榄香烯乳注射液治疗恶性浆膜腔积液临床研究的系统评价
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摘要
研究背景
恶性浆膜腔积液(Malignant serous effusions,MSE)是中晚期恶性肿瘤的常见并发症,干扰呼吸、循环以及消化功能,往往严重地影响抗肿瘤治疗和患者的生存质量,部份患者治疗困难,预后较差,生存期短。有文献报道,恶性积液确诊后,平均存活期为(3.1±0.5)个月,6个月病死率为84%。在临床上有些恶性浆膜腔积液的治疗十分棘手,尽管目前局部治疗的方法较多,如利尿、浆膜腔穿刺放液或引流、腔内注射化疗药物、或生物制剂等疗效常不尽人意、复发率高且有不同程度的毒副反应。
榄香烯(Elemene)是从温莪术中提取的具有抗癌活性的倍半萜烯化合物,为现代中药制剂。该药疗效确切,毒副作用轻微,在延长生存期,改善生活质量,提高病人生存受益和抗转移复发方面与化疗比较有明显优势,并具有高效安全的双向性,可以增强疗效,联合用药既可有效增加疗效,又能在一定程度上减轻不良反应。并可用于介入、腔内化疗及癌性胸、腹水、心包积液的治疗。经循征医学系统评价证实安全有效的广谱靶向抗肿瘤植物药[3]。
现阶段单药应用榄香烯或联合化疗对恶性胸、腹、心包腔积液治疗均对其临床疗效进行了大量的研究与报道。但由于肿瘤的特殊性,迄今尚未见到多中心、大样本的临床试验结果,亦未见这种增效减毒作用的循证医学证据。
根据临床流行病学和循证医学评价文献指导原则,本研究收集1996～2012年间已发表的榄香烯乳注射液(Elemene Emulsion Injection)单药与联合化疗治疗恶性浆膜腔积液的临床随机对照试验(RCT),主要采用系统评价和Meta分析的方法,严格评价研究证据的真实性,进行方法学质量和临床疗效及安全性评价,客观评估研究质量的总体水平及治疗上的优势与不足,并基于GRADE系统作出证据水平分级及推荐等级,以期为临床治疗提供更可靠的循证医学证据。
目的
系统评价(systematic review, SR)榄香烯乳注射液对恶性浆膜腔积液患者治疗的临床疗效、生活质量、毒副反应的影响,并严格评价研究证据的真实性、可靠性及临床适用性,为临床实践决策提供可靠的科学证据。
方法
1.纳入研究文献
1.1.系统检索中文科技期刊数据库(VIP),和中国期刊全文数据库(CNKI)、万方数据知识平台和文献追溯的方法,收集国内1996～2012年间公开发表的关于榄香烯乳注射液治疗恶性浆膜腔积液的临床研究文献。
1.2制定检索策略：采用主题词、关键词相结合的检索方法进行检索：#1榄香烯、#2治疗、#3疗效、#4积液、#5胸水、#6腹水、#7:#1AND#4、#8:#1AND#5、#9:#1AND#6。
1.3确定纳入和排除标准：纳入文献的研究目标为在榄香烯治疗上或联合化疗药物对恶性浆膜腔积液临床观察其治疗获益。排除重复发表、未设立对照组的研究和动物实验,并排除无法判断疗效综述、经验总结、理论探讨、个案报道等类型的研究,并剔除不符合要求的文献。本研究只纳入随机对照试验(RCT)。
1.4干预措施：①榄香烯乳(大连金港制药有限公司制品-国药准字H10960114)vs.化疗药;②榄香烯乳+化疗药vs.化疗药。对照组使用和治疗组相同的常规化疗(药物种类不限)。2组患者采取腔内积液置管闭式引流,然后作腔内注药,同时辅以止吐及其他对症处理的药物,如地塞米松及利多卡因等。
2.判效结局指标
2.1疗效评定标准：采用世界卫生组织(WHO)制定的标准评价：分为CR、PR、SD、NC4组,总有效率=(CR例数+PR例数)/总例数×100%。
2.2生活质量评价指数(quality of life,QOL):采用karnofsky performance status (KPS)评分标准,分为好转、稳定、恶化。
2.3安全性评价：按照WHO抗癌药物急性与亚急性毒副反应分级标准。
3.文献质量评价
3.1严格评价各个相关纳入研究的方法学质量,采用按照Juni等对随机对照试验的4条质量评价标准进行分析评价,质量等级为A级；B级;C级;
3.2按照Cochrane系统评价员手册(5.1.0版)中RCT的偏倚风险评价标准评价纳入研究的方法学质量;
3.3并采用GRADE系统对证据质量和等级推荐进行分级、循证医学(EBM)证据质量进行评价。
4..数据录入及统计分析
在严格质量评价后,对收集的各相关研究进行结局测量指标的数据提取,采Cochrane协作网提供的Revman5.0统计软件进行Meta分析。
a.异质性检验(齐性检验)。根据异质性结果选用进一步的系统评价方法。
b.统计合并效应量(加权合并以相对危险度(Relative Risk, RR)表示),计算效应尺度及95%的置信区间(Confidence Interval,CI)并进行统计推断。
c.图示(森林图)单个试验的结果和合并后的结果。以P<0.05表示具有显著的统计学意义,以P<0.01表示具有非常显著的统计学意义。
d.敏感性分析：测试各个临床试验的疗效结果经Meta整合之后,所得出总体的关于干预的疗效结果,如果各临床试验结果之间差异很大,异质性测试显示有显著性差异,则排除某纳入研究,重新进行Meta分析,其结果与未排除前的结果进行比较,以检验个别研究结论对合并效应量的影响。
d.采用“倒漏斗图”或通过“失安全数”的计算了解潜在的发表偏倚。
e.结果解释、作出结论及评价。
结果
本研究共纳入符合榄香烯乳注射液治疗恶性浆膜腔积液的临床随机对照试验(RCT)31篇中文文献,共纳入1763名患者,其中治疗组903例,对照组860例。治疗组的联合用药或对照组化疗药物以顺铂、金葡素、卡铂、5-FU、IL-2等为主进行治疗。各研究纳入治疗组和对照组的基线条件和基础治疗一致。
1.榄香烯乳注射液治疗恶性浆膜腔积液的Meta分析
纳入的17篇文献,对榄香烯乳单药治疗与单用化疗治疗进行对比,并能获得近期疗效、生活质量、不良反应及生存数据的随机对照试验。967例入组。其中仅1篇文献能提供1年生存率。纳入文献研究质量均为C级。
1.1近期疗效的Meta分析
1.1.1对纳入分析的17项研究近期疗效的Meta分析,综合结果显示,榄香烯组治疗恶性浆膜腔积液疗效优于化疗组RR＝1.03,95%CI：(0.93～1.14),P=0.61。但各组之间差异无统计学意义。
1.1.2对纳入的17项研究近期疗效的总有效率(CR+PR)的Meta分析,两组有效率为84.31%vs.63.44%,RR=1.32,95%CI(1.22,1.43),P<0.01。差异有统计学意义。揭示榄香烯治疗恶性浆膜腔积液的临床疗效明显优于化疗组。
1.2生存质量的Meta分析
对纳入4项研究的Karnofsky评分改善率比较,两组生质存量改善率为69.52%vs.35.23%,RR=1.97,95%CI(1.48,2.64),P<0.01,2组差异有统计学意义,说明榄香烯对恶性浆膜腔积液患者生活质量的改善率明显高于化疗组。
1.3生存率的Meta分析
对纳入1项研究1年生存率的Meta分析,2组1年生存率分别60.00%,31.03%,RR=1.93,95%CI(1.04,3.58),P<0.05。差异有统计学意义。榄香烯合并化疗组的1年生存率高于化疗组。
1.4不良反应的Meta分析
17项研究分为6个组的不良反应发生率的Meta分析,主要为胸痛、腹痛、发热、胃肠道反应、骨髓抑制、肝臀功能损害等。
1.4.1对纳入14项研究胸痛发生率的Meta分析,两组胸痛发生率为29.41%vs.8.97%,RR=2.62,95%CI(1.28,5.37),P<0.01。差异有统计学意义。显示注射榄香烯引起胸痛发生率明显高于化疗药物腔内注射治疗。
1.4.2对纳入2项研究腹痛发生率的Meta分析,两组发生率为8.45%vs.2.73%,RR=3.15,95%CI(0.69,14.42),P=0.14。显示注射榄香烯组与化疗组,两组间腹痛发生率相似,差异无统计学意义。
1.4.3对纳入10项研究发热发生率的Meta分析,两组发生率为21.15%vs.4.64%,RR=3.32,95%CI(1.24,8.84),P<0.05。注射榄香烯治疗恶性浆膜腔积液发热发生率高于化疗药物腔内注射治疗,差异有统计学意义。
1.4.4对纳入15项胃肠道不良反应发生率的Meta分析,两组发生率为6.26%vs.40.52%,RR=0.20,95%CI(0.10,0.37),P<0.01。差异有统计学意义。显示榄香烯组胃肠道反应发生率明显低于化疗组。
1.4.5对纳入14项研究骨髓抑制反应率的Meta分析,两组发生率为0.24%vs.20.66%,RR=0.08,95%CI(0.04,0.17),P<0.01。显示榄香烯组骨髓抑制发生率明显低于化疗组,差异有统计学意义。
1.4.6对纳入9项研究肝、肾功能损害发生率的Meta分析,两组发生率为0.33%vs.8.44%,RR=0.17,95%CI(0.07,0.43),P<0.01。差异有统计学意义。显示榄香烯组肝、肾功能损害低于化疗组。
2.榄香烯乳注射液联合化疗药治疗恶性浆膜腔积液的Meta分析
纳入的14篇文献,是对化疗同时加用榄香烯治疗与单用化疗治疗进行对比,并能获得近期疗效、生活质量、不良反应及生存数据的随机对照试验。796例入组。其中无1篇文献能提供生存率数据。纳入文献研究质量：仅1篇为B级,其馀皆为C级。
2.1近期疗效的Meta分析
2.1.1对纳入分析的14项研究近期疗效的Meta分析,综合结果显示,榄香烯与化疗药物联合组和单纯化疗组治疗恶性浆膜腔积液疗效优于单纯化疗组[RR=0.98,95%CI：(0.79-1.22),P=0.86]。但各组间差异无统计学意义。
2.1.2对纳入的14项研究近期疗效的总有效率(CR+PR)的Meta分析,两组有效率为82.52%vs.58.85%,RR=1.41,95%CI(1.19,1.68),P<0.01。差异有统计学意义。揭示榄香烯可以明显提高化疗药物对恶性浆膜腔积液治疗的临床疗效。
2.2生存质量的Meta分析
对纳入4项研究的Kamofsky评分改善率比较,两组生质存量改善率为65.80vs.33.33%,RR=2.06,95%CI(1.40,3.04),P<0.01。说明榄香烯联合化疗对恶性浆膜腔积液患者生活质量的改善率明显高于单纯化疗组。
2.3不良反应的Meta分析
14项研究分为5个组的不良反应发生率的Meta分析,主要为胸痛、发热、胃肠道反应、骨髓抑制,以及肝肾功能损害等。
2.3.1对纳入7项研究胸痛发生率的Meta分析,两组胸痛发生率为28.70%vs.19.41%,RR=3.15,95%CI(0.81,12.24),P=0.10。差异无统计学意义。显示注射榄香烯与化疗药物联合组与单纯化疗组引起胸痛发生率无明显差异。
2.3.2对纳入5项研究发热发生率的Meta分析,两组发生率为39.39%vs.17.28%,RR=3.71,95%CI(0.80,17.19),P=0.09。差异无统计学意义。显示注射榄香烯与化疗药物联合组与单纯化疗组引起发热发生率无明显差异。
2.3.3对纳入8项胃肠道不良反应发生率的Meta(?)分析,两组发生率为35.39%vs.53.36%,RR=0.66,95%CI(0.54,0.81),P<0.01。2组差异有统计学意义。显示注射榄香烯与化疗药物联合组胃肠道不良反应发生明显低于单纯化疗组。
2.3.4对纳入4项研究骨髓抑制反应率的Meta分析,两组发生率为13.79%vs.50.00%,RR=0.24,95%CI(0.08,0.76),P<0.05。显示榄香烯与化疗药物联合组骨髓抑制发生率低于单纯化疗组。差异有统计学意义。
2.3.5对纳入3项研究肝、肾功能损害发生率的Meta分析,两组发生率为4.65%vs.10.11%,RR=0.49,95%CI(0.17,1.44),P>0.05。差异无统计学意义。显示榄香烯与化疗药物联合组和单纯化疗组肝、肾功能发生无明显差异。
结论
本系统评价结果表明,榄香烯乳注射液单药及联合化疗治疗恶性浆膜腔积液具有明显的优势。治疗组患者的总有效率(CR+PR)、生活质量(KPS)、生存期明显高于对照组患者。榄香烯乳注射的不良反应主要为低热和局部胸痛,同时对症处理可能减轻或避免不良反应的发生。该药避免了应用顺铂等化疗药物所产生的胃肠道反应,骨髓抑制及肝肾功能损害等,增加了疗效。两者联合治疗比单一应用更能有效地控制浆膜腔积液,可以减轻患者的症状,提高生活质量,延长患者生存期,显示出明显的治疗作用。
经本研究Meta分析提示榄香烯乳注射液单药及联合化疗对恶性浆膜腔积液是一种安全、有效的治疗方法,鉴于系统评价和Meta分析属于二次证据,其重要性按级别划分属于一级证据,临床参考价值最大。纳入研究分析的原始文献的异质性明显影响较大,基于纳入研究的文献质量评价为C及GRADE系统的证据质量为2B,可能存在部份偏倚等局限性,尚需进一步开展大规模、高质量的基础和临床研究取得高级别的循证医学证据,指导临床实践。
Background
Malignant 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.
Objective
This 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.
Methodology
1. Inclusion of Research Literature
1.1To 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 Strategy
To 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 Criteria
The 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.
1.4Interventions
①elimene injection (Dalian Jiangang Pharmaceutical Co., Ltd. Product, China's medical permitment NO.H10960114) versus chemo-drugs
②elimene injection plus chemo-drugs versus chemo-drugs
Standard 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 Assessment
2.1Effect 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 WHO
3Literature Quality Evaluation Assessment
3.1To 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 Analysis
After 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 test
Further 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 Analysis
Using 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 evaluation
Results
There 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 effusions
There 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 effects
1.1.1The 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 life
There 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 time
Only 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 effusions
There 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 effects
2.1.1The 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 life
There 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 reactions
The 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.
Conclusion
This 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.
