Immunotherapy Improves Survival and Reduces Brain Metastasis Risk in Limited- Stage Small Cell Lung Cancer Patients Receiving Prophylactic Cranial Irradiation

Immunotherapy Improves Survival and Reduces Brain Metastasis Risk in Limited- Stage Small Cell Lung Cancer Patients Receiving Prophylactic Cranial Irradiation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Immunotherapy Improves Survival and Reduces Brain Metastasis Risk in Limited- Stage Small Cell Lung Cancer Patients Receiving Prophylactic Cranial Irradiation Zifang Liu, Xinyan Zhang, Wenjing Cao, Huacong Jin, Xin Ding This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8542471/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This study aimed to evaluate the impact of immunotherapy on survival and brain metastasis (BM) risk in patients with limited-stage small cell lung cancer (LS-SCLC) undergoing prophylactic cranial irradiation (PCI), and to analyze related prognostic factors. Methods A retrospective analysis was conducted on 103 LS-SCLC patients who received PCI between February 2016 and July 2024. Patients were categorized into immunotherapy (n = 42) and non-immunotherapy (n = 61) groups. The Kaplan-Meier method and Cox proportional hazards models were used for survival and prognostic analysis. Results The median overall survival (mOS) for the entire cohort was 32.0 months (95% CI: 26.8–37.2). The immunotherapy group demonstrated significantly prolonged mOS (38.0 vs. 27.0 months, p = 0.019) and a lower 3-year BM rate (10.8% vs. 31.7%, p = 0.035) compared to the non-immunotherapy group. Subgroup analysis revealed that patients receiving immunotherapy before-PCI (n = 27) had more pronounced OS benefit (mOS: 40.0 vs. 27.0 months, p = 0.007) and lower BM risk (3-year BM rate: 7.7% vs. 31.7%, p = 0.018) than the non-immunotherapy group. Multivariate analysis identified immunotherapy (HR = 0.48, p = 0.008), no smoking history (HR = 0.46, p = 0.004), and the presence of extracranial metastasis (HR = 1.92, p = 0.012) as independent factors for OS. Immunotherapy (HR = 0.25, p = 0.019) and no smoking history (HR = 0.20, p = 0.008) were independent protective factors against BM. Conclusion For LS-SCLC patients receiving PCI, early integration of immunotherapy, particularly before PCI, effectively reduces the incidence of brain metastasis and significantly improves survival. Smoking history remains a significant adverse prognostic factor in clinical management. Figures Figure 1 Figure 2 Figure 3 2. INTRODUCTION Lung cancer remains the leading cause of cancer-related mortality worldwide. Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases[ 1 – 3 ]. As an aggressive neuroendocrine tumor, the median overall survival (OS) for limited-stage SCLC (LS-SCLC) patients following standard chemoradiotherapy is approximately 25–30 months[ 4 , 5 ]. Brain metastasis (BM) poses a major therapeutic challenge and is a common cause of treatment failure in SCLC. Approximately 10–24% of SCLC patients present with BM at initial diagnosis, and over half develop BM during the disease course[ 6 ]. Prophylactic cranial irradiation (PCI) reduces the risk of BM and improves OS in patients who respond well to definitive chemoradiotherapy[ 7 ]. However, BM still occurs in 10–32% of patients after PCI[ 8 – 11 ], and high-risk factors remain controversial. Notably, previous related studies have not adequately addressed the impact of immunotherapy[ 12 – 16 ]. In recent years, immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for SCLC. The ADRIATIC trial demonstrated that durvalumab consolidation therapy after concurrent chemoradiotherapy for LS-SCLC significantly improved both progression-free survival (PFS) and OS[ 17 ]. This study also suggested the potential synergy between PCI and immunotherapy in reducing BM risk. However, the proportion of patients receiving PCI in that trial was limited, and it did not provide sufficient evidence regarding optimal sequencing or beneficiary populations for the combination. Therefore, further investigation is warranted to determine how best to integrate PCI with immunotherapy to maximize efficacy. To address these gaps, this multicenter retrospective study aimed to explore the impact of immunotherapy on OS and BM in LS-SCLC patients receiving PCI and to identify independent high-risk factors for BM after PCI, thereby providing real-world evidence for optimizing comprehensive treatment strategies. 3. MATERIALS AND METHODS 3.1 General Information Clinical data from 103 SCLC patients who underwent PCI between February 2016 and July 2024 at the Affiliated Hospital of Xuzhou Medical University and Xuzhou Cancer Hospital were retrospectively collected. Data were obtained via the hospital's electronic medical record system, including: (1) Demographic characteristics: gender, age, smoking history. (2) Tumor characteristics: restaged using the 9th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. (3) Treatment information: including chemotherapy cycles and regimens, chemoradiotherapy mode (sequential/concurrent), chest radiotherapy dose and fractionation scheme, efficacy evaluation, and the temporal relationship between immunotherapy and PCI, etc. 3.2 Inclusion and Exclusion Criteria Inclusion criteria: (1) Pathologically confirmed SCLC; (2) Clinical stage: limited-stage; (3) Achieved complete remission (CR) or partial remission (PR) after chemoradiotherapy; (4) No intracranial metastasis confirmed by brain MRI prior to PCI; (5) Received standard PCI treatment; (6) No history of other malignant tumors; (7) Complete medical records and follow-up data. Exclusion criteria: (1) Mixed histology type; (2) PCI performed after disease progression; (3) Development of other primary malignancies during the treatment period; (4) Lost to follow-up immediately after PCI; (5) Immunotherapy initiated only after the occurrence of brain metastasis; (6) Severe organ dysfunction or incomplete data. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (Ethics No.: XYFY2025-KL669-01). 3.3 Treatment and Efficacy Evaluation Systemic chemotherapy: All patients received ≥ 2 cycles of platinum-based chemotherapy (primarily etoposide plus platinum) prior to PCI. Chest radiotherapy: Employed conventional fractionation (60–70 Gy/1.8-2.0 Gy per fraction) or accelerated hyperfractionation (45 Gy/1.5 Gy twice daily). Target volumes encompassed residual lesions and originally involved nodal areas after-chemotherapy. PCI: Patients achieving PR or CR after chemoradiotherapy proceeded to PCI, with brain MRI performed in all patients beforehand to rule out metastasis. PCI was delivered using intensity-modulated radiotherapy (IMRT) with a hippocampal-sparing technique (maximum dose to hippocampus < 17 Gy), following a regimen of 25 Gy in 10 fractions. Immunotherapy: Agents, cycles, and timing (before or after PCI) were individualized based on physician's discretion and patient condition. 3.4 Endpoints and Follow-up Intracranial progression-free survival (iPFS) was defined as the time from initial treatment to radiologically confirmed brain metastasis. Overall survival (OS) was defined as the time from initial treatment to death from any cause. Progression-free survival (PFS) was defined as the time from initial treatment to disease progression at any site or death. The last follow-up date was July 2025. After PCI completion, brain MRI or CT scans were performed every 3 months for the first 2 years, every 6 months from years 2 to 5, and annually thereafter. If neurological symptoms such as headache, dizziness, or severe vomiting occurred during follow-up, brain MRI or CT was performed promptly. Follow-up methods included telephone calls, review of medical records during hospital visits, and census data. 3.5 Statistical Analysis Statistical analyses were performed using SPSS 27.0 and R.Studio software. Qualitative data were compared between the immunotherapy and non-immunotherapy groups using the Chi-square test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and between-group differences were assessed with the Log-rank test. Univariate and multivariate Cox proportional hazards regression models were used for prognostic factor analysis. Variables with P < 0.05 in univariate analysis were included in the multivariate analysis. A two-sided P value < 0.05 was considered statistically significant. 