第一部分

全脑放疗和同步加量对肺癌脑转移患者的治疗疗效和预后因素分析

目的：研究分析全脑放疗和同步加量（Whole-Brain Radiotherapy Plus Simultaneous Integrated Boost，SIB-WBRT）治疗肺癌脑转移瘤的疗效及影响预后的因素。

方法：回顾性分析了2015年9月至2021年12月在北京协和医院接受SIB-WBRT的肺癌脑转移患者。处方剂量：全脑40Gy/20F，转移灶推量至56-60Gy/20F。主要终点为颅内无进展生存（iPFS）、次要终点包括总生存（OS）、颅内新发情况和肿瘤控制情况。Kaplan–Meier法描绘和评估iPFS、OS、颅内新发情况和肿瘤控制。Cox模型分析多个相关因素对结果的影响。

结果：本研究共纳入107例患者，接受SIB-WBRT治疗后的所有患者中位iPFS为13.4（95%CI: 4.2-22.6）个月，6、12月iPFS为68.0%（95%CI: 57.4-78.6）和50.8%（95%CI: 38.3-63.3）。病灶局部控制中位时间为37.6（95%CI: 28.3-46.8）个月，6、12月病灶局部控制率为84.3%（95%CI: 80.6-88.0）和73.3%（95%CI: 68.2-78.4）。出现颅内新发灶的中位时间为17.4（95%CI: 14.1-20.8）个月，6、12月颅内控制率为74.5%（95%CI: 64.5-84.5）和61.5%（95%CI: 49.0-74.0）。多因素分析显示患者治疗前脑转移瘤数量与iPFS显著相关（HR=0.4，95%CI： 0.2-0.973，P=0.043）。

结论：SIB-WBRT对脑转移有较好的疗效，治疗后患者的iPFS、病灶局部控制和颅内新发情况中位时间分别为13.4（95%CI: 4.2-22.6）、37. 6（95%CI: 28.3-46.8）和17.4（95%CI: 14.1-20.8）个月。治疗前患者脑转移瘤数量是影响iPFS的因素。

第二部分

肺癌脑转移瘤局部照射的疗效和结果分析

目的：研究分析脑转移患者接受局部照射治疗的疗效，并分析不同因素对患者预后的影响。

方法：以2015年9月至2021年12月本中心收治的接受局部治疗的肺癌脑转移患者作为研究对象。根据不同单次剂量将患者分为三组，单次剂量≥6Gy定义为大分割组，单次剂量4-5Gy定义为中等分割组，单次剂量2-3.5Gy定义为常规分割组。采用Kaplan–Meier方法描绘和评估患者的颅内无进展生存（iPFS）、总生存（OS）、颅内新发情况和肿瘤控制情况。Cox模型分析多个相关因素对结果的影响。

结果：共纳入81例患者，157个转移灶，局部治疗的处方剂量20-60Gy/2-25F，最常用的分次模式为30Gy/5F，BED范围为28-100.8Gy。大分割组49例患者，中等分割组21例患，常规分割组11例患者。入组患者中位OS为22.5（95%CI: 14.1-30.9）个月，中位iPFS为 9.4（95%CI: 6.5-12.3）个月。颅内出现新发病灶的中位时间为11.2（95%CI: 7.2-15.3）个月。三组的iPFS和病灶局部控制无明显差异。患者脑转移治疗期间接受靶向治疗与病灶局部控制（HR=6.0，95%CI： 1.7-22.0，P=0.007）和iPFS（HR=2.7，95%CI: 1.2-6.1，P=0.023）密切相关。