恶性浆膜腔积液(Malignant serous effusions,MSE)是中晚期恶性肿瘤的常见并发症,干扰呼吸、循环以及消化功能,往往严重地影响抗肿瘤治疗和患者的生存质量,部份患者治疗困难,预后较差,生存期短。有文献报道,恶性积液确诊后,平均存活期为(3.1±0.5)个月,6个月病死率为84%。在临床上有些恶性浆膜腔积液的治疗十分棘手,尽管目前局部治疗的方法较多,如利尿、浆膜腔穿刺放液或引流、腔内注射化疗药物、或生物制剂等疗效常不尽人意、复发率高且有不同程度的毒副反应。
榄香烯(Elemene)是从温莪术中提取的具有抗癌活性的倍半萜烯化合物,为现代中药制剂。该药疗效确切,毒副作用轻微,在延长生存期,改善生活质量,提高病人生存受益和抗转移复发方面与化疗比较有明显优势,并具有高效安全的双向性,可以增强疗效,联合用药既可有效增加疗效,又能在一定程度上减轻不良反应。并可用于介入、腔内化疗及癌性胸、腹水、心包积液的治疗。经循征医学系统评价证实安全有效的广谱靶向抗肿瘤植物药[3]。
现阶段单药应用榄香烯或联合化疗对恶性胸、腹、心包腔积液治疗均对其临床疗效进行了大量的研究与报道。但由于肿瘤的特殊性,迄今尚未见到多中心、大样本的临床试验结果,亦未见这种增效减毒作用的循证医学证据。
根据临床流行病学和循证医学评价文献指导原则,本研究收集1996～2012年间已发表的榄香烯乳注射液(Elemene Emulsion Injection)单药与联合化疗治疗恶性浆膜腔积液的临床随机对照试验(RCT),主要采用系统评价和Meta分析的方法,严格评价研究证据的真实性,进行方法学质量和临床疗效及安全性评价,客观评估研究质量的总体水平及治疗上的优势与不足,并基于GRADE系统作出证据水平分级及推荐等级,以期为临床治疗提供更可靠的循证医学证据。
目的
系统评价(systematic review, SR)榄香烯乳注射液对恶性浆膜腔积液患者治疗的临床疗效、生活质量、毒副反应的影响,并严格评价研究证据的真实性、可靠性及临床适用性,为临床实践决策提供可靠的科学证据。
方法
1.纳入研究文献
1.1.系统检索中文科技期刊数据库(VIP),和中国期刊全文数据库(CNKI)、万方数据知识平台和文献追溯的方法,收集国内1996～2012年间公开发表的关于榄香烯乳注射液治疗恶性浆膜腔积液的临床研究文献。
1.2制定检索策略：采用主题词、关键词相结合的检索方法进行检索：#1榄香烯、#2治疗、#3疗效、#4积液、#5胸水、#6腹水、#7:#1AND#4、#8:#1AND#5、#9:#1AND#6。
1.3确定纳入和排除标准：纳入文献的研究目标为在榄香烯治疗上或联合化疗药物对恶性浆膜腔积液临床观察其治疗获益。排除重复发表、未设立对照组的研究和动物实验,并排除无法判断疗效综述、经验总结、理论探讨、个案报道等类型的研究,并剔除不符合要求的文献。本研究只纳入随机对照试验(RCT)。
1.4干预措施：①榄香烯乳(大连金港制药有限公司制品-国药准字H10960114)vs.化疗药;②榄香烯乳+化疗药vs.化疗药。对照组使用和治疗组相同的常规化疗(药物种类不限)。2组患者采取腔内积液置管闭式引流,然后作腔内注药,同时辅以止吐及其他对症处理的药物,如地塞米松及利多卡因等。
2.判效结局指标
2.1疗效评定标准：采用世界卫生组织(WHO)制定的标准评价：分为CR、PR、SD、NC4组,总有效率=(CR例数+PR例数)/总例数×100%。
2.2生活质量评价指数(quality of life,QOL):采用karnofsky performance status (KPS)评分标准,分为好转、稳定、恶化。
2.3安全性评价：按照WHO抗癌药物急性与亚急性毒副反应分级标准。
3.文献质量评价
3.1严格评价各个相关纳入研究的方法学质量,采用按照Juni等对随机对照试验的4条质量评价标准进行分析评价,质量等级为A级；B级;C级;
3.2按照Cochrane系统评价员手册(5.1.0版)中RCT的偏倚风险评价标准评价纳入研究的方法学质量;
3.3并采用GRADE系统对证据质量和等级推荐进行分级、循证医学(EBM)证据质量进行评价。
4..数据录入及统计分析
在严格质量评价后,对收集的各相关研究进行结局测量指标的数据提取,采Cochrane协作网提供的Revman5.0统计软件进行Meta分析。
a.异质性检验(齐性检验)。根据异质性结果选用进一步的系统评价方法。
b.统计合并效应量(加权合并以相对危险度(Relative Risk, RR)表示),计算效应尺度及95%的置信区间(Confidence Interval,CI)并进行统计推断。
c.图示(森林图)单个试验的结果和合并后的结果。以P<0.05表示具有显著的统计学意义,以P<0.01表示具有非常显著的统计学意义。
d.敏感性分析：测试各个临床试验的疗效结果经Meta整合之后,所得出总体的关于干预的疗效结果,如果各临床试验结果之间差异很大,异质性测试显示有显著性差异,则排除某纳入研究,重新进行Meta分析,其结果与未排除前的结果进行比较,以检验个别研究结论对合并效应量的影响。
d.采用“倒漏斗图”或通过“失安全数”的计算了解潜在的发表偏倚。
e.结果解释、作出结论及评价。
结果
本研究共纳入符合榄香烯乳注射液治疗恶性浆膜腔积液的临床随机对照试验(RCT)31篇中文文献,共纳入1763名患者,其中治疗组903例,对照组860例。治疗组的联合用药或对照组化疗药物以顺铂、金葡素、卡铂、5-FU、IL-2等为主进行治疗。各研究纳入治疗组和对照组的基线条件和基础治疗一致。
1.榄香烯乳注射液治疗恶性浆膜腔积液的Meta分析
纳入的17篇文献,对榄香烯乳单药治疗与单用化疗治疗进行对比,并能获得近期疗效、生活质量、不良反应及生存数据的随机对照试验。967例入组。其中仅1篇文献能提供1年生存率。纳入文献研究质量均为C级。
1.1近期疗效的Meta分析
1.1.1对纳入分析的17项研究近期疗效的Meta分析,综合结果显示,榄香烯组治疗恶性浆膜腔积液疗效优于化疗组RR＝1.03,95%CI：(0.93～1.14),P=0.61。但各组之间差异无统计学意义。
1.1.2对纳入的17项研究近期疗效的总有效率(CR+PR)的Meta分析,两组有效率为84.31%vs.63.44%,RR=1.32,95%CI(1.22,1.43),P<0.01。差异有统计学意义。揭示榄香烯治疗恶性浆膜腔积液的临床疗效明显优于化疗组。
1.2生存质量的Meta分析
对纳入4项研究的Karnofsky评分改善率比较,两组生质存量改善率为69.52%vs.35.23%,RR=1.97,95%CI(1.48,2.64),P<0.01,2组差异有统计学意义,说明榄香烯对恶性浆膜腔积液患者生活质量的改善率明显高于化疗组。
1.3生存率的Meta分析
对纳入1项研究1年生存率的Meta分析,2组1年生存率分别60.00%,31.03%,RR=1.93,95%CI(1.04,3.58),P<0.05。差异有统计学意义。榄香烯合并化疗组的1年生存率高于化疗组。
1.4不良反应的Meta分析
17项研究分为6个组的不良反应发生率的Meta分析,主要为胸痛、腹痛、发热、胃肠道反应、骨髓抑制、肝臀功能损害等。
1.4.1对纳入14项研究胸痛发生率的Meta分析,两组胸痛发生率为29.41%vs.8.97%,RR=2.62,95%CI(1.28,5.37),P<0.01。差异有统计学意义。显示注射榄香烯引起胸痛发生率明显高于化疗药物腔内注射治疗。
1.4.2对纳入2项研究腹痛发生率的Meta分析,两组发生率为8.45%vs.2.73%,RR=3.15,95%CI(0.69,14.42),P=0.14。显示注射榄香烯组与化疗组,两组间腹痛发生率相似,差异无统计学意义。
1.4.3对纳入10项研究发热发生率的Meta分析,两组发生率为21.15%vs.4.64%,RR=3.32,95%CI(1.24,8.84),P<0.05。注射榄香烯治疗恶性浆膜腔积液发热发生率高于化疗药物腔内注射治疗,差异有统计学意义。
1.4.4对纳入15项胃肠道不良反应发生率的Meta分析,两组发生率为6.26%vs.40.52%,RR=0.20,95%CI(0.10,0.37),P<0.01。差异有统计学意义。显示榄香烯组胃肠道反应发生率明显低于化疗组。
1.4.5对纳入14项研究骨髓抑制反应率的Meta分析,两组发生率为0.24%vs.20.66%,RR=0.08,95%CI(0.04,0.17),P<0.01。显示榄香烯组骨髓抑制发生率明显低于化疗组,差异有统计学意义。
1.4.6对纳入9项研究肝、肾功能损害发生率的Meta分析,两组发生率为0.33%vs.8.44%,RR=0.17,95%CI(0.07,0.43),P<0.01。差异有统计学意义。显示榄香烯组肝、肾功能损害低于化疗组。
2.榄香烯乳注射液联合化疗药治疗恶性浆膜腔积液的Meta分析
纳入的14篇文献,是对化疗同时加用榄香烯治疗与单用化疗治疗进行对比,并能获得近期疗效、生活质量、不良反应及生存数据的随机对照试验。796例入组。其中无1篇文献能提供生存率数据。纳入文献研究质量：仅1篇为B级,其馀皆为C级。
2.1近期疗效的Meta分析
2.1.1对纳入分析的14项研究近期疗效的Meta分析,综合结果显示,榄香烯与化疗药物联合组和单纯化疗组治疗恶性浆膜腔积液疗效优于单纯化疗组[RR=0.98,95%CI：(0.79-1.22),P=0.86]。但各组间差异无统计学意义。
2.1.2对纳入的14项研究近期疗效的总有效率(CR+PR)的Meta分析,两组有效率为82.52%vs.58.85%,RR=1.41,95%CI(1.19,1.68),P<0.01。差异有统计学意义。揭示榄香烯可以明显提高化疗药物对恶性浆膜腔积液治疗的临床疗效。
2.2生存质量的Meta分析
对纳入4项研究的Kamofsky评分改善率比较,两组生质存量改善率为65.80vs.33.33%,RR=2.06,95%CI(1.40,3.04),P<0.01。说明榄香烯联合化疗对恶性浆膜腔积液患者生活质量的改善率明显高于单纯化疗组。
2.3不良反应的Meta分析
14项研究分为5个组的不良反应发生率的Meta分析,主要为胸痛、发热、胃肠道反应、骨髓抑制,以及肝肾功能损害等。
2.3.1对纳入7项研究胸痛发生率的Meta分析,两组胸痛发生率为28.70%vs.19.41%,RR=3.15,95%CI(0.81,12.24),P=0.10。差异无统计学意义。显示注射榄香烯与化疗药物联合组与单纯化疗组引起胸痛发生率无明显差异。
2.3.2对纳入5项研究发热发生率的Meta分析,两组发生率为39.39%vs.17.28%,RR=3.71,95%CI(0.80,17.19),P=0.09。差异无统计学意义。显示注射榄香烯与化疗药物联合组与单纯化疗组引起发热发生率无明显差异。
2.3.3对纳入8项胃肠道不良反应发生率的Meta(?)分析,两组发生率为35.39%vs.53.36%,RR=0.66,95%CI(0.54,0.81),P<0.01。2组差异有统计学意义。显示注射榄香烯与化疗药物联合组胃肠道不良反应发生明显低于单纯化疗组。
2.3.4对纳入4项研究骨髓抑制反应率的Meta分析,两组发生率为13.79%vs.50.00%,RR=0.24,95%CI(0.08,0.76),P<0.05。显示榄香烯与化疗药物联合组骨髓抑制发生率低于单纯化疗组。差异有统计学意义。
2.3.5对纳入3项研究肝、肾功能损害发生率的Meta分析,两组发生率为4.65%vs.10.11%,RR=0.49,95%CI(0.17,1.44),P>0.05。差异无统计学意义。显示榄香烯与化疗药物联合组和单纯化疗组肝、肾功能发生无明显差异。
结论
本系统评价结果表明,榄香烯乳注射液单药及联合化疗治疗恶性浆膜腔积液具有明显的优势。治疗组患者的总有效率(CR+PR)、生活质量(KPS)、生存期明显高于对照组患者。榄香烯乳注射的不良反应主要为低热和局部胸痛,同时对症处理可能减轻或避免不良反应的发生。该药避免了应用顺铂等化疗药物所产生的胃肠道反应,骨髓抑制及肝肾功能损害等,增加了疗效。两者联合治疗比单一应用更能有效地控制浆膜腔积液,可以减轻患者的症状,提高生活质量,延长患者生存期,显示出明显的治疗作用。
经本研究Meta分析提示榄香烯乳注射液单药及联合化疗对恶性浆膜腔积液是一种安全、有效的治疗方法,鉴于系统评价和Meta分析属于二次证据,其重要性按级别划分属于一级证据,临床参考价值最大。纳入研究分析的原始文献的异质性明显影响较大,基于纳入研究的文献质量评价为C及GRADE系统的证据质量为2B,可能存在部份偏倚等局限性,尚需进一步开展大规模、高质量的基础和临床研究取得高级别的循证医学证据,指导临床实践。
Background
Malignant 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.
Objective
This 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.
Methodology
1. Inclusion of Research Literature
1.1To 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 Strategy
To 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 Criteria
The 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.
1.4Interventions
①elimene injection (Dalian Jiangang Pharmaceutical Co., Ltd. Product, China's medical permitment NO.H10960114) versus chemo-drugs
②elimene injection plus chemo-drugs versus chemo-drugs
Standard 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 Assessment
2.1Effect 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 WHO
3Literature Quality Evaluation Assessment
3.1To 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 Analysis
After 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 test
Further 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 Analysis
Using 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 evaluation
Results
There 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 effusions
There 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 effects
1.1.1The 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 life
There 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 time
Only 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 effusions
There 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 effects
2.1.1The 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 life
There 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 reactions
The 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.
Conclusion
This 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.
引文
[1]汤钊猷.现代肿瘤学.2版[M].上海医科大学出版社,2000：569-571.
[2]国家药典委员会.中华人民共和国药典(一部)[S].北京.化学工业出版社,2000：230.
[3]赵亚利,彭晓霞,王亚东,等.榄香烯注射液治疗肺癌的有效性与安全性评价[J].中国循证医学杂志,2005,5(3).
[4]李河,麦劲壮,方积乾等.Meta分析中漏斗图的绘制[J].循证医学,2007,7(2)：101-106.
[5]陈振东.恶性胸腔积液诊治中的常见问题及其进展[J].中国临床肿瘤学进展,2010：460-462.
[6]Sahn S.The pleura.Am Rev Respir Dis,1988,138:184-234.
[7]Henschke C,Davis S,Romano P,et al.The pathogensis,radiologic evaluation,and therapy of pleural effusion. Radiol Clin North Am,1989,27:1241-1255.
[8]Smith EM,Jayson GC.The current and future management of malignant ascites(J).Clin Oncol,2003, 15(2):59-72.
[9]石晶.恶性腹水西药治疗[J].中外健康文摘,2011,8(6)：236.
[10]Adam RA,Adam YG. Malignat ascites:past,present,and future(J).J Am Coll Surg,2004,198(6):999-1011.
[11]王忻妍,王雅杰.恶性腹腔积液形成机制及其诊断和治疗[J].国际肿瘤学杂志,2008,35(3)：218-220.
[12]Vaitkus PT,Herrmann HC,LeWinter MM.Treatment of malignant pericardial effusion,JAMA,1994, 272:59-64.
[13]黄小青,田华琴,梁贵文,等.内生场热化治疗老年恶性浆膜腔积液[J].CHINA MEDICAL HERALD中国医药导报,2011,8(29)：36.
[14]Psallidas I,Karabela SP,Moschos C,et al.Specific effects of bortezomib against experimental malignant pleural effusion:a preclinical study(J).Mol Cancer,2010,9:56.
