| Background and Purpose:Malignant pericardial efusions (MPcE) is one of the most common complications of terminal cancer. Most cases of MPcE were induced from metastatic tumor (MT). Because the symptom of MPcE is the appeareance of just-before-dying, so we can improve symptom and increase the living quality of the patients through diagnosing and caring MPcE early. We can therapy MPcE with surgery such as percutaneous catheter drainage, sclerosing agent, subxiphoid pericardiostomy, pericardiectomy and pericardiotomy with thoracoscope, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). Although there is no international standard therapy guideline about therapying MPE, all doctors agree with the principle of individualized treatment.Along with the increase of malignant tumor, the incidence of malignant pleural efusions (MPE) also increase and the age of onset is lower. On average, the survival time of the patients with Malignant pleural efusions is shorter. The purpose of therapying Malignant pleural efusions is relieve the symptom of dyspnea, allay the pain, increase the living quality and prolong the survival time. We can therapy malignant pleural efusions with surgery such as therapeutic thoracentesi, pleurodesis, circular intrapleural hyperthemic perfusion, Pleuroperitoneal shunting, Pleurectomy, operation with thoracoscope, and so on, or medcine such as chemical therapy and intracavitary inicetion of drug (chemical drug, biological response modifier or sclerosing agent). To some tumor which is sensitive to radiotherapy, we can use preventive radiation. Only can we use suitalbe methods to therapy malignant pleural efusions in its different clinical stages, the effective rate of contrlling malignant pleural efusions can be improved and the survival time can be prolonged.In so many anti tumor drugs, tumor necrosis factor (TNF) is one of the most powerful drug in killing tumor cells directly, and has been used in therapying many kinds of tumor extensively. TNF has two types ofαandβ, and TNFαhas been mainly studied and used. However, natural TNFαcan induce severe adverse events in the aspects of cardiovascular system, hematological system, nervous system, digestive system and respiratory system, especially uesd in all over the body. Because these adverse events, the clinical application of TNFαhas been limited.From 1990s, in order to improve the curative effect and decrease toxicity, the study of mutated TNFαhas been extensively devolped. Recombinant mutated human TNFαis a kind of mutaed TNFαhaving improved anti-tumor activity and decreased toxicity, which is invented by The Forth Miilitary Medcine Univercity (FMMU) . In August 2003, the first mutated TNFαwhich could be uesd in all over the body was licensed. We found that rmh TNFαinduced only thoracalgia and febrile, seldom reaction of gastrointestinal tract, when used in therapying nonsmall-cell lung cancer (NSCLC). If we gave antipyretic analgesic before TNFαwas used, these adverse events could be relieved. Because the half-life of natural TNFαis only 10-15min, and it has no specific affinity to tumor, the concentration of TNFαcan not be elevated in tumor. In order to improve the curative effect, many people inject natural TNFαinto tumor or cavity and find that the curative effect is improved and the toxity is not increased. The malignant pleural efusions therapying mechanism of rmhTNFαis similar to natural TNFα, including supressing the expression of oncogene, directly killing tumor cells, inducing necrosis of tumor and finally reducing the production of malignant pleural efusions. The high concentration of rmhTNFαcan induce stronger inflammatory reaction, and lead to the necrosis and fibrosis of tumor. It was also proved that high concentration of rmhTNFαcould inhibit the angiogenesis of tumor. So we presumed that rmhTNFαcould be used in ntracavitary inicetion and the concentration could be increased to improve the curative effect meanwhile the toxity might not be increased. If the hypothesis could be approved, the clinical indication of rmhTNFαcould be expanded, and there would be a new method to control malignant pleural efusions. To approve our hypothesis, we carried out this study after liscenced by Ethics Committee.Methods:1. Data of patientsMalignant pericardial efusions: 56 patients with malignant pericardial efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into A group and B group (28/28). 