非小细胞肺癌脑转移靶向药物治疗现状

李博，刘黎明

(蚌埠医学院第一附属医院呼吸科，安徽 蚌埠 233000)

非小细胞肺癌脑转移靶向药物治疗现状

李博，刘黎明

(蚌埠医学院第一附属医院呼吸科，安徽 蚌埠 233000)

非小细胞肺癌脑转移发生率高，是肺癌致死率高的原因之一。目前分子靶向治疗被认为是非小细胞肺癌脑转移治疗的重要手段，被认为是全脑放疗、立体定向放疗和化疗之后肺癌脑转移新的治疗手段。近年来随着肿瘤学的发展，分子靶向治疗在非小细胞肺癌脑转移治疗方面是越来越重要。本文主要针对非小细胞肺癌脑转移靶向治疗现状进行述评。

非小细胞肺癌；脑转移；靶向治疗

肺癌在恶性肿瘤中死亡率最高，占肿瘤死亡人数的13%，每年新增180万肺癌患者[1]。其中非小细胞肺癌占80%～85%，10%～25%的患者已发生脑转移，40%～50%患者治疗中发展为脑转移[2]。脑转移后患者中位生存期(OS)3～6个月[3]。NSCLC脑转移患者传统治疗手段如下：(1)手术治疗：手术治疗有一定局限性，主要适合全身状态好、肺部病灶已控制、无其他器官转移的患者[4-5]。(2)全脑放疗(WBRT)：WBRT是NSCLC脑转移的标准治疗[6]，能快速缓解神经系统症状、提高患者生存期[7]，但生存质量无明显改变[8]。(3)立体定向放射治疗(Stereotactic radiosurgery，SRS)：具有准确定位、剂量聚集和神经并发症状少等特点，患者生存期、生活质量改善不显著。(4)化疗：传统观点认为化疗药物与大分子蛋白结合后[分子量＞400 Da(道尔顿，Dalton，Da，D)是用来衡量原子或分子质量的单位，它被定义为C12原子质量的1/12)]很难通过血脑屏障[9]，这是化疗效果欠佳的根源;有学者提出另一观点，认为肺癌脑转移后血脑屏障有一定的破坏，同时临床试验证实：铂类联合培美曲塞等化疗药物，患者中位生存期(OS)延长3.0～6.0个月[10-12]。总之传统治疗手段一定程度上延长了生存时间，但疗效有限、副反应较大。随着分子靶向药物在临床中的运用，给非小细胞肺癌脑转移患者带来了希望，以及分子生物学、肿瘤学快速发展，大数据在医学中的运用，越来越多的非小细胞肺癌靶点基因被发现，相关靶向药物的问世为NSCLC脑转移患者治疗带来了新方向，本文就分子靶向药物治疗NSCLC脑转移治疗现状进行综述。

1 表皮生长因子受体酪氨酸激酶抑(Epidermal growth factor receptor tyrosine kinase inhibitor，EGFR-TKI)

EGFR是一种跨膜受体，研究表明，EGFR在非小细胞肺癌患者中常常高度表达，因此EGFR突变基因成为EGFR-TKI治疗基因靶点，目前EGFR-TKI已广泛用于NSCLC患者的治疗，其中亚洲、不吸烟、女性患者已取得良好效果[13]，代表药物：吉非替尼(Gefitinib)、厄洛替尼(Erlotinb)。近年来有大量关于EGFR-TKI对NSCLC脑转移治疗的临床报告，发现反应率达80%，中位总生存期(Overall survival，OS)12.9～ 21.9个月，无进展生存期(Progression free survival，PFS) 6.6～11.7个月(见表1)，相比WBRT、SRS、化疗，患者OS、PFS明显增加。但Gefitinib、Erlotinb在治疗NSCLC脑转移患者方面，长期是学者争论的焦点。实验证实，Gefitinib脑脊液浓度能达到血液治疗浓度的1.3%[19]，Erlotinb脑脊液浓度能达到血液治疗浓度的2.77%[20]，可能Erlotinb对患者获益更大，总体上Gefitinib、Erlotinb透过血脑屏障仍较低，随着二代EGFR-TKI药物Afatinib的问世，Hoffknecht等[21]研究发现，Afatinib透过血脑屏障率较高，对Gefitinib和Erlotinb治疗后进展的NSCLC脑转移患者是有效的；Hata等[22]临床发现Erlotinb治疗无效的NSCLC脑转移患者，口服Afatinib(50 mg/d)2个月，发现脑部转移病灶为PR。也许在不久的将来，更多EGFR-TKI药物问世后，会为NSCLC脑转移患者带来福音。

表1 EGFR-TKIs治疗NSCLC脑转移患者的临床试验和研究

2 棘皮动物微管相关蛋白样4间变性淋巴瘤激酶融合基因(Echinoderm microtubule associated protein like 4 anaplastic lymphoma kinase inhibitor，EML4-ALK)抑制剂

