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        Comparative analysis of thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy and intraperitoneal perfusion chemotherapy in the treatment of colorectal cancer

        Date:2014年2月26日 16:20

        Yinghuan Ma, Jing Yang

        Department  of Oncology The 463 th Hospital of  People’s Liberation Army, Liaoning,Shenyang 110042, China.

        [Abstract]   Objective: to compare the effect of coelom continued circulatory hyperthermia perfusion and intraper- itoneal chemotherapy for treatment of colorectal cancer.Methods:  Total of 60 patients with colorectal cancer were enrolled in our hospital from October 2009 to October 2010,with 34 cases male,26 female. All patients were divide into 2 groups. One  group was  treated  with  continued  circulatory  hyperthermia  perfusion, another  group  with  intraperitoneal chemotherapy. Results:  Total efficiency (ORR) was 26.7% in the intraperitoneal chemotherapy group and 36.7% in the coelom continued circulatory hyperthermia perfusion group; The differences  existed  between  two groups  for  the mean progression - free survival time and 1 year survival rates mean progression - free survival  time  and 1 year survival rates was higher  in the  coelom  continued  circulatory  hyperthermia  perfusion  group than  intraperitoneal  chemo- therapy group. Conclusion:  Coelom continued circulatory hyperthermia perfusion has advantages in clinical application comparing to  intraperitoneal chemotherapy   for  treatment  of colorectal cancer.

        [Key words] intraperitoneal hyperthermic perfusion chemotherapy; thermostatic circulatory hyperthermic perfusion chemotherapy; colorectal cancer
        [CLC] R735.3 + 4 [Document ID code] A  DOI: 10.3969/j.issn.1672-4992.2013.04.50
        [Article number] 1672-4992-(2013) 04-0825-03
        Intraperitoneal perfusion chemotherapy (IPC) is a measure of local chemotherapy, its significance lies on increasing tumor local drug concentration and reducing systemic toxic and side effects of drugs, and compared with intravenous chemotherapy the therapy has significantly pharmacokinetic advantage. Intraperitoneal perfusion chemotherapy has been clinically applied for many years and exerts certain effect on control of intraperitoneal tumors [1-3]. From October 2009, our hospital has begun to use TRL thermostatic coelom continued circulatory hyperthermia perfusion machine (CCCHP) in treatment of advanced colorectal cancer. Its working mechanism was that liquid with dissolved chemotherapeutic drugs was continuously thermostatically circulated in the abdominal cavity and best efficacy was achieved through thermal effect combined with chemotherapeutic drugs [4]. From October 2009 to October 2010, our department collected 60 patients with advanced colorectal cancer, and a group received TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy, whereas another group received intraperitoneal perfusion chemotherapy. The efficacies of the two groups were compared and analyzed.

