非小細(xì)胞肺癌腦轉(zhuǎn)移靶向藥物治療現(xiàn)狀

李博，劉黎明

(蚌埠醫(yī)學(xué)院第一附屬醫(yī)院呼吸科，安徽 蚌埠 233000)

非小細(xì)胞肺癌腦轉(zhuǎn)移靶向藥物治療現(xiàn)狀

李博，劉黎明

(蚌埠醫(yī)學(xué)院第一附屬醫(yī)院呼吸科，安徽 蚌埠 233000)

非小細(xì)胞肺癌腦轉(zhuǎn)移發(fā)生率高，是肺癌致死率高的原因之一。目前分子靶向治療被認(rèn)為是非小細(xì)胞肺癌腦轉(zhuǎn)移治療的重要手段，被認(rèn)為是全腦放療、立體定向放療和化療之后肺癌腦轉(zhuǎn)移新的治療手段。近年來隨著腫瘤學(xué)的發(fā)展，分子靶向治療在非小細(xì)胞肺癌腦轉(zhuǎn)移治療方面是越來越重要。本文主要針對非小細(xì)胞肺癌腦轉(zhuǎn)移靶向治療現(xiàn)狀進(jìn)行述評。

非小細(xì)胞肺癌；腦轉(zhuǎn)移；靶向治療

肺癌在惡性腫瘤中死亡率最高，占腫瘤死亡人數(shù)的13%，每年新增180萬肺癌患者[1]。其中非小細(xì)胞肺癌占80%～85%，10%～25%的患者已發(fā)生腦轉(zhuǎn)移，40%～50%患者治療中發(fā)展為腦轉(zhuǎn)移[2]。腦轉(zhuǎn)移后患者中位生存期(OS)3～6個(gè)月[3]。NSCLC腦轉(zhuǎn)移患者傳統(tǒng)治療手段如下：(1)手術(shù)治療：手術(shù)治療有一定局限性，主要適合全身狀態(tài)好、肺部病灶已控制、無其他器官轉(zhuǎn)移的患者[4-5]。(2)全腦放療(WBRT)：WBRT是NSCLC腦轉(zhuǎn)移的標(biāo)準(zhǔn)治療[6]，能快速緩解神經(jīng)系統(tǒng)癥狀、提高患者生存期[7]，但生存質(zhì)量無明顯改變[8]。(3)立體定向放射治療(Stereotactic radiosurgery，SRS)：具有準(zhǔn)確定位、劑量聚集和神經(jīng)并發(fā)癥狀少等特點(diǎn)，患者生存期、生活質(zhì)量改善不顯著。(4)化療：傳統(tǒng)觀點(diǎn)認(rèn)為化療藥物與大分子蛋白結(jié)合后[分子量＞400 Da(道爾頓，Dalton，Da，D)是用來衡量原子或分子質(zhì)量的單位，它被定義為C12原子質(zhì)量的1/12)]很難通過血腦屏障[9]，這是化療效果欠佳的根源;有學(xué)者提出另一觀點(diǎn)，認(rèn)為肺癌腦轉(zhuǎn)移后血腦屏障有一定的破壞，同時(shí)臨床試驗(yàn)證實(shí)：鉑類聯(lián)合培美曲塞等化療藥物，患者中位生存期(OS)延長3.0～6.0個(gè)月[10-12]?？傊畟鹘y(tǒng)治療手段一定程度上延長了生存時(shí)間，但療效有限、副反應(yīng)較大。隨著分子靶向藥物在臨床中的運(yùn)用，給非小細(xì)胞肺癌腦轉(zhuǎn)移患者帶來了希望，以及分子生物學(xué)、腫瘤學(xué)快速發(fā)展，大數(shù)據(jù)在醫(yī)學(xué)中的運(yùn)用，越來越多的非小細(xì)胞肺癌靶點(diǎn)基因被發(fā)現(xiàn)，相關(guān)靶向藥物的問世為NSCLC腦轉(zhuǎn)移患者治療帶來了新方向，本文就分子靶向藥物治療NSCLC腦轉(zhuǎn)移治療現(xiàn)狀進(jìn)行綜述。

1 表皮生長因子受體酪氨酸激酶抑(Epidermal growth factor receptor tyrosine kinase inhibitor，EGFR-TKI)

