is performed to perfuse chemotherapeutic drugs, and meanwhile high-frequency hyperthermic therapy machine is used outside the abdominal cavity to perform irradiation hyperthermic therapy; (2) The chemotherapy liquid is heated and then is perfused into the abdominal cavity. Above methods all have the following problems: when the hyperthermic therapy machine is used to perform irradiation outside the body, the temperature in the abdominal cavity cannot be monitored and controlled; after the chemotherapy liquid is heated and then is perfused into the abdominal cavity, the temperature of chemotherapy perfusion liquid cannot be constantly maintained and the change of the temperature cannot be detected, either; the chemotherapeutic drugs are not evenly distributed; the drainage tubes are easy to block; the overall efficacy does not seem to be stable enough [6, 7]. Among them, the most critical problem is that these methods cannot guarantee during perfusion the temperature of chemotherapy liquid is constant effective temperature.
        Some studies [8] have showed that during the coelom hyperthermic perfusion therapy, more desired therapeutic efficacy can be achieved only if the therapy temperature is higher than 40℃ and lasts for more than 40 minutes. In this group, patients received thermostatic intraperitoneal hyperthermic perfusion chemotherapy by the BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system and the chemotherapy perfusion machine has precise temperature control system [9] to ensure that the temperature is controlled and adjusted in the range of ±0.5℃, so that the organization is not burned while the effective temperature is ensured. The precise control of temperature by the hyperthermic perfusion machine ensures stability of temperature and the efficacy of hyperthermic therapy throughout the process of hyperthermic perfusion therapy. The selected basic drug of gastrointestinal cancer chemotherapy is 5-FU 2.0 which is dissolved into 3000 ml physiological saline as perfusion liquid. In the group, the thoracic drainage tubes were selected as drainage tubes and their diameter was large enough, and they were placed on the bilateral subphrenic sites and the left and right pelvic sites. Among the 4 tubes, chemotherapy liquid was perfused into the abdominal cavity via two tubes and chemotherapy liquid was drained out via other two tubes to perform circulatory perfusion. The thoracic drainage tubes with large diameter were not easily blocked. We checked the drainage tubes extracted after the treatment ended, and found that no lumen of the drainage tubes of 42 patients had been completely blocked. As for the distribution of the drainage tubes, the fact that 4 tubes were crosswise placed in the upper abdominal cavity and pelvic cavity also could ensure perfused chemotherapy liquid fully contacted with the entire abdominal cavity and maximized the effect of perfusion therapy to scour residual tumor cells. As for treatment results of ascites in this group of patients, the total effective rate reached 85.71% which was basically consistent with other reported results in the literature [10, 11]. The general conditions of the patients were also significantly improved, and after perfusion therapy the percentage of patients with KPS score of more than 60 points rose from 57.14% to 83.23%. Although there were fever, abdominal distension, abdominal pain, nausea and vomit, anemia, and other side effects, these side effects were all gradedⅡor fewer thanⅡ, and alleviated spontaneously or alleviated after appropriate symptomatic treatment. Therefore, we believe that for the use of intraperitoneal hyperthermic perfusion chemotherapy in the treatment of malignant ascites, the most important thing is to ensure the temperature of perfusion liquid to be constant throughout the perfusion process. Through the temperature control system of BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system, the temperature can be constantly maintained at 42±0.5℃ to ensure the effective perfusion temperature. That the lumen is unobstructed and perfusion liquid can fully contact with the entire abdominal cavity is also an important factor to improve the effective rate. In this group, the perfusion and drainage tubes were all placed under direct vision (under laparoscopy), and 2 tubes were placed in the bilateral subphrenic sites and another 2 tubes were placed in the pelvic sites for circulatory perfusion to ensure that perfused chemotherapy liquid fully contacted with the entire abdominal cavity, leaving no dead space, so that the perfusion liquid did fully contact with the abdominal cavity. The luminal blockage problem and uneven distribution problem of perfusion liquid were solved, so that good efficacy has been achieved.
        In summary, thermostatic intraperitoneal hyperthermic perfusion chemotherapy effectively controls malignant ascites production of colorectal cancer patients with malignant ascites, thus greatly improves the quality of life of colorectal cancer patients with ascites. Using BR-TRG-Ⅰcoelom hyperthermic perfusion therapy system with precise temperature control to perform thermostatic intraperitoneal hyperthermic perfusion chemotherapy for colorectal cancer accompanied with malignant ascites is safe and effective. Because of the treatment need of the patients, it is difficult to set blank control group, and also because of fewer number of the cases in this group, this method still needs larger sample control study for further verification.

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        (Received Date: April 23, 2012)

        Fund project: Guangdong Province Medical Research Foundation (No. A2009277)
        Author’s unit: Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Guangzhou Medical College, Guangzhou City 510260, Guangdong Province
        Corresponding author: Chuyuan Hong, E-mail: hongchuyuan@sina.com

        Lingnan Modern Clinical Surgery, October, 2012 12(5): 274-276.

        Clinical Research

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