[15]Antunes QNeville E,Duffy J,et al.BTS guidelines for the management of malignant pleural effusions(J).Thorax,2003,58(S20):29-38.
[16]刘介平,张国良.恶性胸腔积液[J].山西医药杂志,2001,30(1)：39-40.
[17]Smith EM,Jayson GC.The current and future management of malignant ascites(J).Clin Oncol,2003,15(2):59-72.
[18]Garrison RN, Kaelin LD, Galloway RH, et a.l Malignant ascites:clinicaland experimental observations[J]. Ann Surg,1986,203:644-651.
[19]Ayantunde AA,Parsons SL.Pattern and prognostic factors in patients with malignant ascites:a retrospective study.Ann Oncol,2007,18(5):945-949.
[20]徐光炜编译.临床肿瘤学[M].沈阳：辽宁教育出版社,1999：685-686.
[21]Laham RJ,Cohcn DJ,Kuntz RE,et al.Pericardial effusion in patients with cancer:outcome with contemporary management strategies.Heart,1996,75(1):67-71.
[22]Skhvatsabaja LV.Secondary malignant lcsions of the heart and pericardium in neoplastic disease. Oncology,1986,43(2):103-106.
[23]孙燕.内科肿瘤学[M].北京：人民卫生出版社,2001,261.
[24]章华萍,徐颖鹤,林荣海.心包引流及腔内注射化疗药物治疗伴填塞症状的恶性心包积液17例分析[J]. 临床萃,2001,(21).
[25]于立恒.恶性胸腔积液的治疗现状与进展[J].肿瘤防治研究,2007,34(12)：973-976.
[26]Rossi CR,Mocellin SL.Pharmacokinetics of intraperi-toneal cisplatin and doxorubicin[J].Surg Oncol Clin N Am,2003,12(3):781-794.
[27]严文跃,钱晓萍,刘宝瑞.恶性胸腔积液的治疗进展[J].现代肿瘤医学,2009,17(7)：1393-1396.
[28]吴艳芳,于雷,王金万.恶性心包积液的内科治疗进展[J].癌症进展,2007,5(4)：352-354.
[29]Becker QGalandi D,Blum HE.Malignant ascites:Systematic review and guideline for treatment.Eur J Cancer,2006,42(5):589-597.
[30]Anderson CB,Philpott GW,Ferguson TB.The treatment of malignant pleural effusions.Cancer,1974, 33:916-922.
[31]Goth QGatzemeir U,Haubingen K,et al.Intrapleural palliative treatment of malignant pleural effusions with mitoxantrone us placebo (pleural tube alone).Ann Oncol,1991,2:213-215.
[32]史宏彰,沙庆棠,杨妍,等.恶性心包积液心包内置管间断引流15例临床分析,1998.
[33]ZHANG TH,LI JL.Clinical application of closed derainage through central veneous catheter indwelled in thorax[J].China Journal of Modern Medicine,2002,12(5):93-94.Chinese
[34]王怀瑾,张阳,刘艳娥,等.癌性腹水超滤浓缩自体腹腔回输的临床研究[J].大连医科大学学报,1999,21(3)：183-186.
[35]孙晓敏,董卫国.恶性腹水的研究进展[J].国外医学·消化系疾病分册,2003,23(6)：375-377.
[36]Lee A,Lau TN, Yeong KY. Support Care Cancer,2000,8(3):493-499.
[37]傅乃武,金兰萍,郭永佃.榄香烯的抗肿瘤作用和药理研究[J].中药通报,1984：92：35-37.
[38]花文峰,蔡绍晖.p-榄香烯抗肿瘤作用的基础与临床研究[J].中药材第,2006,29(1)：93-95.
[39]钱振超.莪术瘤苗的主动免疫保护效应[J].药学通报,1981,12：892-894.
[40]钱振超.各种瘤苗对L615免疫预防效应的进一步实验研究[J].病理生理学报,1985,5：64-67.
[41]傅乃武,金兰萍,郭永佃.p—榄香烯的抗肿痈作用和药理研究[J].中药通报,1984,9(2)：35.
[42]钱振超,金兰萍,郭永佃.莪术瘤苗的主动免疫保护效应：莪术抗癌作用的初步探讨[J].药学学报,1981,12：892.
[43]陈剑群,吴克俭,费素娟.榄香烯乳注射液治疗中晚期消化系肿瘤前后T淋巴细胞亚群的动态观察[J].中国肿瘤临床,1996,23(4)：299-301.
[44]钟永祥.榄香烯的临床前药理研究及临床应用[J].湖南医学,1996,13(2)：119.
[45]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].1990,23(1)：75.
[46]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腹腔积液的Ⅲ期临床观察[J].中国肿瘤临床,1996；23(4)：301-304.
[47]王红梅,廖国佳,李虎城,等.榄香烯乳联合治疗恶性胸腔积液疗效观察[J].中国肿瘤临床,1998,25(增刊)：90.
[48]岳莉,薛海鸥,苏卫红,等.榄香烯乳治疗恶性胸腹水20例临床观察[J].中国肿瘤临床,1998,25(增刊)：81.
[49]董立国.榄香烯治疗消化系恶性肿瘤导致的胸腹腔积液[J].《中国癌症杂志》,2001,11(1).
[50]张蓉,洪婉君,白萍.榄香烯治疗妇科恶性胸腹腔积液[J].中国肿瘤临床,2000,27(1)：71.
[51]黄黎明,胡伯年,李忠麟.榄香烯对不同类型癌性腹水的疗效[J].湖南医学,1996,13(4)：241.
[52]王金万,张和平,孙燕.榄香烯乳治疗晚期恶性肿瘤的Ⅱ期临床试用结果[J].中国新药杂志,1995,4(2)：26.
[53]魏路清,陈萍,王建华.榄香烯乳治疗肺癌胸膜、心包转移的疗效观察[J].中国实用内科杂志,1998,18(10)：607-608.
[54]李开俊,傅鹰,查仲玲.循证医学操作流程的归纳和分析[J].药物流行病学杂志,2003,12(3)：140-141.
[1]Am J.Managenent of malignant pleural effusions[J].Respire Crit Care Med,2000,162(5):1987.
[2]Liu CD, Tilch L,KwanD,et al.Vascular endothelial growth factor is increased in ascites from metastatic Pancreatic CanCer.J Surg Res 2002; 102(1):31-4.
[3]Scott R,Donald D,Timothys L,et al.Maligant ascites of unknown origin[J]. Cancer,1989,(3):753.
[4]崔书中.恶性腹水的治疗现状与进展,第二届“CSCO南方”肿瘤生物治疗与分子靶向治疗论坛：115.
[5]廖熙检.癌胚抗原对良性恶性的心包积液鉴别的临床分析[J].广西医学,1999,3：410-412.
[6]Warren WH.Malignan cies involving the pericardium[J].Semin Thorac Cardiovasc Surg,2000,12(2):119.
[7]Brigden ML.Hematologic and oncologic emergencises.Doing the most good in the least time,Postgrad Med,2001,109:143.
[8]Shepherd FA.Malignant pericardial effusion. Curr Opin Oncol,1997,9(2):170.
[9]DeCamp MM Jr, Mentzer SJ,Swanson SJ,et al. Malignant effusive disease of the pleura and pericardium. Chest,1997,112(4):291S.
[10]宋长顺,蔡鑫,董金风.心包炎10年的病因及近期疗效分析[J].蚌埠医学院学报,1994；19(1)：44.
[11]OliverWP, RobertL. Management ofmalignant pericardial effusion and tamponade[J]. JAMA,1987, 257(8):1088-1092.
[12]孙燕.肿瘤内科学[M].北京：人民卫生出版社,2002：254.
[13]Sahn S. The pleura. Am Rev Respir Dis,1988,138:184-234.
[14]Lynch TJ.Management of malignant pleural effusions.Chest,1993,103:385-389.
[15]Runyon BA.Care of patients with ascites[J].N Engl J Med, 1994, 330(5):337.
[16]Tamsma J. The pathogenesis of ascites. Cancer Treat Res.2007,134:109-18.
[17]Becker G,Galandi D,Blum HE,et al. Malignant ascites:systematic review and guideline for treatment. Eur J Cancer.2006,42(5):589-97.
[18]Atanaekovic D,Block A,de Weerth A,et al.Characterization of effusion-infiltrating T cells:benign versus malignant effusions[J].CIin Cancer Res,2004,10(8):2600-2608.
[19]丁勇敏.白细胞介素18和γ-干扰素联合检测鉴别诊断结核性和恶性胸腔积液的价值和临床意义[D].浙江大学,硕士,2008.
[20]Macaulay VM,O'Byrne KJ,Saunders MP, et al. Phase I study of intra2 pleural batimastat (BB294),a matrix metalloproteinase inhibitor,in the treatment of malignant pleural effusions[J]. Clin Cancer Res,1999,5(3):5132520.
[21]Hurewitz AN, Zueker S, Maneuso P, et al.Human pleural effusions are rich in matrix metalloproteinases[J]. Chest,1992,102(6):1808-1814.
[22]Park KJ,Hwang SC,Sheen SS,et al.Expression of matrix metalloProteinase — 9 in Pleural effusions of tubereulosis and lung cancer[J].Respiration,2005,72(2):166-175.
[23]施劲东.基质金属蛋白酶及其组织抑制物在不同性质胸腔积液诊断和鉴别诊断中的应用[D].复旦大 学,硕士,2009.
[24]Grove CS,Lee YC.Vascular endothelial growth factor:the key mediator in pleural effusion formation[J].Curr Opin Pulm Med,2002,8(4):294-301.
[25]Senger D,Gallis J,Dvorak AM,et al.Tumor cells secrete a vascular permeability factor which promotes ascites fluid accumulation[J].Science,1983,219(4):903-909.
[26]Banerjee SK, YoungHW, Volmer JB,et al. Gene expression profiling in inflammatory airway disease associated with elevated adenosine[J].AmJPhysiol Lung Cell Mol Physiol,2002; 282(2):L169-L182.
[27]Srivastava M, Zurakowski D, Cheifetz P,et al. Elevated serum hepatocyte growth factor in children and young adults with inflammatory bowel disease[J].JPediatr GastroenterolNutr,2001; 33(5):548-553.
[28]罗淼,董德琼,杨瑜浩,等.血管内皮生长因子在恶性胸腔积液中的作用[J].国际呼吸杂志,2006,12(4)：7-9.
[29]Yano S, Shinohara H, Herbst RS, et al. Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells.Am J Pathol,2000,157(6):1893-1903.
[30]Mori A,Arii S,Furutani M, et al. Soluble Flt21 gene therapy for perito2 neal metastases using HVJ2cationic liposomes[J]. Gene Therapy,2000,7 (12):102721033.
[31]Hasumi Y,Mizukami H,Urabe M, et al. Soluble FLT21 expression sup2 presses carcinomatous ascites in nude mice bearing ovarian cancer[J].Cancer Res,2002,62(2):201922023.
[32]Van den Heuvel MM,Smit HJ,Barbierato SB,et al.Talc-induced inflammation in the pleural cavity[J].Eur Respir J,1998,12(6):1419.
[33]Nasreen N,Hartman DL,Mohammed KA,et al.Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells[J].Am J Respir Crit Care Med1998,158(3):971.
[34]Rahman NM,Davies HE,Salzberg M,et al.Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion:a phase I toxicity and dose-escalation study[J].Lancet Oncol,2008,9(10):946-952.
[35]Olivares-Torres CA,Laniado-Laborin R,Chavez-Garcia C,et al.Idopovidone pleurodesis for recurrent pleural effusions[J].Chest,2002,122(2):581.
[36]章华萍,徐颖鹤,林荣海.心包引流及腔内注射化疗药物治疗伴填塞症状的恶性心包积液17例分析[J].临床萃,2001,(21).
[37]吴一龙.肺癌多学科综合治疗的理论与实践[M].北京：人民卫生出版社,2000：277.
[38]王婷婷,刘宝瑞,钱晓萍.恶性腹腔积液的治疗进展[J].临床肿瘤学杂志,2007,12(10)：787-788.
[39]吴艳芳,于雷,王金万.恶性心包积液的内科治疗进展[J].癌症进展杂志,2007,5(4)：352-354.
[40]李磊,陈涛.恶性胸腔积液的治疗现状[J].华中医学杂志,2009,33(4)：223-225.
[41]Antony VB,Loddenkemper R,Astoul P,et al.Management of malignant pleural effusions [J]. Am J Respir Crit Care Med, 2000, 162(5):1987-2001.
[42]Musani AI.Treatment options for malignant pleural effusio[J].Curr Opin Pulm Med,2009, 15(4):380-387.
[43]戴莉莉.恶性胸腔积液的生物免疫治疗进展[J].上海医药,2011,32(2)：80-82.
[44]贾杨.细菌性生物反应调节药治疗癌性胸腹腔积液的进展[J].Herald of Medicine October,2002,21(10): 662-663.
[45]Rosenberg SA,Lotze MT,Yang JC,et al.Expeienee with the use of high dose interleukin-2 in the treatment of 652 cancer patients.Ann Surg,1989,210(4):474.
[46]曹雪涛.白细胞介索-2的基础与临床[M].北京：科学技术出版社,1997：183.
[47]罗科平，刘敬东.白介素-2治疗恶性胸腔积液36例临床观察[J].上海医药,1997,10：27-28.
[48]李佳茵,魏长春Experience for treating malignant pleural effusion with interleukin-Ⅱ in intrapleural administration, Clinical Journal of Chinese Medicine 2010,(2):64.
[49]王焕江.对清膏相对密度测定方法的改进[J].中成药,1999,21(8)：435.
[50]Watanaben,Ruffmr,Metthewsn,et al.Gytotocial radial inhibltors on cytonicity Immuno pharmocal Immunatoxical[J].1998,10:109.
[51]孙军山,刘在海,颜卉,等.TNF腔内注射治疗恶性心包积液20例疗效观察[J].齐鲁肿瘤杂志,1999,6(3)：208-209.
[52]许杰超,闫兵杰,杜海俊,等.TNF腔内注射治疗恶性胸腹水疗效分析[J].河南职工医学院学报,14(2)：152-153.
[53]工俊祥,工金铠.白介素-12、干扰素-γ在急性白血病中的意义与树突状细胞诱导特异性抗白血病免疫应答的体外研究[D].河北医科大学,博士,2004.
[54]薛红健,吴红革,李贵玲,等.γ干扰素治疗恶性胸腹腔积液的临床床观察[J].《肿瘤》2001,21(2)：122-123.
[55]刘力锋.白细胞介素-2及γ-干扰素心包腔内注射治疗恶性心包积液32例[J].中国实用医刊2009,36(18)：56-57
[56]王娟,陶贞霞,刘荣英,等.DC-CIK细胞免疫联合治疗癌性胸腔积液的实验观察[J].中国免疫学杂志,2009,25：278-280.
[57]周清华.肺癌靶向治疗的现状与进展[J].中国肺癌杂志,2003,6(6)：434-440.
[58]Swisher SG,Roth JA,Komaki R,et al.A phase II trial of adenoviral mediated p53 gene transfer in conjunction with radiation therapy in patients with localized non small cell lung cancer[J].Proc Am Soc Clin Oncol,2002,19:461-464.
[59]Brekken RA,Overhoiser JP,Stastny VA,et al.Selective inhibition of VEGF reception 2 activity by a monoclonal anti-VEGF antibody blocks tumor in mice[J].Cancer Res,2000,60(18):5117-5118.
[60]于顺江.抗VEGF肿瘤靶向治疗进展,癌症进展[J].2010,8(2)：175-177.
