·论著··医学循证·

胸腔化疗联合热疗治疗癌性胸腔积液有效性和安全性的Meta分析
胡月1,李征2*,曲雁3*,丁俊琴4,祖淑文5,李海滨1,杨志慧1,李燕红1,谢俊芳1
1.050051河北省石家庄市,河北医科大学第三医院西院全科医学科
2.730000甘肃省兰州市,兰州大学第一附属医院普外科
3.050051河北省石家庄市,河北医科大学第三医院科研处
4.050051河北省石家庄市,河北医科大学第三医院护理部
5.050051河北省石家庄市,河北医科大学第三医院教务处
*通信作者:李征,主治医师;E-mail:lizhenglys@126.com
曲雁,主任医师;E-mail:quyanebm@163.com

    【摘要】目的 系统评价胸腔化疗联合热疗治疗癌性胸腔积液的有效性及安全性。方法2015年8月—2016年1月,计算机检索Cochrane Library、PubMed、EMBase、Web of Science等外文数据库以及中国生物医学文献数据库、中国知网、维普网和万方数据知识服务平台等中文数据库,并辅以补充检索手段,收集比较胸腔化疗联合热疗(联合组)与单纯胸腔化疗(对照组)治疗癌性胸腔积液有效性及安全性的随机对照试验。提取纳入文献资料,包括第一作者、发表时间、样本量、年龄、卡氏评分、化疗方案及结局指标,并进行方法学质量评价。结果共纳入23篇文献,包括1 647例患者,其中联合组819例,对照组828例。5篇文献报道了随机方法,各纳入文献均未说明分配隐藏和盲法实施情况,各文献两组患者基本特征具有可比性,1篇文献有患者失访,各文献均无选择性报告结果偏倚。联合组治疗癌性胸腔积液总有效率〔OR=3.72,95%CI(2.92,4.74)〕、完全缓解率〔OR=2.24,95%CI(1.18,2.78)〕、生活质量改善率〔OR=3.66,95%CI(2.64,5.07)〕均高于对照组(P<0.05)。联合组与对照组恶心呕吐〔OR=0.80,95%CI(0.60,1.06)〕、白细胞计数下降〔OR=0.81,95%CI(0.60,1.10)〕、发热〔OR=0.98,95%CI(0.69,1.40)〕、肝脏损害〔OR=0.45,95%CI(0.11,1.81)〕、气胸〔OR=0.41,95%CI(0.06,2.91)〕、皮肤烫伤〔OR=5.33,95%CI(0.91,31.14)〕发生率比较,差异均无统计学意义(P>0.05);联合组胸痛〔OR=0.34,95%CI(0.16,0.74)〕发生率低于对照组,皮下脂肪硬结〔OR=6.27,95%CI(1.08,36.27)〕发生率高于对照组(P<0.05)。结论与单纯胸腔化疗相比,胸腔化疗联合热疗可提高癌性胸腔积液患者近期疗效,显著改善患者生活质量,并且临床安全性较好,但其长期疗效和安全性评价尚需大样本高质量的研究进一步验证。
    【关键词】胸腔积液,恶性;化学疗法,肿瘤;热疗;疗效;Meta分析
    【中图分类号】R 734.3【文献标识码】ADOI:10.3969/j.issn.1007-9572.2017.00.047
胡月,李征,曲雁,等.胸腔化疗联合热疗治疗癌性胸腔积液有效性和安全性的Meta分析[J].中国全科医学,2017,20(32):4034-4041.[www.chinagp.net]
HU Y,LI Z,QU Y,et al.Efficacy and safety of intrathoracic chemotherapy combined with thermotherapy for malignant pleural effusion:a meta-analysis[J].Chinese General Practice,2017,20(32):4034-4041.