4. RESULTS 4.1 Patient Baseline Characteristics A total of 103 patients were included in this study. The median follow-up time was 26.0 months (range: 10.0–76.0 months). There were no statistically significant differences in baseline characteristics between the immunotherapy group and the non-immunotherapy group, including gender, age, smoking history, stage, treatment regimen, and initial treatment response (all P > 0.05) (Table 1 ). 4.2 Survival Analysis of the Entire Cohort By the last follow-up, 63 patients (61.2%) had died in the entire cohort. The median OS (mOS) for the entire cohort was 32.0 months (95% CI: 26.8–37.2 months). The mOS for the group that developed brain metastasis was 25.0 months, significantly lower than the 33.0 months in the group without brain metastasis (P = 0.035) (Fig. 1 ). 4.3 Impact of Immunotherapy on Survival Outcomes OS: The mOS in the immunotherapy group was 38.0 months (95% CI: 31.5–44.5 months), significantly longer than the 27.0 months (95% CI: 21.8–32.2 months) in the non-immunotherapy group (P = 0.019) (Fig. 2 A). iPFS: The 3-year brain metastasis rate from the start of treatment was 23.3% for the entire cohort. The 3-year brain metastasis rates were 10.8% and 31.7% for the immunotherapy and non-immunotherapy groups, respectively, showing a statistically significant difference (P = 0.035) (Fig. 2 B). PFS: The median PFS (mPFS) was 36.0 months (95% CI: 23.1–48.9 months) in the immunotherapy group and 22.0 months (95% CI: 13.8–30.2 months) in the non-immunotherapy group, with no statistically significant difference between the two groups (P = 0.191) (Fig. 2 C). The 3-year brain metastasis rate from the end of PCI was 28.4% for the entire cohort. The rates were 25.8% and 32.0% for the immunotherapy and non-immunotherapy groups, respectively, also showing a statistically significant difference (P = 0.038). 4.4 Prognostic Factors for OS Univariate analysis showed that smoking (HR = 0.55, 95% CI: 0.33–0.93, P = 0.024), extracranial metastasis (HR = 1.88, 95% CI: 1.13–3.14, P = 0.015), and immunotherapy (HR = 0.54, 95% CI: 0.32–0.92, P = 0.023) were significantly associated with OS (Table 2 ). These prognostic factors were included in the multivariate Cox analysis, which identified smoking (HR = 0.46, 95% CI: 0.27–0.78, P = 0.004), extracranial metastasis (HR = 1.92, 95% CI: 1.15–3.20, P = 0.012), and immunotherapy (HR = 0.48, 95% CI: 0.28–0.83, P = 0.008) as independent prognostic factors for OS. Factors such as age, T stage, N stage, clinical stage, initial treatment response, chemoradiotherapy mode, and radiotherapy fractionation were not significantly correlated with OS (Table 3 ). 4.5 Incidence and Prognostic Factors for Brain Metastasis By the last follow-up, 19 patients (18.4%) had developed brain metastasis. A total of 14 patients had multiple brain metastases, 4 had metastases in both the cerebrum and cerebellum, and 1 had metastasis only in the cerebellum. The largest metastatic lesion measured 25 mm in diameter and was a solitary metastasis in the temporal lobe. Among the 18 patients with cerebral metastasis, the frontal and temporal lobes were the most common sites. Univariate analysis showed that smoking (HR = 0.26, 95% CI: 0.08–0.79, P = 0.017) and immunotherapy (HR = 0.32, 95% CI: 0.11–0.98, P = 0.046) were significantly associated with brain metastasis (Table 2 ). These influencing factors were included in the multivariate analysis, which identified smoking history (HR = 0.20, 95% CI: 0.06–0.66, P = 0.008) and immunotherapy (HR = 0.25, 95% CI: 0.08–0.80, P = 0.019) as independent prognostic factors for brain metastasis (Table 3 ). 4.6 Subgroup Analysis Based on Timing of Immunotherapy Based on the relative timing of immunotherapy and PCI, patients were divided into three groups: before-PCI immunotherapy group (27 cases), after-PCI immunotherapy group (15 cases), and no immunotherapy group (61 cases). The mOS for the three groups was 40.0 months (95% CI: 33.2–46.8 months), 31.0 months (95% CI: 23.9–38.6 months), and 27.0 months (95% CI: 21.8–32.2 months), respectively. The 3-year brain metastasis rates for the three groups were 7.7%, 57.8%, and 31.7%, respectively. Compared to the no immunotherapy group, the before-PCI immunotherapy group showed significantly prolonged OS (P = 0.007) and a significantly lower brain metastasis rate (P = 0.018). In contrast, the after-PCI immunotherapy group showed no statistically significant differences in OS (P = 0.087 for comparison with before-PCI group; P = 0.497 for comparison with no immunotherapy group) or brain metastasis rate (P = 0.121 for comparison with before-PCI group; P = 0.534 for comparison with no immunotherapy group) compared to either of the other two groups (Fig. 3 ). 4.7 Extracranial Progression A total of 43 patients (41.7%) experienced extracranial progression during follow-up. The most common sites of extracranial progression were lymph nodes (24 cases), lung (16 cases), bone (10 cases), liver (9 cases), adrenal glands (8 cases), pancreas (5 cases), pericardium, and pleura. Treatments following extracranial progression included systemic chemotherapy, immunotherapy, targeted therapy, and local radiotherapy to metastatic sites. Table 1 Baseline Characteristics of 103 Patients Non-immunotherapy (n = 61) Immunotherapy (n = 42) P Gender 0.398 Male 44(72.1%) 27(64.3%) Female 17(27.9%) 15(35.7%) Age 0.445 ≤ 60 23(37.7%) 19(45.2%) >60 38(62.3%) 23(54.8%) Smoking 0.668 Yes 36(59.0%) 23(54.8%) No 25(41.0%) 19(45.2%) T Stage 0.323 1 14(23.0%) 6(14.3%) 2 14(23.0%) 14(33.3%) 3 26(42.6%) 14(33.3%) 4 7(11.5%) 8(19.0%) N Stage 0.149 0 9(14.8%) 7(16.7%) 1 9(14.8%) 1(2.4%) 2 26(42.6%) 24(57.1%) 3 17(27.9%) 10(23.8%) TNM Stage 0.749 Ⅰ 5(8.2%) 2(4.8%) Ⅱ 16(26.2%) 9(21.4%) Ⅲ 40(65.6%) 31(73.8%) Chemotherapy 0.156 EC/EP 60(98.4%) 38(90.5%) Other Platinum-based 1(1.6%) 4(9.5%) Chemotherapy Cycles 0.855 ≤ 4 14(23.0%) 9(21.4%) >4 47(77.0%) 33(78.6%) Chemoradiotherapy 0.114 No 12(19.7%) 3(7.1%) Concurrent 18(29.5%) 19(45.2%) Sequential 31(50.8%) 20(47.6%) RT Fractionation 0.167 No 12(19.7%) 3(7.1%) Conventional 46(75.4%) 35(83.3%) Hyperfractionated 3(5.0%) 4(9.5%) Initial Response 0.414 PR 53(86.9%) 34(81.0%) CR 8(13.1%) 8(19.0%) Table 2 Univariate Cox Analysis for OS and BM Risk Factors OS BM HR(95%CI) P HR(95%CI) P Gender(Male vs Female) 0.60(0.34–1.04) 0.069 1.00(0.39–2.57) 0.999 Age(≤ 60 vs >60) 1.38(0.82–2.30) 0.224 1.14(0.46–2.87) 0.775 Smoking(Yes vs No) 0.55(0.33–0.93) 0.024 0.26(0.08–0.79) 0.017 T Stage 1 2 1.09(0.51–2.33) 0.819 0.54(0.12–2.41) 0.418 3 1.50(0.76–2.96) 0.242 1.62(0.51–5.09) 0.411 4 0.61(0.23–1.66) 0.335 0.29(0.03–2.60) 0.267 N Stage 0 1 1.49(0.57–3.93) 0.416 0.95(0.19–4.66) 0.948* 2 1.08(0.53–2.24) 0.827 0.79(0.30–2.10) 0.643* 3 1.04(0.47–2.29) 0.929 1.00 (Reference) TNM Stage Ⅰ Ⅱ 2.18(0.72–6.58) 0.166 1.21(0.42–3.43) 0.727* Ⅲ 1.64(0.59–4.61) 0.345 1.00 (Reference) Chemotherapy(EC/EP vs Other) 2.45(0.96–6.23) 0.061 3.12(0.70-13.85) 0.134 Chemotherapy Cycles(≤ 4 vs >4) 0.58(0.33-1.00) 0.051 1.41(0.41–4.84) 0.589 Chemoradiotherapy No Concurrent 0.77(0.37–1.64) 0.502 0.76(0.22–2.61) 0.667 Sequential 1.25(0.63–2.49) 0.531 0.73(0.22–2.44) 0.611 RT Fractionation Fractionation No Conventional 1.05(0.54–2.04) 0.878 0.76(0.25–2.31) 0.63 Hyperfractionated 0.67(0.19–2.40) 0.537 0.61(0.07–5.52) 0.66 Initial Response(PR vs CR) 0.60(0.13–2.74) 0.152 0.22(0.03–1.69) 0.146 Extracranial Metastasis(No vs Yes) 1.88(1.13–3.14) 0.015 1.95(0.78–4.89) 0.153 Immunotherapy(No vs Yes) 0.54(0.32–0.92) 0.023 0.32(0.11–0.98) 0.046 Note: *: In this study, no patients with clinical stage I or N stage 0 developed BM; therefore, a higher stage was used as the reference group. Table 3 Multivariate Cox Analysis for OS and BM Risk Factors OS BM HR(95%CI) P HR(95%CI) P Smoking(Yes vs No) 0.46(0.27–0.78) 0.004 0.20(0.06–0.66) 0.008 Extracranial Metastasis(No vs Yes) 1.92(1.15–3.20) 0.012 Immunotherapy(No vs Yes) 0.48(0.28–0.83) 0.008 0.25(0.08–0.80) 0.019 5. DISCUSSION This multicenter retrospective