结论：脑转移瘤局部照射是肺癌脑转移患者有效的治疗方式。靶向治疗与脑转移局部照射的预后相关。

第三部分

全脑放疗联合同步推量（SIB-WBRT）和脑转移瘤局部照射治疗肺癌脑转移的治疗疗效比较

目的：比较脑转移瘤局部照射和SIB-WBRT以及先行靶向治疗和先行放疗的疗效，并分析有关因素对预后的影响。

方法：回顾性分析2015年9月至2021年12月在北京协和医院接受SIB-WBRT（全脑40Gy/20F，肿瘤组织同步推量至56-60Gy/20F）和脑转移瘤局部照射（处方剂量范围 20-60Gy/2-25F，最常用的分割模式为30Gy/5F）治疗的肺癌脑转移患者。使用倾向评分匹配分析平衡两组患者基线临床特征，并对两组患者的相关结局指标进行比较。Kaplan–Meier曲线用以描绘颅内无进展生存（iPFS）、总生存（OS）、颅内新发情况和肿瘤控制情况。Cox回归模型用以鉴别与结果相关的因素。同时，在驱动基因阳性非小细胞脑转移患者中比较先行靶向治疗和先行放疗的疗效。

结果：共纳入188例患者，在倾向评分匹配后，SIB-WBRT和脑转移瘤局部照射两组分别有59例患者入选，SIB-WBRT和脑转移瘤局部照射两组患者接受治疗后iPFS（HR=0.8，95%CI:0.4-1.3，P=0.288），OS（HR=1.1，95%CI:0.7-1.8，P=0.653）及颅内新发灶（HR=0.6，95%CI:0.4-1.2，P=0.144）比较均未发现显著差异。但是，局部照射组在病灶局部控制方面表现更佳（HR=0.4，95%CI:0.2-0.8，P=0.005），病灶控制率分别为59.1%（SIB-WBRT）和87.9%（局部照射）。患者肿瘤体积、年龄等因素与病灶局部控制相关。靶向先行比较放疗先行并未在驱动基因阳性非小细胞脑转移患者中显示出疗效优势。

结论：与脑转移瘤局部照射相比较，并未发现SIB-WBRT能够改善肺癌脑转移患者的iPFS。脑转移瘤局部照射对肿瘤的局部控制更具优势。患者的肿瘤体积、年龄等因素可能与转移瘤的局部控制情况相关。靶向先行比较放疗先行在驱动基因阳性非小细胞脑转移患者中并未观察到疗效差异。

Part I

Analysis of Prognostic and Efficacy of Whole-Brain Radiotherapy plus Simultaneous Integrated Boost in Lung Cancer with brain metastases

Objective: To explore the efficacy of Whole-Brain Radiotherapy plus Simultaneous Integrated Boost (SIB-WBRT) in the treatment of lung cancer brain metastases and the factors affecting prognosis.

Methods: This single-arm retrospective study analyzed patients with brain metastases treated with received SIB-WBRT (40Gy/20F of whole brain tissue and tumor tissue pushed to 56-60Gy/20F) at Peking Union Medical College Hospital from September 2015 to December 2021. The patient's outcome measures include primary endpoint intracranial progression free survival (iPFS), secondary endpoint overall survival (OS), intracranial new foci, and tumor control. The Kaplan-Meier method was then used to depict and estimate iPFS, OS, intracranial new foci, and tumor control. Finally, the Cox model was used to analyze the association between some relevant factors and outcomes.

Results: A total of 107 patients were included in the study and the median value of iPFS in these patients treated with SIB-WBRT was 13.4 (95% CI: 4.2-22.6) months, with 68.0% (95% CI: 57.4-78.6) and 50.8% (95% CI: 38.3-63.3) iPFS at 6 and 12 months. The median value of local control was 37.6 (95% CI: 28.3-46.8) months, with local control rates of 84.3% (95% CI: 80.6-88.0) and 73.3% (95% CI: 68.2-78.4) at 6 and 12 months. The median time to appearance of new intracranial foci was 17.4 (95% CI: 14.1-20.8) months, and the 6 and 12 months control rates were 74.5% (95% CI: 64.5-84.5) and 61.5% (95% CI: 49.0-74.0). The number of brain metastases in patients before treatment was significantly associated with iPFS (HR=0.4, 95% CI: 0.2-0.973, P=0.043).

Conclusions: The iPFS, local control, and intracranial new foci of patients with brain metastases after treatment with SIB-WBRT were acceptable. In addition, the number of brain metastases in patients before treatment may be associated with iPFS.