Efficacy and Safety of Intrathoracic Chemotherapy Combined with Thermotherapy for Malignant Pleural Effusion:a Meta-analysisHU Yue1,LI Zheng2*,QU Yan3*,DING Jun-qin4,ZU Shu-wen5,LI Hai-bin1,YANG Zhi-hui1,LI Yan-hong1,XIE Jun-fang1
1.Department of General Practice,West Campus of the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China
2.Department of General Surgery,the First Affiliated Hospital of Lanzhou University,Lanzhou 730000,China
3.Department of Scientific Research,the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China
4.Department of Nursing,the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China
5.Department of Teaching,the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China
*Corresponding authors:LI Zheng,Attending physician;E-mail:lizhenglys@126.com
QU Yan,Chief physician;E-mail:quyanebm@163.com
    【Abstract】ObjectiveTo systematically review the efficacy and safety of intrathoracic chemotherapy combined with thermotherapy (ITCT) for malignant pleural effusion (MPE).MethodsFrom August 2015 to January 2016,a computer-based retrieval was performed in foreign databases such as Cochrane Library,PubMed,EMBase,Web of Science and Chinese ones such as CBM,CNKI,VIP and Wanfang,and supplementary retrieval was also performed with other sources.All relevant randomized controlled trials (RCTs) were collected to compare ITCT(ITCT group) and monotherapy of intrathoracic chemotherapy(ITC group).We extracted the relevant information from the literatures,including the first author,published time,sample size,age,Karnofsky performance status,chemotherapy regimens and outcome indicators.Then we assessed the methodologic quality of included studies.ResultsA total of 23 literatures were included,comprising 1 647 patients,including 819 in the ITCT group and 828 in the ITC group.Five studies reported random methods,yet none of the included studies mentioned the concealment of allocation and blinding.The baseline comparability of the two groups had fine balance.One study had loss of follow-up.There was no selective outcome reporting in any of the included studies.Total effective rate〔OR=3.72,95%CI(2.92,4.74)〕,complete remission rate〔OR=2.24,95%CI(1.81,2.78)〕 and improving rate of life quality〔OR=3.66,95%CI(2.64,5.07)〕 of ITCT group were superior to those of ITC group and there were all significant difference (P<0.05).There were no significant difference between the two groups on the incidence of nausea and vomiting 〔OR=0.80,95%CI(0.60,1.06)〕,leukocytopenia 〔OR=0.81,95%CI(0.60,1.10)〕,fever 〔OR=0.98,95%CI(0.69,1.40)〕,hepatic lesion 〔OR=0.45,95%CI(0.11,1.81)〕,pneumothorax 〔OR=0.41,95%CI(0.06,2.91)〕 and skin scald 〔OR=5.33,95%CI(0.91,31.14)〕.The incidence of stethalgia in ITCT group was lower than ITC group 〔OR=0.34,95%CI(0.16,0.74)〕,the incidence of subcutaneous fat scleroma in ITCT group was higher than ITC group 〔OR=6.27,95%CI(1.08,36.27)〕,and there were all significant difference (P<0.05).ConclusionCompared with ITC,ITCT can significant improve short-term curative effect and life quality of patients with MPE;additionally,it is safe and feasible.But its long-term survival rate and security still needs to be further verified by more large sample and high quality studies.
