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        Clinical research of continuous hyperthermic intraperitoneal perfusion chemotherapy combining with intravenous chemotherapy to treat advanced gastrointestinal tumors

        Date:2014年2月26日 10:35

        Yanjie Zhao, Ruibin Wang, Shifeng Qiao

        [Abstract] Objective: In order to explore an effective treatment for advanced gastrointestinal tumors, Clinical studies and preliminary efficacy evaluation were performed in continuous hyperthermic intraperitoneal perfusion chemotherapy (Hyperthermic intraperitoneal chemoperfusion, HIPC), intraperitoneal chemotherapy and simple intravenous chemotherapy. Methods: A retrospective analysis of 53 patients with advanced gastrointestinal tumors, admitted from September, 1999 to October, 2003, was performed. The patients received HIPC + intravenous chemotherapy (HIPC+IVC, 14 cases), simple intravenous chemotherapy (SIVC, 21cases) and conventional intraperitoneal chemotherapy + intravenous chemotherapy (IPC+IVC, 18 cases) for more than 2 courses, respectively. The difference of efficacies was analyzed. Results: there were significant differences in the recession rates and total efficacies between HIPC+IVC group and HIPC+IVC group or SIVC group (P <0.05), and HIPC+IVC had significant advantage in the treatment of metastatic ascites (P <0.05), but the advantage of lessening hepatic metastases cannot be affirmed (P> 0.05). The therapy caused smaller systemic side effects than SIVC and more weakly harmed the immune system of the body. The patients in HIPC+IVC group significantly improved the quality of life, and had higher clinical benefit rate. Conclusion: For patients with advanced gastrointestinal tumors, HIPC+IVC has better efficacy, less side effects, fewer days of hospitalization, lower average hospitalization fee and higher benefit/investment.
        [Key words] gastrointestinal tumors, intraperitoneal chemotherapy, hyperthermic perfusion, intravenous chemotherapy
         
        Gastrointestinal cancer is a main malignant tumor to threat the health of the people in our country. According to statistics from Ministry of Health, the annual mortality rate of only gastric cancer in China in 90s reached 2521/100,000 [1] , representing the first among malignant tumors. Currently the treatment of gastrointestinal tumors mainly is surgical radical excision, but for patients with cancer metastasis in moderate and advanced stage, because gastrointestinal venous blood returns to the portal vein system, cancer cells are easily transferred to the liver through the portal vein. When primary tumor invades the whole layer of serosa or lymph node metastasis invades the whole layer of the capsule, tumor cells shed, adhere and are planted on the peritoneum, and invade interstitial tissue and reproduce, leading to intraperitoneal recurrence and metastasis. Clinical observations indicate that most patients with gastrointestinal tumors have died of intraperitoneal or hepatic metastases. Literature has reported that after gastric cancer radical operations 5-year survival rate is only 39% to 45%, postoperative resection site recurrence rate is 60-90%, peritoneal metastasis rate is up to 50% and hepatic metastasis rate is 30%. For such patients, through intravenous chemotherapy the drug concentration in a focus is limited. If the concentration of chemotherapeutic drugs is simply increased, systemic toxic and side effects will correspondingly increase thus the efficacy of high-dose intravenous chemotherapy is often not ideal. In the past, we often used IPC+ IVC treatment; although the efficacy was improved to some extent, the incidence of chemical peritonitis was high and abdominal local side effects were large. In recent years, the academic community has put forward an opinion that HIPC+ IVC can effectively prevent and treat intraperitoneal recurrence and hepatic metastasis after operations of gastrointestinal tumors [2, 3], and can improve the quality of life of the patients [4]. We used the continuous perfusion machine to perform HIPC+ IVC treatment in patients and have specifically observed its effect.

        Materials and Methods
        1.General information: 53 patients with advanced gastrointestinal tumors were admitted from September, 1999 to October, including 34 males and 19males. The median age was 50.5 years (32 to 69 years). Specific grouping is shown in Table 1 and metastases of patients in each group are showed in Table 2.

