| BackgroundMalignant serous effusions are common complications caused by Intermediate and advanced-stage malignant tumor, interfering with their respiratory, circulatory and digestive functions and affecting clinical anti-tumor treatment and the patients’ quality of life. Some of these patients are hard to treat with poor prognosis and short survival time. According to the literature we collected, once the definite diagnosis of MSE is made, the average survival time is3.1±0.5months, and morality rate within6months is84percent. It’s rather difficult to find an appropriate treatment for MSE in the clinic. Although methods of local treatment are quite selective, such as diuresis, piercing, drainage of serous effusions and intracavitary injection of chemo-drugs or biological drugs, the effect is not quite satisfying with high recurrence rate and toxicity and side effects in various degrees.Elemene emulsion is an anticancer activity of extract-Sesquiterpenes, derived from Rhizoma Curcumae. With reliable curative effects and mild side effects, this new drug has its obvious advantage in prolonging life expectancy, improving life quality and survival benefits, decreasing the rate of metastasis and recurrence comparing with a single treatment with chemotherapy drugs. Meanwhile, its bidirectional treating effect not only intensifies treating efficacy, but also decreases side effects to some extent. It also applies to the intervention operation, intracavitary injections of chemo-drugs and treatment of malignant pleural fluids, ascites and pericardial effusions. Besides, after the systematic review of evidence-based medicine, elimene emulsion is confirmed as a broad-spectrum and targeting anticancer botanical extract, which is also safe and effective.At present stage there are plenty of studies and publications on the clinical effects of elimene emulsion in treating malignant pleural, abdominal and pericardial effusions solely or with combination chemotherapy. However, with the particularity of tumor, there’s no result of clinical trials based on multi-center and large sample and its ability to enhance clinical effects and reduce toxicity still remains unconfirmed in an evidence-based manner.This study collected randomized controlled trials (RCT) of elemene injections in treating malignant serous effusions with or without chemotherapy from1996to2012according to the documents evaluation rules set by epidemiology and EBM, mainly adopting methods of systematic reviews and meta-analysis to objectively evaluate the authenticity of research evidence, quality of methodologies, clinical efficacy and safety, overall quality of research and strengths and weakness of treatment. Besides, research evidence was classified, graded and recommended based on GRADE system in order to be more reliable in guiding clinical practice.ObjectiveThis research aims to assess the effects of elimene injection in treating malignant serous effusions from such aspects as clinical efficacy, quality of life, toxicity and side effects, and to critically evaluate the authenticity, reliability and clinical applicability of research evidence for the purpose of providing scientific support for clinical practice.Methodology1. Inclusion of Research Literature1.1To collect clinical research documents about elimene injection in treating malignant serous effusions published during years between1996and2012from databases as VIP Database for Chinese Technical Periodicals (VIP), China National Knowledge Infrastructure (CNKI) and WANFANG data platform.1.2Search StrategyTo search research literature by grouping index words:category1elimene injection, category2treatment, category3effectiveness, category4effusion, category5pleural fluid, category6ascites, category7elimene injection and effusion, category8elimene injection and pleural fluid, category9elimene injection and ascites.1.3Inclusion and Exclusion CriteriaThe objective of this research is to observe the clinical effectiveness of elimene injections in treating malignant serous effusions with or without chemotherapy drugs. Duplicated researches or publications, studies without control groups or animal experiments, and reviews, summaries of clinical experience, theoretical investigations or case reports with indefinite efficacy descriptions were excluded. Only randomized controlled trials (RCT) were included.1.4Interventions①elimene injection (Dalian Jiangang Pharmaceutical Co., Ltd. Product, China’s medical permitment NO.H10960114) versus chemo-drugs②elimene injection plus chemo-drugs versus chemo-drugsStandard chemo-drugs were used both in the control group and the experimental group. Both groups applied drainage of serous effusions and intercavitary injection. According to indications of patients