非小細胞肺癌腦轉移靶向藥物治療現狀

李博，劉黎明

(蚌埠醫學院第一附屬醫院呼吸科，安徽 蚌埠 233000)

非小細胞肺癌腦轉移靶向藥物治療現狀

李博，劉黎明

(蚌埠醫學院第一附屬醫院呼吸科，安徽 蚌埠 233000)

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

非小細胞肺癌；腦轉移；靶向治療

肺癌在惡性腫瘤中死亡率最高，占腫瘤死亡人數的13%，每年新增180萬肺癌患者[1]。其中非小細胞肺癌占80%～85%，10%～25%的患者已發生腦轉移，40%～50%患者治療中發展為腦轉移[2]。腦轉移后患者中位生存期(OS)3～6個月[3]。NSCLC腦轉移患者傳統治療手段如下：(1)手術治療：手術治療有一定局限性，主要適合全身狀態好、肺部病灶已控制、無其他器官轉移的患者[4-5]。(2)全腦放療(WBRT)：WBRT是NSCLC腦轉移的標準治療[6]，能快速緩解神經系統癥狀、提高患者生存期[7]，但生存質量無明顯改變[8]。(3)立體定向放射治療(Stereotactic radiosurgery，SRS)：具有準確定位、劑量聚集和神經并發癥狀少等特點，患者生存期、生活質量改善不顯著。(4)化療：傳統觀點認為化療藥物與大分子蛋白結合后[分子量＞400 Da(道爾頓，Dalton，Da，D)是用來衡量原子或分子質量的單位，它被定義為C12原子質量的1/12)]很難通過血腦屏障[9]，這是化療效果欠佳的根源;有學者提出另一觀點，認為肺癌腦轉移后血腦屏障有一定的破壞，同時臨床試驗證實：鉑類聯合培美曲塞等化療藥物，患者中位生存期(OS)延長3.0～6.0個月[10-12]。總之傳統治療手段一定程度上延長了生存時間，但療效有限、副反應較大。隨著分子靶向藥物在臨床中的運用，給非小細胞肺癌腦轉移患者帶來了希望，以及分子生物學、腫瘤學快速發展，大數據在醫學中的運用，越來越多的非小細胞肺癌靶點基因被發現，相關靶向藥物的問世為NSCLC腦轉移患者治療帶來了新方向，本文就分子靶向藥物治療NSCLC腦轉移治療現狀進行綜述。

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在非小細胞肺癌患者中常常高度表達，因此EGFR突變基因成為EGFR-TKI治療基因靶點，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)。近年來有大量關于EGFR-TKI對NSCLC腦轉移治療的臨床報告，發現反應率達80%，中位總生存期(Overall survival，OS)12.9～ 21.9個月，無進展生存期(Progression free survival，PFS) 6.6～11.7個月(見表1)，相比WBRT、SRS、化療，患者OS、PFS明顯增加。但Gefitinib、Erlotinb在治療NSCLC腦轉移患者方面，長期是學者爭論的焦點。實驗證實，Gefitinib腦脊液濃度能達到血液治療濃度的1.3%[19]，Erlotinb腦脊液濃度能達到血液治療濃度的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]研究發現，Afatinib透過血腦屏障率較高，對Gefitinib和Erlotinb治療后進展的NSCLC腦轉移患者是有效的；Hata等[22]臨床發現Erlotinb治療無效的NSCLC腦轉移患者，口服Afatinib(50 mg/d)2個月，發現腦部轉移病灶為PR。也許在不久的將來，更多EGFR-TKI藥物問世后，會為NSCLC腦轉移患者帶來福音。

