曲妥珠单抗联合SOX化疗方案对HER-2阳性进展期胃癌有效性和安全性的系统评价和Meta分析
摘 要：目的:系统评价曲妥珠单抗(T-mab)联合替吉奥+奥沙利铂(SOX)治疗人表皮生长因子受体-2(HER-2)阳性进展期胃癌的临床有效性和安全性。方法:计算机检索PubMed、EMbase、Web of Science、The Cochrane Library、中国知网、中国生物医学文献、万方和维普数据库，搜集国内外公开发表的有关T-mab联合SOX治疗HER-2阳性进展期胃癌的研究，检索时限均从建库至2021年8月15日。由两名研究者独立筛选文献、提取资料和评价纳入研究的偏倚风险后，采用RevMan 5.4进行Meta分析。结果:共纳入8项研究，包括678例HER-2阳性进展期胃癌患者。Meta分析结果显示：与对照组相比，T-mab联合SOX组在部分缓解[RR=1.34,95%CI(1.10,1.63),P=0.003]、总有效率[RR=1.36,95%CI(1.17,1.58),P<0.000 1]和疾病控制率[RR=1.28,95%CI(1.17,1.39),P<0.000 01]方面具有显著效果。但在改善完全缓解[RR=1.43,95%CI(0.96,2.12),P=0.08]和疾病稳定[RR=1.11,95%CI(0.86,1.43),P=0.43]方面无统计学差异。试验组的恶心呕吐发生率[RR=0.76,95%CI(0.57,1.00),P=0.05]低于对照组，而两组间其余不良反应的差异均无统计学意义。结论:现有证据表明，T-mab联合SOX可提高HER-2阳性进展期胃癌患者的治疗有效率，改善患者的生活质量，并且降低部分不良反应的发生率，因此，值得在临床上推广应用。
关键词:胃癌;曲妥珠单抗;替吉奥;奥沙利铂; Meta分析;
Efficacy and safety of trastuzumab combined with SOX chemotherapy regimen for
HER-2 positive advanced gastric cancer: A systematic review and Meta-analysis
FU Liangyin
CHU Xiajing ZHANG Guangming LU Tingting WANG Yongfeng
YANG Kehu
CAI Hui
The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial
Hospital)
Evidence- Based Transformation Institute Gansu Provincial Hospital Evidence-Based
Medicine Center, School of Basic Medical Sciences,Lanzhou University Evidence Based Social
Science Research Center,School of Public Health,Lanzhou University Key Laboratory of Evidence
Based Medicine and Knowledge Translation of Gansu Province
Abstract：
Objective:To systematically evaluate the clinical efficacy and safety of trastuzumab(T-mab)combined with S-1+oxaliplatin(SOX) for human epidermal growth factor receptor-2(HER-2) positive advanced gastric cancer.Methods:We searched PubMed, Embase, Web of Science, The Cochrane Library, CNKI,CBM,WanFang Data, and VIP from inception to August 15,2021,to collect studies about T-mab combined with SOX for HER-2 positive advanced gastric cancer.Two reviewers independently screened literatures, extracted data, and assessed the risk of bias of included studies.Meta-analysis was performed using RevMan 5.4 software.Results:Eight studies involving 678 HER-2 positive advanced gastric cancer patients were included.Meta-analysis showed that the T-mab combined with SOX group(the trial group) was superior to the control group in partial remission(RR=1.34,95%CI 1.10,1.63,P=0.003),overall response rate(RR=1.36,95%CI 1.17 to 1.58,P<0.000 1) and disease control rate(RR=1.28,95%CI 1.17 to 1.39,P<0.000 01),while there were no statistical significances in complete remission(RR=1.43,95%CI 0.96 to 2.12,P=0.08) and stable disease(RR=1.11,95%CI 0.86 to 1.43,P=0.43).Compared with the control group, the incidence of nausea and vomiting(RR=0.76,95%CI 0.57 to 1. 00,P = 0. 05) was lower in the trial group. However,other adverse reactions showed no significant differences between intervention and control groups. Conclusion: Trastuzumab combined with SOX in the treatment of HER-2 positive advanced gastric cancer could significantly improve the overall survival rate and patients' quality of life and decrease the incidence of some adverse reactions. Therefore,it is worthy of application in clinical practice.
