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张蓉, 陈薇雅, 甘洁民, 赵虎, 顾兆祥. EGFR抑制剂治疗EGFR突变型晚期非小细胞肺癌的Meta分析. 检验医学, 2013, 28(6): 506-511
ZHANG Rong, CHEN Weiya, GAN Jiemin, ZHAO Hu, GU Zhaoxiang. Meta analysis on advanced NSCLC with EGFR mutations treated randomly by EGFR inhibitors. Labratory Medicine, 2013, 28(6): 506-511  
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EGFR抑制剂治疗EGFR突变型晚期非小细胞肺癌的Meta分析
张蓉, 陈薇雅, 甘洁民, 赵虎, 顾兆祥
复旦大学附属华东医院,上海 200040
通讯作者:顾兆祥,联系电话:021-62483180-20251。

作者简介:张蓉,女,1970年生,学士,副主任医师,主要从事免疫学和分子生物学研究。

摘要
目的 利用Meta分析评估表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKIs)一线治疗晚期EGFR突变型非小细胞肺癌(NSCLC)的疗效。方法 在PubMed和Embase文献数据库中检索2004年1月至2012年4月发表的相关文献。制定纳入标准对文献进行筛选以保证纳入研究的同质性。由2名评价者独立评价所纳入研究的质量,提取资料并交叉核对。符合标准的研究采用RevMan5.1软件进行Meta分析。对总有效率(ORR)选择相对危险度(RR)作为效应尺度指标,对无进展生存时间(PFS)和总生存时间(OS)计算风险比(HR),同时计算95%可信区间(CI)。结果 6个Ⅲ期随机对照试验符合全部纳入标准,含1 030例NSCLC患者。Meta分析显示,接受EGFR-TKIs治疗患者与接受化疗的患者相比具有较高的ORR (RR=2.19, 95%CI=1.68~2.15,P<0.000 01)和较长的PFS(HR= 0.43, 95%CI=0.35~0.52,P<0.000 01);而OS差异无统计学意义(HR= 0.98, 95%CI=0.81~1.18,P=0.80)。结论 EGFR-TKIs一线治疗晚期NSCLC是有效的。为预测一线使用EGFR-TKIs的疗效,应对晚期NSCLC患者进行EGFR基因突变检测。
关键词: 表皮生长因子受体; 突变; 非小细胞肺癌; 酪氨酸激酶抑制剂; Meta分析
中图分类号:R446.61 文献标志码:A 文章编号:1673-8640(2013)06-0506-06
Meta analysis on advanced NSCLC with EGFR mutations treated randomly by EGFR inhibitors
ZHANG Rong, CHEN Weiya, GAN Jiemin, ZHAO Hu, GU Zhaoxiang
Huadong Hospital, Fudan University, Shanghai 200040, China
Abstract
Objective To use Meta analysis to evaluate the efficacy of epidermal growth factor receptor(EGFR)- tyrosine kinase inhibitors (TKIs) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Methods Relevant literatures were searched through PubMed and Embase databases from January 2004 to April 2012. The implement standards for literature-selection were used to ensure the homogeneity of research. Two reviewers evaluated independently the quality of the included studies and extracted the data. Meta analysis was performed by RevMan 5.1 software. Risk ratio (RR) as efficacy index was chosen by overall response rate (ORR), and hazard ratios (HR) were calculated by progression-free survival (PFS) and overall survival (OS) times. The 95% confidence interval(CI) was calculated simultaneously. Results Six phase Ⅲrandomly controlled trials were included for a total of 1 030 patients with NSCLS. This Meta analysis showed a statistical significance in ORR (RR= 2.19, 95%CI= 1.68-2.15,P< 0.000 01)and PFS (HR = 0.43, 95%CI = 0.35-0.52,P< 0.000 01) for patients who received EGFR-TKIs compared with patients who received chemotherapy. No statistical significance was observed in OS (HR = 0.98, 95%CI = 0.81-1.18, P = 0.80). Conclusions EGFR-TKIs are effective as first-line treatment for advanced NSCLC. The EGFR mutation testing should be made for advanced NSCLC patients to predict efficacy to first-line therapy with EGFR-TKIs.
Keyword: Epidermal growth factor receptor; Mutation; Non-small cell lung cancer; Tyrosine kinase inhibitor; Meta analysis
引言