    【Key words】Pleural effusion,malignant;Chemotherapy,cancer;Thermotherapy;Effectiveness;Meta-analysis

    统计显示,2012年全球新发癌症患者约1 410万例,同时约820万例患者死于癌症[1]。鼻咽癌、肺癌及消化系肿瘤晚期患者常伴有胸腔积液,严重影响患者的生活质量和生存时间,如不及时治疗可造成患者呼吸循环功能障碍、低蛋白血症等并发症,严重者甚至危及生命。胸腔化疗是治疗恶性胸腔积液的首选,但其临床疗效有限。肿瘤热疗作为一种特色疗法,近年来发展迅速,The Lancet Onclolgy发表的一篇研究显示,热疗能有效杀伤癌细胞,并有助于增强化疗敏感性[2]。相关临床试验初步显示胸腔化疗联合热疗可有效地控制恶性胸腔积液并改善患者生活质量,但前期研究多为散在小样本试验,偏倚风险各异且统计学检验效能不足。本研究采用Meta分析方法系统评价胸腔化疗联合热疗治疗癌性胸腔积液的有效性及安全性,为临床实践决策和循证指南的制定提供依据。
1   资料与方法
1.1  文献纳入及排除标准   纳入标准:(1)确诊为伴有癌性胸腔积液的肿瘤患者,肿瘤类型不限;(2)联合组采用胸腔化疗联合热疗,对照组仅单纯采用胸腔化疗,胸腔热疗实施方式为应用体外热疗仪进行的胸腔局部热疗;(3)结局指标包括总有效率、完全缓解率、生活质量改善率及毒副作用发生率;(4)研究类型为随机对照试验,分配隐藏或盲法不作要求;(5)文献来源期刊收录在2015年SCI、PubMed、中国科学引文数据库(CSCD)、北京大学中文核心数据库、中国科技核心(CSTPCD)数据库。排除标准:会议摘要、重复发表文献及总体质量明显较差文献。
1.2  文献检索及筛选   2015年8月—2016年1月,计算机检索Cochrane Library、PubMed、EMBase、Web of Science等外文数据库以及中国生物医学文献数据库(CBM)、中国知网(CNKI)、维普网(VIP)和万方数据知识服务平台(Wanfang)等中文数据库,时间限制为建库至2016-01-06,语种不限。追溯纳入文献的参考文献以补充检索,同时应用Google Scholar、Medical Matrix等搜索引擎实施扩展检索。将数据库导出的检索结果统一导入EndNote X5文献管理软件,在对不同数据库可能重复收录的文献进行去重工作后,根据纳入、排除标准进行文献筛选,对文献题目和摘要全面审查,淘汰明显背离纳入标准的文献,对初步选定的文献全部查阅全文,进一步淘汰不合格文献,从而确定最终的纳入文献。两位研究员(胡月、曲雁)对文献检索及筛选独立操作并交叉核对,有意见分歧通过讨论深入研究并由第3位研究员(李征)裁定。
1.3  资料提取及偏倚风险评估   精读最终纳入的文献并进行资料提取,包括第一作者、发表时间、样本量、年龄、卡氏评分、化疗方案及结局指标。对文献中缺乏的重要资料尝试通过电话或邮件等方式与作者联系进行补充,对无法直接获得而仅存在于图表中的数据尝试通过AutoCAD 18.2或DraftSight 11.3软件进行提取[3-4]。参考Cochrane标准进行文献偏倚风险评估,重点评估条目如下:(1)随机分配方法,即产生随机序列所用的具体方法;(2)分配隐藏及其实施的具体方法;(3)各组基线情况可比性;(4)盲法,包括是否对结果测量者和统计分析人员施盲;(5)对失访情况的报道及结果数据的完整性;(6)是否选择性报告结果;(7)其他偏倚来源。两位研究员(胡月、丁俊琴)对资料提取及偏倚风险评估独立操作并交叉核对,有意见分歧通过讨论深入研究并由第3位研究员(李征)裁定。