other drugs would be used such as dexamethasone, lidocaine, etc..2.Outcome Indexes for Clinical Effect Assessment2.1Effect Evaluation Standard:the WHO Evaluation Standard has four groups:Complete Response (CR), Partial Response (PR), Stable Disease (SD) and No Change (NC). Overall effectiveness=(CR sample size+PR sample size)/total sample size×100%.2.2Quality of Life Assessment Index ((QOL):karnofsky performance status (KPS) rating scales: bettering, stable and worsening.2.3Safety Evaluation Index:Toxicity of Anticancer Drugs Grading Scale made by WHO3Literature Quality Evaluation Assessment3.1To assess the quality of methodologies that involved in the research and evaluate random controlled trials based on four quality assessment criteria professor Juni proposed with rating grade A, B and C;3.2To assess the quality of methodologies that involved in the research according to Risk of Bias Criteria of RCT in Cochrane Reviewers’Handbook (5.1.0version);3.3To grade evidence and recommendations and evaluate evidence quality of EBM via GRADE system.4. Data Entry and Statistical AnalysisAfter strict quality assessment, meta-analysis of outcome indexes extracted from each studies was carried out by statistical software Revman5.0provided by Cochrane Collaboration.a. Homogeneity testFurther systematic review was needed for results of heterogeneity test;b. To calculate combined effect size (weighted combination is represented by relative risk (RR)), effect magnitude and95%confidence interval (CI) for statistical reference;c. To display results of each test and combined results with forest plots; P<0.05indicates statistical significance, and P<0.01means significant difference.d. Sensitivity AnalysisUsing sensitivity analysis to analyze overall effectiveness after medical interventions based on the integration of effectiveness of every single clinical trial. If the result of each single test was different and the result of each single test via homogeneity test also indicated the significant difference, this specific single test was excluded and meta-analysis was re-applied for the total results after exclusion. Comparing results before and after exclusion to test the influence some single tests could have on combined effect size.e. To analyze potential publication bias via "fail-safe number" or "funnel plots";f. Results interpretation, conclusion and evaluationResultsThere were31literature about clinical RCT studying the effects of elemene injections in treating malignant serous effusions in this research. This sample contained1,763control subjects, 903cases of the experimental group and860cases of the control group. The chemotherapy drugs used in the experimental group and the control group mainly included cisplatinum, staphylococcin, carboplatinum,5-FU and IL-2. The baseline conditions and initial therapy for each test were identical.1. Meta-analysis of the effectiveness of Elemene injections in the treatment of malignant serous effusionsThere were17research documents comparing the treating effects of malignant serous effusions with elemene injections or chemotherapy drugs respectively and providing valuable data of short-term effects, quality of life, adverse reactions and survival time via RCT with967cases included. Only one could provide the rate of one-year survival time. The literature quality was grade C.1.1Meta-analysis of short-term effects1.1.1The meta-analysis of short-term effects listed in17literature showed that the experimental group with elemene injections had better treating effects than the control group with chemotherapy drugs. The relative risk reported as1.03with a95%CI (0.93to1.14), P=0.61. The observed difference is not statistically significant.1.1.2According to meta-analysis of overall effectiveness (CR+PR) of short-term effects, the efficacy of the experimental group versus the efficacy of the control group was84.31%versus63.44%, and the relative risk was1.32(95%CI1.22to1.43), P<0.01. The differences were statistically significant. This result showed that elemene injections had better clinical effects in treating malignant serous effusions than chemotherapy drugs.1.2Meta-analysis of quality of lifeThere were4documents studying the improvement rate via Kamofsky index. The rate of improvement of the experimental group was69.52%, while that of the control group was35.23%, and the relative risk was1.97(95%CI1.48to2.64), P<0.01. The differences were statistically significant. This result showed that the group treated with elemene injections was more effective than the control group from the aspect of improving patients’quality of life.1.3Meta-analysis of survival timeOnly one included document provided valuable data for the meta-analysis of one-year survival time of MSE patients. The rate