表皮生长因子受体(epidermal growth factor receptor, EGFR)属于酪氨酸激酶受体,其介导的信号转导途径调节细胞的生长、增殖和分化。在癌变的细胞株中发现EGFR 酪氨酸激酶区常发生各种突变,这些突变和酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)的疗效密切相关。2004 年Paez 等[ 1]和Lynch等[ 2] 首先报道了TKIs对EGFR发生激活突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者具有明显的疗效,且女性、非吸烟者、腺癌患者、亚洲人更容易发生EGFR激活突变。近年来,以吉非替尼(gefitinib)和厄罗替尼(erlotinib)为代表的EGFR-TKIs已成为晚期NSCLC靶向治疗的热点。2011年 “中国肺癌高峰共识会”的与会专家一致认为,具有EGFR突变的NSCLC在生物学行为、治疗策略、临床预后等方面完全有别于没有EGFR突变的肺癌,应将其从目前的肺癌分类中独立出来而成为“EGFR 突变型肺癌”[ 3]。本研究通过对Ⅲ期临床随机对照试验的更新资料进行Meta分析,评估EGFR-TKIs或标准化疗药物一线治疗EGFR突变型晚期NSCLC的功效。

材料和方法
一、 检索文献和提取资料

在PubMed和Embase数据库中查找相关英文文献。检索式为:(lung cancer OR NSCLC) AND (epidermal growth factor receptor OR EGFR) AND (mutation*) AND (tyrosine kinase inhibitor OR TKI)。由2位研究者(有执业资质的副主任和主任医师)分别阅读和筛选检索得到的所有摘要,达成一致后获取相关摘要的全文,并进一步浏览各相关文献和综述的参考文献及引文目录,以寻找其他相关文献。另外,还检索了重大肿瘤学术会议论文集和学位论文等。为尽量保持纳入文献的同质性,制定文献的纳入标准为:(1) 2004年1月至2012年3月发表的英文文献;(2)研究对象为以前未化疗的NSCLC患者,EGFR突变阳性(主要为外显子19的缺失突变或外显子21上的L858R替代突变);(3) 干预组以吉非替尼或厄罗替尼为一线治疗药物;(4) 对照组一线常规化疗;(5) 文中提供了中位无进展生存时间(progression-free survival,PFS)和/或总生存期(overall survival,OS) 数据; (6) 随机对照的Ⅲ期临床试验;(7) 当2个或多个研究涉及重复研究对象时,取最新发表的数据;(8)各研究中病例组和对照组的基因型分布进行Hardy-weinberg遗传平衡检验符合Hardy-weinberg平衡。

二、 统计学方法

采用Cochrane协作网提供的RevMan 5.1统计软件。对总有效率(overall response rate,ORR)计数资料选择相对危险度( risk ratio,RR)作为效应尺度指标,所有时间到事件数据(PFS、OS)用方差倒数和随机效应模型合并和计算风险比(hazard ratio,HR),同时计算95%可信区间(confidence interval, CI)。使用方差倒数法需要有每项研究的效应估计值和标准误,如未能从试验报告中直接获得此数据,参照Tierney等的方法计算[ 4]。RR>1 表示试验组的效应量大于对照组,而HR < 1 反映试验组的效应大于对照组。数据间异质性通过 Q检验和 I2评估 ,当 Q检验 P<0.1 且 I2>50%时认为研究间存在异质性。试验药物( 吉非替尼和厄罗替尼)效应之间行亚组分析。假设检验采用 χ2检验, P<0.05表示差异有统计学意义。绘制漏斗图和计算失效安全系数(fail-safe number, Nfs)以评价是否存在偏倚。

结果
一、

纳入文献中符合标准的文献7篇[ 5, 6, 7, 8, 9, 10, 11],共6项研究,1 030例研究对象。 表1列出所有纳入文献的一般资料。另外11篇Ⅲ期临床试验文献被排除的原因包括:(1) 试验组TKIs为2线治疗[ 12, 13, 14, 15](4篇)或为TKIs联合化疗[ 16, 17, 18, 19](4篇);(2) 对照组使用安慰剂而非标准化疗[ 20, 21, 22] (3篇)。

表1 EGFR-TKIs与化疗一线治疗EGFR突变型晚期NSCLC的一般资料[ 5, 6, 7, 8, 9, 10, 11]
二、 EGFR突变

从6项研究中提取有效数据,EGFR突变者为1 030例,其中42例未报告突变类型。988例中,外显子19缺失突变者占54.8%,外显子21 L858R点突变者占42.8%,其他突变者占2.4%。

三、ORR(6项试验共975例, WJTOG3405研究[ 8]中为117例)

EGFR-TKIs 组ORR为71.1% (354/498),明显高于化疗组33.5% (160/477),差异有统计学意义 (RR =2.19,95% CI = 1.68~2.15, P<0.000 01);吉非替尼与厄罗替尼亚组比较差异无统计学意义( χ2 = 1.77, P= 0.18),见 图1。

图1 EGFR-TKIs一线治疗NSCLC ORR的Meta分析

四、PFS(6项试验共1 030例)