[61]蔡艳军.贝伐单抗联合顺铂对VEGF高表达的荷卵巢癌裸鼠腹水抑制作用的实验研究[D].第一军医大学,硕士,2004.
[62]Harada K, Supriatno, YoshidaH, et al. Vesnarinone inhibits angiogenesis and tumorigenicity of human oral squamous cell carcinoma cells by suppressing the expression of vascular endothelial growth factor and interleukin-8[J]. Int J Oncol,2005,27 (6):1489.
[63]Hajitou A, Grignet C, Devy L, et al. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells[J]. FASEB J,2002,16(13): 1802.
[64]Sack U, Hoffmann M, Zhao X J, et al. Vascular endothelial growth factor in pleural effusions of different origin[J]. Eur Respir J,2005,25(4):600.
[65]姜子瑜,秦叔逵.新型重组人血管内皮抑素联合榄香烯注射液治疗恶性腹水的实验研究[D].南京中医药大学,2012,博士.
[66]魏红梅,秦叔逵.新型重组人血管内皮抑制素(恩度)对小鼠腹水瘤的抑制作用及其相关机制研究[D].南京军区南京总医院博士后工作站,2010.
[67]方长清,郭晓宁,李淼,等.MMP-2、VEGF在肺腺癌细胞中的表达及其意义[J].中国组织化学与细胞化学杂志,2010,19(4)：372-376.
[68]刘敏.MMP-3和MMP-7在良恶性胸腔积液中的表达及意义[J].中国现代医生,2012,50(7)：127-128.
[69]范玉晶,韩明子.基质金属蛋白酶-2、-9在恶性腹水中的表达[J].黑龙江医学,2009,33(10)：730-732.
[70]Fang J,Shing Y,yan L, et al. Matrix metalloproteinase-2 is required for switch to the angiogenic phentype in a tumor model[J].Proc Natl Acad Sci USA,2000,97(8):3884-3889.
[71]黄丹,吴波.基质金属蛋白酶抑制剂治疗癌症的临床前景[J].国外医学药学分册,2001,28(2)：87-89.
[72]王陇德.临床技术操作规范·核医学分册[M].北京：人民军医出版社,2004：56.
[73]谭天秩.我国放射性核素治疗的现状和展望[J].中华核医学杂志,1994,14(3)：186-188.
[74]崔书中.恶性腹水的治疗现状与进展[J].第二届”CSCO一南方”肿瘤生物治疗与分子靶向治疗论坛：118.
[75]袁翎,单娟,杨建伟.32P胸腔灌注治疗恶性胸水5例的临床分析[J].中国医师杂志,2006,8(9)：1287.
[76]王凤月.榄香烯乳胸、腹腔注药治疗恶性积液疗效观察[J].中国实用区学研究杂志,2002,1(2)：121-122.
[77]刘琳,陈宝安,秦叔逵,等.三氧化二砷联合华蟾素抗裸鼠人肝癌移植瘤血管新生的作用[J].中国中西医结合杂志,2011,31(1)：67-71.
[78]李宝林,赵晓辉,王笑宇,等.三氧化二砷治疗肺癌合并胸腔积液临床疗效分析[J].中国医学工程,2011,19(5)：53-54.
[79]周琴.华蟾素注射液胸腹腔灌注治疗恶性胸腹腔积液的临床研究[D].北京中医药大学,硕士,2012.
[80]王丽茹,刘立君,张晨瑶.康莱特治疗恶性胸腔积液的临床研究[J].陕西肿瘤医学,2002,10(2)：144.
[81]李惠华,刘亮,张弛,等.康莱特治疗非小细胞肺癌恶性胸腔积液的临床观察[J].中国医药指南,2012,10(21)：438-439.
[82]张明智,张喜爱,周超锋,付晓瑞.紫杉醇腹腔内灌注联合康莱特治疗晚期肝癌腹腔积液疗效观察[J].Chinese General Practice,2011,14(8) 2800-2802.
[83]李平,胡育新,张垃.香茹多糖治疗恶性腹水的临床观察[J].中国肿瘤生物治疗杂志,2001,8(2)：145-146.
[84]李民,苏兴仁.鸦胆子油乳剂对艾氏腹水癌细胞杀伤动力学研究[J].中草药,1981,(12)：4.
[85]周洁,孟勇.鸦胆子汕乳腹腔灌注治疗恶性腹水23例临床观察[J].基层医学论坛,2004,8(8)：692-693.
[1]Sorm F,Holub M,Sykora V,et al.Terpenes XLVI Sesquiterpenic hydrocarbons from Sweet-flag oil[J].Coll Czech Commun)1953,18(3):554-560.
[2]Weinheimer AJ,Youngblood WW,Washecheck PH,et al.Chemistry of coelenterates XVIII isolation of the elasive(-)-germacrene-A from the gorgonian,Eunicea mammosa[J].Tetrahedron Letter,1970,(7):497-500.
[3]林启寿.中草药成分化学[M].北京：科学出版社,1977,584.
[4]植木宽,甲斐原守夫,坂川正之,等.Antitumor activity of plant constituents.I[J].药学杂志,1961,811(11)：1641-1644.
[5]《全国中草药汇编》编写组.全国中草药汇编.北京：人民卫生出版社,1988,685.
[6]旅大市肿瘤防治办公室.中药莪术治疗宫颈癌的初步研究,1972.7(内部资料).
[7]辽宁省肿瘤防治研究办公室.中草药—温莪术治疗恶性肿瘤的初步研究,1974.3(内部资料).
[8]郭永田.温莪术挥发油中榄香烯的分离.中药通报,1983,8(3)：31.
[9]秦叔逵,钱军,杨爱珍,等.榄香烯乳抗肺癌细胞的实验研究[J].肿痛防治研究,1996,23(4)：251-254.
[10]LI QQ,WANG GD,HUANG FR,et al.Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cells[J].J Pharm Pharmacol,2010,62(8):1018-1027.
[11]WANG G,LI X,HUANG F,et al.Antitumor effect of beta-el-emene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death[J].Cell Mol Life Sci,2005,62(7-8):881-893.
[12]LI X,WANG G,ZHAO J,et al.Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase[J].Cell Mol Life Sci,2005,62(7-8):894-904.
[13]TAO L,ZHOU L,ZHENG L,et al.Elemene displays anti-canc-er ability on laryngeal cancer cells in vitro and in vivo[J].Cancer Chemother Pharmacol,2006,58(1):24-34.
[14]WU XS,XIE T,LIN J,et al.An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas[J].J Pharm Pharmacol,2009,61 (12):1653-1656.
[15]LI QQ,WANG G,REED E,et al.Evaluation of cisplatin in combination with beta-elemene as a regimen for prostate cancer chemotherapy[J].Basic Clin Pharmacol Toxicol,2010,107(5):868-876.
[16]ZHAO J,LI QQ,ZOU B,et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma[J].Int J Oncol,2007,31(2):241-252.
[17]时继慧,李成章,刘德兰.中药通报,1981,36(6).
[18]肖立森,李佩兰,陆炜炎,等.MTT法检测榄香烯对人癌细胞敏感性的研究[J].中国肿瘤临床,1996,23(3)：223-4.
[19]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].1990,23(1)：75.
[20]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腹腔积液的Ⅲ期临床观察[J].中国肿痛临床,1996, 23(4)：301-304.
[21]何文,胡长路,裘慰伯.B超对肺癌急症的诊断及疗效评估[J].中华肿瘤杂志,1997,19(5)：374-376.
[22]朱先萍.第八局全国中西医结合肿瘤学术会议论文集,重庆铁路医院肿瘤科(重庆400053),2000：130.
[23]师国强.榄香烯乳胸腔内注射治疗恶性胸腔积液的疗效观察[J].实用诊断与治疗杂志,2007,21(5)：373-374.
[24]葛晓燕.榄香烯乳治疗恶性腹水53例临床疗效观察[J].交通医学,2001,15(1)：37.
[25]王培民,周力,姜琼.榄香烯乳、顺铂治疗恶性腹水疗效的对照观察[J].中国医院药学杂志,1999,19(7)：420-421.
[26]江联萍,戴月娣,陶莉.榄香烯、博莱霉素以及两药联合治疗恶性胸腔积液临床观察[J].《中国癌症杂志》2009,19(3)：218-219.
[27]车德海,于雁,张华,等.培美曲塞与卡铂静脉化疗联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤的临床观察[J].临床肿瘤学杂志,2011,16(4)：356-356.
[28]HazarikaM, White RM, Johnson JR, et a.l FDA drug approval summaries:pemetrexed (Alimta) [J].Oncologist,2004,9(5):482-488.
[29]孙江涛,冯笑山,郭琳.奥沙利铂联合榄香烯乳低张渗透压灌注治疗恶性胸水疗效观察[J].中国误诊学杂志,2007,7(7)：1468-1469.
[30]张涛,赵宜良,徐惠绵.榄香烯联合化疗治疗胃癌晚期腹水的研究[J].中国临床实学,2008,2(5)：59-60.
[31]李翠兰,王明民.卡铂与榄香烯乳联合应用治疗恶性腹水的疗效观察[J].中国中西医结合杂志,1996,16(9)：565-566.
[32]周晓园,陶凯.榄香烯联合胞必佳及利尿剂治疗Ⅳ期恶性肿痈胸腹水21例[J].中国中西医结合杂志,2001,21(10)：775-776.
[33]崔瑞刚.榄香烯联合白介素-2胸腔灌注治疗恶性胸水的临床观察[D].北京中医药大学,硕士,2011.
[34]许凤仙.榄香烯乳加高聚金葡素治疗恶性胸水疗效观察及护理[J].浙江临床医学,2003,5(12)：956-957.
[35]张金兰,孙素华,陈俊荣.高聚金葡素并用化疗治疗中晚期恶性肿瘤的临床效果[J].肿瘤防治研究,1996,23(2)：118.
[36].Hegewisch-Becker S,Gruber Y,Corovic A,et al.Whole-body hyperthermia(41.8℃)combined with bimonthly oxaliplatin,highdose leucovorin and 5-fluorouracil 48-hour continuous in fusion in pretreated metastatic colorectal cancer:a phase Ⅱ study[J].Ann Oncol,2002,9(4):1197-1204.
[37]Novak P,Moros EG,Parry JJ,et al.Experience with a small animal hyperthermia ultrasound system(SAHUS):report on 83 tumours[J].Phys Med Biol,2005,50(21):5127-5139.
[38]孙俊忠,冀绪广,臧克,等.胸腔热灌洗联合榄香烯乳治疗恶性胸腔积液疗效观察[J].中国厂矿医学,2009,22(5)：532-533.
[39]赵桂梅,许永慧,于淑红.榄香烯乳、微波透热联合应用治疗卵巢癌腹水临床观察[J].内蒙古民族大学学报(自然科学版),200217(4)：350-351.
[40]Zhon HY,Hon JS,Wang Y.Dose-and time-dependence of elemene in the induction of apoptosis in two glioma cell lines[J].Chinese,2006,284:270-271.
[41]万旭英,陈哲.榄香烯乳治疗晚期原发性肝癌腹水20例[J].安徽中层学院学报,2002,21(1)：22-23.
[42]马秀丽,魏俊青.榄香烯乳治疗肺癌所致恶性胸腔积液疗效观察[J].山西中医学报,2003,4(2)：51.
[43]潘年松,盛勇,张学愈,等.莪术抗肿瘤作用与品种和加工工艺的关系[J].中国中医药信息杂志,2006,13(8)：35·
[44]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腔积液的Ⅲ期临床观察[J].中国肿瘤临床,1996,23(4)：301.
[45]尚耀华,李墨林,范治璐.p—榄香烯预防浅表性膀胱癌复发基础与临床研究进展[J].大连医科大学学报,2009,31(2)：215—218.
[46]许浪,刘丹,晏丹,等.榄香烯对肺癌细胞凋亡的影响[J].数理医药学杂志,2009,22(2)：154-155.
[47]鞠建峰,于维萍,傅春升,等.p-榄香烯的现代研究及临床应用概况[J].齐鲁药事,2008,27(9)：546-548.
[48]王秀敏,英杰,赵春杰,等.p-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4)：289-320.
[49]杨烨,工仙平,郁琳琳,等.榄香烯抗癌作用机理的研究[J].榄香烯乳注射液临床应用与基础研究论文集,1996：10-13.
[50]时继慧.温莪术挥发油的实验药理研究[J].中药通报,1981,6(6)：32-33.
[51]实用药物指南,见：榄香烯乳的药理作用及体内过程[M].人民军医出版社出版,北京,2000,第1版,264.
[52]遵义医学院肿瘤研究组病理生理小组[J].肿瘤防治研究,1974,(1)：46-48.
[53]遵义医学院肿瘤研究组病理生理小组：本期本刊.
[54]辽宁中医学院卫生防疫教研组等[J].辽宁抗癌战讯,1974(1)：67-74.
[55]肿瘤研究组病理生理小组,莪术抗癌作用原理的初步实骤研究-Ⅲ.体外杀瘤作用的进一步观察,1975：26-30.
[56]傅乃武,金兰萍,郭永,等.β-榄香烯的抗肿瘤作用和药理学研究[J].中药通报,1984,9(2)：35.
[57]杨骅,王仙平,高力,等.榄香烯诱导HL-60细胞程序死亡[J].中国肿瘤生物治疗杂志,1995,2(4)：351-352.
[58]郭建忠,张世渊,吉宏明,等.p-榄香烯诱导ECV-304细胞早期凋亡的实验研究[J].内蒙古民族大学学报,2009,15(5)：24-26.
[59]Zheng S,Yang H,zhang S,et al.Initial study on naturally occurring products from traditional Chinese herbs and vegetables for chemoprevention[J].J Cell Biochem,1997,27:106-112.
[60]龚敏,梁鑫淼,崔晓楠.榄香烯对人肝癌HepG-2细胞增殖及拓扑异构酶表达的影响[J].中国药理学通报,2011,27(60)：839-843.
[61]姚轶群,徐英辉,周洪语,等.ERK在榄香烯抑制大鼠C6胶质瘤细胞增殖中的作用[J].肿瘤,2007,27(10)：777-779.
[62]WANG G,I X.UANG F,t al. Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death[J].Cell Mol Life Sci,2005,62(7-8):881-893.
[63]LI X,WANG G,ZHAO J,et al.Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase[J].Cell Mol Life Sci,2005,62(7-8):894-904.
[64]YAO YQ,DING X,JIA YC, et al. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation[J].Cancer Lett,2008,264(1):127-134.
[65]左云飞,张耀铮,郑军.利用流式细胞术研究榄香烯对肝癌腹水痈细胞系Hca-F25/CL-16A3的抗肿瘤作用[J].大连医科大学学报,2000,22(1)：46-49.
[66]YatwinMB,Seet.Clinical Pmsects for Iiposome[J].Medical Physics,1982,2:159.
[67]张培彤,朴炳奎.肿瘤细胞表面血小板免疫相关抗原的表达及其意义[J].中国肿瘤临床与康复,20018(5)：119-121.
[68]李道睿,祁鑫,于明薇,等.榄香烯对人肺癌细胞表面所表达与侵袭转移相关黏附蛋白的影响[J].中华中医药学刊2007,25(10)：2170-2172.
[69]Davidson B,Goldberg I,Bemer A,et al.Expression of membmne-type 1,2,and 3 matrix metaUoproteinases messenger RNA in ovarian Carcinoma cells in serous effusions.Am J Clin Patho 1,2001,115(4):517-524.