1.4  统计学方法   采用Cochrane协作网提供的RevMan 5.3软件进行统计学分析。采用Q检验(P值)和I2值评价文献的异质性,如P>0.1,I2<50%表明同质性较好,以固定效应模型实施合并分析;否则,采用Meta回归分析或亚组分析,或适当选用随机效应模型;部分不宜进行Meta合并或无充分数据的指标则采用定性分析。以P<0.05为差异有统计学意义。
2   结果
2.1  文献检索及筛选结果   初筛获得文献473篇,排除重复文献124篇,阅读文题及摘要排除251篇,查阅全文后排除75篇(其中来源于日本的一项研究因采用的热疗方式及对照组的设置不符合纳入标准而排除[5]),最终纳入23篇文献[6-28],其中英文文献1篇[8]。文献筛选流程见图1。
 
2.2  纳入文献的基本特征和质量评价   23篇文献[6-28]共纳入1 647例患者,其中联合组819例,对照组828例。多数文献纳入患者卡氏评分>50分,预计生存时间超过3个月。5篇文献[9,13,18,22-23]报道了随机方法,各纳入文献均未说明分配隐藏和盲法实施情况,各文献两组患者基本特征(如性别、年龄、临床分期等)具有可比性,1篇文献[8]有患者失访,各文献均无选择性报告的偏倚。纳入文献基本特征及质量评价见表1、2。

 
2.3  Meta分析
2.3.1  有效性   23篇文献[6-28]均报道了联合组和对照组治疗癌性胸腔积液总有效率,各文献间无统计学异质性(P=0.99,I2=0),采用固定效应模型进行Meta分析。结果显示,联合组治疗癌性胸腔积液总有效率高于对照组,差异有统计学意义〔OR=3.72,95%CI(2.92,4.74),P<0.000 01,见图2〕。
 
    23篇文献[6-28]均报道了联合组和对照组治疗癌性胸腔积液完全缓解率,各文献间无统计学异质性(P=0.71,I2=0),采用固定效应模型进行Meta分析。结果显示,联合组治疗癌性胸腔积液完全缓解率高于对照组,差异有统计学意义〔OR=2.24,95%CI(1.18,2.78),P<0.000 01,见表3〕。13篇文献[6-7,10-11,13-16,19-23]报道了联合组和对照组治疗癌性胸腔积液生活质量改善率,各文献间无统计学异质性(P=0.99,I2=0),采用固定效应模型进行Meta分析。结果显示,联合组治疗癌性胸腔积液生活质量改善率高于对照组,差异有统计学意义〔OR=3.66,95%CI(2.64,5.07),P<0.000 01,见表3〕。CHEN等[8]研究观察了两组远期疗效,联合组中位生存时间为8.9个月,优于对照组中位生存时间的6.2个月。
2.3.2  安全性   Meta分析结果显示,联合组与对照组恶心呕吐、白细胞计数下降、发热、肝脏损害、气胸、皮肤烫伤发生率比较,差异均无统计学意义(P>0.05);联合组胸痛发生率低于对照组,皮下脂肪硬结发生率高于对照组,差异均有统计学意义(P<0.05,见表3)。
 
2.4  发表偏倚   对纳入文献总有效率的发表偏倚评价显示,漏斗图对称性较好,受发表偏倚影响的可能性较小(见图3)。

3   讨论
    癌性胸腔积液是晚期癌症患者常见并发症,其来源常为鼻咽癌、肺癌及消化系肿瘤等。癌细胞侵犯胸膜使其毛细血管通透性增加,侵犯淋巴系统阻塞淋巴管道,导致渗出增多而回吸收减少,从而使胸腔积液病理性聚积。癌性胸腔积液使大量的体液、清蛋白和血细胞丢失,同时大量癌性胸腔积液影响肺活动度,压迫心脏和纵隔,严重影响患者的心肺功能,导致胸闷、心悸和呼吸困难等症状,更甚者发生呼吸、循环衰竭,患者生活质量下降并严重影响预后。因此,迅速而高效地控制癌性胸腔积液是整个癌症治疗过程中的重要环节。