EGFR-TKIs组的中位PFS为8.4~13.1个月,化疗组为4.6 ~ 6.7个月。2组比较,EGFR-TKIs组PFS长于化疗组,差异有统计学意义(HR=0.43,95% CI=0.35~0.52, P< 0.000 01)。根据不同的TKIs(吉非替尼或厄罗替尼)分别与相应化疗组进行亚组分析,吉非替尼或厄罗替尼亚组PFS均长于化疗组,差异有统计学意义(HR=0.43,95% CI=0.32~0.58; P<0.000 01 和 HR=0.43,95% CI=0.33~0.55; P<0.000 01)。而吉非替尼与厄罗替尼间比较差异无统计学意义( χ2 = 0.00, P=0.97),见 图2。

图2 EGFR-TKIs一线治疗NSCLC PFS的Meta分析

五、 OS(5项试验共876例)

EGFR-TKIs组的OS中位数范围为19.3~30.9个月,化疗组为19.5~30.5个月。2组OS差异无统计学意义(HR = 0.98,95% CI=0.81~1.18, P=0.80),见 图3。

图3 EGFR-TKIs一线治疗NSCLC OS的Meta分析

六、偏倚评估

1.发表偏倚 发表偏倚漏斗图见 图4。图大致呈倒漏斗形,左右基本对称,提示无发表偏倚或发表偏倚较小。

图4 Meta分析漏斗图

2.Nfs评估 根据麦劲壮等[ 23]计量资料Nfs的估计方法,当 P=0 .05或 P=0.01时,Nfs可用如下公式进行估计:Nfs0.05=(∑ Z/1.64)2-k;Nfs0.01=(∑ Z/2.33)2-k,其中k为纳入研究(文献)的个数, Z为各独立研究的 z值;通过统计学软件SAS 8.0计算得Nfs0.05=109,Nfs0.01=51,Nfs比较大,说明发表性偏倚的影响程度小,提示结论被推翻的可能性较小。

讨论

通过对1 030例EGFR突变的晚期NSCLC患者一线EGFR-TKIs或铂类为基础的双重化疗资料Meta分析,得出如下结论:首先,接受EGFR-TKIs治疗的患者ORR明显高于接受化疗者;其次,EGFR-TKIs治疗与化疗相比明显改善PFS;第三,2组相比OS差异无统计学意义。OS的结果可能被一些情况混淆,如较高比例患者接受了不同类型后续治疗,尤其是药物的交叉治疗。另外,与化疗相比,接受TKIs一线治疗的患者有较好的与健康相关的生活质量和较低的毒性反应[ 24]。

EGFR是目前国内、外研究者公认的一项肿瘤靶向治疗分子。目前靶向EGFR的药物主要有2类:一类是作用于EGFR胞外区的单克隆抗体,这类抗体能与EGFR胞外配体结合部位结合,阻断EGFR与其配体的结合,从而阻断下游信号转导途径;另一类是作用于胞内酪氨酸激酶活性区域的TKIs,如吉非替尼和厄罗替尼。TKIs主要为小分子喹啉类化合物,能够与细胞内酪氨酸激酶结构域上三磷酸腺苷位点竞争性结合,可逆性、选择性地抑制EGFR相关的酪氨酸激酶活性及细胞内磷酸化过程,进而抑制EGFR下游的信号转导,从而阻断EGFR诱导的体外肿瘤细胞的生长,加速细胞凋亡、拮抗血管生成、抑制肿瘤转移、阻断肿瘤生长[ 25]。Paez 等[ 1]和Lynch等[ 2]率先报道了肺癌细胞中EGFR 酪氨酸激酶活化致编码区基因突变是靶向药物治疗奏效的一个必要的前提条件。NSCLC 中,EGFR 突变可发生在外显子18~21区,常见为外显子19的缺失突变或外显子21上的L858R替代突变。IPASS[ 6]、WJTOG3405[ 8]和NEJ002[ 9]3个吉非替尼一线治疗晚期NSCLC的研究结果显示,外显子19缺失和21外显子L858R突变亚组间比较PFS差异无统计学意义。

基于Ⅲ期随机对照试验的结果,国外建议考虑使用EGFR-TKIs一线治疗(以前没有接受化疗或EGFR-TKIs治疗)的NSCLC患者应该进行EGFR突变检测,以确定是否一线使用EGFR-TKIs治疗或化疗[ 26]。国内推荐对EGFR突变型晚期NSCLC 一线使用EGFR-TKIs,直至疾病进展或毒性不能耐受;对于EGFR 突变状态未知的患者,不推荐一线使用EGFR-TKIs[ 3]。

The authors have declared that no competing interests exist.

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