[70]李悦.B-榄香烯对血管内皮细胞增殖、凋亡、成血管能力及MMP-2、MMP-9活性的影响[D].中国医科大学,硕士,2009.
[71]刘敏.MMP-3和MMP-7在良恶性胸腔积液中的表达及意义[J].中国现代医生,2012,50(7)：127-128.
[72]姚淑娟,刘伯阳,胡芳.榄香烯对荷瘤鼠NK和I L-2活性的影响[J].药物研究,2000,9(4)：19-20.
[73]钱军.抗癌新药-榄香烯的药理及临床.中国肿瘤临床[J].1996；23(6)：453-5.
[74]张学军,杜权,丁秀萍,等.榄香烯乳对r—DNA转录活性的影响及意义[J].中国肿瘤临床,1999,26(6)：1-3.
[75]左云飞,张耀睁,魏巍,等.榄香烯对肝癌腹水痈细胞系Hca_F25/CL-16A3的抗肿瘤作用及对细胞周期的影响[J].中药药理与临床,1999,15(5)：24.
[76]周云,杜英,范魁生.榄香烯乳胸腔灌注对恶性胸水渗出液相关淋巴细胞(EAL)增殖及其LAK活性的增强作用实验研究[J].中国肿瘤临床,1997,2(9)：709-712.
[77]陈龙邦,臧静,王靖华.β-榄香烯对荷瘤小鼠免疫功能的影响[J].肿瘤防治研究,1998,25(1)：54.
[78]Ohno I.Tanno Y,Yamauchi K.Gene expression and production of tumor necrosis factor by a rat bnsophilie Leukemia cell line with IgE receptor triggering.Immunology,1990;70: 88.
[79]Gruss HJ,Brach MA,Drexler HG, et al.Expression of cytokine genes, cytokine receptor genes and transcription factors in cultured Hodkin and Reed-Sternberg cells.Cancer Res,1992;15:3353.
[80]左云飞,张耀铮,庞焕.榄香烯对肝癌腹水瘤细胞系Hca-F25/CL-16A3(?)勺抗肿瘤作用机理的实验研究V.榄香烯对小鼠血清中肿瘤坏死因子及层粘连蛋白水平的影响[J].中药药理与临床,1997；13(6)：38-39.
[81]钱振超,王大庆,金成刚,等.瘤苗特异性主动免疫治疗及其机制的实验研究[J].中国肿瘤生物治疗杂志,1995,2(2)：120-126.
[82]Cheng Yuan Baohuo,Fu Tihui,et al.Establishment and some biological characteristice of a spleen CTL cell line form cell vaccine(TCV)immunized inbred 615 mouse[J].Biotherapy,1991,5(6):1222-1227.
[83]沈洁,郭连英,施广霞,等.榄香烯复合痈苗免疫治疗对肿痈生长和脾细胞细胞毒活性的影响[J].大连 医科大学学报,2000,22(1)：4-6.
[84]赵卫红,施广霞,袁小林,等.榄香烯复合瘸苗对Hca-F肝癌小鼠的免疫治疗效应及对IL-10与IL-12分泌的影响[J].中国肿瘤生物治疗杂志,2001,8(2)：126-129.
[85]金梅,白雪,胡景慧.榄香烯复合抗肿瘤疫苗免疫的效应机制[J].中国农业科学,2004,37(9)：1379-1384.
[86]Fu NW.Bulletin of Chinese Materia Mediea,1984;9(2):35.
[87]崔秀云,李德山,B-榄香烯对RNA聚合酶活性的抑制及与DNA的结合[J].中国药理学通报,1991,7(3)：228-230.
[88]Begleiter A.Cancer Res,1983;43:481.
[89]Pastan I.et al.Multiplt-drug rtsistamce in buman cancer.NEngl J Med, 1987, 316:1388.
[90]Breuninger LM, Saptarshi P, Gaughan K,et al·Expression of multidrug resistance-associated protein in NIH/373 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution[J]·Cancer Res,1995,55:5342
[91]王宝成,郭军,狄剑时,等·榄香烯乳剂与肿瘤多药耐药的基础研究[J].中国肿瘤临床,1996,23(2)：143-146.
[92]SM IT JJ, MOL CA, VAN DEEMTER L,et al.Characterization of the promoter region of the hum an MDR3P-glycoprotein gene [J]-BiochemiBiophys Acta,1995,1261 (1):44-56-
[93]王利,魏品康,秦志丰,等.榄香烯对耐药胃癌细胞的逆转实验研究[J].成都中医药大学学报.2005,28(2)：51-53.
[1]Villar J,Carroli G,Belizan JM.Predictive ability of meta-analyses of randomized controlled trials[J].Lanced, 1995;345:772-776.
[2]Juni P,Ahman DG, EggerM·Assessing the quality of controlled clinical trials[J], BMJ,2001,323 (7303):42
[3]Higgins JPT,Green S(editors).Cochrane Handbook for System-atic Reviews of Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration,2011.Available from www.cochrane-handbook.org.
[4]Howard Balshem, Mark Helfanda, Holger J.Schunemann, GRADE指南：Ⅲ.证据质量分级(GRADE Guidelines:3.Rating the Quality of Evidence)[J].中国循证医学杂志,2011,11(4)：451-455.
[5]Gordon H Guyatt,Andrew D Oxman,Gunn E Vist, GRADE:证据质量和推荐强度分级的共识(GRADE：an Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations), [J].中国循证医学杂志,Chin J Evid-based Med 2009,9(1):8-11
[6]GRADEpro.[Computer program].Version 3.2 for Windows.Jan Brozek,Andrew Oxman,Holger Schunemann,2008.
[7]Gordon H Guyatt,Andrew D Oxman,Gunn E Vist,et al.GRADE:an Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations[J].Chin J Evid-based Med 2009,9(1):8-11.
[8]循证医学中证据的质量分级[J].现代康复,2001,5(2)：73.
[9]李强.评价疗效结果的几个新指标[J]World Chin J Digest.2000,8(6):702-703.
[10]魏丽娟,董惠娟Meta分析中异质性的识别与处理[J].第二军医大学学报,2006,27(4)：449-450.
[11]廖海江,金水高Meta分析的应用策略与进展[J].数理医药学杂志,2003,16：541-544.
[12]李河,麦劲壮,方积乾等Meta分析中漏斗图的绘制[J].循证医学,2007,7(2)：101-106.
[13]Egger M,Smith G.Bias in location and selection of studies.BMJ,1998,316(7124):61-66.
[14]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].中国肿瘤临床,1996,23(1)：75.
[15]林顺通,邱庆南.榄香烯治疗晚期肺癌癌性胸水临床观察[J].福建医药杂志,1996,18(3)：90.
[16]王培民,周力,姜琼,等.榄香烯乳、顺铂治疗恶性腹水疗效的对照观察[J].中国医院药学杂志,1999(19)7：420-421.
[17]钱秀芬.胸腔注射榄香烯乳、顺铂治疗癌性胸腔积液疗效观察[J].医学文选,2000,19(1)：29-30.
[18]叶爱和,夏晓阳.榄香烯乳治疗胸腔积液的临床分析[J].河北医学,2001,7(9).
[19]王萍,王珏.榄香烯乳胸腔内灌注治疗晚期肺癌伴胸水临床观察[J].现代医药卫生,2002,18(3)：180.
[20]上凤月.榄香烯乳胸、腹腔注药治疗恶性积液疗效观察[J].中国实用区学研究杂志,2002,1(2)：121-122.
[21]古立新,范峰.榄香烯乳注射液胸腔内注射治疗恶性胸腔积液疗效观察[J].现代中西医结合杂志,2003,12(7)：708-709.
[22]白显利.腔内注射榄香烯乳及顺铂治疗恶性胸腔积液疗效观察[J].现代中西医结合杂志,2005,14(3)：321-322.
[23]师国强.榄香烯乳胸腔内注射治疗恶性胸腔积液的疗效观察[J].实用诊断与治疗杂志,2007,21(5)：373-374.
[24]孙俊忠,冀绪广,等.胸腔热灌洗联合榄香烯乳治疗恶性胸腔积液疗效观察[J].中国厂矿医学,2009,22(5)：532-533.
[25]陆建明.胸腔置管引流并注入榄香烯治疗恶性胸腔积液30例临床观察[J].浙江中医杂志,2011,46(6)：422.
[26]仲几春,张道松,朱云.榄香烯乳治疗恶性胸腔积液96例临床分析[J].齐鲁医学杂志,2011,26(6)：551.
[27]武海松,陈平.榄香烯乳胸腔内注射治疗恶性胸腔积液的临床研究[J].中国医药指南,2011,9(32)：165-166.
[28]孔一名.榄香烯乳胸腔内灌注治疗恶性胸腔积液临床分析[J].现代医药卫生,2012,28(10)：1521-1522.
[29]周聆,叶维洁,张为强.射频透热分别联合榄香烯乳与金葡素胸腔内注射治疗恶性胸腔积液[J].中国临床医学,2012,19(1)：25-26.
[30]孙岚英.榄香烯注射液联合胸腔内注射治疗肺癌并恶性胸腔积液临床观察[J].中国社区医师.医学专业,2012,10(14)：80.
[31]李翠兰,王明民.卡铂与榄香烯乳联合应用治疗恶性腹水的疗效观察[J].中国中西医结合杂志,1996,16(9)：565-566.
[32]蒋有娟,丁惠珍,刘晓丹,等.注入榄香烯和顺铂治疗癌性胸腔积液17例[J].新医学,1997,28(8)：418-419.
[33]贾正飞.榄香烯加顺铂胸腔内灌注治疗恶性胸水20例[J].CANCER RESEARCH AND CLINIC,1997, 9(3):198.
[34]欧阳学农,陈曦,曾金雄.榄香烯乳与白细胞介素—2联合应用治疗恶性胸腔积液[J].中国肿瘤临床,1997,24(4)：315-316.
[35]赵智辅,郭兴里,孙淑娟,等.胸腔闭式引流加榄香烯乳顺铂腔内注射治疗恶性胸水的疗效观察[J].黑龙江医学,1999,11(185)：30.
[36]张万海,金平.中药制剂榄香烯乳联合顺铂治疗癌性胸水疗效观察[J].中国中医药信息杂志,2000,7(9)：69.
[37]黄平.闭式引流腔内注射顺铂、榄香烯乳治疗恶性胸腔积液[J].右江民族医学院学报,2000,22(6)：899-900.
[38]叶元芬,沈依信,刘玉环.榄香烯乳治疗卵巢癌腹水86例[J].宁渡大学学报(理工版),2001,14(2).
[39]陈建清,钟小红,吴晓安,等.置管引流联合榄香烯顺铂治疗恶性胸水的疗效观察[J].中国肿瘤临床,2004,31(19)：1127-1129.
[40]李志杰,张媛.榄香烯联合化疗治疗肺癌合并恶性胸腔积液疗效观察[J].中国误诊学杂志,2006,6(20)：3932-3933.
[41]田迎棠,李明,刘伟,等.大剂量顺铂加榄香烯序贯胸腔注射治疗恶性胸水[J].中原医刊,2007,34(3)：50.
[42]张涛,赵宜良,徐惠绵.榄香烯联合化疗治疗胃癌晚期腹水的研究[J].中国临床实用医学,2008, 2(5)：59-60.
[43]高延,赵文硕,富琦,等.榄香烯乳联合顺铂治疗恶性胸腔积液的疗效观察[J].河北医科大学学报,2010,31(12)·1479-1481.
[44]王晋舜.腹腔内注射榄香烯乳与双通路化疗联合治疗癌性腹水临床观察[J].中国实用乡村医生杂志,2012,19(4)：51-52.
[45]MILLAR J W, HUNFER A M, HERE N W. Intraleuralim-muno-therapy with CP in recurrent malignant pleural effusions[J]. Thorax,1980,35:856.
[46]Ostrowski MJ, Dmrt MCF et al. Anassessment of the long term results of controlling the reaeeumulation of malignant effusions using intraeavity Bleomyein.Can-eer, 1986, 57:721.
[47]韩守宜,董娥,滕杰,等.榄香烯乳剂静脉滴注导致静脉炎的防治方法进展[J].中国肿痈临床,1998,25(11)：854-855.
[48]孙洁,刘峥,杨建良,等.并用硫酸镁防治榄香烯乳注射液导致静脉炎的疗效观察[J].中国肿瘤临床,1999,26(5)：1-2.
[49]刘寄萍,周小凤.63例避免榄香烯乳注射液静脉输液致静脉炎的方法研究[J].重庆医学,1999,28(5)：364-365.
[50]张洲,裴志东,王牧民,等.并用盐酸普鲁卡因及654-2对防治榄香烯乳静脉炎的效果观察[J].中国肿瘤临床,1998；25(增刊)：64.
[51]胡杰,吴慧群.解决中药榄香烯乳静脉注射引起静脉炎的新方法[J].中国肿瘤临床,1998；25(增刊)：70.
[52]王贤成,吕真.对榄香烯乳静滴致静脉炎的临床预防研究[J].中国肿瘤临床,1998；25(增刊)：157.
[53]李志杰,张媛.榄香烯联合化疗治疗肺癌合并恶性胸腔积液疗效观察[J].中国误诊学杂志,2006,6(20)：3932-3933.
[54]陶喜民,高文斌.榄香烯乳注射液的不良反应及防治[J].药物不良反应杂志,2003,(6)：390-391.
[55]高文斌,唐玉新.榄香烯乳剂的几种少见不良反应及其临床防治[J].罕少疾病杂志,2000,7(1),42.
[56]明红霞,王永杰.顺铂联合艾迪腔内注射治疗恶性胸腔积液21例分析[J].中国误诊学杂志,2007,7(3)：605.
[57]李建君,王鹏.榄香烯乳静滴致不良反应[J].药物不良反应杂志,2003,5(1)：49.
[58]郭乃武.榄香烯的抗肿瘤作用和药理学研究[J].中药学报,1994,2：35.
[59]周小娟,赵新汉,孙红,等.榄香烯治疗恶性肿瘤后并发消化道出血2例报告[J].北京中医药大学学报,1996,(4)：66.
[60]徐爱乡.静注榄香烯诱发肝癌脑出血一例[J].中国肿痈临床,1998,25(增刊.上)：142.
[61].Gordon Guyatt,Andrew D. Oxman,Elie Akl,GRADE Guidelines:1. Introduction to GRADE Evidence Profiles and Summary of Findings Tables[J].中国循证医学杂志,2011,11(4)：437-445.
[2]国家药典委员会.中华人民共和国药典(一部)[S].北京.化学工业出版社,2000：230.
[3]赵亚利,彭晓霞,王亚东,等.榄香烯注射液治疗肺癌的有效性与安全性评价[J].中国循证医学杂志,2005,5(3).
[4]李河,麦劲壮,方积乾等.Meta分析中漏斗图的绘制[J].循证医学,2007,7(2)：101-106.
[5]陈振东.恶性胸腔积液诊治中的常见问题及其进展[J].中国临床肿瘤学进展,2010：460-462.
[6]Sahn S.The pleura.Am Rev Respir Dis,1988,138:184-234.
[7]Henschke C,Davis S,Romano P,et al.The pathogensis,radiologic evaluation,and therapy of pleural effusion. Radiol Clin North Am,1989,27:1241-1255.
[8]Smith EM,Jayson GC.The current and future management of malignant ascites(J).Clin Oncol,2003, 15(2):59-72.
[9]石晶.恶性腹水西药治疗[J].中外健康文摘,2011,8(6)：236.