of survival time of the experimental group was60.00%, while that of the control group was31.03%, and the relative risk was1.93(95%CI1.04to3.58), P<0.05. The differences were statistically significant. The rate of one-year survival time of the experimental group was higher than the control group.1.4Meta-analysis of adverse reactions The adverse reactions mentioned in17included documents could be divided into six categories:chest pain, abdominal pain, fever, gastrointestinal tract side effects, bone marrow suppression and liver and kidney impairment. The method of meta-analysis was applied to each group.1.4.1There were14documents related to the incidence of chest pain. Via meta-analysis, the incidence rate of chest pain in the experimental group was29.41%, while that in the control group was8.97%, and relative risk was2.62(95%CI1.28to5.37), P<0.01. The differences were statistically significant. It was more likely to cause chest pain when treating with elemene injections instead of chemotherapy.1.4.2Two studies about the incidence of abdominal pain were included for meta-analysis. The incidence rate of abdominal pain in the experimental group was8.45%, while that in the control group was2.73%, and relative risk was3.15(95%CI0.69to14.42), P=0.14. According to the data, the incidence rate of abdominal pain of both groups had no significant difference.1.4.3There were10documents providing data about the incidence of fever for meta-analysis, the incidence rate of fever in the experimental group was21.51%, while that in the control group was4.64%, and RR was3.32(95%CI1.24to8.84),P<0.05. The differences were statistically significant. It was more likely to cause fever when treating malignant serous effusions with elemene injections instead of chemotherapy.1.4.4Fifteen documents mentioned the incidence of gastrointestinal tract side effects. After meta-analysis, the incidence rate of gastrointestinal tract side effects in the experimental group was6.26%, while that in the control group was40.52%, and relative risk was0.20(95%CI0.10to0.37), P<0.01. The differences were statistically significant. The result indicated that the incidence rate of gastrointestinal tract side effects was lower in the group treated with elemene injections than in the chemotherapy group.1.4.5Fourteen documents were collected to study the incidence of bone marrow suppression with the method of meta-analysis. The incidence rate of bone marrow suppression in the experimental group was0.24%, while that in the control group was20.66%, and relative risk was0.08(95%CI0.04to0.17),P<0.01. This result indicated that the incidence rate of bone marrow suppression was lower in the experimental group than in the control group. The differences were statistically significant.1.4.6We collected9documents to study the incidence rate of liver and kidney impairment of both treating method. Based on the data of meta-analysis, the incidence rate of liver and kidney impairment in the experimental group was0.33%, while that in the control group was8.44%, and relative risk was0.17(95%CI0.07to0.43), P<0.01. The differences were statistically significant. It was less likely to cause liver and kidney impairment when treating with elemene injections than with the chemotherapy.2. Meta-analysis of the effectiveness of Elemene injections combined with chemotherapy in treating malignant serous effusionsThere were14research documents comparing the treating effects between chemo-drugs only and with elemene injections combined, which provided valuable data to assess short-term effects, quality of life, adverse reactions and survival time via RCT with796cases included. No research could provide the rate of1-year survival time. Only one document’s quality reached B, the rest included in this research were C.2.1Meta-analysis of short-term effects2.1.1The meta-analysis of short-term effects extracted from14included documents showed that better treating effects could be gained when combining elemene injections with chemotherapy in treating malignant serous effusions than the control group with chemotherapy drugs only. The relative risk reported as0.98with a95%CI (0.79to1.22), P=0.86. There was no significant difference among groups.2.1.2According to meta-analysis of overall effectiveness (CR+PR) of short-term effects, the effects of the experimental group versus the effects of the control group was82.52%versus58.85%, and the relative risk was1.41(95%CI1.2219to1.68), P<0.01. The differences were statistically significant. According to the analysis, elemene injections could significantly improve clinical effectiveness of chemotherapy in treating malignant serous effusions.2.2Meta-analysis of quality of lifeThere were4documents comparing the rate of improvement via Kamofsky