analysis revealed that for LS-SCLC patients receiving PCI, combining immunotherapy before PCI maximally reduces the risk of brain metastasis and significantly prolongs OS. Furthermore, smoking was identified as a significant adverse prognostic risk factor. These findings provide real-world evidence for optimizing the comprehensive treatment strategy for LS-SCLC. In this study, the addition of immunotherapy significantly improved patient OS and reduced the brain metastasis rate, with benefits primarily concentrated in the subgroup receiving immunotherapy prior to PCI. This finding aligns with and reinforces the results of the recently published ADRIATIC trial, which demonstrated both OS and PFS benefits with durvalumab versus placebo, regardless of whether patients received PCI[ 17 ]. A post-hoc analysis of that trial identified brain metastasis as the most common site of recurrence, and PCI significantly impacted this risk: the brain metastasis rate was only 2.8% in patients receiving durvalumab plus PCI, compared to 11.5% in the durvalumab monotherapy group. In the placebo group, the rate was 6.3% for those receiving PCI versus 19.5% for those not receiving PCI. This suggests a potential synergistic effect between PCI and immunotherapy in reducing brain metastasis. Our results can be viewed as a validation and deeper exploration of this pattern in a real-world setting, indicating that the period before PCI is a critical window for immunotherapy to exert its prophylactic, brain-protective effect. In contrast, initiating immunotherapy after PCI (often as salvage therapy) did not demonstrate significant benefit. The mechanisms underlying this phenomenon require further investigation. Current research on immunotherapy in LS-SCLC is limited. Drawing insights from studies in other cancer types: radiotherapy can disrupt tight junctions of cerebrovascular endothelial cells, increasing blood-brain barrier permeability; induce tumor cell death, releasing a large number of tumor-associated antigens and activating dendritic cell antigen presentation; upregulate MHC class I molecules on tumor cells, adhesion molecules like VCAM-1 on tumor vascular endothelial cells, and PD-L1 expression on tumor cells. Meanwhile, immune checkpoint inhibitors (ICIs) can restore immune cells' ability to recognize and eliminate tumor cells[ 18 – 20 ]. In summary, the local effects of radiotherapy can activate and enhance systemic immune responses, leading to the regression of distant, radiographically undetectable micrometastases—the "abscopal effect." Concurrently, the long-lived memory T cells generated by the combination of radiotherapy and immunotherapy can provide durable immune surveillance, thereby reducing the risk of long-term metastasis. It is noteworthy that this study found immunotherapy significantly improved OS but did not prolong PFS. This "dissociation" between PFS and OS benefit is not uncommon in cancer immunotherapy and was also observed in the STIMULI trial for LS-SCLC[ 21 ]. This may reflect the unique mode of action of immunotherapy: it may not completely prevent short-term radiographic progression, but by inducing sustained immune memory and altering the pattern of disease progression, it ultimately translates into long-term survival benefit—the so-called "tailing effect." The ADRIATIC trial showed immunotherapy primarily reduced the rate of distant metastases, including brain metastases[ 17 ], suggesting its effect on controlling subclinical micrometastases might be more directly reflected in long-term survival rather than short-term PFS. Therefore, OS remains the ultimate efficacy measure for LS-SCLC patients receiving immunotherapy. Additionally, we observed that in our study's non-immunotherapy group, few patients progressed more than 24 months after treatment initiation, and all patients had completed PCI within 17 months. This may be because, prior to the publication of the ADRIATIC results, a significant proportion of LS-SCLC patients in real-world practice received immunotherapy as salvage therapy only after disease progression following PCI. This study reaffirms that smoking is an independent adverse prognostic factor for LS-SCLC patients, associated with increased risks of both death and brain metastasis, consistent with findings from multiple clinical studies[ 22 – 26 ]. The underlying mechanisms may involve two aspects: first, long-term smoking leads to reduced cardiopulmonary functional reserve, limiting the tolerance and full implementation of chemoradiotherapy and immunotherapy; second, studies as early as 2017 have suggested a link between smoking and accelerated brain metastasis development in lung cancer[ 27 ]. Wu SY et al. conducted a deeper investigation into this phenomenon, finding that nicotine in cigarettes increases the expression of genes such as arginase-1, arginase-2, and CD204, and activates the JAK/STAT3 signaling pathway, promoting M2-type microglial polarization. This leads to increased secretion of insulin-like growth factor-1 (IGF1) and chemokine CCL20, thereby accelerating the rapid formation of brain metastases[ 28 ]. While this study provides a detailed analysis of prognostic factors affecting LS-SCLC patients after PCI, with particular focus on the therapeutic value of immunotherapy in this population, it has certain limitations. First, as a retrospective analysis from centers within the same region, selection bias and confounding bias are inevitable. Second, for patients in the "after-PCI immunotherapy" group, it was difficult to precisely retrospectively ascertain the exact disease status (e.g., whether progression to extensive-stage had already occurred) at the time immunotherapy was initiated. This may have partially affected the efficacy evaluation for this subgroup. Prospective clinical trials are ultimately needed to confirm these findings. In conclusion, within the comprehensive treatment of LS-SCLC, early integration of immunotherapy before PCI can effectively reduce the brain metastasis rate and significantly prolong patient OS, highlighting the importance of optimizing treatment sequencing. Smoking is a clear adverse prognostic factor and should be fully considered in clinical decision-making. Declarations Author Contributions: Conceptualization, Liu Zifang and Ding Xin; methodology, Liu Zifang; software, Zhang Xinyan; validation, Liu Zifang and Ding Xin; formal analysis, Zhang Xinyan; investigation, Cao Wenjing; resources, Jin Huacong; data curation, Liu Zifang; writing—original draft preparation, Liu Zifang; writing—review and editing, Liu Zifang and Ding Xin; project administration, Ding Xin; funding acquisition, Ding Xin.All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Major Project of Basic Science (Natural Science) Research in Jiangsu Province Higher Education Institutions ,grant number 24KJA320009. Institutional Review Board Statement: The study was performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and approved by the Medical Ethics Committee of The Affiliated Hospital of Xuzhou Medical University (Ethics Approval No.: XYFY2025-KL669-01). Informed Consent Statement: Written informed consent has been obtained from the patients to publish this paper. Data Availability Statement: Original data are available from the corresponding author on reasonable request. The corresponding author had final responsibility for the decision to submit for publication. Conflicts of Interest: The authors declare no conflicts of interest. References Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS (2021) Lung cancer. Lancet 398:535–554. https://doi.org/10.1016/s0140-6736(21)00312-3 Han B, Zheng R, Zeng H et al (2024) Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 4:47–53. https://doi.org/10.1016/j.jncc.2024.01.006 Gazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17:725–737. https://doi.org/10.1038/nrc.2017.87 Bogart J, Wang X, Masters G et al (2023) High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538. J Clin Oncol 41:2394–2402. https://doi.org/10.1200/jco.22.01359 Faivre-Finn C, Snee M, Ashcroft L et al (2017) Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 