64 patients with malignant pleural efusions, which were finally diagnosed through pathology or cytology, were randomly seperated into C group and D group (32/32). The content of this study, the potential benefit and risk were told to the guardian of the patients. After one patient definitely indicated that they agreed to participate in this study and signed in informed consent, the patient was selected to be studied. The patients of A and C group were injected intracavitarily with 15 million IU rmhTNFαthrough percutaneous catheter, twice per week, four times in all. The patients of B and D group were injected with 5 million IU rmhTNFα.2. Methods of evaluating therapeutic efficacyB ultrasound and CT were used to measure the amount of pericardial or pleural efusions, and the size of measurable focus. We recorded the vital sign, clinical symptom, Karnofsky performance status (KPS) score, and quality of life before and after therapy. The complications were also recorded. One month after therapy, we evaluated the curative effect and adverse events according WHO standard.3. Statistical analysis: SPSS 12 softare was used to compare the short-term efficacy, long- term efficacy, the improvement of quality of life, and the incidence of adverse events between the two groups.Results:1. Evaluation of curative effectMalignant pericardial efusions: The overall reaction rate of the two groups was 73.2%, the reaction rate of A group was 92.8% (26/28), and the reaction rate of B group was 53.5% (15/28). The differece of statistics was significant between the two groups (P<0.05).Malignant pleural efusions: The overall reaction rate of the two groups was 73.4%, the reaction rate of C group was 90.6% (29/32), and the reaction rate of D group was 56.2% (18/32). The differece of statistics was significant between the two groups (P<0.05).2. Evaluation of complicationsMalignant pericardial efusions: The febrile rate of A group was 67.8% (19/28), and the febrile rate of B group was 60.7% (17/28). The differece of statistics was not significant between the two groups (P=0.781). The pain rate of A group was 42.8% (12/28), and the pain rate of B group was 39.2% (3/28). The differece of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 10.7% (3/28), and the pain rate of B group was 7.1% (2/28). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.Malignant pleural efusions: The febrile rate of A group was 67.2% (22/32), and the febrile rate of B group was 71.8% (23/32). The differece of statistics was not significant between the two groups (P= 1.00). The pain rate of A group was 43.7% (14/32), and the pain rate of B group was 43.7% (14/32). The difference of statistics was not significant (P= 1.00). The nausea or vomit rate of A group was 12.5% (4/32), and the pain rate of B group was 15.6% (5/32). The differece of statistics was not significant (P= 1.00). All the patients of the two groups did not show toxity to hematological system and damage to heart, liver and kidney.3. Evaluation of quality of lifeAfter injection of rmhTNFα, no matter how the dose was, the quality of life of the most patients had been improved. The spirit of the patients turned better, their appetite improved, their physical capacity increased, the pain relieved, the quality of sleeping improved and KPS score elevated.Malignant pericardial efusions: The KPS score of 26 patients of A group increased more than 10 scores after therapy (92.8%), the KPS score of 18 patients of B group increased (64.2%), the difference of statistics was significant between the two groups (P<0.05).Malignant pleural efusions: The KPS score of 30 patients of C group increased more than 10 scores after therapy (93.7%), the KPS score of 21 patients of D group increased (65.6%), the difference of statistics was significant between the two groups (P<0.05).Conclusion:1. rmhTNFαcan be used to therapy malignant pericardial or pleural efusions, and the curative effect is significant. The mechanism includes directly killing tumor cells, inducing atoptosis, and anti-angiogenesis.2. Compared to using 5 million IU rmhTNFα, using 15 million IU can apparantly improve the curative effect, meanwhile don not increase the toxity. The reasons may be that using rmhTNFαintracavitarily can directly destruct epithelial tissue arround tumor and make tumor exposed thoroughly, so the concertration of drug can be higher. Because the rmhTNFαinjected intracavitarily does not reach to blood directly, the adverse events of high dose are similar to that of low dose. 3. We also find that the quality of life of the most patients has been improved apparantly after injection. It is supposed that rmhTNFαcan improve immunity, increase the killing activity of monocyte, macrophage, T cell and NK cell, and relieve cachexia.
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