胸腔镜肺叶切除术中肺动、静...疗效与安全性影响的系统评价_白向豆.pdf

肿瘤防治研究2023年第50卷第1期 Cancer Res Prev Treat,2023,Vol.50,No.169doi:10.3971/j.issn.1000-8578.2023.22.0593胸腔镜肺叶切除术中肺动、静脉切断顺序对非小细胞肺癌患者手术疗效与安全性 影响的系统评价白向豆1，洪子强1，崔百强1，杨宁1，贺晓阳1，金大成2，苟云久1,2Effect of Sequence of Pulmonary Artery and Vein Transection in Thoracoscopic Lobectomy on Efficacy and Safety of Patients with Non-small Cell Lung Cancer:A Systematic EvaluationBAI Xiangdou1,HONG Ziqiang1,CUI Baiqiang1,YANG Ning1,HE Xiaoyang1,JIN Dacheng2,GOU Yunjiu1,21.The First Clinical Medical College of Gansu University of Chinese Medicine,Lanzhou 730000,China;2.Department of Thoracic Surgery,Gansu Provincial Hospital,Lanzhou 730000,ChinaCorresponding Author:GOU Yunjiu,E-mail:Abstract:Objective To systematically evaluate the effect of sequence of pulmonary artery and vein transection in thoracoscopic lobectomy on the efficacy and safety of patients with non-small cell lung cancer.Methods PubMed,EMbase,Web of Science,The Cochrane Library,CNKI,Wanfang,VIP and CBM databases were searched for the researches on The post-operative efficacy of pulmonary arteriovenous and pulmonary vein resection sequence in thoracoscopic lobectomy for non-small cell lung cancer.The retrieval time is from the database construction to May 2022.Meta-analysis was performed using RevMan 5.4 software.Results Eight articles were included,including 3 randomized controlled studies and 5 cohort studies,with a total of 1810 patients.Meta-analysis results showed that:The operative time(MD=13.34,95%CI(7.36,19.32),P0.0001)and intraoperative blood loss(MD=45.29,95%CI(40.24,50.35),P0.0001)in the group with priority pulmonary vein resection were significantly higher than those in the group with priority pulmonary vein resection.The difference was statistically significant.However,the benefits of OS(HR=1.34,95%CI(1.12,1.60),P=0.001)and DFS(HR=1.44,95%CI(1.18,1.76),P=0.0003)in the group of priority pulmonary vein transection were significantly better than those in the group of priority pulmonary artery transection,with statistically significant differences.Conclusion Priority pulmonary vein transection during thoracoscopic lobectomy effectively improved patients OS and DFS,resulting in higher survival benefit for patients with non-small cell lung cancer,but intraoperative bleeding and operation time are more than those with priority pulmonary artery transection.Key words:Non-small cell lung cancer;Lobectomy;Pulmonary artery;Pulmonary vein;Detachment sequence;Comparison of curative effects;Systematic reviewFunding:Gansu Provincial Peoples Hospital National scientific research project training program general project(No.19SYPYB-28);Gansu Province Health Industry Research Plan Project(No.GSWSKY2017-56);Gansu Provincial Science and Technology Planning Project(No.20JR10RA388)Competing interests:The authors declare that they have no competing interests.