We retrospectively analyzed the clinical characteristics of SCLC BM patients who received brain radiation therapy from 2013 to 2023. All patients received treatment from Tianjin Cancer Institute and Hospital. This study was approved by the ethics committee of Tianjin Medical University Cancer Hospital. This research on patient services in our hospital was an analysis of patients’ medical data, which did not involve human experiments or compensation. The Tianjin Medical University Cancer Hospital approved the study data collection from the hospital information system. It is typically diagnosed in small biopsies or cytology specimens, demonstrating neuroendocrine features of SCLC (9). All clinical data of patients are from outpatient or inpatient clinical records. The patient underwent standardized physical examinations, including CT scans of the neck, chest, and abdomen, brain MRI, as well as ECT or PET/CT. ES-SCLC was defined in this study depending on the staging system of the Veterans Administration Lung Study Group, (VALG).

All patients underwent chemotherapy and/or combined concurrent radiotherapy/sequential TRT. Chemotherapy strategies: The etoposide(100 mg from days 1 to 5) with either cisplatin (30 mg/m from days 1 to 3) or carboplatin (500 mg for day 1) (platinum–etoposide) as the first-line chemotherapy regimen. The median chemotherapy cycles are 6 (range 2-6). TRT strategies: The tumor and metastatic lymph nodes were defined as the GTV. The CTV encompassed the tumor bed after chemotherapy, and the draining area of metastatic lymph nodes before chemotherapy, which was expanded from the GTV by a 5 mm uniform margin. The PTV was evenly extended 0.5 to 1cm uniform margin on the basis of CTV. The prescription dose was 50-63Gy in 25-30 fractions, 1.8-2.1 Gy per fraction at one fraction per day. All patients were treated WBRT with radiation boost by IMRT or SRS. The WBRT plus a radiation boost strategy: WBRT was performed with 6 MV photon beams using opposed lateral fields (90° and 270°) with a total dose of 30 Gy (3 Gy per fraction administered in 10 fractions at one fraction per day). The SRS was administered using a Cyberknife (Accuracy, Sunnyvale,California, USA) or X-knife after the WBRT in 56 patients. The GTV encompassed contrast-enhancing tumor on MRI and were reviewed by the radiation oncologist and the neurosurgeon based on the tumor volume, tumor location, and neurological symptoms. The PTV was defined as the 1 to 2 mm margin to the GTV. The administered radiation dose was 8.5-19 Gy in 1-3fractions with 6.3-18.0 Gy per fraction and one fraction per day(BED=10.3-29.9Gy). The IMRT simultaneous integrated boost WBRT (WBRT-SIB) was administered in 65 patients. The GTV was contoured based on the tumor from contrast-enhanced MRI scans. The PTV of brain metastases (PTVbm) was defined as the 3mm margin to the GTV with the dose of 35-50 Gy in 10 fractions with 3.5-5 Gy per fraction and one fraction per day. In general, we treated BMs less than 10 mm in maximum diameter with a prescription of 50 Gy(BED=75Gy); BMs larger than 10 mm but smaller than 30 mm with 40 Gy(BED=56Gy); and BMs larger than 30mm and less than 40 mm with 35Gy(BED=47.25Gy). The prescription of dose fractionation was consistent with previous clinical trials (10, 11). The PTV was expanded from the contour of the brain by the 3mm uniform margin with the dose of 30 Gy in 10 fractions with 3 Gy per fraction and one fraction per day.

Acute toxicity reactions are classified according to CTCAE version 5.0, and late toxicity is classified according to RTOG standards. Evaluate the efficacy of solid tumors according to RECIST 1.1. Repeat the baseline assessment every two cycles and every 6-8 weeks after treatment interruption until the disease progresses. Intracranial overall survival (iOS)is defined as the period from the start of BM diagnosis by imaging (MRI or enhanced CT) until the event occurs or the last follow-up. Intracranial local control survival (iLC) is defined as the time from the start of BM diagnosis by imaging (MRI or enhanced CT) until the first event of intracranial local failure.

All survival analyses were conducted using the Kaplan Meier method. Compare survival curves between different groups using logarithmic rank test and use χ² test and compare classified data. Cox proportional hazard regression model was used for Multivariate analysis of survival rate. Two groups of patients were subjected in a 1:1 ratio by PSM to analyze and control the confounding variables, including diagnosis-specific Graded Prognostic Assessment (DS-GPA) score, number of intracranial metastases, maximum diameter of metastases, and progression of extracranial diseases. In this study, the p-values were all one-way tests, and there was a statistically significant difference between groups when p<0.05. All analyses were conducted using SPSS software version 25.0.

