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脑转移瘤的治疗进展
中华转移性肿瘤杂志, 2019,2(1) : 1-4. DOI: 10.3760/cma.j.issn.2096-5400.2019.01.001
引用本文: 蒋力扬, 邢力刚, 于金明. 脑转移瘤的治疗进展 [J] . 中华转移性肿瘤杂志,2019,2 (1): 1-4. DOI: 10.3760/cma.j.issn.2096-5400.2019.01.001
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脑转移瘤是最常见的颅内肿瘤,颅脑转移也是肿瘤患者远处转移的常见部位。由于常需要同时治疗颅内及颅外病变,脑转移患者的治疗成为肿瘤学家的挑战。成人肿瘤中,肺癌(36%~64%)、乳腺癌(15%~25%)和黑色素瘤(5%~20%)最易发生脑转移[1]。此外,不同肿瘤出现脑转移后的生存预后也各不相同。例如,HER2阳性的乳腺癌脑转移患者生存期可长达2年以上,而无驱动基因突变的非小细胞肺癌脑转移患者的平均生存期很不尽如人意,即便是卡氏评分高的年轻患者也仅为1年左右[2]。除了需要考虑到原发肿瘤的类型,脑转移患者的预后与患者卡氏评分、驱动基因突变情况、年龄、神经认知功能、脑转移数目等也息息相关[3]。对于不同生存预后的脑转移患者选择个体化的治疗手段是至关重要的。局部治疗如外科切除、立体定向放射外科(stereotactic radiosurgery, SRS)和全脑放疗(whole-brain radiotherapy, WBRT)依旧是有症状的脑转移患者的主要治疗方法;而对于无症状或轻微症状患者,应用全身治疗如靶向治疗、免疫治疗显得更为重要[3]

一、手术及术后放疗

与单纯WBRT相比,手术加WBRT能够显著延长单一脑转移患者的生存期,手术也成为单一脑转移患者的标准治疗[4,5]。而随后的临床试验证实手术加术后WBRT尽管没有延长总生存时间,但是能够显著降低脑转移复发的概率和死于神经系统疾病的风险[6]。另外,对于脑转移灶>3 cm或者全身性疾病进展患者,无论原发肿瘤类型如何,术后行WBRT能够显著减少局部和远处复发[7]。而与术后WBRT相比,术后行SRS的总生存时间尽管相似,但SRS延长了认知功能减退时间。术后SRS可以作为WBRT的替代选择[8]

二、SRS

SRS的实施依赖于立体定向装置,使用伽马刀或直线加速器,精确定位<3 cm的病灶。与传统放疗相比,SRS单次剂量更高,总放疗次数更少,因此能够更好地保护正常组织。RTOG9508试验表明,针对单一脑转移患者,行WBRT+SRS相较WBRT可以显著延长总生存时间[9]。然而在<4个脑转移灶的患者中行SRS+WBRT治疗尽管降低了颅内复发风险,但并未得到总生存率的提高,且认识功能下降更为显著[10,11,12]。荟萃分析表明在<50岁、存在1~4个脑转移灶的患者中,相较SRS+WBRT,单纯SRS治疗并没有降低远处复发率,反而取得了更好的生存获益[13]。而对于超过4个脑转移灶的患者应用SRS仍存在争议[14]

三、WBRT

单纯WBRT适用于不适合手术或放射外科治疗,尤其是预后因素较差、预期寿命较短的脑转移患者。RTOG7606和RTOG9104临床试验确定了WBRT的标准剂量为30 Gy/10F,而20 Gy/4F的短程放疗与标准剂量相比也得到了相似的疗效[15,16,17]。但值得注意的是,WBRT会导致患者轻度认知功能障碍,包括学习、记忆障碍以及不同程度的脑白质损伤和脑皮质萎缩。QUARTZ试验表明针对无法手术或不适合立体定向放疗的脑转移患者,与单纯地塞米松支持治疗相比,WBRT的加入并不能带来生活质量调整的临床获益[18]。RTOG0614试验证明WBRT加美金刚联合应用可以显著延长认知衰退时间[19]。认知障碍可能是由负责学习、记忆信息整合以及短期记忆信息储存的重要部位——海马受辐射损伤所致[20]。RTOG0933研究表明在WBRT中保护海马能够起到保护记忆以及提高生活质量的作用[21]。NRG CC001(NCT02360215)临床试验的初步报道显示WBRT+海马保护+美金刚相较WBRT+美金刚能够明显阻止认知功能障碍。