摘 要：目的 系统评价胸腔镜下肺叶切除术中肺动、静脉切断顺序对非小细胞肺癌患者手术的疗收稿日期：2022-05-31；修回日期：2022-08-29基金项目：甘肃省人民医院国家级科研项目培育计划一般项目（19SYPYB-28）；甘肃省卫生行业科研计划项目（GSWSKY2017-56）；甘肃省科技计划项目（20JR10RA388）作者单位：1.730000 兰州，甘肃中医药大学第一临床医学院；2.730000 兰州，甘肃省人民医院胸外一科通信作者：苟云久（1974-），男，博士，主任医师，主要从事胸部肿瘤的微创手术治疗，E-mail:作者简介：白向豆（1996-），男，硕士在读，主要从事胸部肿瘤的治疗临床研究效与安全性。方法 检索PubMed、EMbase、Web of Science、The Cochrane Library、中国知网、万方、维普和CBM数据库，搜索关于胸腔镜下肺叶切除术中肺动、静脉切断顺序对非小细胞肺癌手术后疗效的研究，检索时限均为建库至2022年5月。采用RevMan 5.4软件进行Meta分析。结果 最终纳入8篇文献，其中包括3篇随机对照研究、5篇队列研究，总共包含1 810例患者。肿瘤防治研究2023年第50卷第1期 Cancer Res Prev Treat,2023,Vol.50,No.170Meta分析结果显示：术中优先离断肺静脉组在手术时间（MD=13.34,95%CI（7.36,19.32）,P0.0001）、术中出血量（MD=45.29,95%CI（40.24,50.35）,P50%）时，采用随机效应模型；否则采用固定效应模型。敏感度分析检验结果的稳定性，根据漏斗图来判断发表偏倚。2 结果2.1 纳入研究及其基本特征最终纳入8篇文献，其中包括3篇随机对照研究（RCT）、5篇队列研究，总共包含1 810例病例，纳入研究的基本信息及队列研究质量评价见表1，肿瘤防治研究2023年第50卷第1期 Cancer Res Prev Treat,2023,Vol.50,No.171RCT研究质量评价见表2，文献筛查流程，见图1。2.2 Meta分析结果Meta分析结果显示，术中优先离断肺静脉组在手术时间（MD=13.34,95%CI（7.36,19.32），P0.0001）、术中出血量（MD=45.29,95%CI（40.24,50.35）,P0.0001）方面均显著高于优先离断肺动脉组，差异均具有统计学意义。但是优先离断肺静脉组患者的OS（HR=1.34,95%CI（1.12,1.60）,P=0.001）和DFS（HR=1.44,95%CI（1.18,1.76）,P=0.0003）均显著优于肺动脉组，差异均有统计学意义，见表3、图23。2.3 敏感度分析对各指标进行分析时，将纳入的各个研究在RevMan软件中逐一剔除后再进行合并分析，发现结果变化不明显，说明纳入研究的文章异质性较低，研究结论可靠。2.4 发表偏倚我们以OS获益分析为例绘制了漏斗图，发现各项研究均匀分布在漏斗图的两侧，并且没有一项研究分布在漏斗图外面，说明本研究的发表偏倚较小，见图4。3 讨论肺叶切除术作为A期非小细胞肺癌的经典外科手术已在临床实践中使用了数十年21。相比于传统开胸手术，胸腔镜手术以其创伤小、出血少、术后恢复快等优点已被广泛应用于临床22-23。受限于有限的操作空间，胸腔镜下肺叶切除术中每一个手术动作都力求简洁有效，随着NSCLC患者的增加，为改善患者预后，降低手术表1 纳入文献一般资料Table 1 General information of the included literatureStudyYearNationVein groupArtery groupStudy typeNOS scoreTimeHe HH122019China 33 27 Cohort study82012-2013Kozak A132013Poland170215RCT-1999-2003Li FW142015China174 93Cohort study82006-2013Sumitomo R152018Japan104 83Cohort study72007-2013Wei SY182019China210210RCT-2016-2018Jiang GC192014China152 76Cohort study72006-2012Jiao M162019China 89 84Cohort study82016-2018Bai HP202016China 45 45RCT-2012-2015RCT:randomized controlled trial.表2 RCT研究质量评价表Table 2 RCT study quality evaluation tableStudyRandom sequence generationAllocation concealmentBlinding of participants and personnelBlinding of outcome assessmentIncomplete outcome dataSelective reportingOther biasKozak A13Low riskLow riskUnclearLow riskLow riskLow riskUnclearWei SY18Low risk Unclear Unclear UnclearLow riskLow riskUnclearBai HP20Low riskLow riskUnclearLow riskLow riskLow riskUnclear图1 文献筛选流程图Figure 1 Flow diagram of literature search and selection表3 胸腔镜下肺叶切除术中不同肺动、静脉离断顺序对非小细胞肺癌患者术后疗效的Meta分析结果Table 3 Results of Meta-analysis about the effect of sequence of the pulmonary artery and vein transection in thoracoscopic lobectomy on efficacy of patients with NSCLCIndicatorsStudyPulmonary veins/pulmonary arteriesHeterogeneity testModelResults of Meta-analysisI2/%PMD(95%CI)POperation time514-16,19-20564/381190.29Fixation 7.36,19.320.0001Bleeding514-16,19-20564/38190 0.001Random40.24,50.350.0001肿瘤防治研究2023年第50卷第1期 Cancer Res Prev Treat,2023,Vol.50,No.172难度，标准化手术程序的制定已成为热门研究课题24。尤其以肺叶切除术中肺动、静脉不同的离断顺序对患者术后疗效的争论，至今仍未有较高质量的临床证据予以定论。