        1 Materials and methods
        1. Subjects of study and grouping
        60 patients with colorectal cancer in our hospital from October 2009 to October 2010 were enrolled, including 34 males and 26 females, and were 36-75 years with a median age of 58 years. The 60 cases were diagnosed as stage III b-IV patients with postoperative recurrence or stage IV patients who were not suitable for operation and who and their relatives only agreed to receive local intraperitoneal perfusion chemotherapy. The 60 cases were divided into two groups, based on their own free will. The intraperitoneal perfusion chemotherapy group was referred to as IPC group; TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was referred to as CCCHP group. Each of the two groups included 30 patients. Systemic ECOG score was 0-2 points. The expected survival period was ≥3 months. During grouping, the differences of cancer staging, pathological types, gastrointestinal cancers, age, sex, physical conditions and other factors between the two groups of patients were tried to eliminate as far as possible. After treatment, one-year follow-up was performed. If conditions of illness related to intraperitoneal perfusion progressed, the patients were switched to other treatments and were excluded from this study.
        1.2 Treatment methods
        Intraperitoneal perfusion chemotherapy group (IPC group): The puncture point was selected on the intersection of middle 1/3 section and lateral 1/3 section of the connection line between the left/right anterior superior iliac spine and the navel. At first, 2000ml physiological saline, including 500ml one containing dexamethasone10mg, 500ml one containing 5- fluorouracil 0.8g/m2 and 1000 one, was heated to 43℃. Lidocaine local anesthesia was performed on the selected puncture site, and then abdominal puncture was performed and the 2000ml physiological saline was infused in the abdominal cavity.
        TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy (CCCHP group): General puncture was performed to establish the inflow passage. An infusion device was connected and 500ml warm saline was perfused. It was ensured that liquid flowed within the puncture without resistance. The pipe of the TRL circulation machine was connected and the temperature was set at 45℃-45.5℃. Hyperthermic saline was unidirectionally perfused. Usually, it was appropriate that 2500ml-3500ml liquid was maintained in the abdominal cavity when a patient felt mild abdominal distention. Then another puncture was performed and the outlet of the needle was connected to the pipe of the circulation machine to start circulatory hyperthermic therapy. During the circulation, inflow temperature was regulated to 43.5℃-44.5℃ and the outflow temperature was usually 39.5℃-40.5℃ in the abdominal cavity. The flow rate was 150ml/min-200ml/min and thermostatic circulation lasted for 50-60 minutes. The temperature in the body was kept at 42℃-43℃. 20 minutes after the beginning of the circulation, 5-fluorouracil 0.8g/m2 was injected into the circulatory pipe. Finally, partial liquid was discharged and not less than 1500ml liquid was remained in the abdominal cavity. According to the amount of the discharged liquid, 5-fluorouracil specific amount was calculated and then more 5-fluorouracil was intraperitoneally injected for supplement so as to allow 5 - fluorouracil in the abdominal cavity to reach 0.8g/m2.
        After the end of intraperitoneal perfusion, each patient in both groups was asked to repeatedly change position in the bed for 2 hours, changing position once every 15 minutes, so as to make liquid medicine extensively contact with the abdominal cavity. 2-3 weeks later, the treatment can be repeated. After 6 courses, the therapy ended.
        1.3 Evaluation criteria of efficacy
        According to RESIST 1.1 efficacy evaluation criteria of solid tumors: Complete remission (CR): all target foci disappeared. Partial remission (PR): the sum of long diameters of baseline foci reduced ≥30%. Progressive disease (PD): the sum of long diameters of baseline foci increased ≥20% or new foci emerged; Stable disease (SD): the sum of long diameters of baseline foci reduced but did not reach PR or increased but did not reach PD. Evaluation of non-target foci: CR: all non-target foci disappeared and tumor marker levels were normal; SD: one or more non-target foci existed and/or tumor markers were higher than normal, and the state persisted; PD: One or more new foci emerged or/and non-target foci progressed. Progression-free-survival period (PFS): it was referred to as interval from the beginning of intraperitoneal perfusion chemotherapy to recurrence or progression of the tumor. One-year survival rate: it was referred to as the percentage of the number of persons who survived for 1 year after the beginning of treatment in a group.
        1.4 statistical methods
        SPSS 13.0 statistical software was applied for statistical analysis. Progression-free-survival period and one-year survival rate were treated by Kaplan-Meier test. P <0.05 was considered statistically significant.

        2 Results
        2.1 Short-term efficacy
        IPC group included 30 patients among whom CR+PR were 8 cases, and the effective rate (RR) was 26.7%; CCCHP group included 30 patients among whom CR+PR were 11 cases, and the effective rate (RR) was 36.7%. In this study, the effective rate in TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was higher than intraperitoneal perfusion chemotherapy group (Table 1).

        Table 1 Comparison of the effective rates between IPC group and CCCHP group (n)

        Group

        n

        CR

        PR

        PD

        SD

        CR + PR ( % )

        IPC
        group

        30

        2

        6

        10

        12

        26.7

        CCCHP group

        30

        3

        8

        9

        10

        36.7

         

        2.2 Progression-free-survival period and one-year survival rate
        Until October 2011, the follow-up had lasted for 12 months. The progression-free-survival period of IPC group was 7.5 months and that of CCCHP group was 11.2 months. Kaplan-Meier test was performed to compare the numbers of months of average progression-free-survival periods between the two groups and P <0.05, indicating that there was difference between the average progression-free-survival periods of the two groups. Kaplan-Meier test was also performed to compare one-year survival rates between the two groups and P <0.05, indicating that there was difference between the one-year survival rates of the two groups. The progression-free-survival period and the one-year survival rate of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group were higher than intraperitoneal perfusion chemotherapy group (Table 2).