The patient characteristics of 121 patients were shown in Table 1 . The majority of patients are male (n=100, 82.6%). The median age is 61 years (range 18-83 years). Most patients have severe smoking (smoking index ≥ 400, n=90,74.4%). Most patients have a superior Karnofsky performance status (KPS) score (KPS score ≥ 80, n=107, 88.4). The most common metastatic organs are as follows: 40 cases (33.1%) had bone metastasis; 21 cases (17.4%) had distant lymph node metastasis; 20 cases (16.5%) had lung metastasis; 15 cases (12.4%) had pleural metastasis; 14 cases (11.6%) had adrenal metastasis; Liver metastasis occurred in 12 cases (10.0%). Most patients received more than 4 cycles of chemotherapy (n=115, 95.0%). 86 patients (71.1%) responded to chemotherapy. Only 14 patients received immunotherapy (immune checkpoint inhibitors, ICIs), and 5 patients received treatment with arotinib.

The median follow-up time was 18.6 months (ranging from 6.30 to 85.7months) with 2 patients lost to follow-up. The 2-year incidence of iOS and iLC was 15.4% and 70.3%, respectively ( Figure 1 ). 92 patients died of disease progression, 1 patient died of radiation pneumonia, and 2 patients developed radiation brain necrosis. A few of patients have experienced treatment related toxic side effects, mainly including nausea, vomiting, dizziness, headache, leukopenia, radiation brain necrosis, etc. (The side effects of the low dose group and the high dose group are shown in Table 2 ).

Assess the predictive significance of patient and disease characteristics for iOS. Due to the small number (only 5) patients who were treated with arotinib, this factor is not suitable for analysis. In univariate analysis related to iOS, extracranial disease control (p=0.023), higher DS-GPA (≥2) (p=0.016), immunotherapy (p=0.049), low dose (p=0.030), and WBRT+SIB (p=0.009) were significantly associated with an increase in survival rate ( Table 3 ). Age, gender, weight loss, smoking history, TRT dosage, and the time interval for BM after diagnosis were not significantly observed in staging and the number of brain metastases (all factors p>0.05). Multivariate covariates analysis of factors related to iOS were further analyzed with p<0.05 in univariate Cox regression model analysis. The extracranial progress control (p=0.049) and higher DS-GPA (≥2) (p=0.014) can significantly improve iOS by multivariate analysis ( Table 3 ). However, there was no significant difference in immunotherapy, BM radiotherapy strategy and radiotherapy dose (p>0.05 for all factors).

This study divided 121 patients into two groups according to BM radiotherapy, with 65 receiving low dose treatment and 56 receiving high dose. As shown in Table 4 , compared to the low dose group, the high dose group had more patients with more weight loss >5%(9.2%vs33.9%, p=0.001), a smaller maximum diameter of BMs (53.8%vs73.2%, p=0.022), longer interval from diagnosis of SCLC to BMs (36.9% vs69.6%, p=0.000)and SRS (1.5%vs96.4%, p=0.000), which resulted in an imbalance between the two groups, and there was no significant difference in other baseline characteristics between the two treatment groups. Because the difference between SIB and SRS was too significant, and the majority of the low dose group had SIB and the majority of high dose group had SBRT, so the brain radiotherapy strategy factor was excluded. After a 1:1 PSM analysis, the baseline characteristics of the two groups of patients were well balanced ( Table 5 ). The low dose group (n=49) was significantly superior than that of the high dose group (n=49) about the 2-year iOS (47.1% vs 30.7%, P=0.025), while there was no increasing significantly about the 2-year iLC in high dose(65.3% vs 91.9%, P=0.267) ( Figure 2 ).

Further analysis was conducted on the prognosis of the low and high dose groups in different DS-GPA scores. It was found that in the GPA<2 subgroup, the 2-year iOS in the low dose group was significantly superior than that in the high dose group (65.3% and 25.0%, respectively, at, p=0.019), while in the DS-GPA ≥ 2 subgroup, there was no significant difference between the low dose group and high dose group (31.6% and 28.8%, respectively, p=0.502); in the DS-GPA<2 subgroup, there was no significant difference between the low dose group and high dose group in the 2-year iLC (100% and 100%, respectively). In the DS-GPA ≥ 2 subgroup, the 2-year iLC of the low dose group was significantly inferior than that of the high dose group (52.2% and 91.7%, respectively, p=0.044) ( Figure 3 ).