        Table 1 Grouping of the Patients

         

        Total
        cases

        Gastric
        cancer

        Colon
        cancer

        Rectal cancer

        HIPC+IVC

        14

        7

        4

        3

        SIVC

        21

        10

        5

        6

        IPC+IVC

        18

        9

        6

        3

        Total

        53

        26

        15

        12

        Table 2 Tumor Metastasis

             

        Ascites

        hepatic
        metastasis

        Intraperitoneal extra-hepatic
        metastasis or recurrence

        Distant
        metastasis

        HIPC
        +IVC

        7

        5

        3

        2

        SIVC

        10

        6

        6

        5

        IPC+IVC

        8

        5

        5

        4

        Total

        25

        16

        14

        11

         

        2. Short-term efficacy was evaluated according to WHO uniform criteria [5]. (1) Complete remission (CR): A visible tumor completely disappeared and the state had lasted for more than 1 month; (2) Partial remission (PR): The product of the two largest diameters of the tumor which is perpendicular to each other decreased by more than 50%, and the state had lasted for more than 1 month; (3) Stable disease (SD): The product of the two largest diameters of the tumor which is perpendicular to each other decreased by less than 50% or increased by less than 25%, and the state had lasted for more than 1 month; (4) Progressive disease (PD): The product of the two largest diameters of the tumor which is perpendicular to each other increased by more than 25%.
        3. Adverse reactions were evaluated according to WHO criteria in 1981 [5].
        4. Treatment methods:
        (1) HIPC+IVC group specific treatment regimen: IVC used fluorouracil (5-FU) 300 mg/m2 which was intravenously infused; day 1 to day 5, calcium folinate (CF) 100 mg/m2 was intravenously infused 2 hours before 5-FU had been administered. One course lasted for 21 days. HIPC was performed weekly. RHL-2000 perfusion machine was used to circularly perfuse 2000-2500ml of hyperthermic physiological saline at 44℃, cisplatin (DDP) 40 mg/m2, 5-FU 500 mg/m2, dexamethasone 10mg and gentamicin 160,000 U. The whole perfusion process lasted for more than two hours. At the inlet and outlet there were strict temperature control devices. At the outlet the temperature was controlled at 41℃ and at the inlet the temperature was controlled at 44℃. If WBC was <4.0×109/L or platelets was <80×109/L, chemotherapy might be delayed until blood returned to normal, and then the next chemotherapy began.
        (2) SIVC group specific chemotherapy regimen: 5-FU 500mg/m2 was intravenously infused; day 1 to day 5, CF 200mg/m2 was intravenously infused 2 hours before 5-FU had been administered; day 1 and day 3, DDP 30mg/m2 was intravenously infused. One course lasted for 21 days.
        (3) Intravenous chemotherapy and intraperitoneal chemotherapy of IPC+IVC group were the same as those of HIPC+IVC group, and the difference is that IPC+IVC did not perform hyperthermic perfusion.
        5. Statistical analysis: Exact probability and Ridit analysis were used to compare efficacies between two groups. P <0.05 showed that the difference was statistically significant.

        Results
        1.Comparison of efficacies: see Table 3. The difference between remission rates of HIPC+IVC group and SIVC group was statistically significant (P <0.05). The difference between remission rates of HIPC+IVC group and IPC+IVC group was not statistically significant (P> 0.05). Ridit analysis was performed for HIPC+ IVC group and SIVC group, HIPC+IVC group and IPC+ IVC group, respectively, P <0.05, indicating that in the total efficacy, HIPC+IVC group has significant advantage, compared to the other two groups.

        Table 3 Comparison of efficacies of three treatments

         

        CR

        PR

        SD

        PD

        Remission rate (%)

        Progression rate (%)

        HIPC+IVC
        Group

        1

        8

        4

        1

        64.3

        7.1

        SIVC
        Group

        0

        5

        11

        5

        23.8

        23.8

        IPC+IVC
        group

        0

        6

        9

        3

        33.3

        16.7

         

        2. Comparison of efficacies of three therapies for hepatic metastases: see Table 4. Comparing HIPC+IVC group with SIVC or with IPC+ IVC group, respectively, the difference was not significant (P> 0.05).

        Table 4 Comparison of efficacies of hepatic metastases

         

        hepatic
        metastasis
        total cases

        Lessening
        by more than
        50%

        Effect-
        ive rate(%)

        HIPC+IVC
        group

        5

        4

        80.0

        SIVC
        group

        6

        2

        33.3

        IPC+IVC
        group

        5

        2

        40.0

         

        3. Comparison of efficacies of three therapies for metastatic ascites: see Table 5. Comparing HIPC+ IVC group with SIVC group, the difference was significant (P <0.05). Comparing HIPC+IVC group with IPC+IVC group, the difference was not significant (P> 0.05).

        Table 5 Comparison of efficacies of Metastatic ascites

         

        ascites
        total cases

        Lessening by more
        than 50%

        Effective
        rate (%)

        HIPC+IVC
        group

        7

        6

        71.4

        SIVC
        group

        10

        3

        30.0

        IPC+IVC
        group

        8

        4

        50.0

         

        4. Improvement of the quality of life of the patients of the three groups: KPS scores of the three groups of patients before treatment and after two courses of treatment were compared [6] (asymptomatic free activity was evaluated as 100 points, symptomatic free activity was 90, lying in bed < 50% was 60-80, lying in bed > 50% was 40-60 and completely lying in bed was 10-40). After treatment, compared with the score before treatment, increasing more than 20 points was regarded as significant improvement, increasing 10-19 was improvement, increasing or decreasing less than 10 was stabilization, and decreasing more than 10 was decline. Specific data of the three groups was shown in Table 6.