EGFR是一種跨膜受體，研究表明，EGFR在非小細(xì)胞肺癌患者中常常高度表達(dá)，因此EGFR突變基因成為EGFR-TKI治療基因靶點(diǎn)，目前EGFR-TKI已廣泛用于NSCLC患者的治療，其中亞洲、不吸煙、女性患者已取得良好效果[13]，代表藥物：吉非替尼(Gefitinib)、厄洛替尼(Erlotinb)。近年來有大量關(guān)于EGFR-TKI對NSCLC腦轉(zhuǎn)移治療的臨床報(bào)告，發(fā)現(xiàn)反應(yīng)率達(dá)80%，中位總生存期(Overall survival，OS)12.9～ 21.9個(gè)月，無進(jìn)展生存期(Progression free survival，PFS) 6.6～11.7個(gè)月(見表1)，相比WBRT、SRS、化療，患者OS、PFS明顯增加。但Gefitinib、Erlotinb在治療NSCLC腦轉(zhuǎn)移患者方面，長期是學(xué)者爭論的焦點(diǎn)。實(shí)驗(yàn)證實(shí)，Gefitinib腦脊液濃度能達(dá)到血液治療濃度的1.3%[19]，Erlotinb腦脊液濃度能達(dá)到血液治療濃度的2.77%[20]，可能Erlotinb對患者獲益更大，總體上Gefitinib、Erlotinb透過血腦屏障仍較低，隨著二代EGFR-TKI藥物Afatinib的問世，Hoffknecht等[21]研究發(fā)現(xiàn)，Afatinib透過血腦屏障率較高，對Gefitinib和Erlotinb治療后進(jìn)展的NSCLC腦轉(zhuǎn)移患者是有效的；Hata等[22]臨床發(fā)現(xiàn)Erlotinb治療無效的NSCLC腦轉(zhuǎn)移患者，口服Afatinib(50 mg/d)2個(gè)月，發(fā)現(xiàn)腦部轉(zhuǎn)移病灶為PR。也許在不久的將來，更多EGFR-TKI藥物問世后，會(huì)為NSCLC腦轉(zhuǎn)移患者帶來福音。

表1 EGFR-TKIs治療NSCLC腦轉(zhuǎn)移患者的臨床試驗(yàn)和研究

2 棘皮動(dòng)物微管相關(guān)蛋白樣4間變性淋巴瘤激酶融合基因(Echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase inhibitor，EML4-ALK)抑制劑

ML4-ALK是NSCLC中新發(fā)現(xiàn)的癌變驅(qū)動(dòng)基因[23]，約3%～7%的NSCLC患者含有此癌變驅(qū)動(dòng)基因，不與EGFR、K-ras、HER2及BRAF突變基因共存[24]。ALK抑制劑主要是通過與ALK、c-Met、ROS-1多靶點(diǎn)驅(qū)動(dòng)基因結(jié)合，再與位于細(xì)胞膜內(nèi)側(cè)酪氨酸激酶ATP結(jié)合域相結(jié)合，達(dá)到阻斷該通路的信號(hào)傳導(dǎo)來實(shí)現(xiàn)腫瘤細(xì)胞生長抑制和凋亡[25]。目前代表藥物：克唑替尼(Crizotinib)，但學(xué)者發(fā)現(xiàn)Crizotinib腦脊液藥物濃度僅僅是血液濃度的0.26%[26-27]，對NSCLC腦轉(zhuǎn)移患者可能效果欠佳，但學(xué)者Nir Peled等[28]和Kinoshita等[29]報(bào)告的兩例臨床病案，口服Crizotinib后，顱內(nèi)轉(zhuǎn)移病灶前者完全緩解(CR)、后者部分緩解(PR)；學(xué)者Daniel等[30]臨床單臂實(shí)驗(yàn)(n=888)，發(fā)現(xiàn)其中首次口服Crizotinib患者，顱內(nèi)病灶DCR 56%，顱內(nèi)病灶未進(jìn)展時(shí)間(TTP)7個(gè)月；而Crizotinib為二線治療患者，顱內(nèi)病灶DCR 62%，TTP 13.2個(gè)月，差異具有統(tǒng)計(jì)學(xué)意義，綜上所述，Crizotinib對NSCLC腦轉(zhuǎn)移患者是有效的，但克唑替尼的耐藥性和ALK野生型患者治療無效等問題也成為治療的瓶頸。第二代ALK抑制劑藥物：Ceritinib和Alectinib，不僅克服Crizotinib耐藥問題而且分子量偏小[31]，但Ceritinib在NSCLC腦轉(zhuǎn)移的臨床報(bào)告仍不多見；而學(xué)者Ajimizu等[32]報(bào)告臨床個(gè)案，發(fā)現(xiàn)Crizotinib治療無效后，口服Alectinib 300 mg，2次/d，兩周后顱內(nèi)轉(zhuǎn)移病灶完全緩解。也有學(xué)者Shirish等[33]研究發(fā)現(xiàn)，非小細(xì)胞肺癌腦轉(zhuǎn)移患者21人，口服Alectinib 600 mg/d，顱內(nèi)病灶有效率為52%，CR 6人，PR 5人，SD 8人，更令人興奮的是在動(dòng)物模型實(shí)驗(yàn)中，發(fā)現(xiàn)Alectinib在腦組織濃度達(dá)到血液治療濃度[34]，總之ALK抑制劑對NSCLC腦轉(zhuǎn)移是有效的。