18:1116–1125. https://doi.org/10.1016/s1470-2045(17)30318-2 石远凯 (2021) 肺癌脑转移中国治疗指南(2021年版). Chinese Journal of Oncology 43 Aupérin A, Arriagada R, Pignon JP et al (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476–484. https://doi.org/10.1056/nejm199908123410703 Chen Y, Wang Y, Ren F et al (2022) Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study. Respir Res 23:274. https://doi.org/10.1186/s12931-022-02196-2 Farris MK, Wheless WH, Hughes RT et al (2019) Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary? Pract Radiat Oncol 9:e599–e607. https://doi.org/10.1016/j.prro.2019.06.014 Pan L, Fan X, Wang L et al (2023) Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the magnetic resonance imaging era. Cancer Med 12:2484–2492. https://doi.org/10.1002/cam4.5082 Ito K, Nakajima Y, Minakami S et al (2024) Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the modern magnetic resonance imaging era may be omitted: a propensity score-matched analysis. J Radiat Res 65:805–812. https://doi.org/10.1093/jrr/rrae087 Levy A, Le Péchoux C, Mistry H et al (2019) Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer Patients: Secondary Findings From the Prospective Randomized Phase 3 CONVERT Trial. J Thorac Oncol 14:294–297. https://doi.org/10.1016/j.jtho.2018.09.019 Guo D, Jing W, Zhu H et al (2018) Clinical value of carcinoembryonic antigen for predicting the incidence of brain metastases and survival in small cell lung cancer patients treated with prophylactic cranial irradiation. Cancer Manag Res 10:3199–3205. https://doi.org/10.2147/cmar.S175043 Manapov F, Klöcking S, Niyazi M et al (2012) Primary tumor response to chemoradiotherapy in limited-disease small-cell lung cancer correlates with duration of brain-metastasis free survival. J Neurooncol 109:309–314. https://doi.org/10.1007/s11060-012-0894-4 Yonemori K, Sumi M, Fujimoto N, Ito Y, Imai A, Kagami Y, Ikeda H (2005) Pro-gastrin-releasing peptide as a factor predicting the incidence of brain metastasis in patients with small cell lung carcinoma with limited disease receiving prophylactic cranial irradiation. Cancer 104:811–816. https://doi.org/10.1002/cncr.21238 Sas-Korczyńska B, Korzeniowski S, Wójcik E (2010) Comparison of the effectiveness of late and early prophylactic cranial irradiation in patients with limited-stage small cell lung cancer. Strahlenther Onkol 186:315–319. https://doi.org/10.1007/s00066-010-2088-3 Cheng Y, Spigel DR, Cho BC et al (2024) Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med 391:1313–1327. https://doi.org/10.1056/NEJMoa2404873 Pin Y, Paix A, Todeschi J, Antoni D, Proust F, Noël G (2020) Brain metastasis formation and irradiation by stereotactic radiation therapy combined with immunotherapy: A systematic review. Crit Rev Oncol Hematol 149:102923. https://doi.org/10.1016/j.critrevonc.2020.102923 Paisana E, Cascão R, Alvoeiro M et al (2025) Immunotherapy in lung cancer brain metastases. NPJ Precis Oncol 9:130. https://doi.org/10.1038/s41698-025-00901-0 Rios-Hoyo A, Arriola E (2023) Immunotherapy and brain metastasis in lung cancer: connecting bench side science to the clinic. Front Immunol 14:1221097. https://doi.org/10.3389/fimmu.2023.1221097 Peters S, Pujol JL, Dafni U et al (2022) Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4–12 STIMULI trial. Ann Oncol 33:67–79. https://doi.org/10.1016/j.annonc.2021.09.011 Rudin CM, Brambilla E, Faivre-Finn C, Sage J (2021) Small-cell lung cancer. Nat Rev Dis Primers 7:3. https://doi.org/10.1038/s41572-020-00235-0 Pesch B, Kendzia B, Gustavsson P et al (2012) Cigarette smoking and lung cancer–relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 131:1210–1219. https://doi.org/10.1002/ijc.27339 Torres-Durán M, Curiel-García MT, Ruano-Ravina A et al (2021) Small-cell lung cancer in never-smokers. ESMO Open 6:100059. https://doi.org/10.1016/j.esmoop.2021.100059 Liu X, Jiang T, Li W et al (2018) Characterization of never-smoking and its association with clinical outcomes in Chinese patients with small-cell lung cancer. Lung Cancer 115:109–115. https://doi.org/10.1016/j.lungcan.2017.11.022 Sun JM, Choi YL, Ji JH et al (2015) Small-cell lung cancer detection in never-smokers: clinical characteristics and multigene mutation profiling using targeted next-generation sequencing. Ann Oncol 26:161–166. https://doi.org/10.1093/annonc/mdu504 Shenker RF, McTyre ER, Ruiz J et al (2017) The Effects of smoking status and smoking history on patients with brain metastases from lung cancer. Cancer Med 6:944–952. https://doi.org/10.1002/cam4.1058 Wu SY, Xing F, Sharma S et al (2020) Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J Exp Med 217. https://doi.org/10.1084/jem.20191131 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8542471","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":581483077,"identity":"12c69e16-5dfe-470c-90e5-aa68f70a72fc","order_by":0,"name":"Zifang Liu","email":"","orcid":"","institution":"Xuzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zifang","middleName":"","lastName":"Liu","suffix":""},{"id":581483078,"identity":"7d8d39fc-a5e3-43f9-818f-b6129e537949","order_by":1,"name":"Xinyan Zhang","email":"","orcid":"","institution":"Xuzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xinyan","middleName":"","lastName":"Zhang","suffix":""},{"id":581483080,"identity":"71415ef7-5dc7-4816-9e10-4e7d44858d6f","order_by":2,"name":"Wenjing Cao","email":"","orcid":"","institution":"Xuzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Cao","suffix":""},{"id":581483081,"identity":"d35b110e-8bac-4368-8059-6ab326518586","order_by":3,"name":"Huacong Jin","email":"","orcid":"","institution":"Xuzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Huacong","middleName":"","lastName":"Jin","suffix":""},{"id":581483082,"identity":"3dbebbad-7468-4cf6-9131-2d7053359a1a","order_by":4,"name":"Xin Ding","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYDCCwyDCgEGOjb2x8eEHUrQY8/EcbjaWIErLAQiVOE8ivU2AhxgdfMd5D7/mKbhjzCb5sI1BgsFOTreBgBbJw3xpljMMnsmxSSe2PShgSDY2O0BAi8FhHjODDwaHjYFa2g0kGA4kbiNKS4LB4cQ2yYNtEjxEajF+8AGkRYKRSC2SQFsYZ4AcxpMIDGQDIvzCd/6M8WeeP4fl5NuPP3z4ocJOjqAWIGBDikADwspBgJm4ZDIKRsEoGAUjFwAAU6tArZ8r6QgAAAAASUVORK5CYII=","orcid":"","institution":"Affiliated Hospital of Xuzhou Medical College","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Ding","suffix":""}],"badges":[],"createdAt":"2026-01-07 14:09:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8542471/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8542471/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101398201,"identity":"e613835f-4e4e-4183-8784-a8ccfc79c0b1","added_by":"auto","created_at":"2026-01-29 09:40:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33535,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of OS between BM and non-BM groups.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8542471/v1/4b60c7243bf5264e10e6800c.png"},{"id":101365726,"identity":"f74d8fa0-1669-450c-911e-bf16cb60248c","added_by":"auto","created_at":"2026-01-29 00:57:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":91099,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of OS (A) and iPFS (B) and PFS(C) between Immunotherapy and Non-immunotherapy Groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8542471/v1/1761b89061ecf719a5d9874e.png"},{"id":101365724,"identity":"66575317-4b58-415e-8a30-64c9d6c18810","added_by":"auto","created_at":"2026-01-29 00:57:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":51224,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of OS (A) and iPFS (B) based on Immunotherapy Timing.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8542471/v1/ad0b3a4d81480b0dfab894be.png"},{"id":102295167,"identity":"dd1529fb-c3b8-474d-952a-6fdf33ef5239","added_by":"auto","created_at":"2026-02-10 10:09:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020441,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8542471/v1/beceadcf-6388-4339-92ac-0aa3bc42cf10.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immunotherapy Improves Survival and Reduces Brain Metastasis Risk in Limited- Stage Small Cell Lung Cancer Patients Receiving Prophylactic Cranial Irradiation","fulltext":[{"header":"2. INTRODUCTION","content":"\u003cp\u003eLung cancer remains the leading cause of cancer-related mortality worldwide. Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. As an aggressive neuroendocrine tumor, the median overall survival (OS) for limited-stage SCLC (LS-SCLC) patients following standard chemoradiotherapy is approximately 25\u0026ndash;30 months[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Brain metastasis (BM) poses a major therapeutic challenge and is a common cause of treatment failure in SCLC. Approximately 10\u0026ndash;24% of SCLC patients present with BM at initial diagnosis, and over half develop BM during the disease course[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Prophylactic cranial irradiation (PCI) reduces the risk of BM and improves OS in patients who respond well to definitive chemoradiotherapy[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, BM still occurs in 10\u0026ndash;32% of patients after PCI[\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and high-risk factors remain controversial. Notably, previous related studies have not adequately addressed the impact of immunotherapy[\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for SCLC. The ADRIATIC trial demonstrated that durvalumab consolidation therapy after concurrent chemoradiotherapy for LS-SCLC significantly improved both progression-free survival (PFS) and OS[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This study also suggested the potential synergy between PCI and immunotherapy in reducing BM risk. However, the proportion of patients receiving PCI in that trial was limited, and it did not provide sufficient evidence regarding optimal sequencing or beneficiary populations for the combination. Therefore, further investigation is warranted to determine how best to integrate PCI with immunotherapy to maximize efficacy.\u003c/p\u003e \u003cp\u003eTo address these gaps, this multicenter retrospective study aimed to explore the impact of immunotherapy on OS and BM in LS-SCLC patients receiving PCI and to identify independent high-risk factors for BM after PCI, thereby providing real-world evidence for optimizing comprehensive treatment strategies.\u003c/p\u003e"},{"header":"3. MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e3.1 General Information\u003c/h2\u003e \u003cp\u003eClinical data from 103 SCLC patients who underwent PCI between February 2016 and July 2024 at the Affiliated Hospital of Xuzhou Medical University and Xuzhou Cancer Hospital were retrospectively collected. Data were obtained via the hospital's electronic medical record system, including: (1) Demographic characteristics: gender, age, smoking history. (2) Tumor characteristics: restaged using the 9th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. (3) Treatment information: including chemotherapy cycles and regimens, chemoradiotherapy mode (sequential/concurrent), chest radiotherapy dose and fractionation scheme, efficacy evaluation, and the temporal relationship between immunotherapy and PCI, etc.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Inclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003eInclusion criteria: (1) Pathologically confirmed SCLC; (2) Clinical stage: limited-stage; (3) Achieved complete remission (CR) or partial remission (PR) after chemoradiotherapy; (4) No intracranial metastasis confirmed by brain MRI prior to PCI; (5) Received standard PCI treatment; (6) No history of other malignant tumors; (7) Complete medical records and follow-up data. Exclusion criteria: (1) Mixed histology type; (2) PCI performed after disease progression; (3) Development of other primary malignancies during the treatment period; (4) Lost to follow-up immediately after PCI; (5) Immunotherapy initiated only after the occurrence of brain metastasis; (6) Severe organ dysfunction or incomplete data. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (Ethics No.: XYFY2025-KL669-01).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Treatment and Efficacy Evaluation\u003c/h2\u003e \u003cp\u003eSystemic chemotherapy: All patients received\u0026thinsp;\u0026ge;\u0026thinsp;2 cycles of platinum-based chemotherapy (primarily etoposide plus platinum) prior to PCI. Chest radiotherapy: Employed conventional fractionation (60\u0026ndash;70 Gy/1.8-2.0 Gy per fraction) or accelerated hyperfractionation (45 Gy/1.5 Gy twice daily). Target volumes encompassed residual lesions and originally involved nodal areas after-chemotherapy. PCI: Patients achieving PR or CR after chemoradiotherapy proceeded to PCI, with brain MRI performed in all patients beforehand to rule out metastasis. PCI was delivered using intensity-modulated radiotherapy (IMRT) with a hippocampal-sparing technique (maximum dose to hippocampus\u0026thinsp;\u0026lt;\u0026thinsp;17 Gy), following a regimen of 25 Gy in 10 fractions. Immunotherapy: Agents, cycles, and timing (before or after PCI) were individualized based on physician's discretion and patient condition.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Endpoints and Follow-up\u003c/h2\u003e \u003cp\u003eIntracranial progression-free survival (iPFS) was defined as the time from initial treatment to radiologically confirmed brain metastasis. Overall survival (OS) was defined as the time from initial treatment to death from any cause. Progression-free survival (PFS) was defined as the time from initial treatment to disease progression at any site or death. The last follow-up date was July 2025. After PCI completion, brain MRI or CT scans were performed every 3 months for the first 2 years, every 6 months from years 2 to 5, and annually thereafter. If neurological symptoms such as headache, dizziness, or severe vomiting occurred during follow-up, brain MRI or CT was performed promptly. Follow-up methods included telephone calls, review of medical records during hospital visits, and census data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS 27.0 and R.Studio software. Qualitative data were compared between the immunotherapy and non-immunotherapy groups using the Chi-square test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and between-group differences were assessed with the Log-rank test. Univariate and multivariate Cox proportional hazards regression models were used for prognostic factor analysis. Variables with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analysis were included in the multivariate analysis. A two-sided P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Patient Baseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 103 patients were included in this study. The median follow-up time was 26.0 months (range: 10.0\u0026ndash;76.0 months). There were no statistically significant differences in baseline characteristics between the immunotherapy group and the non-immunotherapy group, including gender, age, smoking history, stage, treatment regimen, and initial treatment response (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Survival Analysis of the Entire Cohort\u003c/h2\u003e \u003cp\u003eBy the last follow-up, 63 patients (61.2%) had died in the entire cohort. The median OS (mOS) for the entire cohort was 32.0 months (95% CI: 26.8\u0026ndash;37.2 months). The mOS for the group that developed brain metastasis was 25.0 months, significantly lower than the 33.0 months in the group without brain metastasis (P\u0026thinsp;=\u0026thinsp;0.035) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Impact of Immunotherapy on Survival Outcomes\u003c/h2\u003e \u003cp\u003eOS: The mOS in the immunotherapy group was 38.0 months (95% CI: 31.5\u0026ndash;44.5 months), significantly longer than the 27.0 months (95% CI: 21.8\u0026ndash;32.2 months) in the non-immunotherapy group (P\u0026thinsp;=\u0026thinsp;0.019) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003eiPFS: The 3-year brain metastasis rate from the start of treatment was 23.3% for the entire cohort. The 3-year brain metastasis rates were 10.8% and 31.7% for the immunotherapy and non-immunotherapy groups, respectively, showing a statistically significant difference (P\u0026thinsp;=\u0026thinsp;0.035) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003ePFS: The median PFS (mPFS) was 36.0 months (95% CI: 23.1\u0026ndash;48.9 months) in the immunotherapy group and 22.0 months (95% CI: 13.8\u0026ndash;30.2 months) in the non-immunotherapy group, with no statistically significant difference between the two groups (P\u0026thinsp;=\u0026thinsp;0.191) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eThe 3-year brain metastasis rate from the end of PCI was 28.4% for the entire cohort. The rates were 25.8% and 32.0% for the immunotherapy and non-immunotherapy groups, respectively, also showing a statistically significant difference (P\u0026thinsp;=\u0026thinsp;0.038).