Part II

Efficacy and Outcomes of Local irradiation of lung cancer brain metastases

Objective: The aim of this study was to investigate the efficacy and outcomes of local irradiation brain metastases in patients with brain metastases and to analyze the prognostic impact of factors.

Methods: The study focused on patients with lung cancer brain metastases who underwent local irradiation from September 2015 to December 2021 at our center. Patients were divided into three groups based on different single doses: those with a single dose(≥6Gy) were classified as the hypofraction, those with a single dose(4-5Gy) were categorized as the moderately hypofraction, and those with a single dose(2-3.5Gy) were labeled as the conventionally fraction. Kaplan-Meier analysis were used to assess iPFS, OS, incidence of new intracranial lesions, and tumor control outcomes for the patients. Univariate and multivariate Cox regression analyses were performed to identify variables that impact patient prognosis.

Results: A total of 81 patients with 157 metastatic lesions were included in the study. The prescribed doses for local treatments ranged from 20-60Gy/2-25F, with the most common fractionation scheme being 30Gy/5F. The BED ranged from 28-100.8Gy. There were 49 patients in the hypofraction, 21 patients in the moderately hypofraction, and 11 patients in the conventionally fraction. The median OS for the enrolled patients was 22.5 months (95% CI: 14.1-30.9), and the median iPFS was 9.4 months (95% CI: 6.5-12.3). The median time to the development of new intracranial lesions was 11.2 months (95% CI: 7.2-15.3). There was no significant difference in iPFS and local control among the three groups, including the hypofraction, moderately hypofraction, and conventionally fraction. During the course of brain metastasis treatment, the receipt of targeted therapy was closely associated with local control (HR=6.0，95%CI： 1.7-22.0，P =0.007) and iPFS (HR=2.7, 95% CI: 1.2-6.1, P =0.023).

Conclusion: Local irradiation is an effective treatment modality for patients with lung cancer brain metastases. Targeted therapy is associated with the prognosis of brain metastasis patients undergoing local irradiation.

Part III

Comparing Whole-Brain Radiotherapy Plus Simultaneous Integrated Boost and Local Irradiation for Lung Cancer Brain Metastases

Objective: This study aimed to assess the difference in effectiveness between two treatment modalities, as well as prior targeted therapy and prior radiotherapy, and identify predictors for lung cancer patients with brain metastases.

Methods: Lung cancer patients with brain metastases who received SIB-WBRT (whole brain 40Gy/20F, tumor tissue was simultaneously boosted to 56-60Gy/20F) and local irradiation (prescription dose rang: 20-60Gy/2-25F, the majority was delivered with 30Gy/5F) at Peking Union Medical College Hospital from September 2015 to December 2021were researched. Propensity score matching analysis was used to balance the confounders between 2 groups. Kaplan-Meier curve was utilized to depict iPFS, OS, newly-onset intracranial disease and tumor control. Cox regression analysis was conducted to assess the association between relevant factors and outcomes. Comparing the treatment effectiveness between prior targeted therapy and prior radiotherapy in patients with driver gene mutation.

Results: After Propensity score matching, 59 patients were respectively enrolled in SIB-WBRT and local irradiation group. Difference was not observed in iPFS (HR=0.8, 95%CI: 0.4-1.3, P=0.288), OS (HR=1.1, 95%CI: 0.7-1.8, P=0.653) and newly-onset intracranial disease (HR=0.6, 95%CI: 0.4-1.2, P=0.144) between the two groups. The local irradiation group might be superiority over SIB-WBRT group in the local control time (HR=0.4, 95% CI: 0.2-0.8, P=0.005). Besides, tumor volume and other factors were closely associated with local control. Prior targeted therapy versus prior radiotherapy did not show any therapeutic advantage in patients with driver gene positive non-small cell brain metastases.

Conclusion: SIB-WBRT was not able to improve iPFS when compared to local irradiation for lung cancer patients with brain metastases. Local irradiation demonstrated superiority over SIB-WBRT in local control. Besides, tumor volume and other factors status may be associated with local control of disease. For brain metastases lung cancer patients with driver gene mutation, prior targeted therapy and prior radiotherapy had the same efficacy.