        Table 6 Improvement in the quality of life

         

        Significant
        improvement

        Improvement

        Stabilization

        decline

        Clinical
        benefit rate (%)

        HIPC+IVC

        5

        5

        3

        1

        71.4

        SIVC

        4

        4

        10

        3

        38.1

        IPC+IVC

        5

        4

        7

        2

        50.0

         

        5. Toxic and side reactions: the patients of the three groups had mild toxic and side reactions, mainly including gastrointestinal reactions and bone marrow suppression (see Table 7).

        Table 7 Comparison of toxic and side reactions

         

        Grade I-II

        Grade III-IV

        HIPC+IVC
        group

        SIVC
        group

        IPC+IVC
        group

        HIPC+IVC
        group

        SIVC
        group

        IPC+IVC
        group

        Leukopenia

        4

        13

        5

        0

        2

        1

        Thrombocytopenia

        2

        6

        4

        0

        1

        0

        Nausea, vomiting

        2

        12

        3

        0

        1

        0

        Mucositis

        2

        3

        2

        0

        0

        0

        Diarrhea

        1

        1

        2

        0

        0

        0

        Abdominal Distension, Abdominal pain

        0

        2

        1

        0

        0

        0

        Baldness

        2

        3

        2

        0

        0

        0

        Infection

        1

        2

        1

        0

        0

        0

        Ileus

        1

        1

        2

        0

        0

        1

         

        6. Comparison of economic benefit: see Table 8.

        Table 8 Comparison of economic benefit

         

        HIPC+IVC

        SIVC

        IPC+IVC

        Average hospitalization day per course

        6.8

        10.5

        7.3

        Average hospitalization fee per course (Yuan)

        2835.6

        4233.5

        2571.2

         

        Discussion
        Hyperthermia selectively harms tumor tissue because compared with normal tissue cells tumor tissue cells has different thermal tolerance [7]. Due to anatomical structural difference between tumor tissue and normal tissue, blood flow in tumor tissue is larger than normal tissue, and heat dissipation is difficult. Heating causes further hypoxia of tumor tissue, decrease of pH value, and inadequate nutrition, thus damages tumor tissue cells. Normal tissue cells can tolerate 47℃ of hyperthermia for 1 hour, while at 43℃ for 1 hour irreversible impairment of tumor tissue cells emerges. Moreover, HIPC increases permeability of tumor cell membrane, and increases the response rate of cells to drugs [8]. In addition, chemotherapy drugs have a synergistic effect with hyperthermic therapy to enhance killing effect on tumor cells, and heating also can inhibit repair of tumor cells after the chemotherapy [9]. Large-capacity hyperthermic perfusion can still reduce the stimulating effect of chemotherapy drugs on peritoneum to reduce sclerosing peritonitis incidence to some extent.
        HIPC may exert certain effect on reversing multidrug resistance of tumor cells. We have performed animal experiments. The experimental animals were randomly divided into two groups. One group received IPC and another group received HIPC. The results showed that the concentration of chemotherapeutic drugs in tumor cells of the animals in HIPC group was higher than IPC group, indicating that HIPC may reverse multidrug resistance of tumor cells to some extent. However, it still needs further experimental studies.
        While HIPC+IVC improves the efficacy and the quality of life, reduces the economic pressure of the patients. Because HIPC+IVC has small systemic side effects, it reduces the economic pressure of the patients caused by the support treatment, reduces probability of using WBC colony stimulating factor, erythropoietin, etc., reduces the number of blood transfusions, and shortens hospital stay of the patients. Therefore, it reduces the patients’ hospitalization fee and greatly reduces the economic burden on the patients.
        About efficacy of hepatic metastases, because our study sample size is too small, statistical significance is not large. Meanwhile, this is a hot topic discussed in the current academic community and sample needs to be accumulated for further study.
        HIPC+IVC efficacy is certain and its systemic toxic and side effects are small. However, because the chemotherapy drugs directly contact with the abdominal cavity, possibility of chemical peritonitis and intestinal obstruction caused by the method is still larger than SIVC though it is smaller than IPC+IVC. The research on this aspect should be intensified to allow HIPC to be better applied in clinical practice.

        References
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        (Received Date: February 21, 2005)

        Author: Beijing Railway General Hospital 100038

        Clinical Medicine, September, 2005, 25(9): 34-36

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