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Prognostic Factors for OS\u003c/h2\u003e \u003cp\u003eUnivariate analysis showed that smoking (HR\u0026thinsp;=\u0026thinsp;0.55, 95% CI: 0.33\u0026ndash;0.93, P\u0026thinsp;=\u0026thinsp;0.024), extracranial metastasis (HR\u0026thinsp;=\u0026thinsp;1.88, 95% CI: 1.13\u0026ndash;3.14, P\u0026thinsp;=\u0026thinsp;0.015), and immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.54, 95% CI: 0.32\u0026ndash;0.92, P\u0026thinsp;=\u0026thinsp;0.023) were significantly associated with OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These prognostic factors were included in the multivariate Cox analysis, which identified smoking (HR\u0026thinsp;=\u0026thinsp;0.46, 95% CI: 0.27\u0026ndash;0.78, P\u0026thinsp;=\u0026thinsp;0.004), extracranial metastasis (HR\u0026thinsp;=\u0026thinsp;1.92, 95% CI: 1.15\u0026ndash;3.20, P\u0026thinsp;=\u0026thinsp;0.012), and immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.48, 95% CI: 0.28\u0026ndash;0.83, P\u0026thinsp;=\u0026thinsp;0.008) as independent prognostic factors for OS. Factors such as age, T stage, N stage, clinical stage, initial treatment response, chemoradiotherapy mode, and radiotherapy fractionation were not significantly correlated with OS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Incidence and Prognostic Factors for Brain Metastasis\u003c/h2\u003e \u003cp\u003eBy the last follow-up, 19 patients (18.4%) had developed brain metastasis. A total of 14 patients had multiple brain metastases, 4 had metastases in both the cerebrum and cerebellum, and 1 had metastasis only in the cerebellum. The largest metastatic lesion measured 25 mm in diameter and was a solitary metastasis in the temporal lobe. Among the 18 patients with cerebral metastasis, the frontal and temporal lobes were the most common sites.\u003c/p\u003e \u003cp\u003eUnivariate analysis showed that smoking (HR\u0026thinsp;=\u0026thinsp;0.26, 95% CI: 0.08\u0026ndash;0.79, P\u0026thinsp;=\u0026thinsp;0.017) and immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.32, 95% CI: 0.11\u0026ndash;0.98, P\u0026thinsp;=\u0026thinsp;0.046) were significantly associated with brain metastasis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These influencing factors were included in the multivariate analysis, which identified smoking history (HR\u0026thinsp;=\u0026thinsp;0.20, 95% CI: 0.06\u0026ndash;0.66, P\u0026thinsp;=\u0026thinsp;0.008) and immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.25, 95% CI: 0.08\u0026ndash;0.80, P\u0026thinsp;=\u0026thinsp;0.019) as independent prognostic factors for brain metastasis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Subgroup Analysis Based on Timing of Immunotherapy\u003c/h2\u003e \u003cp\u003eBased on the relative timing of immunotherapy and PCI, patients were divided into three groups: before-PCI immunotherapy group (27 cases), after-PCI immunotherapy group (15 cases), and no immunotherapy group (61 cases). The mOS for the three groups was 40.0 months (95% CI: 33.2\u0026ndash;46.8 months), 31.0 months (95% CI: 23.9\u0026ndash;38.6 months), and 27.0 months (95% CI: 21.8\u0026ndash;32.2 months), respectively. The 3-year brain metastasis rates for the three groups were 7.7%, 57.8%, and 31.7%, respectively. Compared to the no immunotherapy group, the before-PCI immunotherapy group showed significantly prolonged OS (P\u0026thinsp;=\u0026thinsp;0.007) and a significantly lower brain metastasis rate (P\u0026thinsp;=\u0026thinsp;0.018). In contrast, the after-PCI immunotherapy group showed no statistically significant differences in OS (P\u0026thinsp;=\u0026thinsp;0.087 for comparison with before-PCI group; P\u0026thinsp;=\u0026thinsp;0.497 for comparison with no immunotherapy group) or brain metastasis rate (P\u0026thinsp;=\u0026thinsp;0.121 for comparison with before-PCI group; P\u0026thinsp;=\u0026thinsp;0.534 for comparison with no immunotherapy group) compared to either of the other two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Extracranial Progression\u003c/h2\u003e \u003cp\u003eA total of 43 patients (41.7%) experienced extracranial progression during follow-up. The most common sites of extracranial progression were lymph nodes (24 cases), lung (16 cases), bone (10 cases), liver (9 cases), adrenal glands (8 cases), pancreas (5 cases), pericardium, and pleura. Treatments following extracranial progression included systemic chemotherapy, immunotherapy, targeted therapy, and local radiotherapy to metastatic sites.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of 103 Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-immunotherapy (n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImmunotherapy (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.398\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44(72.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27(64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(27.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15(35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(37.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19(45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38(62.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23(54.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.668\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36(59.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23(54.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(41.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19(45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.323\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(23.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(23.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26(42.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7(11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(14.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(14.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26(42.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24(57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(27.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNM Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.749\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2(4.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16(26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40(65.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31(73.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEC/EP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60(98.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38(90.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Platinum-based\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy Cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.855\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(23.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47(77.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33(78.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(19.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18(29.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19(45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequential\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31(50.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20(47.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT Fractionation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(19.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConventional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46(75.