[10]Adam RA,Adam YG. Malignat ascites:past,present,and future(J).J Am Coll Surg,2004,198(6):999-1011.
[11]王忻妍,王雅杰.恶性腹腔积液形成机制及其诊断和治疗[J].国际肿瘤学杂志,2008,35(3)：218-220.
[12]Vaitkus PT,Herrmann HC,LeWinter MM.Treatment of malignant pericardial effusion,JAMA,1994, 272:59-64.
[13]黄小青,田华琴,梁贵文,等.内生场热化治疗老年恶性浆膜腔积液[J].CHINA MEDICAL HERALD中国医药导报,2011,8(29)：36.
[14]Psallidas I,Karabela SP,Moschos C,et al.Specific effects of bortezomib against experimental malignant pleural effusion:a preclinical study(J).Mol Cancer,2010,9:56.
[15]Antunes QNeville E,Duffy J,et al.BTS guidelines for the management of malignant pleural effusions(J).Thorax,2003,58(S20):29-38.
[16]刘介平,张国良.恶性胸腔积液[J].山西医药杂志,2001,30(1)：39-40.
[17]Smith EM,Jayson GC.The current and future management of malignant ascites(J).Clin Oncol,2003,15(2):59-72.
[18]Garrison RN, Kaelin LD, Galloway RH, et a.l Malignant ascites:clinicaland experimental observations[J]. Ann Surg,1986,203:644-651.
[19]Ayantunde AA,Parsons SL.Pattern and prognostic factors in patients with malignant ascites:a retrospective study.Ann Oncol,2007,18(5):945-949.
[20]徐光炜编译.临床肿瘤学[M].沈阳：辽宁教育出版社,1999：685-686.
[21]Laham RJ,Cohcn DJ,Kuntz RE,et al.Pericardial effusion in patients with cancer:outcome with contemporary management strategies.Heart,1996,75(1):67-71.
[22]Skhvatsabaja LV.Secondary malignant lcsions of the heart and pericardium in neoplastic disease. Oncology,1986,43(2):103-106.
[23]孙燕.内科肿瘤学[M].北京：人民卫生出版社,2001,261.
[24]章华萍,徐颖鹤,林荣海.心包引流及腔内注射化疗药物治疗伴填塞症状的恶性心包积液17例分析[J]. 临床萃,2001,(21).
[25]于立恒.恶性胸腔积液的治疗现状与进展[J].肿瘤防治研究,2007,34(12)：973-976.
[26]Rossi CR,Mocellin SL.Pharmacokinetics of intraperi-toneal cisplatin and doxorubicin[J].Surg Oncol Clin N Am,2003,12(3):781-794.
[27]严文跃,钱晓萍,刘宝瑞.恶性胸腔积液的治疗进展[J].现代肿瘤医学,2009,17(7)：1393-1396.
[28]吴艳芳,于雷,王金万.恶性心包积液的内科治疗进展[J].癌症进展,2007,5(4)：352-354.
[29]Becker QGalandi D,Blum HE.Malignant ascites:Systematic review and guideline for treatment.Eur J Cancer,2006,42(5):589-597.
[30]Anderson CB,Philpott GW,Ferguson TB.The treatment of malignant pleural effusions.Cancer,1974, 33:916-922.
[31]Goth QGatzemeir U,Haubingen K,et al.Intrapleural palliative treatment of malignant pleural effusions with mitoxantrone us placebo (pleural tube alone).Ann Oncol,1991,2:213-215.
[32]史宏彰,沙庆棠,杨妍,等.恶性心包积液心包内置管间断引流15例临床分析,1998.
[33]ZHANG TH,LI JL.Clinical application of closed derainage through central veneous catheter indwelled in thorax[J].China Journal of Modern Medicine,2002,12(5):93-94.Chinese
[34]王怀瑾,张阳,刘艳娥,等.癌性腹水超滤浓缩自体腹腔回输的临床研究[J].大连医科大学学报,1999,21(3)：183-186.
[35]孙晓敏,董卫国.恶性腹水的研究进展[J].国外医学·消化系疾病分册,2003,23(6)：375-377.
[36]Lee A,Lau TN, Yeong KY. Support Care Cancer,2000,8(3):493-499.
[37]傅乃武,金兰萍,郭永佃.榄香烯的抗肿瘤作用和药理研究[J].中药通报,1984：92：35-37.
[38]花文峰,蔡绍晖.p-榄香烯抗肿瘤作用的基础与临床研究[J].中药材第,2006,29(1)：93-95.
[39]钱振超.莪术瘤苗的主动免疫保护效应[J].药学通报,1981,12：892-894.
[40]钱振超.各种瘤苗对L615免疫预防效应的进一步实验研究[J].病理生理学报,1985,5：64-67.
[41]傅乃武,金兰萍,郭永佃.p—榄香烯的抗肿痈作用和药理研究[J].中药通报,1984,9(2)：35.
[42]钱振超,金兰萍,郭永佃.莪术瘤苗的主动免疫保护效应：莪术抗癌作用的初步探讨[J].药学学报,1981,12：892.
[43]陈剑群,吴克俭,费素娟.榄香烯乳注射液治疗中晚期消化系肿瘤前后T淋巴细胞亚群的动态观察[J].中国肿瘤临床,1996,23(4)：299-301.
[44]钟永祥.榄香烯的临床前药理研究及临床应用[J].湖南医学,1996,13(2)：119.
[45]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].1990,23(1)：75.
[46]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腹腔积液的Ⅲ期临床观察[J].中国肿瘤临床,1996；23(4)：301-304.
[47]王红梅,廖国佳,李虎城,等.榄香烯乳联合治疗恶性胸腔积液疗效观察[J].中国肿瘤临床,1998,25(增刊)：90.
[48]岳莉,薛海鸥,苏卫红,等.榄香烯乳治疗恶性胸腹水20例临床观察[J].中国肿瘤临床,1998,25(增刊)：81.
[49]董立国.榄香烯治疗消化系恶性肿瘤导致的胸腹腔积液[J].《中国癌症杂志》,2001,11(1).
[50]张蓉,洪婉君,白萍.榄香烯治疗妇科恶性胸腹腔积液[J].中国肿瘤临床,2000,27(1)：71.
[51]黄黎明,胡伯年,李忠麟.榄香烯对不同类型癌性腹水的疗效[J].湖南医学,1996,13(4)：241.
[52]王金万,张和平,孙燕.榄香烯乳治疗晚期恶性肿瘤的Ⅱ期临床试用结果[J].中国新药杂志,1995,4(2)：26.
[53]魏路清,陈萍,王建华.榄香烯乳治疗肺癌胸膜、心包转移的疗效观察[J].中国实用内科杂志,1998,18(10)：607-608.
[54]李开俊,傅鹰,查仲玲.循证医学操作流程的归纳和分析[J].药物流行病学杂志,2003,12(3)：140-141.
[1]Am J.Managenent of malignant pleural effusions[J].Respire Crit Care Med,2000,162(5):1987.
[2]Liu CD, Tilch L,KwanD,et al.Vascular endothelial growth factor is increased in ascites from metastatic Pancreatic CanCer.J Surg Res 2002; 102(1):31-4.
[3]Scott R,Donald D,Timothys L,et al.Maligant ascites of unknown origin[J]. Cancer,1989,(3):753.
[4]崔书中.恶性腹水的治疗现状与进展,第二届“CSCO南方”肿瘤生物治疗与分子靶向治疗论坛：115.
[5]廖熙检.癌胚抗原对良性恶性的心包积液鉴别的临床分析[J].广西医学,1999,3：410-412.
[6]Warren WH.Malignan cies involving the pericardium[J].Semin Thorac Cardiovasc Surg,2000,12(2):119.
[7]Brigden ML.Hematologic and oncologic emergencises.Doing the most good in the least time,Postgrad Med,2001,109:143.
[8]Shepherd FA.Malignant pericardial effusion. Curr Opin Oncol,1997,9(2):170.
[9]DeCamp MM Jr, Mentzer SJ,Swanson SJ,et al. Malignant effusive disease of the pleura and pericardium. Chest,1997,112(4):291S.
[10]宋长顺,蔡鑫,董金风.心包炎10年的病因及近期疗效分析[J].蚌埠医学院学报,1994；19(1)：44.
[11]OliverWP, RobertL. Management ofmalignant pericardial effusion and tamponade[J]. JAMA,1987, 257(8):1088-1092.
[12]孙燕.肿瘤内科学[M].北京：人民卫生出版社,2002：254.
[13]Sahn S. The pleura. Am Rev Respir Dis,1988,138:184-234.
[14]Lynch TJ.Management of malignant pleural effusions.Chest,1993,103:385-389.
[15]Runyon BA.Care of patients with ascites[J].N Engl J Med, 1994, 330(5):337.
[16]Tamsma J. The pathogenesis of ascites. Cancer Treat Res.2007,134:109-18.
[17]Becker G,Galandi D,Blum HE,et al. Malignant ascites:systematic review and guideline for treatment. Eur J Cancer.2006,42(5):589-97.
[18]Atanaekovic D,Block A,de Weerth A,et al.Characterization of effusion-infiltrating T cells:benign versus malignant effusions[J].CIin Cancer Res,2004,10(8):2600-2608.
[19]丁勇敏.白细胞介素18和γ-干扰素联合检测鉴别诊断结核性和恶性胸腔积液的价值和临床意义[D].浙江大学,硕士,2008.
[20]Macaulay VM,O'Byrne KJ,Saunders MP, et al. Phase I study of intra2 pleural batimastat (BB294),a matrix metalloproteinase inhibitor,in the treatment of malignant pleural effusions[J]. Clin Cancer Res,1999,5(3):5132520.
[21]Hurewitz AN, Zueker S, Maneuso P, et al.Human pleural effusions are rich in matrix metalloproteinases[J]. Chest,1992,102(6):1808-1814.
[22]Park KJ,Hwang SC,Sheen SS,et al.Expression of matrix metalloProteinase — 9 in Pleural effusions of tubereulosis and lung cancer[J].Respiration,2005,72(2):166-175.
[23]施劲东.基质金属蛋白酶及其组织抑制物在不同性质胸腔积液诊断和鉴别诊断中的应用[D].复旦大 学,硕士,2009.
[24]Grove CS,Lee YC.Vascular endothelial growth factor:the key mediator in pleural effusion formation[J].Curr Opin Pulm Med,2002,8(4):294-301.
[25]Senger D,Gallis J,Dvorak AM,et al.Tumor cells secrete a vascular permeability factor which promotes ascites fluid accumulation[J].Science,1983,219(4):903-909.
[26]Banerjee SK, YoungHW, Volmer JB,et al. Gene expression profiling in inflammatory airway disease associated with elevated adenosine[J].AmJPhysiol Lung Cell Mol Physiol,2002; 282(2):L169-L182.
[27]Srivastava M, Zurakowski D, Cheifetz P,et al. Elevated serum hepatocyte growth factor in children and young adults with inflammatory bowel disease[J].JPediatr GastroenterolNutr,2001; 33(5):548-553.
[28]罗淼,董德琼,杨瑜浩,等.血管内皮生长因子在恶性胸腔积液中的作用[J].国际呼吸杂志,2006,12(4)：7-9.
[29]Yano S, Shinohara H, Herbst RS, et al. Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells.Am J Pathol,2000,157(6):1893-1903.
[30]Mori A,Arii S,Furutani M, et al. Soluble Flt21 gene therapy for perito2 neal metastases using HVJ2cationic liposomes[J]. Gene Therapy,2000,7 (12):102721033.
[31]Hasumi Y,Mizukami H,Urabe M, et al. Soluble FLT21 expression sup2 presses carcinomatous ascites in nude mice bearing ovarian cancer[J].Cancer Res,2002,62(2):201922023.
[32]Van den Heuvel MM,Smit HJ,Barbierato SB,et al.Talc-induced inflammation in the pleural cavity[J].Eur Respir J,1998,12(6):1419.
[33]Nasreen N,Hartman DL,Mohammed KA,et al.Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells[J].Am J Respir Crit Care Med1998,158(3):971.
[34]Rahman NM,Davies HE,Salzberg M,et al.Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion:a phase I toxicity and dose-escalation study[J].Lancet Oncol,2008,9(10):946-952.
[35]Olivares-Torres CA,Laniado-Laborin R,Chavez-Garcia C,et al.Idopovidone pleurodesis for recurrent pleural effusions[J].Chest,2002,122(2):581.
[36]章华萍,徐颖鹤,林荣海.心包引流及腔内注射化疗药物治疗伴填塞症状的恶性心包积液17例分析[J].临床萃,2001,(21).
[37]吴一龙.肺癌多学科综合治疗的理论与实践[M].北京：人民卫生出版社,2000：277.
[38]王婷婷,刘宝瑞,钱晓萍.恶性腹腔积液的治疗进展[J].临床肿瘤学杂志,2007,12(10)：787-788.
[39]吴艳芳,于雷,王金万.恶性心包积液的内科治疗进展[J].癌症进展杂志,2007,5(4)：352-354.
[40]李磊,陈涛.恶性胸腔积液的治疗现状[J].华中医学杂志,2009,33(4)：223-225.
[41]Antony VB,Loddenkemper R,Astoul P,et al.Management of malignant pleural effusions [J]. Am J Respir Crit Care Med, 2000, 162(5):1987-2001.
[42]Musani AI.Treatment options for malignant pleural effusio[J].Curr Opin Pulm Med,2009, 15(4):380-387.
[43]戴莉莉.恶性胸腔积液的生物免疫治疗进展[J].上海医药,2011,32(2)：80-82.
[44]贾杨.细菌性生物反应调节药治疗癌性胸腹腔积液的进展[J].Herald of Medicine October,2002,21(10): 662-663.
[45]Rosenberg SA,Lotze MT,Yang JC,et al.Expeienee with the use of high dose interleukin-2 in the treatment of 652 cancer patients.Ann Surg,1989,210(4):474.
[46]曹雪涛.白细胞介索-2的基础与临床[M].北京：科学技术出版社,1997：183.
[47]罗科平，刘敬东.白介素-2治疗恶性胸腔积液36例临床观察[J].上海医药,1997,10：27-28.
[48]李佳茵,魏长春Experience for treating malignant pleural effusion with interleukin-Ⅱ in intrapleural administration, Clinical Journal of Chinese Medicine 2010,(2):64.
[49]王焕江.对清膏相对密度测定方法的改进[J].中成药,1999,21(8)：435.
[50]Watanaben,Ruffmr,Metthewsn,et al.Gytotocial radial inhibltors on cytonicity Immuno pharmocal Immunatoxical[J].1998,10:109.
[51]孙军山,刘在海,颜卉,等.TNF腔内注射治疗恶性心包积液20例疗效观察[J].齐鲁肿瘤杂志,1999,6(3)：208-209.
[52]许杰超,闫兵杰,杜海俊,等.TNF腔内注射治疗恶性胸腹水疗效分析[J].河南职工医学院学报,14(2)：152-153.
[53]工俊祥,工金铠.白介素-12、干扰素-γ在急性白血病中的意义与树突状细胞诱导特异性抗白血病免疫应答的体外研究[D].河北医科大学,博士,2004.
[54]薛红健,吴红革,李贵玲,等.γ干扰素治疗恶性胸腹腔积液的临床床观察[J].《肿瘤》2001,21(2)：122-123.
[55]刘力锋.白细胞介素-2及γ-干扰素心包腔内注射治疗恶性心包积液32例[J].中国实用医刊2009,36(18)：56-57
[56]王娟,陶贞霞,刘荣英,等.DC-CIK细胞免疫联合治疗癌性胸腔积液的实验观察[J].中国免疫学杂志,2009,25：278-280.