四、靶向治疗

由于传统细胞毒性化疗药物血脑屏障通透性差,脑转移单纯化疗的作用极其有限[22]。靶向药物的出现为脑转移的治疗提供了更好的解决方案,在脑转移治疗中有确定疗效的靶向药物可考虑作为无症状或症状轻微的脑转移患者的一线治疗[23]。一项研究证明无症状脑转移患者应用一代EGFR-TKI药物(吉非替尼或厄洛替尼)的颅内有效率为73.9%,总生存期为18.8月[24]。LUX-Lung 8试验显示第二代EGFR-TKI阿法替尼的颅内有效率比一代药物更高[25]。LUX-Lung 3和LUX-Lung 6试验的数据分析显示相比较一线化疗,应用阿法替尼治疗脑转移能够得到更长的无进展生存期,然而两者间并没有统计学意义[26]。T790M突变患者适用于第三代EGFR-TKI药物奥希替尼。FLAURA研究显示对于无症状脑转移患者,应用奥希替尼比应用一代药物具有更高的疾病无进展生存时间(15.2月比9.6月,P<0.001)[27]。BLOOM临床试验得出AZD3759有着更好的血脑屏障通透性及确切的临床疗效[28]。一项荟萃分析表明放疗联合EGFR-TKI能够提高治疗有效率及总生存时间[29]。对于ALK突变患者,一代药物克唑替尼的有效率为18%[30]。新一代的ALK抑制剂如艾乐替尼、色瑞替尼及劳拉替尼具有更好的血脑屏障通透性,颅内控制率更加令人满意[31,32,33]

五、免疫治疗

免疫检查点抑制剂能够增强肿瘤特异性T细胞应答,并且活化的T细胞能够透过完整的血脑屏障[34]。现目前,免疫检查点抑制剂如nivolumab、pembrolizumab、ipilimumab和atezolizumab已在多种肿瘤治疗中显示出比化疗更高的疗效,然而针对脑转移的前瞻性免疫治疗研究数据有限。对于非小细胞肺癌无症状脑转移患者,pembrolizumab的颅内有效率为33%,且并没有增加神经系统不良反应[35]。对于黑色素瘤的无症状脑转移患者,nivolumab与ipilimumab联合应用后颅内有效率高达42%~55%,可作为一线治疗应用于临床实践[36,37]。然而令人遗憾的是针对有症状的脑转移患者应用免疫治疗的效果依旧不明朗。由于SRS能够产生一系列的促免疫原性作用,如凋亡的诱导、树突细胞的活化、血脑屏障通透性和检查点表达水平的增加,SRS与免疫治疗的联合为脑转移的治疗开辟了新的大陆[38]。同时,"远隔效应"理论进一步支持这两个治疗方式的联合[39]。SRS与免疫治疗的联合在非小细胞肺癌脑转移患者中显示出良好的颅内控制率,而在SRS先于或同时实施免疫治疗相比较免疫治疗先于SRS的颅内控制率有显著的统计学差异[40]。目前,仍需更多的前瞻性临床试验探索SRS与免疫治疗联合的最佳时机、先后顺序以及SRS剂量。

总之,虽然脑转移瘤的预后不令人满意,但是针对脑转移瘤的研究从未停歇。单一的局部治疗如手术、SRS和WBRT对于脑转移的控制不佳,现如今手术与放疗、SRS与WBRT的联合逐步提高了脑转移治疗的有效性。随着肿瘤治疗逐渐精准,肿瘤治疗跨入靶向及免疫时代,对于优势人群的靶向治疗及免疫治疗让我们看到了曙光,放疗与靶向及免疫治疗的联合更是为治疗增添了信心。

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