肺癌是全世界最常见且病死率最高的恶性肿瘤 ^［1］，其中非小细胞肺癌（NSCLC）约占肺癌的85%。初治的NSCLC患者有7.4%～10%伴脑转移，初治没有脑转移的NSCLC患者30%～50%最终发生脑转移 ^［2］，其中腺癌的脑转移发生率最高。约30%局部晚期NSCLC患者在有效局部区域治疗后脑转移成为首个失败部位 ^［3］，大部分患者明确诊断时脑转移为多发。随着影像技术的发展，局部区域治疗手段的进步和各种靶向治疗药物的成功应用，脑转移瘤的发生率有逐渐增高的趋势。脑转移瘤的原发部位亦以NSCLC为最常见。没有对原发部位进行限定的脑转移瘤临床研究中，绝大多数包含了相当比例的NSCLC。因此，有关脑转移瘤治疗的临床研究所得出的结论基本上适用于NSCLC脑转移瘤患者。脑转移瘤的治疗手段包括：全脑放疗（WBRT）、手术、立体定向外科（SRS）、化疗、靶向治疗等，也可以是上述治疗手段的联合。本文重点对非小细胞肺癌脑转移瘤的治疗进行综述。

脑转移瘤预后很差，脑转移瘤不做治疗中位生存期（OS）仅1个月，激素治疗后中位OS约2个月，WBRT后中位OS 约3～6个月 ^［4，5］，SRS治疗后中位OS约5～11个月。大部分NSCLC伴脑转移患者脑内转移瘤是多发的，WBRT是多发脑转移瘤患者的标准治疗 ^［6］。对于未经选择的NSCLC脑转移瘤患者，WBRT的客观反应率约38%～45% ^［7，8］，中位OS约5个月。EGFR敏感突变的NSCLC脑转移患者WBRT的客观反应率高于EGFR野生型患者（54% vs. 24%），EGFR敏感突变是NSCLC脑转移独立的预后因子 ^［9，10］。多项前瞻性随机对照研究 ^［11-19］未显示出不同分割次数、不同剂量的WBRT之间的疗效差异，30Gy/10F依然是当前WBRT的标准剂量。

手术治疗亦是NSCLC脑转移瘤的有效治疗手段之一。手术治疗可迅速解除颅高压和压迫症状，并明确病理诊断。随着放疗的普及，手术在脑转移瘤中的应用逐渐减少，现主要作为RPA1级、症状明显或对放疗抗拒的患者的治疗选择。

SRS对于单发和多发脑转移瘤治疗有效，回顾性研究提示，SRS较WBRT改善了1～3个脑转移瘤患者的中位OS ^［20-22］。尽管缺乏Ⅲ期临床研究，多个回顾性研究提示，单发脑转移瘤患者SRS ^［23-27］与手术 ^［28-30］疗效相当。一般情况好的NSCLC单个脑转移患者经手术或SRS后中位生存期超过10个月 ^{［29，31］}。因此，SRS可以作为1～3个脑转移瘤患者的首先推荐治疗。

两个前瞻性随机对照研究显示，手术+WBRT较WBRT延长了可手术单个脑转移瘤患者的中位生存期 ^{［28，30］}，而另一个随机对照研究 ^［31］却未能显示手术+WBRT在OS上的优势。此外，前瞻性非随机研究和回顾性研究亦显示手术+WBRT 的OS优于WBRT。与单纯手术相比，术后辅助WBRT改善了PS评分≤2单个可手术脑转移瘤患者的局部控制率，减少了神经系统相关死亡率 ^［29］，但入组病例数较少，无法回答术后WBRT是否改善了OS。因此，对于PS评分好的单个可手术切除的脑转移瘤患者，手术+WBRT是首先推荐的治疗。

RTOG9508研究 ^［32］显示，WBRT联合SRS较单用WBRT显著提高了单发脑转移瘤患者的OS（6.5 vs 4.9月），显著改善了1～3个脑转移瘤患者的脑内局部控制率和KPS评分。亚组分析提示，肺鳞癌脑转移患者的OS亦可能从WBRT联合SRS治疗中获益。荟萃分析显示 ^［33］，SRS后辅助WBRT较单独SRS显著降低了脑转移瘤复发率和新发脑转移瘤发生率，但不改善1年生存率，且增加了晚期神经毒性。由于WBRT对认知功能潜在影响 ^［34］，对于1～4个脑转移瘤患者，先行SRS治疗，将WBRT作为挽救治疗是一种合理的选择。而对于RPA1级单发脑转移瘤患者，手术+WBRT ^［28］和SRS+WBRT ^［35］均为可以首先考虑的治疗选择。

非小细胞肺癌脑转移一线化疗的有效率为17%～50% ^［36-42］，脑转移瘤的化疗有效率与脑外病灶的有效率相似。这可能是因为脑转移瘤患者的血脑屏障（BBB）已部分破坏 ^［43］，脑内和脑外肿瘤组织中的化疗药物浓度相似 ^［44］。因此，NSCLC脑转移的患者可以按照晚期NSCLC的化疗方案进行化疗。

