全脑低剂量放疗联合ICI及鞘内化疗治疗非小细胞肺癌脑膜转移的安全性与疗效分析

Efficacy and safety of whole-brain low-dose radiotherapy combined with ICI andintrathecal chemotherapy for leptomeningeal metastases from lung cancer

    摘要
  • 摘要:
    目的 探索经全脑低剂量放疗（whole-brain low-dose radiotherapy，WB-LDRT）联合程序性死亡受体-1（programmed cell death protein-1，PD-1）抑制剂信迪利单抗及培美曲塞鞘内化疗（intrathecal pemetrexed，IP）的联合治疗方案治疗难治性非小细胞肺癌（non-small cell lung cancer，NSCLC）伴脑膜转移（leptomeningeal metastases，LM）的疗效和安全性。
    方法 回顾性分析2022年12月至2024年5月于四川大学华西医院收治的8例NSCLC伴LM患者的临床资料。患者男性4例，女性4例，年龄34～58岁，中位年龄49岁。所有患者均接受WB-LDRT联合免疫检查点抑制剂（immune checkpoint inhibitor，ICI）及鞘内化疗方案治疗，根据神经肿瘤评估标准（RANO）进行疗效评价；以及卡氏体力状态评分标准（KPS）体力状态评分，评估患者生命质量；根据常见不良事件评价标准（CTCAE）5.0版评估不良反应。生存分析采用Kaplan-Meier法；通过单细胞测序分析患者治疗前后脑脊液细胞亚群分类占比，并行细胞基因表达差异分析。
    结果 接受治疗8例患者RANO标准评估最佳临床疗效，5例（62.5%）评价为好转，3例（37.5%）评价为稳定；8例患者治疗前中位 KPS 评分为30（20～50）分，治疗后中位 KPS 评分明显提高，为60（40～90）分（P=0.000 9）；8例患者观察到神经症状的缓解率为100%（8/8）；中位神经系统无进展生存期（neurological progression-free survival，NPFS）为12个月。P1患者脑脊液单细胞测序结果提示，WB-LDRT治疗后患者脑脊液细胞分群中T细胞比率较治疗前明显上升（治疗前vs. 治疗后：6.08% vs. 68.87%），肿瘤细胞比率明显下降（治疗前vs.治疗后：12.92% vs. 0.60%）；WB-LDRT治疗后脑脊液T细胞显著上调基因包括CCL5及CXCL13等。
    结论 采用WB-LDRT联合方案（WB-LDRT+IP+ICI）治疗NSCLC伴LM可明显缓解患者神经症状、改善患者生存质量及延长颅内无进展生存生存时间，是一种安全有效的治疗措施。

     

    Abstract:
    Objective To explore the efficacy and safety of whole-brain low-dose radiotherapy (LDRT ) combined with PD-1 inhibitor sintilimab and intrathecal pemetrexed (IP) for the treatment of refractory non-small cell lung cancer (NSCLC) with leptomeningeal metastases (LM).
    Methods Retrospective analysies were was performed on eight NSCLC patients with LM at the West China Hospital of Sichuan University from December 2022 to May 2024. Among the eight patients, there were four were males and four were females, with a median age of 49 years (rangeing, between 34 to 58 years). All patients were treated with whole-brain LDRT combined with immune checkpoint inhibitor (ICI) and intrathecal chemotherapy regimens, and the therapeutic efficacy was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria and the Karnofsky physical status (KPS) score. Adverse reactions were assessed according to the Common Criteria for the Evaluation of Adverse Events (CTCAE version 5.0). Survival analysis was performed using the Kaplan-Meier method. The classification proportion of cerebrospinal fluid subsets before and after treatment was analyzed using by single-cell sequencing, and the differential analysis of gene expression in parallel cells was performed.
    Results The best clinical treatment effects in eight patients were were evaluated using the RANO criteria: five patients (62.5%) were evaluated as improved and three (37.5%) as stable. The median KPS score of the eight patients was 30 (20-50) before treatment, which was significantly improved to 60 (40-90) after treatment (P=0.000 9). The remission rate of neurological symptoms was 100% (8/8) in eight patients. The median neurological progression-free survival (NPFS) was 12 months. The results of single-cell sequencing in CSF of patientss (P1) showed that the proportion of T cells in the patient samples after whole-brain LDRT treatment was significantly higher than that before treatment (6.08% vs. 68.87%), and the proportion of tumor cells was significantly lower (12.92% vs. 0.6%). The differential analysis of gene expression showed that CCL5 and CXCL13 were significantly upregulated in T cells of CSF after WB-LDRT treatment.
    Conclusions The combination of whole-brain LDRT with ICI and IP in the treatment of NSCLC with LM can significantly alleviate neurological symptoms, improve quality of life and prolong the NPFS of patients, which is a safe and effective treatment.

     

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