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35(83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperfractionated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53(86.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34(81.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(13.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8(19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Cox Analysis for OS and BM Risk Factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender(Male vs Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.60(0.34\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00(0.39\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(\u0026le;\u0026thinsp;60 vs \u0026gt;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.38(0.82\u0026ndash;2.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.224\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.14(0.46\u0026ndash;2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.775\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking(Yes vs No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.55(0.33\u0026ndash;0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.26(0.08\u0026ndash;0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.09(0.51\u0026ndash;2.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.54(0.12\u0026ndash;2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.418\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.50(0.76\u0026ndash;2.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.62(0.51\u0026ndash;5.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.61(0.23\u0026ndash;1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29(0.03\u0026ndash;2.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.49(0.57\u0026ndash;3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95(0.19\u0026ndash;4.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.948*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.08(0.53\u0026ndash;2.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.827\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.79(0.30\u0026ndash;2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.643*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.04(0.47\u0026ndash;2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.929\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00 (Reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNM Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.18(0.72\u0026ndash;6.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.21(0.42\u0026ndash;3.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.727*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.64(0.59\u0026ndash;4.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00 (Reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy(EC/EP vs Other)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.45(0.96\u0026ndash;6.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12(0.70-13.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy Cycles(\u0026le;\u0026thinsp;4 vs \u0026gt;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.58(0.33-1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.41(0.41\u0026ndash;4.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.589\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.77(0.37\u0026ndash;1.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76(0.22\u0026ndash;2.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.667\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequential\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.25(0.63\u0026ndash;2.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73(0.22\u0026ndash;2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT Fractionation Fractionation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConventional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.05(0.54\u0026ndash;2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76(0.25\u0026ndash;2.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperfractionated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.67(0.19\u0026ndash;2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.537\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.61(0.07\u0026ndash;5.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Response(PR vs CR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.60(0.13\u0026ndash;2.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.22(0.03\u0026ndash;1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtracranial Metastasis(No vs Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.88(1.13\u0026ndash;3.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.95(0.78\u0026ndash;4.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunotherapy(No vs Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.54(0.32\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.32(0.11\u0026ndash;0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: *: In this study, no patients with clinical stage I or N stage 0 developed BM; therefore, a higher stage was used as the reference group.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate Cox Analysis for OS and BM Risk Factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking(Yes vs No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.46(0.27\u0026ndash;0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20(0.06\u0026ndash;0.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtracranial Metastasis(No vs Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.92(1.15\u0026ndash;3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunotherapy(No vs Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.48(0.28\u0026ndash;0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25(0.08\u0026ndash;0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"5. DISCUSSION","content":"\u003cp\u003eThis multicenter retrospective analysis revealed that for LS-SCLC patients receiving PCI, combining immunotherapy before PCI maximally reduces the risk of brain metastasis and significantly prolongs OS. Furthermore, smoking was identified as a significant adverse prognostic risk factor. These findings provide real-world evidence for optimizing the comprehensive treatment strategy for LS-SCLC.\u003c/p\u003e \u003cp\u003eIn this study, the addition of immunotherapy significantly improved patient OS and reduced the brain metastasis rate, with benefits primarily concentrated in the subgroup receiving immunotherapy prior to PCI. This finding aligns with and reinforces the results of the recently published ADRIATIC trial, which demonstrated both OS and PFS benefits with durvalumab versus placebo, regardless of whether patients received PCI[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A post-hoc analysis of that trial identified brain metastasis as the most common site of recurrence, and PCI significantly impacted this risk: the brain metastasis rate was only 2.8% in patients receiving durvalumab plus PCI, compared to 11.5% in the durvalumab monotherapy group. In the placebo group, the rate was 6.3% for those receiving PCI versus 19.5% for those not receiving PCI. This suggests a potential synergistic effect between PCI and immunotherapy in reducing brain metastasis. Our results can be viewed as a validation and deeper exploration of this pattern in a real-world setting, indicating that the period before PCI is a critical window for immunotherapy to exert its prophylactic, brain-protective effect. In contrast, initiating immunotherapy after PCI (often as salvage therapy) did not demonstrate significant benefit. The mechanisms underlying this phenomenon require further investigation. Current research on immunotherapy in LS-SCLC is limited. Drawing insights from studies in other cancer types: radiotherapy can disrupt tight junctions of cerebrovascular endothelial cells, increasing blood-brain barrier permeability; induce tumor cell death, releasing a large number of tumor-associated antigens and activating dendritic cell antigen presentation; upregulate MHC class I molecules on tumor cells, adhesion molecules like VCAM-1 on tumor vascular endothelial cells, and PD-L1 expression on tumor cells. Meanwhile, immune checkpoint inhibitors (ICIs) can restore immune cells' ability to recognize and eliminate tumor cells[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In summary, the local effects of radiotherapy can activate and enhance systemic immune responses, leading to the regression of distant, radiographically undetectable micrometastases\u0026mdash;the \"abscopal effect.