替莫唑胺BBB穿透率高，脑脊液浓度可达血浆浓度的30%～40% ^［45］，其治疗曾行一线化疗NSCLC脑转移的有效率为5%～10% ^［46-49］。因此，替莫唑胺可以作为NSCLC脑转移的二线治疗选择。替莫唑胺具有良好的耐受性，与其他化疗药物的联用是可行的 ^［50］，脑转移瘤的客观缓解率可进一步提高。

荟萃分析显示 ^［51］，在EGFR敏感突变的晚期NSCLC中，一线TKI治疗与化疗相比显著改善了客观反应率和PFS，从而确立了TKI在晚期NSCLC中的地位，但这些研究大部分不包含脑转移瘤患者。尽管TKI在脑脊液中的浓度很低 ^{［52，53］}，TKI可以在NSCLC脑转移瘤中选择性聚集 ^［54］，因此TKI可以有效治疗脑转移瘤。多个研究 ^［55］显示TKI治疗NSCLC脑转移瘤疗效显著。CTONG0803 ^［56］显示，EGFR基因敏感突变的患者（8例）厄洛替尼二线治疗无颅外进展的NSCLC脑转移患者的有效率为75%，中位无进展生存期15.2个月，中位OS37.5个月。多个研究显示，原发灶的EGFR状态是脑转移瘤的疗效预测因子 ^{［55，57-59］}。在EGFR敏感突变的患者中，脑转移瘤TKI治疗的有效率为75%～83% ^{［56，58，60］}，明显高于化疗和WBRT。EGFR不同基因型之间的NSCLC脑转移患者TKI治疗疗效亦有所不同，Iuchi等报道 ^［61］，19外显子缺失突变患者的PFS和OS均显著优于21外显子点突变的患者。

Kim等 ^［62］报道，TKI治疗优势人群NSCLC脑转移瘤患者，脑转移瘤和肺癌原发灶的有效率无显著差异（74% vs. 70%）。而另有报道 ^{［63，64］}认为肺癌原发灶和脑转移瘤之间的EGFR突变状态可能不同。由于临床上很难获得脑转移瘤的标本，NSCLC原发灶EGFR突变状态是NSCLC脑转移瘤有效实用的预测因子。上述研究入组的均为无症状脑转移患者，因此TKI可以作为EGFR敏感突变无症状NSCLC脑转移患者的一线治疗选择，一部分患者可能不需要WBRT的参与。

NSCLC脑转移瘤中的EGFR突变率较高，有报道高达63% ^［65］。回顾性研究显示，发生脑转移的NSCLC患者EGFR的突变率高于未发生脑转移的患者。EGFR突变的NSCLC患者脑转移瘤发生率亦高于EGFR无突变者，伴EGFR突变的NSCLC脑转移患者预后较好 ^［9］。

Omuro等 ^［66］报道，TKI治疗后5年脑转移发生率可以高达60%；Lee等 ^［67］报道TKI治疗晚期NSCLC患者临床获益者脑转移瘤发生率显著高于TKI治疗无效者（26% vs. 4%），提示TKI治疗与脑转移瘤发生率高相关。相反，Heon等 ^［68］报道，晚期NSCLC患者TKI治疗后脑转移瘤发生率显著降低；Chen等和Ceresoli等 ^{［69，70］}报道，晚期NSCLC患者TKI治疗后脑转移瘤中位发生时间显著长于未行TKI治疗者；Heon等 ^［71］报道，对于EGFR敏感突变的NSCLC患者，一线TKI治疗比化疗的脑转移瘤发生率低；这些研究提示晚期NSCLC患者TKI治疗后脑转移瘤发生率较低。因此，对于晚期NSCLC患者而言，TKI治疗与脑转移瘤的发生率之间的关系尚无定论。

在未经选择的NSCLC脑转移患者中 ^［72-74］，TKI的有效率波动范围较大（10%～81%）。而以临床病理特征选择的优势人群中 ^62，75，TKI的有效率较高且波动较小（69%和70%）。在EGFR野生型NSCLC脑转移患者中，TKI治疗脑转移瘤的有效率约为10%。

回顾性研究提示 ^［76］，EGFR敏感突变的肺腺癌脑转移患者WBRT与TKI治疗后效果佳，OS可达33个月，与EGFR敏感突变而无脑转移晚期NSCLC的OS相似。WBRT组的OS 与TKI组无差异，而脑内局控率和脑内病灶进展时间WBRT组优于TKI组。

上述小样本Ⅱ期临床研究和回顾性研究（包括个案报道）提示TKI在EGFR敏感突变NSCLC脑转移中的治疗结果令人鼓舞。但无TKI与脑放疗或化疗对比的Ⅲ期研究结果发表，亦无WBRT+TKI与单独TKI、WBRT或化疗对比的Ⅲ期研究发表，因此，EGFR敏感突变NSCLC脑转移瘤患者TKI单用或联合应用的价值有待大样本的前瞻性研究进一步明确。