Keyword：
gastric cancer; trastuzumab; S-1; oxaliplatin; Meta-analysis;
胃癌是全球第五大常见恶性肿瘤，严重危害着人类的健康，据统计，每年约有超过100万的新发病例[1]。同时，由于胃癌早期症状不明显，大多数患者被确诊时已处于晚期，错过手术治疗的最佳时期，因此其死亡率较高[2]。对于晚期胃癌患者，化疗是主要治疗手段，在提高患者无病生存率及总体生存率方面均发挥了巨大的作用[3]。人表皮生长因子受体2(HER-2)是胃癌发生的关键驱动因素[4],相关研究表明[5],在局部晚期、复发或转移的胃癌与胃食管交界处腺癌中，有22.1%的患者HER-2基因在肿瘤中呈特异性过表达。HER-2过表达或扩增已被证实为胃癌的一个潜在预后因素，并被认为 是一个有效的治疗靶点[6,7,8]。曲妥珠单抗 (T-mab)是一种靶向治疗药物，具有抑制HER-2基因表达，抑制肿瘤生长和转移的作用[9]。因此对于HER-2阳性胃癌患者，T-mab联合化疗成为了标准治疗[10]。替吉奥+奥沙利铂(SOX)联合治疗是近年来较为常用的胃癌化疗方案，具有良好的耐受性，已被广泛应用于临床晚期胃癌[11,12]。对于T-mab联合化疗，具体的化疗方法并未形成统一意见。因此本研究系统评价T-mab联合SOX治疗HER-2阳性进展期胃癌的安全性和有效性，以期为临床合理用药提供参考。
1 资料与方法
1.1 纳入与排除标准
1.1.1 研究类型
随机对照试验(randomized controlled trial, RCT)或队列研究。
1.1.2 研究对象
①年龄≥18岁，无种族和性别限制。②进展期胃癌患者。③经免疫组化和(或)荧光原位杂交技术检测确诊HER-2阳性。
1.1.3 干预措施
试验组采用T-mab联合SOX治疗，对照组采用SOX、T-mab联合伊立替康+奥沙利铂(IP)或卡培他滨+奥沙利铂(XELOX)治疗。
1.1.4 结局指标
完全缓解(complete remission, CR)、部分缓解(partial remission, PR)、疾病稳定(stable disease, SD)、总有效率(overall response rate, ORR)、疾病控制率(disease control rate, DCR)及恶心呕吐、骨髓抑制等相关不良反应。
1.1.5 排除标准
①重复研究；②无主要结局指标；③会议摘要。
1.2 文献检索策略
计算机检索PubMed、EMbase、Web of Science、The Cochrane Library、CNKI、CBM、WanFang Data和VIP数据库，搜集国内外公开发表的有关T-mab联合SOX治疗HER-2阳性进展期胃癌的研究，检索时限均从建库至2021年8月15日。采用主题词和自由词相结合的方式进行检索。英文检索词包括：gastric cancer、stomach cancer、stomach neoplasm、trastuzumab、S-1、oxaliplatin; 中文检索词包括：胃癌、胃瘤、胃肿瘤、曲妥珠单抗、替吉奥、奥沙利铂。
1.3 文献筛选及资料提取
由2位评价员独立筛选文献、提取资料并交叉核对，如遇分歧，则咨询第三方协助判断，缺乏的资料尽量与作者联系予以补充。文献筛选时首先阅读文题和摘要，在排除明显不相关的文献后，进一步阅读全文，以确定最终是否纳入。资料提取内容主要包括：①第一作者；②发表年份；③干预和对照措施；④样本量及男女人数；⑤年龄；⑥体力状况评分；⑦肿瘤分期；⑧偏倚风险评价的关键要素；⑨所关注的结局指标。
1.4 纳入研究的偏倚风险评价
RCT研究由2名研究者按照Cochrane手册5.1.0推荐的RCT偏倚风险评估工具进行偏移风险评价，队列研究采用NOS质量评价表进行评价。