目前，较多的研究25-27显示，术中优先结扎肺动脉可显著减少术中出血，有效减少术区渗血，在术区视野暴露等方面有其无法替代的优势。正因为此种优势，大多数临床医生在术中会优先选择离断肺动脉，从而降低手术难度，同时减少出血也有利于患者术后恢复。但是近年来，部分研究28-29提示，在术后对患者血清癌胚抗原的检测中发现，术中优先离断肺动脉的患者术后血清癌胚抗原的含量显著升高，同时外周肿瘤细胞的检出率也大幅升高。部分学者30认为术中首先结扎肺静脉或许可有效阻止肿瘤细胞经肺静脉外溢，从而使患者获得更高的生存获益。本Meta分析结果显示，术中优先离断肺静脉组的术中出血量显著高于肺动脉组，同时肺静脉组的手术时间也长于肺动脉组。这与白和平20等的结论一致。笔者认为造成这种差异的原因主要是由于早期阻断肺动脉血供，减少血液向残肺中积聚，显著降低了术中出血量，可以有效阻止术区渗血，从而可以提供一个较为清晰的手术视野，加快了手术进程。同时由于较早的结扎离断了图2 胸腔镜下肺叶切除术中肺动、静离断顺序对非小细胞肺癌患者OS的影响Meta分析结果Figure 2 Meta-analysis of effect of the sequence of pulmonary artery and vein transection in thoracoscopic lobectomy on OS of patients with NSCLC图3 胸腔镜下肺叶切除术中肺动、静离断顺序对非小细胞肺癌患者DFS的影响Meta分析结果Figure 3 Meta-analysis of effect of the sequence of pulmonary artery and vein transection in thoracoscopic lobectomy on DFS of patients with NSCLC图4 优先离断肺动脉和优先离断肺静脉组在OS获益分析中对比的漏斗图Figure 4 Funnel plot of comparison between the priority pulmonary vein and artery transection groups in OS benefit analysis肿瘤防治研究2023年第50卷第1期 Cancer Res Prev Treat,2023,Vol.50,No.173肺静脉，引起残肺内淤血，导致残肺体积增大，残肺质地变硬，难以压缩牵拉。在胸腔镜下有限的操作空间内，后续对处理支气管、肺动脉时的视野暴露极为不便，而且由于肺动脉的解剖游离本身难度较大，这更加增大了手术难度，进而延长了手术时间。同时反复牵拉也会再次增加术中出血的风险。但是焦敏16等却认为二者在术中出血量及手术时间中的对比没有显著差异，笔者反复阅读纳入的研究后认为，造成这种差异的原因主要是由于未将肿瘤位置及大小纳入亚组分析，由于各肺叶切除手术难度不同，可能会对手术时间的分析带来偏倚。本研究发现，相比于肺动脉组，优先离断肺静脉组患者的OS、DFS更高。这与Wei等18的研究结论一致，孔祥楠30等学者在其研究中也指出，术中优先结扎肺静脉患者术后外周血肿瘤相关指标较动脉组显著降低。同时部分研究31认为，肺静脉作为肿瘤细胞脱落外溢转移的流出道，应该优先结扎处理。笔者认为，术中切割、挤压、牵拉、灼烧等操作带瘤组织时，可能会导致肿瘤细胞脱落进入血液循环并导致转移。而胸腔镜下肺叶切除术中需要反复抓握和操作带瘤肺叶，如果可以优先结扎肺静脉，使其静脉流出道阻塞，则可以有效阻止肿瘤细胞从肺癌组织中脱落后外溢，从而降低远处转移的风险，以此来使患者获得更高的OS与DFS。本研究的局限性包括：（1）纳入Meta分析的研究较少，且纳入研究的患者总数较少，可能会降低本研究结果的可信度；（2）仅纳入3篇RCT研究，同时纳入的中文研究较多，文献质量较低，对最终的结果或许会有所影响；（3）部分研究分组人数不均，甚至相差较大，对纳入该组的分析结果或许有所影响；（4）由于纳入的部分研究对TNM分期描述模糊，笔者无法得知所纳入的患者术前是否有淋巴结转移，无法进行亚组分析。因此对于患者预后指标的分析或许存在偏倚；（5）由于纳入研究中未严格规定患者术后是否进行了化疗、靶向治疗、免疫治疗及其剂量，故而对其生存数据的分析可能会带来偏倚；（6）由于涉及生存数据的提取，对于已经明确给出两组患者HR及其95%置信区间的文献，笔者所计算的Log HR及SE误差较小，但对于仅绘制了生存曲线的文献，笔者使用Engauge Digitizer 11.1软件和Tierney计算表格计算其HR时，所得结果或许误差较大，或许对OS、DFS的分析有所影响。因此对于这两组血管离断顺序的有效性及安全性，仍需要更多高质量的RCT研究来得出更加精确的结果以便对临床应用进行指导。综上所述，本研究结果表明，胸腔镜下肺叶切除术中优先离断肺静脉可以有效提高患者的OS与DFS，虽然术中出血风险升高，但可使非小细胞肺癌患者获得更高的生存获益，在临床工作中值得推荐。由于纳入研究较少，对于远期疗效仍需要更多大规模、多中心的临床试验及长期随访来证实，从而更精确的指导临床应用。参考文献：1 Manerikar A,Querrey M,Cerier E,et al.Comparative Effectiveness of Surgical Approaches for Lung CancerJ.J Surg Res,2021,263:274-284.2 Kim HK.Video-Assisted Thoracic Surgery LobectomyJ.J Chest Surg,2021,54(4):239-245.3 Jiang Y,Su Z,Liang H,et al.Video-assisted thoracoscopy for lung cancer:who is the future of thoracic surgery?J.J Thorac Dis,2020,12(8):4427-4433.4 Ujiie H,Gregor A,Yasufuku K.Minimally invasive surgical approaches for lung cancerJ.Expert Rev Respir Med,2019,13(6):571-578.5 Katopodis P,Anikin V,Kishore U,et al.Circulating tumour cells and circulating cell-free DNA in patients with lung cancer:a comparison between thoracotomy and video-assisted thoracoscopic surgeryJ.BMJ Open Respir Res,2021,8(1):e000917.6 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