临床前研究提示，放疗和TKI联合具有增敏作用。而多个研究提示，既往曾行全脑放疗的患者TKI治疗后疾病控制率提高，并有改善生存的趋势，因而曾行全脑放疗可能是NSCLC脑转移患者好的预后因子。但这究竟是因为WBRT破坏了BBB，还是选择偏倚或其他原因尚不得而知。

多个研究显示，WBRT同步联合TKI治疗有增敏作用而且耐受性好。在EGFR基因突变状态未明的患者中，WBRT+TKI的有效率为81%和71%，显著高于单独WBRT或化疗 ^{［77，78］}。在EGFR基因敏感突变的患者中，WBRT+TKI的有效率高达84%，EGFR敏感突变的患者有效率显著高于无突变者 ^［10］。

然而，RTOG 0320 ^［79］研究将NSCLC伴1～3个脑转移瘤的患者随机分为单纯放疗组（WBRT+SRS）和联合治疗组（WBRT+SRS+替莫唑胺或TKI），结果联合治疗组的OS差于单纯放疗组，尽管统计学无差异。该研究入组的患者未经EGFR基因选择，而且不属于EGFR基因敏感突变优势人群，因此非EGFR敏感突变患者中脑放疗联合TKI治疗需要谨慎。

对于无症状的脑转移瘤患者，一线单独化疗与化疗后WBRT相比，有效率和OS并无差异；接近1/3一线仅行化疗的患者死于脑外疾病进展而脑转移瘤获得控制，在整个病程中并不需要WBRT ^［80］。两个前瞻性随机对照Ⅱ期 ^{［81，82］}研究显示，WBRT联合替莫唑胺较单用WBRT显著提高了脑转移瘤的有效率，但未显著改善OS。RTOG 0320研究 ^［79］亦显示，放疗（WBRT+SRS）与替莫唑胺联合不能改善NSCLC伴1～3个脑转移瘤患者的OS。因此，WBRT联合化疗在NSCLC脑转移瘤中的地位尚未确立。

晚期NSCLC患者很少仅有脑转移瘤，经全脑放疗后大部分患者最终并非死于脑转移瘤，相当一部分患者死于肺癌原发灶进展 ^{［83，84］}。多项回顾性研究 ^［85-88］显示，对于无纵隔淋巴结转移（N0-1）的NSCLC脑转移瘤患者，肺癌和脑转移瘤的联合手术切除可以提高生存率，异时脑转移的患者预后优于同时脑转移者。手术治疗后中位生存期可达10～27个月，2年生存率28%～54%，5年生存率11%～24%。与之相仿，多个回顾性研究 ^{［5，89-93］}显示，肺癌原发灶的积极放射治疗同样可以改善非小细胞肺癌脑转移瘤患者的预后。这些患者的脑转移瘤接受了全脑放疗、SRS、手术或联合治疗，大部分研究只入组了单发脑转移瘤的患者，也有部分研究包含了多发脑转移瘤的患者。接受肺癌原发灶放疗的患者生存与接受手术的患者相仿，中位生存期达15.5～31.8个月，2年生存率为16%～60%。在这些原发灶和脑转移瘤均接受了积极治疗的患者中，腺癌、初诊时低CEA水平、KPS评分好、年轻、N0-1、无脑外转移瘤和诱导化疗反应率高等提示预后良好。因此，在预后较好的NSCLC脑转移瘤患者中，既针对原发灶又针对脑转移瘤的积极治疗可能是有益的，但缺乏前瞻性随机对照研究的证据。对于原发灶的处理，N0-1的患者可以选择手术，N2-3的患者选择放化疗。

NSCLC脑转移瘤的治疗选择主要包括WBRT、手术、SRS、TKI等。多发脑转移瘤的标准治疗为WBRT，不同剂量及分割的WBRT之间疗效无显著差异。SRS的疗效与手术相当。手术/SRS+WBRT治疗单个脑转移瘤患者的有效率和脑内控制率最高。对于单个脑转移瘤而言，手术/SRS+WBRT较单用WBRT改善了OS。SRS+WBRT治疗1～4个脑转移瘤较单用SRS改善了局部控制，但未显著改善OS；由于WBRT的潜在神经毒性，单用SRS也是合理的选择。按照NSCLC一线化疗的方案治疗NSCLC脑转移瘤患者，脑转移瘤与原发灶有效率相似。在EGFR敏感突变患者中，TKI治疗NSCLC脑转移疗效突出，有效率显著高于WBRT和化疗。对于无症状NSCLC脑转移患者，一线单用TKI可能是合理的，部分患者最终死于脑外疾病进展而无须WBRT。WBRT同期联合TKI治疗有效率高，是否能较一线单用TKI或WBRT改善OS值得进一步研究。WBRT同期联合化疗提高了NSCLC脑转移瘤患者的有效率，但未改善OS。预后好的NSCLC脑转移患者可能从原发灶的手术治疗或放疗中获益，对于预后良好的患者可以考虑积极地治疗原发灶。

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