1.5 统计学分析
采用RevMan 5.4软件进行Meta分析。连续性变量采用加权均数差(WMD)作为效应指标，如果连续性变量的数据之间的单位不一致，则采用标准化均数差(SMD)作为效应指标。二分类数据采用相对危险度(RR)作为效应指标。各个效应指标都计算其95%可信区间(95%CI)以及P值。采用χ2检验分析各研究结果间是否存在的异质性，并结合I2定量判断异质性的大小。若各研究间无统计学异质性，则采用固定效应模型进行Meta分析；若各研究间存在统计学异质性，则进一步分析异质性来源，在排除明显临床异质性的影响后，采用随机效应模型进行Meta分析。
2 结果
2.1 文献检索结果
初检出相关文献859篇，经逐层筛选后，最终纳入8项研究[13,14,15,16,17,18,19,20],共678例患者。文献筛选流程及 结果见图1。
2.2 纳入研究的基本特征与偏倚风险评价结果
纳入研究的基本特征和队列研究的质量评价见表1,RCT研究的偏倚风险评价结果见表2。
2.3 Meta分析结果
2.3.1 完全缓解
共8篇研究[13,14,15,16,17,18,19,20]报告了完全缓解情况，固定效应模型Meta分析结果显示T-mab+SOX组与对照组间差异无统计学意义[RR=1.43,95%CI(0.96,2.12),P=0.08] (图2)。
2.3.2 部分缓解
共8篇研究[13,14,15,16,17,18,19,20]报告了部分缓解情况，固定效应模型Meta分析结果显示T-mab+SOX组与对照组间差异有统计学意义[RR=1.34,95%CI(1.10,1.63),P=0.003],亚组分析结果显示，与T-mab+SOX组相比，SOX组[RR=1.79,95%CI(1.23,2.59),P=0.002]差异有 统计学意义，T-mab+IP组[RR=1.18, 95%CI(0.93,1.50),P=0.17]和T-mab+XELOX组[RR=1.26,95%CI(0.57,2.82),P=0.57]差异无统计学意义(图3)。
2.3.3 疾病稳定
共8篇研究[13,14,15,16,17,18,19,20]报告了疾病稳定情况，固定效应模型Meta分析结果显示，SOX联合T-mab组与对照组间差异无统计学意义[RR=1.11,95%CI(0.86,1.43),P=0.43](图4)。
2.3.4 总有效率
共8篇研究[13,14,15,16,17,18,19,20]报告了总有效率，固定效应模型Meta分析结果显示T-mab+SOX组与对照组间差异有统计学意义[RR=1.36, 95%CI(1.17,1.58),P<0.000 1],亚组分析结果显示， 与T-mab+SOX组相比，SOX组[RR=1.94,95%CI(1.38,2.71),P= 0.000 1]和T-mab+IP组[RR=1.21,95%CI(1.02,1.43),P=0.03]差异均有统计学意义，T-mab+XELOX组[RR=1.24,95%CI(0.60,2.56),P=0.55]差异无统计学意义(图5)。
2.3.5 疾病控制率
共8篇研究[13,14,15,16,17,18,19,20]报告了疾病控制率，固定效应模型Meta分析结果显示T-mab+SOX组与对照组间差异有统计学意义[RR=1.28,95%CI(1.17,1.39),P<0.000 01],亚组分析结果显示，与T-mab+SOX相比，SOX组[RR=1.61,95%CI(1.32,1.97),P<0.000 01] 与T-mab+IP组[RR=1.19,95%CI(1.08,1.32),P=0.000 5]差异均有统计学意义，T-mab+XELOX组[RR=0.98,95%CI(0.76,1.28),P=0.89]差异无统计学意义(图6)。