ML4-ALK是NSCLC中新发现的癌变驱动基因[23]，约3%～7%的NSCLC患者含有此癌变驱动基因，不与EGFR、K-ras、HER2及BRAF突变基因共存[24]。ALK抑制剂主要是通过与ALK、c-Met、ROS-1多靶点驱动基因结合，再与位于细胞膜内侧酪氨酸激酶ATP结合域相结合，达到阻断该通路的信号传导来实现肿瘤细胞生长抑制和凋亡[25]。目前代表药物：克唑替尼(Crizotinib)，但学者发现Crizotinib脑脊液药物浓度仅仅是血液浓度的0.26%[26-27]，对NSCLC脑转移患者可能效果欠佳，但学者Nir Peled等[28]和Kinoshita等[29]报告的两例临床病案，口服Crizotinib后，颅内转移病灶前者完全缓解(CR)、后者部分缓解(PR)；学者Daniel等[30]临床单臂实验(n=888)，发现其中首次口服Crizotinib患者，颅内病灶DCR 56%，颅内病灶未进展时间(TTP)7个月；而Crizotinib为二线治疗患者，颅内病灶DCR 62%，TTP 13.2个月，差异具有统计学意义，综上所述，Crizotinib对NSCLC脑转移患者是有效的，但克唑替尼的耐药性和ALK野生型患者治疗无效等问题也成为治疗的瓶颈。第二代ALK抑制剂药物：Ceritinib和Alectinib，不仅克服Crizotinib耐药问题而且分子量偏小[31]，但Ceritinib在NSCLC脑转移的临床报告仍不多见；而学者Ajimizu等[32]报告临床个案，发现Crizotinib治疗无效后，口服Alectinib 300 mg，2次/d，两周后颅内转移病灶完全缓解。也有学者Shirish等[33]研究发现，非小细胞肺癌脑转移患者21人，口服Alectinib 600 mg/d，颅内病灶有效率为52%，CR 6人，PR 5人，SD 8人，更令人兴奋的是在动物模型实验中，发现Alectinib在脑组织浓度达到血液治疗浓度[34]，总之ALK抑制剂对NSCLC脑转移是有效的。

3 血管内皮生长因子(Vascular endothelial growth foctor，VEGF)拮抗剂

VEGF在恶性肿瘤血管中常常是高度表达，VEGF拮抗剂是通过与VEGF结合达到约束肿瘤新生血管生成，最终减少肿瘤细胞组织间的渗透压，增加其他化疗药物向肿瘤组织内的渗透，提高非小细胞肺癌治疗效果[35-37]，代表药物：贝伐珠单抗(Bevacizumab)。在治疗非小细胞肺癌脑转移方面，许多学者考虑到Bevacizumab有并发脑出血风险，被排除在治疗之外；近年来一个多中心、开放性、非随机对照的大型临床试验[38-39]数据发现贝伐珠单抗是基本安全的、有效的，学者Kim等[40]报道的临床个案，发现铂类治疗无效，联合Bevacizumab后，患者颅内转移病灶PR。学者Benjamin Besse等[41]临床Ⅱ期实验发现，Bevacizumab联合Carboplatin(卡铂)和Paclitaxel(紫杉醇)，PFS=6.7个月，OS=16.0个月(95%Cl 5.7～7.1，P＜0.05)，差异具有统计学意义，总之Bevacizumab在非小细胞肺癌脑转移患者是安全的、有效的。

4 血管内皮生长因子受体2(Vascular endothelial growth factor receptor-2 VEGFR-2)拮抗剂

VEGFR-2拮抗剂是通过与VEGFR-2结合后阻断血管生成，达到抑制肿瘤细胞快速生长和转移的效果。代表药物：雷莫芦单抗(Ramucirumab)，关于Ramucirumab在非小细胞肺癌脑转移的运用临床报告仍不多见，但一项全球性、随机性、双盲的临床Ⅲ期试验研究[42]发现Ramucirumab在晚期非小细胞肺癌(含有脑转移患者)治疗上能延长患者PFS、OS，也许在不久的将来，更多VEGFR-2拮抗剂的问世，会为非小细胞肺癌脑转移患者治疗带来希望。

5 靶向免疫治疗

免疫靶向治疗是通过与一种PD-1(抑制抗肿瘤免疫原性的免疫检测点分子)抑制剂受体相结合，解除PD-1通路介导的对免疫应答的抑制，达到抗肿瘤作用的治疗方法[43-45]，已成为肿瘤治疗的研究热点，其中Nivolumab对晚期非小细胞肺癌治疗在不断增加[46-48]。一项全球性、多中心参与的随机大型临床实验证明[49-50]，Nivolumab能延长PFS、OS，也许在不久的将来，更多免疫靶向药物的问世会为非小细胞肺癌脑转移患者治疗带来曙光。

6 展 望

靶向药物在非小细胞肺癌脑转移患者治疗上取得一定效果，仍未完全达到人们的期望，也许在不久的将来，随着肿瘤分子生物学的发展，最新的基因测序技术进步和大数据在医学中的运用，更多诱发非小细胞肺癌的突变基因被发现，相关靶向药物问世后，那时人们可以根据自身情况选择适合的靶点药物，对患者进行个体化治疗，最终达到提高疗效，使非小细胞肺癌脑转移患者获益。

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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)

刘黎明。E-mail：bbmcllm@126.com。