NSCLC合并软脑膜转移治疗选择
软脑膜转移（leptomeningeal metastasis，LM）是指肿瘤细胞转移至软脑膜和蛛网膜下腔，也可称为肿瘤脑膜炎。非小细胞肺癌软脑膜转移（NSCLC-LM）的发生率约为3.8%，84-96%为腺癌，约1/3 LM合并脑实质转移[1]。其中驱动基因阳性的NSCLC占58.8%[2]。LM不经治疗的中位生存期大约是6~8W，经过基因靶向治疗和免疫靶向治疗的NSCLC-LM患者 1年生存率约19%[3-6]。对于伴有敏感基因突变NSCLC-LM患者首选在分子靶向治疗基础上联合抗血管生成或鞘内灌注治疗[1,7-10]，对于无敏感基因突变NSCLC-LM患者推荐采用含铂双药化疗联合抗血管生成及鞘内灌注化疗[11,12]。虽然免疫治疗逐渐弱化了晚期无敏感基因突变NSCLC患者一线化疗的地位，但是目前脑膜转移免疫治疗相关疗效数据有限，因为这些患者通常被排除在临床实验外。关于免疫治疗NSCLC脑膜转移目前只有一些小样本数据报道[13,14]。该患者合并RET融合突变，但因为药物可及性问题采用培美曲塞联合卡铂联合贝伐珠单抗一线治疗，并结合了甲氨蝶呤鞘内灌注化疗。
脑部放疗在NSCLC软脑膜转移中的作用
局部放疗适用于LM引起的马尾神经综合征，颅神经麻痹。放疗可以使得30%脊髓CSF循环受阻得到缓解，50%颅内CSF循环受阻得到缓解，并且可以减轻CSF内化疗的毒性，提高其疗效。根据ESMO专家组建议，颅神经病变的RT靶区应包括颅底，基底池以及第一、二颈椎。马尾神经综合征的靶区应该包括腰骶椎[6]。WBRT可以考虑在弥漫性结节或者症状性线型LM或者合并有颅内脑实质转移时使用，但现有的回顾性分析未发现WBRT可以提高LM患者的生存[15,16]。该患者行全身化疗联合鞘内灌注化疗后颅内病灶控制不佳，故结合了全脑放疗。
局部放疗在寡进展IV期NSCLC中的作用
对于寡进展延用系统治疗联合局部放疗的疗效分析多集中在靶向治疗，且多为回顾性研究，局部放疗以SBRT为优[17]。来自美国罗拉多大学癌症中心的一项回顾性研究显示，对于伴有EGFR敏感突变或ALK融合患者一线靶向治疗后寡进展，继续使用靶向药物联合寡进展病灶局部消融治疗，可以延缓靶向药物耐药时间并进一步获得6个月的无进展生存[18]。随后开展的前瞻性研究也显示对于ALK融合IV期NSCLC患者克唑替尼一线治疗寡进展后对寡进展病灶进行局部消融治疗可通过增加局部控制率进一步延长生存，并且行SBRT患者获益更显著[19]。NCCN指南也推荐晚期NSCLC在系统治疗过程中出现寡进展，对寡进展病灶进行局部消融治疗可以进一步延长系统治疗的获益时间。该患者一线治疗控制了1年左右时出现左肺病灶寡进展，结合寡进展病灶SBRT治疗后病情继续控制了半年的时间。
放疗联合免疫在IV期NSCLC中的作用
对Keynote-001二次分析显示，接受帕博利珠单抗治疗前接受过局部放疗的患者PFS及OS较未接受放疗患者均有显著获益[20]。回顾性研究显示，一线化疗方案失败后NSCLC患者接受纳武单抗联合放疗较单纯纳武单抗治疗，ORR、PFS及OS均显著提高，联合放疗为纳武单抗治疗疗效的独立预后因子[17,21,22]。PEMBRO-RT是一项评估转移性NSCLC患者在Pembrolizumb治疗前针对单个病灶行SBRT能否增强肿瘤缓解效果的多中心II期临床研究，主要研究终点为在12周时将ORR从对照组20%提高到50%。结果显示12周时联合治疗组ORR为36%，对照组为18%，联合治疗组PFS为6.6个月，对照组为1.9个月，联合治疗组OS为15.9个月，对照组为7.6个月[23]。该患者在采用纳武单抗治疗时同时结合了左颈部淋巴结放疗，一是考虑左颈部淋巴结的压迫症状，二是考虑免疫与放疗的协同作用。
总结
该病例为初诊伴有RET融合的NSCLC-LM患者，一线采用全身化疗联合抗血管生成联合鞘内灌注化疗，并结合了脑部放疗、肺部寡进展病灶放疗。二线采用免疫联合抗血管生成治疗，以及导致疼痛症状的左颈部淋巴结放疗，目前生存期达2年，PS评分1分。体现了放射治疗在IV期NSCLC患者中的重要作用，同时也体现了NSCLC-LM患者个体化综合治疗的重要性。
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