2.3.5 疾病控制率
共8篇研究[13,14,15,16,17,18,19,20]报告了疾病控制率，固定效应模型Meta分析结果显示T-mab+SOX组与对照组间差异有统计学意义[RR=1.28,95%CI(1.17,1.39),P<0.000 01],亚组分析结果显示，与T-mab+SOX相比，SOX组[RR=1.61,95%CI(1.32,1.97),P<0.000 01] 与T-mab+IP组[RR=1.19,95%CI(1.08,1.32),P=0.000 5]差异均有统计学意义，T-mab+XELOX组[RR=0.98,95%CI(0.76,1.28),P=0.89]差异无统计学意义(图6)。
3 讨论
本系统评价和Meta分析结果显示，T-mab联合SOX治疗可显著提高HER-2阳性进展期胃癌患者的部分缓解率、总有效率和疾病控制率，但对于完全缓解和疾病稳定的效果不显著。亚组分析结果显示：与T-mab+IP和T-mab+XELOX相比较，T-mab+SOX在部分缓解和总有效率方面效果并不显著。此外，在安全性方面，T-mab联合SOX方案会显著减少患者的恶心呕吐发生率。
胃癌是最常见的癌症类型之一，它也是癌症相关死亡最常见的原因之一[21],对人类的生命安全造成很大的威胁。对于HER-2阳性胃癌患者，本研究结果表明，T-mab+SOX相比于单用SOX或T-mab+IP可显著改善总生存率。而亚组分析结果显示，与T-mab+XELOX相比，T-mab+SOX没有很好的效果，有临床研究发现[20],这两组方案疗效相当，但SOX联合T-mab的不良反应发生率较少、安全性更好，值得临床推广，因其纳入的样本量以及这方面的文献均较少，还需进一步临床研究。对于晚期、不能手术切除或复发的胃癌或胃食管交界处癌(晚期胃癌),多项治疗指南推荐氟尿嘧啶类(替吉奥、卡培他滨等)和铂类(奥沙利铂、顺铂等)联合化疗作为一线治疗，包括联合曲妥珠单抗治疗HER-2阳性肿瘤[22,23,24,25,26]。有研究显示，部分胃癌患者的HER-2表达阳性，曲妥珠单抗可以选择性结合HER-2的细胞外结构域，其抗肿瘤作用尚不完全清楚，但可能的机制包括抑制PI3K/AKT和哺乳动物雷帕霉素靶点(mTOR),诱导细胞凋亡[27,28,29,30]。SOX化疗方案对晚期胃癌的总有效率和疾病治愈率分别可达59%和84%[31,32],是晚期胃癌的常用化疗方案。因此，虽然曲妥珠单抗联合化疗对HER-2阳性胃癌有很好的效果，但具体的化疗方案仍没有确定，所以探寻新的化疗方案联合曲妥珠单抗对提高患者的治疗有效率以及疾病控制至关重要。为此，本文搜集了常用化疗方案曲妥珠单抗联合SOX对HER-2阳性胃癌患者效果的文献来探寻新的治疗方案。
随着系统评价和Meta分析在医学领域的逐步推广[33],其理念、思想和方法逐步渗透到其他各个研究领域，并且被越来越多地加以应用[34,35]。本文严格按照Cochrane协作网的方法和要求所撰写，但仍存在一定的局限性：①各个研究在药物选择、剂量、频次、疗程及胃癌分期等方面不统一，可能对评价结果产生影响；②由于纳入文献均为中文文献且样本量小，故要想获得确凿的证据尚需要扩大样本；③缺少长期疗效指标。
综上所述，与对照组相比，T-mab联合SOX化疗方案对HER-2阳性进展期胃癌患者的有效性和疾病控制疗效较好，明显改善患者的预后，并且可降低部分不良反应发生率，值得在临床上推广应用。受研究数量和质量的限制，本研究仍需开展更多高质量研究予以验证。
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