表1 EGFR-TKIs治療NSCLC腦轉移患者的臨床試驗和研究

2 棘皮動物微管相關蛋白樣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中新發現的癌變驅動基因[23]，約3%～7%的NSCLC患者含有此癌變驅動基因，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多靶點驅動基因結合，再與位于細胞膜內側酪氨酸激酶ATP結合域相結合，達到阻斷該通路的信號傳導來實現腫瘤細胞生長抑制和凋亡[25]。目前代表藥物：克唑替尼(Crizotinib)，但學者發現Crizotinib腦脊液藥物濃度僅僅是血液濃度的0.26%[26-27]，對NSCLC腦轉移患者可能效果欠佳，但學者Nir Peled等[28]和Kinoshita等[29]報告的兩例臨床病案，口服Crizotinib后，顱內轉移病灶前者完全緩解(CR)、后者部分緩解(PR)；學者Daniel等[30]臨床單臂實驗(n=888)，發現其中首次口服Crizotinib患者，顱內病灶DCR 56%，顱內病灶未進展時間(TTP)7個月；而Crizotinib為二線治療患者，顱內病灶DCR 62%，TTP 13.2個月，差異具有統計學意義，綜上所述，Crizotinib對NSCLC腦轉移患者是有效的，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腦轉移的臨床報告仍不多見；而學者Ajimizu等[32]報告臨床個案，發現Crizotinib治療無效后，口服Alectinib 300 mg，2次/d，兩周后顱內轉移病灶完全緩解。也有學者Shirish等[33]研究發現，非小細胞肺癌腦轉移患者21人，口服Alectinib 600 mg/d，顱內病灶有效率為52%，CR 6人，PR 5人，SD 8人，更令人興奮的是在動物模型實驗中，發現Alectinib在腦組織濃度達到血液治療濃度[34]，總之ALK抑制劑對NSCLC腦轉移是有效的。

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

VEGF在惡性腫瘤血管中常常是高度表達，VEGF拮抗劑是通過與VEGF結合達到約束腫瘤新生血管生成，最終減少腫瘤細胞組織間的滲透壓，增加其他化療藥物向腫瘤組織內的滲透，提高非小細胞肺癌治療效果[35-37]，代表藥物：貝伐珠單抗(Bevacizumab)。在治療非小細胞肺癌腦轉移方面，許多學者考慮到Bevacizumab有并發腦出血風險，被排除在治療之外；近年來一個多中心、開放性、非隨機對照的大型臨床試驗[38-39]數據發現貝伐珠單抗是基本安全的、有效的，學者Kim等[40]報道的臨床個案，發現鉑類治療無效，聯合Bevacizumab后，患者顱內轉移病灶PR。學者Benjamin Besse等[41]臨床Ⅱ期實驗發現，Bevacizumab聯合Carboplatin(卡鉑)和Paclitaxel(紫杉醇)，PFS=6.7個月，OS=16.0個月(95%Cl 5.7～7.1，P＜0.05)，差異具有統計學意義，總之Bevacizumab在非小細胞肺癌腦轉移患者是安全的、有效的。

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

VEGFR-2拮抗劑是通過與VEGFR-2結合后阻斷血管生成，達到抑制腫瘤細胞快速生長和轉移的效果。代表藥物：雷莫蘆單抗(Ramucirumab)，關于Ramucirumab在非小細胞肺癌腦轉移的運用臨床報告仍不多見，但一項全球性、隨機性、雙盲的臨床Ⅲ期試驗研究[42]發現Ramucirumab在晚期非小細胞肺癌(含有腦轉移患者)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，會為非小細胞肺癌腦轉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分子)抑制劑受體相結合，解除PD-1通路介導的對免疫應答的抑制，達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，其中Nivolumab對晚期非小細胞肺癌治療在不斷增加[46-48]。一項全球性、多中心參與的隨機大型臨床實驗證明[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為非小細胞肺癌腦轉移患者治療帶來曙光。

6 展 望

靶向藥物在非小細胞肺癌腦轉移患者治療上取得一定效果，仍未完全達到人們的期望，也許在不久的將來，隨著腫瘤分子生物學的發展，最新的基因測序技術進步和大數據在醫學中的運用，更多誘發非小細胞肺癌的突變基因被發現，相關靶向藥物問世后，那時人們可以根據自身情況選擇適合的靶點藥物，對患者進行個體化治療，最終達到提高療效，使非小細胞肺癌腦轉移患者獲益。

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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。