[57]周清华.肺癌靶向治疗的现状与进展[J].中国肺癌杂志,2003,6(6)：434-440.
[58]Swisher SG,Roth JA,Komaki R,et al.A phase II trial of adenoviral mediated p53 gene transfer in conjunction with radiation therapy in patients with localized non small cell lung cancer[J].Proc Am Soc Clin Oncol,2002,19:461-464.
[59]Brekken RA,Overhoiser JP,Stastny VA,et al.Selective inhibition of VEGF reception 2 activity by a monoclonal anti-VEGF antibody blocks tumor in mice[J].Cancer Res,2000,60(18):5117-5118.
[60]于顺江.抗VEGF肿瘤靶向治疗进展,癌症进展[J].2010,8(2)：175-177.
[61]蔡艳军.贝伐单抗联合顺铂对VEGF高表达的荷卵巢癌裸鼠腹水抑制作用的实验研究[D].第一军医大学,硕士,2004.
[62]Harada K, Supriatno, YoshidaH, et al. Vesnarinone inhibits angiogenesis and tumorigenicity of human oral squamous cell carcinoma cells by suppressing the expression of vascular endothelial growth factor and interleukin-8[J]. Int J Oncol,2005,27 (6):1489.
[63]Hajitou A, Grignet C, Devy L, et al. The antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells[J]. FASEB J,2002,16(13): 1802.
[64]Sack U, Hoffmann M, Zhao X J, et al. Vascular endothelial growth factor in pleural effusions of different origin[J]. Eur Respir J,2005,25(4):600.
[65]姜子瑜,秦叔逵.新型重组人血管内皮抑素联合榄香烯注射液治疗恶性腹水的实验研究[D].南京中医药大学,2012,博士.
[66]魏红梅,秦叔逵.新型重组人血管内皮抑制素(恩度)对小鼠腹水瘤的抑制作用及其相关机制研究[D].南京军区南京总医院博士后工作站,2010.
[67]方长清,郭晓宁,李淼,等.MMP-2、VEGF在肺腺癌细胞中的表达及其意义[J].中国组织化学与细胞化学杂志,2010,19(4)：372-376.
[68]刘敏.MMP-3和MMP-7在良恶性胸腔积液中的表达及意义[J].中国现代医生,2012,50(7)：127-128.
[69]范玉晶,韩明子.基质金属蛋白酶-2、-9在恶性腹水中的表达[J].黑龙江医学,2009,33(10)：730-732.
[70]Fang J,Shing Y,yan L, et al. Matrix metalloproteinase-2 is required for switch to the angiogenic phentype in a tumor model[J].Proc Natl Acad Sci USA,2000,97(8):3884-3889.
[71]黄丹,吴波.基质金属蛋白酶抑制剂治疗癌症的临床前景[J].国外医学药学分册,2001,28(2)：87-89.
[72]王陇德.临床技术操作规范·核医学分册[M].北京：人民军医出版社,2004：56.
[73]谭天秩.我国放射性核素治疗的现状和展望[J].中华核医学杂志,1994,14(3)：186-188.
[74]崔书中.恶性腹水的治疗现状与进展[J].第二届”CSCO一南方”肿瘤生物治疗与分子靶向治疗论坛：118.
[75]袁翎,单娟,杨建伟.32P胸腔灌注治疗恶性胸水5例的临床分析[J].中国医师杂志,2006,8(9)：1287.
[76]王凤月.榄香烯乳胸、腹腔注药治疗恶性积液疗效观察[J].中国实用区学研究杂志,2002,1(2)：121-122.
[77]刘琳,陈宝安,秦叔逵,等.三氧化二砷联合华蟾素抗裸鼠人肝癌移植瘤血管新生的作用[J].中国中西医结合杂志,2011,31(1)：67-71.
[78]李宝林,赵晓辉,王笑宇,等.三氧化二砷治疗肺癌合并胸腔积液临床疗效分析[J].中国医学工程,2011,19(5)：53-54.
[79]周琴.华蟾素注射液胸腹腔灌注治疗恶性胸腹腔积液的临床研究[D].北京中医药大学,硕士,2012.
[80]王丽茹,刘立君,张晨瑶.康莱特治疗恶性胸腔积液的临床研究[J].陕西肿瘤医学,2002,10(2)：144.
[81]李惠华,刘亮,张弛,等.康莱特治疗非小细胞肺癌恶性胸腔积液的临床观察[J].中国医药指南,2012,10(21)：438-439.
[82]张明智,张喜爱,周超锋,付晓瑞.紫杉醇腹腔内灌注联合康莱特治疗晚期肝癌腹腔积液疗效观察[J].Chinese General Practice,2011,14(8) 2800-2802.
[83]李平,胡育新,张垃.香茹多糖治疗恶性腹水的临床观察[J].中国肿瘤生物治疗杂志,2001,8(2)：145-146.
[84]李民,苏兴仁.鸦胆子油乳剂对艾氏腹水癌细胞杀伤动力学研究[J].中草药,1981,(12)：4.
[85]周洁,孟勇.鸦胆子汕乳腹腔灌注治疗恶性腹水23例临床观察[J].基层医学论坛,2004,8(8)：692-693.
[1]Sorm F,Holub M,Sykora V,et al.Terpenes XLVI Sesquiterpenic hydrocarbons from Sweet-flag oil[J].Coll Czech Commun)1953,18(3):554-560.
[2]Weinheimer AJ,Youngblood WW,Washecheck PH,et al.Chemistry of coelenterates XVIII isolation of the elasive(-)-germacrene-A from the gorgonian,Eunicea mammosa[J].Tetrahedron Letter,1970,(7):497-500.
[3]林启寿.中草药成分化学[M].北京：科学出版社,1977,584.
[4]植木宽,甲斐原守夫,坂川正之,等.Antitumor activity of plant constituents.I[J].药学杂志,1961,811(11)：1641-1644.
[5]《全国中草药汇编》编写组.全国中草药汇编.北京：人民卫生出版社,1988,685.
[6]旅大市肿瘤防治办公室.中药莪术治疗宫颈癌的初步研究,1972.7(内部资料).
[7]辽宁省肿瘤防治研究办公室.中草药—温莪术治疗恶性肿瘤的初步研究,1974.3(内部资料).
[8]郭永田.温莪术挥发油中榄香烯的分离.中药通报,1983,8(3)：31.
[9]秦叔逵,钱军,杨爱珍,等.榄香烯乳抗肺癌细胞的实验研究[J].肿痛防治研究,1996,23(4)：251-254.
[10]LI QQ,WANG GD,HUANG FR,et al.Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cells[J].J Pharm Pharmacol,2010,62(8):1018-1027.
[11]WANG G,LI X,HUANG F,et al.Antitumor effect of beta-el-emene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death[J].Cell Mol Life Sci,2005,62(7-8):881-893.
[12]LI X,WANG G,ZHAO J,et al.Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase[J].Cell Mol Life Sci,2005,62(7-8):894-904.
[13]TAO L,ZHOU L,ZHENG L,et al.Elemene displays anti-canc-er ability on laryngeal cancer cells in vitro and in vivo[J].Cancer Chemother Pharmacol,2006,58(1):24-34.
[14]WU XS,XIE T,LIN J,et al.An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomas[J].J Pharm Pharmacol,2009,61 (12):1653-1656.
[15]LI QQ,WANG G,REED E,et al.Evaluation of cisplatin in combination with beta-elemene as a regimen for prostate cancer chemotherapy[J].Basic Clin Pharmacol Toxicol,2010,107(5):868-876.
[16]ZHAO J,LI QQ,ZOU B,et al.In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinoma[J].Int J Oncol,2007,31(2):241-252.
[17]时继慧,李成章,刘德兰.中药通报,1981,36(6).
[18]肖立森,李佩兰,陆炜炎,等.MTT法检测榄香烯对人癌细胞敏感性的研究[J].中国肿瘤临床,1996,23(3)：223-4.
[19]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].1990,23(1)：75.
[20]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腹腔积液的Ⅲ期临床观察[J].中国肿痛临床,1996, 23(4)：301-304.
[21]何文,胡长路,裘慰伯.B超对肺癌急症的诊断及疗效评估[J].中华肿瘤杂志,1997,19(5)：374-376.
[22]朱先萍.第八局全国中西医结合肿瘤学术会议论文集,重庆铁路医院肿瘤科(重庆400053),2000：130.
[23]师国强.榄香烯乳胸腔内注射治疗恶性胸腔积液的疗效观察[J].实用诊断与治疗杂志,2007,21(5)：373-374.
[24]葛晓燕.榄香烯乳治疗恶性腹水53例临床疗效观察[J].交通医学,2001,15(1)：37.
[25]王培民,周力,姜琼.榄香烯乳、顺铂治疗恶性腹水疗效的对照观察[J].中国医院药学杂志,1999,19(7)：420-421.
[26]江联萍,戴月娣,陶莉.榄香烯、博莱霉素以及两药联合治疗恶性胸腔积液临床观察[J].《中国癌症杂志》2009,19(3)：218-219.
[27]车德海,于雁,张华,等.培美曲塞与卡铂静脉化疗联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤的临床观察[J].临床肿瘤学杂志,2011,16(4)：356-356.
[28]HazarikaM, White RM, Johnson JR, et a.l FDA drug approval summaries:pemetrexed (Alimta) [J].Oncologist,2004,9(5):482-488.
[29]孙江涛,冯笑山,郭琳.奥沙利铂联合榄香烯乳低张渗透压灌注治疗恶性胸水疗效观察[J].中国误诊学杂志,2007,7(7)：1468-1469.
[30]张涛,赵宜良,徐惠绵.榄香烯联合化疗治疗胃癌晚期腹水的研究[J].中国临床实学,2008,2(5)：59-60.
[31]李翠兰,王明民.卡铂与榄香烯乳联合应用治疗恶性腹水的疗效观察[J].中国中西医结合杂志,1996,16(9)：565-566.
[32]周晓园,陶凯.榄香烯联合胞必佳及利尿剂治疗Ⅳ期恶性肿痈胸腹水21例[J].中国中西医结合杂志,2001,21(10)：775-776.
[33]崔瑞刚.榄香烯联合白介素-2胸腔灌注治疗恶性胸水的临床观察[D].北京中医药大学,硕士,2011.
[34]许凤仙.榄香烯乳加高聚金葡素治疗恶性胸水疗效观察及护理[J].浙江临床医学,2003,5(12)：956-957.
[35]张金兰,孙素华,陈俊荣.高聚金葡素并用化疗治疗中晚期恶性肿瘤的临床效果[J].肿瘤防治研究,1996,23(2)：118.
[36].Hegewisch-Becker S,Gruber Y,Corovic A,et al.Whole-body hyperthermia(41.8℃)combined with bimonthly oxaliplatin,highdose leucovorin and 5-fluorouracil 48-hour continuous in fusion in pretreated metastatic colorectal cancer:a phase Ⅱ study[J].Ann Oncol,2002,9(4):1197-1204.
[37]Novak P,Moros EG,Parry JJ,et al.Experience with a small animal hyperthermia ultrasound system(SAHUS):report on 83 tumours[J].Phys Med Biol,2005,50(21):5127-5139.
[38]孙俊忠,冀绪广,臧克,等.胸腔热灌洗联合榄香烯乳治疗恶性胸腔积液疗效观察[J].中国厂矿医学,2009,22(5)：532-533.
[39]赵桂梅,许永慧,于淑红.榄香烯乳、微波透热联合应用治疗卵巢癌腹水临床观察[J].内蒙古民族大学学报(自然科学版),200217(4)：350-351.
[40]Zhon HY,Hon JS,Wang Y.Dose-and time-dependence of elemene in the induction of apoptosis in two glioma cell lines[J].Chinese,2006,284:270-271.
[41]万旭英,陈哲.榄香烯乳治疗晚期原发性肝癌腹水20例[J].安徽中层学院学报,2002,21(1)：22-23.
[42]马秀丽,魏俊青.榄香烯乳治疗肺癌所致恶性胸腔积液疗效观察[J].山西中医学报,2003,4(2)：51.
[43]潘年松,盛勇,张学愈,等.莪术抗肿瘤作用与品种和加工工艺的关系[J].中国中医药信息杂志,2006,13(8)：35·
[44]王金万,张和平,孙燕.榄香烯乳治疗恶性胸腔积液的Ⅲ期临床观察[J].中国肿瘤临床,1996,23(4)：301.
[45]尚耀华,李墨林,范治璐.p—榄香烯预防浅表性膀胱癌复发基础与临床研究进展[J].大连医科大学学报,2009,31(2)：215—218.
[46]许浪,刘丹,晏丹,等.榄香烯对肺癌细胞凋亡的影响[J].数理医药学杂志,2009,22(2)：154-155.
[47]鞠建峰,于维萍,傅春升,等.p-榄香烯的现代研究及临床应用概况[J].齐鲁药事,2008,27(9)：546-548.
[48]王秀敏,英杰,赵春杰,等.p-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4)：289-320.
[49]杨烨,工仙平,郁琳琳,等.榄香烯抗癌作用机理的研究[J].榄香烯乳注射液临床应用与基础研究论文集,1996：10-13.
[50]时继慧.温莪术挥发油的实验药理研究[J].中药通报,1981,6(6)：32-33.
[51]实用药物指南,见：榄香烯乳的药理作用及体内过程[M].人民军医出版社出版,北京,2000,第1版,264.
[52]遵义医学院肿瘤研究组病理生理小组[J].肿瘤防治研究,1974,(1)：46-48.
[53]遵义医学院肿瘤研究组病理生理小组：本期本刊.
[54]辽宁中医学院卫生防疫教研组等[J].辽宁抗癌战讯,1974(1)：67-74.
[55]肿瘤研究组病理生理小组,莪术抗癌作用原理的初步实骤研究-Ⅲ.体外杀瘤作用的进一步观察,1975：26-30.
[56]傅乃武,金兰萍,郭永,等.β-榄香烯的抗肿瘤作用和药理学研究[J].中药通报,1984,9(2)：35.
[57]杨骅,王仙平,高力,等.榄香烯诱导HL-60细胞程序死亡[J].中国肿瘤生物治疗杂志,1995,2(4)：351-352.
[58]郭建忠,张世渊,吉宏明,等.p-榄香烯诱导ECV-304细胞早期凋亡的实验研究[J].内蒙古民族大学学报,2009,15(5)：24-26.
[59]Zheng S,Yang H,zhang S,et al.Initial study on naturally occurring products from traditional Chinese herbs and vegetables for chemoprevention[J].J Cell Biochem,1997,27:106-112.
[60]龚敏,梁鑫淼,崔晓楠.榄香烯对人肝癌HepG-2细胞增殖及拓扑异构酶表达的影响[J].中国药理学通报,2011,27(60)：839-843.
[61]姚轶群,徐英辉,周洪语,等.ERK在榄香烯抑制大鼠C6胶质瘤细胞增殖中的作用[J].肿瘤,2007,27(10)：777-779.
[62]WANG G,I X.UANG F,t al. Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death[J].Cell Mol Life Sci,2005,62(7-8):881-893.
[63]LI X,WANG G,ZHAO J,et al.Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase[J].Cell Mol Life Sci,2005,62(7-8):894-904.
[64]YAO YQ,DING X,JIA YC, et al. Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation[J].Cancer Lett,2008,264(1):127-134.
[65]左云飞,张耀铮,郑军.利用流式细胞术研究榄香烯对肝癌腹水痈细胞系Hca-F25/CL-16A3的抗肿瘤作用[J].大连医科大学学报,2000,22(1)：46-49.