    单纯的胸腔穿刺抽液或胸腔闭式引流不能有效控制癌性胸腔积液的增长,且因胸腔积液大量丢失易造成低蛋白血症及电解质紊乱等症状。全身化疗控制胸腔积液的效果较差,常以局部治疗为主,胸腔化疗是治疗癌性胸腔积液最常见的方法之一[29-30],药动学优势明显,效果优于静脉化疗,且全身毒副作用较小。胸腔化疗的作用机制主要是化疗药物刺激胸膜,导致化学性胸膜炎并产生粘连从而控制积液生成;此外化疗药物渗透到肿瘤组织直接杀灭癌细胞,同时胸腔内的药物在吸收入体循环后可再次到达肿瘤组织进行杀伤。 
    热疗于1985年被美国食品药品监督管理局认证为继手术、放疗、化疗、生物治疗之后的第5大肿瘤治疗手段。热疗是运用热效应及其继发效应选择性地杀死癌细胞并抑制癌细胞转移的一种特色疗法。相关研究已经证实化疗与热疗治疗肿瘤有互补增效的作用[5,31-35]。化疗与热疗协同抗癌机制主要有:热疗能促进化疗药物攻入癌细胞;热因子使化疗药物与癌细胞DNA交联增强;热因子通过对癌细胞DNA修复及合成等的抑制能加强癌细胞对化疗药物的敏感性,从而逆转其耐药性;化疗联合热疗能促进癌细胞凋亡发生;乏氧和富氧细胞对热疗及化疗不同的敏感性决定了热化疗互补增效的抗癌作用。
    本研究系统评价结果显示,胸腔化疗联合热疗综合疗法治疗癌性胸腔积液可提高近期疗效,有效控制胸腔积液,改善患者生活质量,并且临床安全性较好。此外应特殊注意的是,热疗有利于改善患者的抗肿瘤免疫功能[36-38],热疗对抗肿瘤免疫能力的正向调节作用可能是联合疗法提高疗效的关键因素之一。
    本研究纳入文献均采用了体外热疗仪的热疗方式,虽然具体实施方案可能各有不同,但其作用本质同为热量,所以并无临床异质性。联合组胸痛发生率低于对照组,可能为热疗缓解疼痛所致,但同时联合组热疗所致脂肪硬结的发生风险增加。胸痛及脂肪硬结症状轻微,一般可自然消失或对症处理后好转,对患者生活质量影响较小。KIMURA等[5]研究设置了胸腔热灌注化疗组(A组)、单纯胸腔热灌注组(B组)及空白对照组(C组),通过B组与C组的比较发现,热疗除辅助化疗增效外,其本身也有独立的治疗效果,该研究更加确定了热疗在癌性胸腔积液治疗中的应用价值。
    伴随着循证医学的发展,肿瘤热疗被不断证实其独特的抗癌作用。然而热疗的效果受到各种临床因素的影响,其临床实施如无严格的质量保证,可能会收效甚微[39],临床实施标准有待进一步加强和改进[40]。精确靶向热疗和无创实时测温是关键突破点,为进一步提高疗效和安全性,尚需精准控制热剂量,有效降低热耐受,科学调控热化疗联合的时间顺序,熟练把握热化疗的实施方式和组配剂量。热疗技术的成熟,有待于热疗生物学和热疗工程学的不断突破。
    综上所述,相比于单纯胸腔化疗,胸腔化疗联合热疗的综合疗法治疗癌性胸腔积液能提高近期疗效,有效改善患者的生活质量,并且临床安全性较好。在临床实践中可根据患者的具体情况选择适当的热疗方案,选用合适的化疗药物配伍和剂量。同时尚需在实践中不断改进热疗的临床技术,不断提高热疗的疗效和临床安全性。为保证纳入文献的质量,本研究对纳入文献的来源期刊进行了筛选,Meta分析结果的证据级别较高,结论可靠,但仍存在一定的局限性:(1)部分文献对随机和盲法的实施不清楚;(2)远期疗效数据不足,且未见有文献报道经济学指标数据,建议后期的临床试验注意保证随访长度并积极开展经济学数据的收集分析,以实现对胸腔化疗联合热疗治疗癌性胸腔积液有效性、安全性及临床经济学的全面评价。
    作者贡献:胡月进行课题设计与实施、文献检索及筛选、资料收集整理、撰写论文并对文章负责;丁俊琴、祖淑文负责资料收集和评估;李海滨、杨志慧、李燕红、谢俊芳负责数据处理及核对;李征进行数据分析及论文修改;李征、曲雁进行质量控制及审校。
    本文无利益冲突。
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(收稿日期:2016-12-15;修回日期:2017-07-07)
(本文编辑:吴立波)