        Table 2 Comparison of the progression-free-survival periods and
        The one-year survival rates between IPC group and CCCHP group

        Group

        n

        Progression-free survival
        period (months)

        One-year survival rate (%)

        IPC
        group

        30

        7.5

        56.7

        CCCHP group

        30

        11.2

        70.0

        P

         

        <0.05

        <0.05

         

         

         

         

         

        3Discussion
        In the past, 60 patients all had received oxaliplatin plus 5-fluorouracil systemic combination chemotherapy regimens, and after disease progression all of them were switched to intraperitoneal perfusion chemotherapy regimens. The effective rate of intraperitoneal perfusion of drugs: The effective rate (RR) of intraperitoneal perfusion chemotherapy group including 30 patients was 26.7%, whereas that of TRL thermostatic imtraperitoneal continued circulatory hyperthermic perfusion chemotherapy group including 30 patients was 36.7%. The effective rate of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was higher than intraperitoneal perfusion chemotherapy group. Progression-free-survival period: The progression-free-survival period of intraperitoneal perfusion chemotherapy group was 7.5 months, whereas that of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was 11.2 months. The progression-free-survival period of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was higher than intraperitoneal perfusion chemotherapy group. One-year survival rate: The one-year survival rate of intraperitoneal perfusion chemotherapy group was 56.7%, whereas that of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was 70%. The one-year survival rate of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group was higher than intraperitoneal perfusion chemotherapy group. Comparing the effective rate, progression-free-survival period and one-year survival rate, those of TRL thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy group were all higher than intraperitoneal perfusion chemotherapy group.
        Cancerous ascites emerges when malignant tumors progress to advanced stage, and seriously affects quality of life of patients. Within several hours after intraperitoneal administration of chemotherapeutic drug, the drug concentration in the abdominal cavity is 2.5-8 times higher than those in plasma [5-6], and constantly and long-lastingly high concentrations of anticancer drug environment can be formed in the abdominal cavity, the portal vein and the liver, whereas little drug enters the systemic circulation. Compared with traditional intravenous chemotherapy, intraperitoneal administration not only increases the concentration of anticancer drug in the abdominal cavity but also prolongs the contact time of cancer cells and drug, and meanwhile, because the intraperitoneal drug is mainly absorbed via the portal vein, can exert stronger killing effect on cancerous thrombosis and cancer cells transferred to the liver via the portal vein [7-8]. The design of intraperitoneal perfusion chemotherapy is based on the mechanisms of the anatomic structural characteristics of the abdominal cavity, rationality and effectiveness of regional chemotherapeutic pharmacokinetics, and synergistic effect of anticancer.
        Thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy has been another new method of combining hyperthermic therapy with intraperitoneal perfusion chemotherapy in recent years. It has the following effects [9-10]: (1) Due to continuous thermostatic hyperthermic circulation, it can be ensured that the tumor local region is heated to 40℃-43℃ to  kill large numbers of tumor cells without harming normal tissue cells resulting in selective tumor hyperthermic therapy effect; (2) Physical clearance and tumor-reduced effect. Circulatory perfusion therapy can make effusion become "active water" from "dead water" along with circulation to be continuously rinsed, replaced and drained. In a short time, tumor-reduction speed is fast, therefore, a lot of patients with ascites cannot be controlled with conventional hyperthermic therapy for 6-12 times but after thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy for 2-3 times they are significantly relieved, resulting in obviously shortening the treatment course. Constantly rinsing can allow fibrin, necrotic tissue and other tangible materials depositing among intestinal loops, visceral organs and the surface of cancer cells to fall off and swim along with circulatory mechanical scouring. It is often seen that after treatment for 1-2 times, more fibrin, necrotic tissue and even wrapped cyst membrane are discharged along with drainage liquid, leading to decreased chances of adhesions and package. (3) Drug sensitizing effect: Due to the continuous thermal effect, chemotherapeutic drugs are sensitized. Perfusion liquid is heated to 45℃±0.5℃, and conventional abdominal puncture needles are used to establish dual passages. Inflow temperature is maintained at 43.5℃-44℃ and Outflow temperature is 41.5℃-42℃, and the temperature in the abdominal cavity is maintained at approximately 43℃ for 60 minutes. By prolonging heating time, efficacy of intraperitoneal hyperthermic chemotherapy can be significantly enhanced. The effective rate of thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy to treat cancerous ascites in observation group was 36.7% and was higher than simple intraperitoneal perfusion chemotherapy group, indicating that thermostatic intraperitoneal continued circulatory hyperthermic perfusion chemotherapy is one of the effective methods to treat advanced colorectal cancer.

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        (Editing and proofreading: Xiaotong Jing)

        [Received date] Mar 30, 2012
        [Author’s unit] Department of Oncology, No. 463 Hospital of People's Liberation Army, Shenyang City 110042
        [About the author] Yinghuan Ma (1976 - ), male, born in Siping city, master, attending physician, mainly engages in lung, breast, gastrointestinal cancer chemotherapy research work. E-mail: myh463@yahoo.com.cn

        Modern Oncology, April, 2013, 21(04): 825-827.

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