[66]YatwinMB,Seet.Clinical Pmsects for Iiposome[J].Medical Physics,1982,2:159.
[67]张培彤,朴炳奎.肿瘤细胞表面血小板免疫相关抗原的表达及其意义[J].中国肿瘤临床与康复,20018(5)：119-121.
[68]李道睿,祁鑫,于明薇,等.榄香烯对人肺癌细胞表面所表达与侵袭转移相关黏附蛋白的影响[J].中华中医药学刊2007,25(10)：2170-2172.
[69]Davidson B,Goldberg I,Bemer A,et al.Expression of membmne-type 1,2,and 3 matrix metaUoproteinases messenger RNA in ovarian Carcinoma cells in serous effusions.Am J Clin Patho 1,2001,115(4):517-524.
[70]李悦.B-榄香烯对血管内皮细胞增殖、凋亡、成血管能力及MMP-2、MMP-9活性的影响[D].中国医科大学,硕士,2009.
[71]刘敏.MMP-3和MMP-7在良恶性胸腔积液中的表达及意义[J].中国现代医生,2012,50(7)：127-128.
[72]姚淑娟,刘伯阳,胡芳.榄香烯对荷瘤鼠NK和I L-2活性的影响[J].药物研究,2000,9(4)：19-20.
[73]钱军.抗癌新药-榄香烯的药理及临床.中国肿瘤临床[J].1996；23(6)：453-5.
[74]张学军,杜权,丁秀萍,等.榄香烯乳对r—DNA转录活性的影响及意义[J].中国肿瘤临床,1999,26(6)：1-3.
[75]左云飞,张耀睁,魏巍,等.榄香烯对肝癌腹水痈细胞系Hca_F25/CL-16A3的抗肿瘤作用及对细胞周期的影响[J].中药药理与临床,1999,15(5)：24.
[76]周云,杜英,范魁生.榄香烯乳胸腔灌注对恶性胸水渗出液相关淋巴细胞(EAL)增殖及其LAK活性的增强作用实验研究[J].中国肿瘤临床,1997,2(9)：709-712.
[77]陈龙邦,臧静,王靖华.β-榄香烯对荷瘤小鼠免疫功能的影响[J].肿瘤防治研究,1998,25(1)：54.
[78]Ohno I.Tanno Y,Yamauchi K.Gene expression and production of tumor necrosis factor by a rat bnsophilie Leukemia cell line with IgE receptor triggering.Immunology,1990;70: 88.
[79]Gruss HJ,Brach MA,Drexler HG, et al.Expression of cytokine genes, cytokine receptor genes and transcription factors in cultured Hodkin and Reed-Sternberg cells.Cancer Res,1992;15:3353.
[80]左云飞,张耀铮,庞焕.榄香烯对肝癌腹水瘤细胞系Hca-F25/CL-16A3(?)勺抗肿瘤作用机理的实验研究V.榄香烯对小鼠血清中肿瘤坏死因子及层粘连蛋白水平的影响[J].中药药理与临床,1997；13(6)：38-39.
[81]钱振超,王大庆,金成刚,等.瘤苗特异性主动免疫治疗及其机制的实验研究[J].中国肿瘤生物治疗杂志,1995,2(2)：120-126.
[82]Cheng Yuan Baohuo,Fu Tihui,et al.Establishment and some biological characteristice of a spleen CTL cell line form cell vaccine(TCV)immunized inbred 615 mouse[J].Biotherapy,1991,5(6):1222-1227.
[83]沈洁,郭连英,施广霞,等.榄香烯复合痈苗免疫治疗对肿痈生长和脾细胞细胞毒活性的影响[J].大连 医科大学学报,2000,22(1)：4-6.
[84]赵卫红,施广霞,袁小林,等.榄香烯复合瘸苗对Hca-F肝癌小鼠的免疫治疗效应及对IL-10与IL-12分泌的影响[J].中国肿瘤生物治疗杂志,2001,8(2)：126-129.
[85]金梅,白雪,胡景慧.榄香烯复合抗肿瘤疫苗免疫的效应机制[J].中国农业科学,2004,37(9)：1379-1384.
[86]Fu NW.Bulletin of Chinese Materia Mediea,1984;9(2):35.
[87]崔秀云,李德山,B-榄香烯对RNA聚合酶活性的抑制及与DNA的结合[J].中国药理学通报,1991,7(3)：228-230.
[88]Begleiter A.Cancer Res,1983;43:481.
[89]Pastan I.et al.Multiplt-drug rtsistamce in buman cancer.NEngl J Med, 1987, 316:1388.
[90]Breuninger LM, Saptarshi P, Gaughan K,et al·Expression of multidrug resistance-associated protein in NIH/373 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution[J]·Cancer Res,1995,55:5342
[91]王宝成,郭军,狄剑时,等·榄香烯乳剂与肿瘤多药耐药的基础研究[J].中国肿瘤临床,1996,23(2)：143-146.
[92]SM IT JJ, MOL CA, VAN DEEMTER L,et al.Characterization of the promoter region of the hum an MDR3P-glycoprotein gene [J]-BiochemiBiophys Acta,1995,1261 (1):44-56-
[93]王利,魏品康,秦志丰,等.榄香烯对耐药胃癌细胞的逆转实验研究[J].成都中医药大学学报.2005,28(2)：51-53.
[1]Villar J,Carroli G,Belizan JM.Predictive ability of meta-analyses of randomized controlled trials[J].Lanced, 1995;345:772-776.
[2]Juni P,Ahman DG, EggerM·Assessing the quality of controlled clinical trials[J], BMJ,2001,323 (7303):42
[3]Higgins JPT,Green S(editors).Cochrane Handbook for System-atic Reviews of Interventions Version 5.1.0 [updated March 2011].The Cochrane Collaboration,2011.Available from www.cochrane-handbook.org.
[4]Howard Balshem, Mark Helfanda, Holger J.Schunemann, GRADE指南：Ⅲ.证据质量分级(GRADE Guidelines:3.Rating the Quality of Evidence)[J].中国循证医学杂志,2011,11(4)：451-455.
[5]Gordon H Guyatt,Andrew D Oxman,Gunn E Vist, GRADE:证据质量和推荐强度分级的共识(GRADE：an Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations), [J].中国循证医学杂志,Chin J Evid-based Med 2009,9(1):8-11
[6]GRADEpro.[Computer program].Version 3.2 for Windows.Jan Brozek,Andrew Oxman,Holger Schunemann,2008.
[7]Gordon H Guyatt,Andrew D Oxman,Gunn E Vist,et al.GRADE:an Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations[J].Chin J Evid-based Med 2009,9(1):8-11.
[8]循证医学中证据的质量分级[J].现代康复,2001,5(2)：73.
[9]李强.评价疗效结果的几个新指标[J]World Chin J Digest.2000,8(6):702-703.
[10]魏丽娟,董惠娟Meta分析中异质性的识别与处理[J].第二军医大学学报,2006,27(4)：449-450.
[11]廖海江,金水高Meta分析的应用策略与进展[J].数理医药学杂志,2003,16：541-544.
[12]李河,麦劲壮,方积乾等Meta分析中漏斗图的绘制[J].循证医学,2007,7(2)：101-106.
[13]Egger M,Smith G.Bias in location and selection of studies.BMJ,1998,316(7124):61-66.
[14]张万岭,王华庆,李丽庆.抗癌新药榄香烯乳胸腔内灌注治疗恶性胸水Ⅱ期临床小结[J].中国肿瘤临床,1996,23(1)：75.
[15]林顺通,邱庆南.榄香烯治疗晚期肺癌癌性胸水临床观察[J].福建医药杂志,1996,18(3)：90.
[16]王培民,周力,姜琼,等.榄香烯乳、顺铂治疗恶性腹水疗效的对照观察[J].中国医院药学杂志,1999(19)7：420-421.
[17]钱秀芬.胸腔注射榄香烯乳、顺铂治疗癌性胸腔积液疗效观察[J].医学文选,2000,19(1)：29-30.
[18]叶爱和,夏晓阳.榄香烯乳治疗胸腔积液的临床分析[J].河北医学,2001,7(9).
[19]王萍,王珏.榄香烯乳胸腔内灌注治疗晚期肺癌伴胸水临床观察[J].现代医药卫生,2002,18(3)：180.
[20]上凤月.榄香烯乳胸、腹腔注药治疗恶性积液疗效观察[J].中国实用区学研究杂志,2002,1(2)：121-122.
[21]古立新,范峰.榄香烯乳注射液胸腔内注射治疗恶性胸腔积液疗效观察[J].现代中西医结合杂志,2003,12(7)：708-709.
[22]白显利.腔内注射榄香烯乳及顺铂治疗恶性胸腔积液疗效观察[J].现代中西医结合杂志,2005,14(3)：321-322.
[23]师国强.榄香烯乳胸腔内注射治疗恶性胸腔积液的疗效观察[J].实用诊断与治疗杂志,2007,21(5)：373-374.
[24]孙俊忠,冀绪广,等.胸腔热灌洗联合榄香烯乳治疗恶性胸腔积液疗效观察[J].中国厂矿医学,2009,22(5)：532-533.
[25]陆建明.胸腔置管引流并注入榄香烯治疗恶性胸腔积液30例临床观察[J].浙江中医杂志,2011,46(6)：422.
[26]仲几春,张道松,朱云.榄香烯乳治疗恶性胸腔积液96例临床分析[J].齐鲁医学杂志,2011,26(6)：551.
[27]武海松,陈平.榄香烯乳胸腔内注射治疗恶性胸腔积液的临床研究[J].中国医药指南,2011,9(32)：165-166.
[28]孔一名.榄香烯乳胸腔内灌注治疗恶性胸腔积液临床分析[J].现代医药卫生,2012,28(10)：1521-1522.
[29]周聆,叶维洁,张为强.射频透热分别联合榄香烯乳与金葡素胸腔内注射治疗恶性胸腔积液[J].中国临床医学,2012,19(1)：25-26.
[30]孙岚英.榄香烯注射液联合胸腔内注射治疗肺癌并恶性胸腔积液临床观察[J].中国社区医师.医学专业,2012,10(14)：80.
[31]李翠兰,王明民.卡铂与榄香烯乳联合应用治疗恶性腹水的疗效观察[J].中国中西医结合杂志,1996,16(9)：565-566.
[32]蒋有娟,丁惠珍,刘晓丹,等.注入榄香烯和顺铂治疗癌性胸腔积液17例[J].新医学,1997,28(8)：418-419.
[33]贾正飞.榄香烯加顺铂胸腔内灌注治疗恶性胸水20例[J].CANCER RESEARCH AND CLINIC,1997, 9(3):198.
[34]欧阳学农,陈曦,曾金雄.榄香烯乳与白细胞介素—2联合应用治疗恶性胸腔积液[J].中国肿瘤临床,1997,24(4)：315-316.
[35]赵智辅,郭兴里,孙淑娟,等.胸腔闭式引流加榄香烯乳顺铂腔内注射治疗恶性胸水的疗效观察[J].黑龙江医学,1999,11(185)：30.
[36]张万海,金平.中药制剂榄香烯乳联合顺铂治疗癌性胸水疗效观察[J].中国中医药信息杂志,2000,7(9)：69.
[37]黄平.闭式引流腔内注射顺铂、榄香烯乳治疗恶性胸腔积液[J].右江民族医学院学报,2000,22(6)：899-900.
[38]叶元芬,沈依信,刘玉环.榄香烯乳治疗卵巢癌腹水86例[J].宁渡大学学报(理工版),2001,14(2).
[39]陈建清,钟小红,吴晓安,等.置管引流联合榄香烯顺铂治疗恶性胸水的疗效观察[J].中国肿瘤临床,2004,31(19)：1127-1129.
[40]李志杰,张媛.榄香烯联合化疗治疗肺癌合并恶性胸腔积液疗效观察[J].中国误诊学杂志,2006,6(20)：3932-3933.
[41]田迎棠,李明,刘伟,等.大剂量顺铂加榄香烯序贯胸腔注射治疗恶性胸水[J].中原医刊,2007,34(3)：50.
[42]张涛,赵宜良,徐惠绵.榄香烯联合化疗治疗胃癌晚期腹水的研究[J].中国临床实用医学,2008, 2(5)：59-60.
[43]高延,赵文硕,富琦,等.榄香烯乳联合顺铂治疗恶性胸腔积液的疗效观察[J].河北医科大学学报,2010,31(12)·1479-1481.
[44]王晋舜.腹腔内注射榄香烯乳与双通路化疗联合治疗癌性腹水临床观察[J].中国实用乡村医生杂志,2012,19(4)：51-52.
[45]MILLAR J W, HUNFER A M, HERE N W. Intraleuralim-muno-therapy with CP in recurrent malignant pleural effusions[J]. Thorax,1980,35:856.
[46]Ostrowski MJ, Dmrt MCF et al. Anassessment of the long term results of controlling the reaeeumulation of malignant effusions using intraeavity Bleomyein.Can-eer, 1986, 57:721.
[47]韩守宜,董娥,滕杰,等.榄香烯乳剂静脉滴注导致静脉炎的防治方法进展[J].中国肿痈临床,1998,25(11)：854-855.
[48]孙洁,刘峥,杨建良,等.并用硫酸镁防治榄香烯乳注射液导致静脉炎的疗效观察[J].中国肿瘤临床,1999,26(5)：1-2.
[49]刘寄萍,周小凤.63例避免榄香烯乳注射液静脉输液致静脉炎的方法研究[J].重庆医学,1999,28(5)：364-365.
[50]张洲,裴志东,王牧民,等.并用盐酸普鲁卡因及654-2对防治榄香烯乳静脉炎的效果观察[J].中国肿瘤临床,1998；25(增刊)：64.
[51]胡杰,吴慧群.解决中药榄香烯乳静脉注射引起静脉炎的新方法[J].中国肿瘤临床,1998；25(增刊)：70.
[52]王贤成,吕真.对榄香烯乳静滴致静脉炎的临床预防研究[J].中国肿瘤临床,1998；25(增刊)：157.
[53]李志杰,张媛.榄香烯联合化疗治疗肺癌合并恶性胸腔积液疗效观察[J].中国误诊学杂志,2006,6(20)：3932-3933.
[54]陶喜民,高文斌.榄香烯乳注射液的不良反应及防治[J].药物不良反应杂志,2003,(6)：390-391.
[55]高文斌,唐玉新.榄香烯乳剂的几种少见不良反应及其临床防治[J].罕少疾病杂志,2000,7(1),42.
[56]明红霞,王永杰.顺铂联合艾迪腔内注射治疗恶性胸腔积液21例分析[J].中国误诊学杂志,2007,7(3)：605.
[57]李建君,王鹏.榄香烯乳静滴致不良反应[J].药物不良反应杂志,2003,5(1)：49.
[58]郭乃武.榄香烯的抗肿瘤作用和药理学研究[J].中药学报,1994,2：35.
[59]周小娟,赵新汉,孙红,等.榄香烯治疗恶性肿瘤后并发消化道出血2例报告[J].北京中医药大学学报,1996,(4)：66.
[60]徐爱乡.静注榄香烯诱发肝癌脑出血一例[J].中国肿痈临床,1998,25(增刊.上)：142.
[61].Gordon Guyatt,Andrew D. Oxman,Elie Akl,GRADE Guidelines:1. Introduction to GRADE Evidence Profiles and Summary of Findings Tables[J].中国循证医学杂志,2011,11(4)：437-445.