index. The improvement rate of the experimental group was65.80%, while that of the control group was33.33%, and the relative risk was2.06(95%CI1.40to3.04), P<0.01. The differences were statistically significant. This result showed that the improvement rate of patients’QOL was obviously higher when treating with elemene injections and chemotherapy combined than the control group adopting chemotherapy only.2.3Meta-analysis of adverse reactionsThe adverse reactions mentioned in14included documents could be divided into five categories, chest pain, fever, gastrointestinal tract side effects, bone marrow suppression and liver and kidney impairment. Meta-analysis was done respectively.2.3.1There were7documents related to the incidence of chest pain. Via meta-analysis the incidence rate of chest pain in the experimental group was28.70%, while that in the control group was19.41%, and relative risk was3.15(95%CI0.81to12.24), P=0.10. There was no significant difference in decreasing the incidence rate of chest pain between the experimental group and the control group.2.3.2There were5documents providing data about the incidence of fever for meta-analysis, the incidence rate of fever in the experimental group was39.39%, while that in the control group was17.28%, and relative risk was3.71(95%CI0.80to17.19), P=0.09. There was no significant difference in decreasing the incidence rate of fever when treating with elemene injections and chemotherapy combined or chemotherapy only.2.3.3Eight documents were collected to study the incidence rate of gastrointestinal tract side effects with the method of meta-analysis. The incidence rate of gastrointestinal tract side effects in the experimental group was35.39%, while that in the control group was53.36%, and relative risk was0.66(95%CI0.54to0.81), P<0.01. The differences were statistically significant. This indicated that the incidence rate of gastrointestinal tract side effects was lower when treating with elemene injections and chemotherapy combined than with chemotherapy only.2.3.4There were4documents focusing on the incidence of bone marrow suppression. The incidence rate of bone marrow suppressions in the experimental group was13.79%, while that in the control group was50.00%, and relative risk was0.24(95%CI0.08to0.76), P<0.05. The differences were statistically significant, indicating that the incidence rate of bone marrow suppressions was lower when treating with elemene injections and chemotherapy combined than with chemotherapy only.2.3.5We collected3documents to study the incidence rate of liver and kidney impairment of both treating method. Based on the result of meta-analysis, the incidence rate of liver and kidney impairment in the experimental group was4.65%, while that in the control group was10.11%, and relative risk was0.49(95%CI0.17to1.44), P>0.05. There was no significant difference in decreasing the incidence rate of liver and kidney impairment in both groups.ConclusionThis research suggests that elemene injections have obvious advantages in treating malignant serous effusions with or without chemo-drugs over the control group treating with chemotherapy only. Indexes like overall treating effectiveness (CR+PR), QOL (KPS) and survival time in the experimental group were significantly higher than in the control group. The main side effects of elemene injections are low fever and chest pain, but such side effects could be avoided or reduced when dealing with indications carefully. Elemene injections decreased those adverse reactions as gastrointestinal tract side effects, bone marrow suppression and impairment of liver and kidney when treating with chemotherapy like cisplatinum, at the same time elemene injections improved clinical effectiveness. When elemene injections and chemotherapy were used together, the treating effectiveness could be significant. For example, serous effusions could be controlled more effectively, symptoms of patients could be reduced, quality of life could be improved and their survival time could be lengthened.This research indicates that it’s safe and effective to treat malignant serous effusions with elemene injections with or without chemotherapy. Systematic review and meta-analysis was regarded as the indirect evidence, but it was graded as the first-rate evidence considering its importance and was of great value for clinical practice. Besides, considering the homogeneity of original literature (literature quality was C and EBM evidence quality was2B according to GRADE system), limitations like partial biases might be existed. Therefore, large-scale and high quality research should be further carried out for more reliable EBM evidence to guide clinical practice. |
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