在致癌基因驱动的肺癌中，局部治疗的时机、技术和分子特征对大脑控制的影响。
Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.
机构信息
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg, Germany; Department of Radiology and Nuclear Medicines, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
出版信息
ESMO Open. 2021 Jun;6(3):100161. doi: 10.1016/j.esmoop.2021.100161. Epub 2021 Jun 2.
BACKGROUND
The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
This study included all epidermal growth factor receptor-mutated (EGFR, n = 108) and anaplastic lymphoma kinase-rearranged (ALK, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases.
RESULTS
Median overall survival (OS) was 49.1 months for ALK and 19.5 months for EGFR patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR and ALK subsets.
CONCLUSIONS
Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR/ALK NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.
背景
酪氨酸激酶抑制剂（TKI）疗效的提高要求重新评估致癌基因驱动的非小细胞肺癌（NSCLC）脑转移（BM）的局部治疗（LT）。
患者和方法
本研究纳入了 2009 年至 2019 年间在海德堡胸科医院诊断为 BM 的所有表皮生长因子受体突变（EGFR，n=108）和间变性淋巴瘤激酶重排（ALK，n=33）的 TKI 初治 NSCLC 患者。87 例患者（62%）接受了早期 LT，54 例（38%）接受了延迟（n=34；24%）或未接受 LT（n=20；14%）。LT 包括立体定向放疗（SRT；n=40；34%）或全脑放疗（WBRT；n=77；66%），而 19 例患者进行了神经外科切除术。
结果
ALK 患者的中位总生存期（OS）为 49.1 个月，EGFR 患者的中位 OS 为 19.5 个月（P=0.001），颅内无进展生存期（icPFS）相似（分别为 15.7 个月和 14.0 个月，P=0.80）。尽管早期 LT 患者的 BM 更大且更有症状（P<0.001），但这些患者的 icPFS 更长[风险比（HR）0.52；P=0.024]，而 OS 无差异（HR 1.63；P=0.12），与放疗技术（SRT 与 WBRT）和病变数量无关。高风险的致癌基因突变，即非-del19 EGFR 突变和“短”EML4-ALK 融合（主要为变体 3，E6:A20），与颅内进展较早相关（HR 2.97；P=0.001）。在 EGFR 和 ALK 亚组的单独分析中，早期 LT 延长 icPFS 的效果也很明显。
结论
尽管早期 LT 更常用于预后不良的病例，但在接受 TKI 治疗的 EGFR/ALK NSCLC 患者中，早期 LT 仅延长了 icPFS，而未延长 OS。鉴于生存获益的缺乏，以及 WBRT 的神经认知效应，多发性或多灶性 BM 患者可能受益于延迟放疗或多发性或选择性病变的放射外科治疗。对于 SRT 候选者，早期放疗改善肿瘤控制的效果应与潜在毒性和新型 TKI 的增强颅内活性相权衡。高风险的 EGFR/ALK 变体与颅内早期失败相关，并确定了可能受益于更积极治疗的患者。
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