3 血管內(nèi)皮生長因子(Vascular endothelial growth foctor，VEGF)拮抗劑

VEGF在惡性腫瘤血管中常常是高度表達(dá)，VEGF拮抗劑是通過與VEGF結(jié)合達(dá)到約束腫瘤新生血管生成，最終減少腫瘤細(xì)胞組織間的滲透壓，增加其他化療藥物向腫瘤組織內(nèi)的滲透，提高非小細(xì)胞肺癌治療效果[35-37]，代表藥物：貝伐珠單抗(Bevacizumab)。在治療非小細(xì)胞肺癌腦轉(zhuǎn)移方面，許多學(xué)者考慮到Bevacizumab有并發(fā)腦出血風(fēng)險(xiǎn)，被排除在治療之外；近年來一個(gè)多中心、開放性、非隨機(jī)對照的大型臨床試驗(yàn)[38-39]數(shù)據(jù)發(fā)現(xiàn)貝伐珠單抗是基本安全的、有效的，學(xué)者Kim等[40]報(bào)道的臨床個(gè)案，發(fā)現(xiàn)鉑類治療無效，聯(lián)合Bevacizumab后，患者顱內(nèi)轉(zhuǎn)移病灶PR。學(xué)者Benjamin Besse等[41]臨床Ⅱ期實(shí)驗(yàn)發(fā)現(xiàn)，Bevacizumab聯(lián)合Carboplatin(卡鉑)和Paclitaxel(紫杉醇)，PFS=6.7個(gè)月，OS=16.0個(gè)月(95%Cl 5.7～7.1，P＜0.05)，差異具有統(tǒng)計(jì)學(xué)意義，總之Bevacizumab在非小細(xì)胞肺癌腦轉(zhuǎn)移患者是安全的、有效的。

4 血管內(nèi)皮生長因子受體2(Vascular endothelial growth factor receptor-2 VEGFR-2)拮抗劑

VEGFR-2拮抗劑是通過與VEGFR-2結(jié)合后阻斷血管生成，達(dá)到抑制腫瘤細(xì)胞快速生長和轉(zhuǎn)移的效果。代表藥物：雷莫蘆單抗(Ramucirumab)，關(guān)于Ramucirumab在非小細(xì)胞肺癌腦轉(zhuǎn)移的運(yùn)用臨床報(bào)告仍不多見，但一項(xiàng)全球性、隨機(jī)性、雙盲的臨床Ⅲ期試驗(yàn)研究[42]發(fā)現(xiàn)Ramucirumab在晚期非小細(xì)胞肺癌(含有腦轉(zhuǎn)移患者)治療上能延長患者PFS、OS，也許在不久的將來，更多VEGFR-2拮抗劑的問世，會(huì)為非小細(xì)胞肺癌腦轉(zhuǎn)移患者治療帶來希望。

5 靶向免疫治療

免疫靶向治療是通過與一種PD-1(抑制抗腫瘤免疫原性的免疫檢測點(diǎn)分子)抑制劑受體相結(jié)合，解除PD-1通路介導(dǎo)的對免疫應(yīng)答的抑制，達(dá)到抗腫瘤作用的治療方法[43-45]，已成為腫瘤治療的研究熱點(diǎn)，其中Nivolumab對晚期非小細(xì)胞肺癌治療在不斷增加[46-48]。一項(xiàng)全球性、多中心參與的隨機(jī)大型臨床實(shí)驗(yàn)證明[49-50]，Nivolumab能延長PFS、OS，也許在不久的將來，更多免疫靶向藥物的問世會(huì)為非小細(xì)胞肺癌腦轉(zhuǎn)移患者治療帶來曙光。

6 展 望

靶向藥物在非小細(xì)胞肺癌腦轉(zhuǎn)移患者治療上取得一定效果，仍未完全達(dá)到人們的期望，也許在不久的將來，隨著腫瘤分子生物學(xué)的發(fā)展，最新的基因測序技術(shù)進(jìn)步和大數(shù)據(jù)在醫(yī)學(xué)中的運(yùn)用，更多誘發(fā)非小細(xì)胞肺癌的突變基因被發(fā)現(xiàn)，相關(guān)靶向藥物問世后，那時(shí)人們可以根據(jù)自身情況選擇適合的靶點(diǎn)藥物，對患者進(jìn)行個(gè)體化治療，最終達(dá)到提高療效，使非小細(xì)胞肺癌腦轉(zhuǎn)移患者獲益。

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Current situation of targeted therapy of brain metastases from non-small-cell lung cancer.

LI Bo,LIU Li-ming. Department of Respiratory Medicine,the First Affiliated Hospital of Bengbu Medical College,Bengbu 233000,Anhui,CHINA

Brain metastases,with high incidence,are the main cause of high mortality in non-small cell lung cancer(NSCLC).Targeted therapy has become an important treatment for brain metastases from NSCLC after whole-brain radiation therapy,stereotactic radiosurgery and chemotherapy.In recent years,with the development of oncology,targeted therapy is becoming more and more important.This review mainly summarizes the current situation of targeted therapy in the treatment of brain metastases from NSCLC.

Non-small cell lung cancer(NSCLC);Brain metastases;Targeted therapy

R734.2

A

1003—6350（2016）09—1477—04

10.3969/j.issn.1003-6350.2016.09.035

2015-07-22)

劉黎明。E-mail：bbmcllm@126.com。