\" Concurrently, the long-lived memory T cells generated by the combination of radiotherapy and immunotherapy can provide durable immune surveillance, thereby reducing the risk of long-term metastasis.\u003c/p\u003e \u003cp\u003eIt is noteworthy that this study found immunotherapy significantly improved OS but did not prolong PFS. This \"dissociation\" between PFS and OS benefit is not uncommon in cancer immunotherapy and was also observed in the STIMULI trial for LS-SCLC[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This may reflect the unique mode of action of immunotherapy: it may not completely prevent short-term radiographic progression, but by inducing sustained immune memory and altering the pattern of disease progression, it ultimately translates into long-term survival benefit\u0026mdash;the so-called \"tailing effect.\" The ADRIATIC trial showed immunotherapy primarily reduced the rate of distant metastases, including brain metastases[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], suggesting its effect on controlling subclinical micrometastases might be more directly reflected in long-term survival rather than short-term PFS. Therefore, OS remains the ultimate efficacy measure for LS-SCLC patients receiving immunotherapy. Additionally, we observed that in our study's non-immunotherapy group, few patients progressed more than 24 months after treatment initiation, and all patients had completed PCI within 17 months. This may be because, prior to the publication of the ADRIATIC results, a significant proportion of LS-SCLC patients in real-world practice received immunotherapy as salvage therapy only after disease progression following PCI.\u003c/p\u003e \u003cp\u003eThis study reaffirms that smoking is an independent adverse prognostic factor for LS-SCLC patients, associated with increased risks of both death and brain metastasis, consistent with findings from multiple clinical studies[\u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The underlying mechanisms may involve two aspects: first, long-term smoking leads to reduced cardiopulmonary functional reserve, limiting the tolerance and full implementation of chemoradiotherapy and immunotherapy; second, studies as early as 2017 have suggested a link between smoking and accelerated brain metastasis development in lung cancer[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Wu SY et al. conducted a deeper investigation into this phenomenon, finding that nicotine in cigarettes increases the expression of genes such as arginase-1, arginase-2, and CD204, and activates the JAK/STAT3 signaling pathway, promoting M2-type microglial polarization. This leads to increased secretion of insulin-like growth factor-1 (IGF1) and chemokine CCL20, thereby accelerating the rapid formation of brain metastases[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile this study provides a detailed analysis of prognostic factors affecting LS-SCLC patients after PCI, with particular focus on the therapeutic value of immunotherapy in this population, it has certain limitations. First, as a retrospective analysis from centers within the same region, selection bias and confounding bias are inevitable. Second, for patients in the \"after-PCI immunotherapy\" group, it was difficult to precisely retrospectively ascertain the exact disease status (e.g., whether progression to extensive-stage had already occurred) at the time immunotherapy was initiated. This may have partially affected the efficacy evaluation for this subgroup. Prospective clinical trials are ultimately needed to confirm these findings.\u003c/p\u003e \u003cp\u003eIn conclusion, within the comprehensive treatment of LS-SCLC, early integration of immunotherapy before PCI can effectively reduce the brain metastasis rate and significantly prolong patient OS, highlighting the importance of optimizing treatment sequencing. Smoking is a clear adverse prognostic factor and should be fully considered in clinical decision-making.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization,\u0026nbsp;Liu Zifang and Ding Xin; methodology, Liu Zifang; software, Zhang Xinyan; validation, Liu Zifang and Ding Xin; formal analysis, Zhang Xinyan; investigation,\u0026nbsp;Cao Wenjing; resources, Jin Huacong; data curation, Liu Zifang; writing—original draft preparation, Liu Zifang; writing—review and editing, Liu Zifang\u0026nbsp;and Ding Xin; project administration,\u0026nbsp;Ding Xin; funding acquisition,\u0026nbsp;Ding Xin.All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research was funded by the Major Project of Basic Science (Natural Science) Research in Jiangsu Province Higher Education Institutions ,grant number 24KJA320009.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u003c/strong\u003e The study was performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and approved by the Medical Ethics Committee of The Affiliated Hospital of Xuzhou Medical University (Ethics Approval No.: XYFY2025-KL669-01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u003c/strong\u003e Written informed consent has been obtained from the patients to publish this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eOriginal data are available from the corresponding author on reasonable request. The corresponding author had final responsibility for the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS (2021) Lung cancer. Lancet 398:535\u0026ndash;554. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0140-6736(21)00312-3\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(21)00312-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan B, Zheng R, Zeng H et al (2024) Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 4:47\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jncc.2024.01.006\u003c/span\u003e\u003cspan address=\"10.1016/j.jncc.2024.01.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17:725\u0026ndash;737. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nrc.2017.87\u003c/span\u003e\u003cspan address=\"10.1038/nrc.2017.87\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogart J, Wang X, Masters G et al (2023) High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung Cancer: CALGB 30610 (Alliance)/RTOG 0538. J Clin Oncol 41:2394\u0026ndash;2402. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/jco.22.01359\u003c/span\u003e\u003cspan address=\"10.1200/jco.22.01359\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaivre-Finn C, Snee M, Ashcroft L et al (2017) Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol 18:1116\u0026ndash;1125. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s1470-2045(17)30318-2\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(17)30318-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e石远凯 (2021) 肺癌脑转移中国治疗指南(2021年版). Chinese Journal of Oncology 43\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAup\u0026eacute;rin A, Arriagada R, Pignon JP et al (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476\u0026ndash;484. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/nejm199908123410703\u003c/span\u003e\u003cspan address=\"10.1056/nejm199908123410703\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Y, Wang Y, Ren F et al (2022) Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study. Respir Res 23:274. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12931-022-02196-2\u003c/span\u003e\u003cspan address=\"10.1186/s12931-022-02196-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFarris MK, Wheless WH, Hughes RT et al (2019) Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary? Pract Radiat Oncol 9:e599\u0026ndash;e607. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.prro.2019.06.014\u003c/span\u003e\u003cspan address=\"10.1016/j.prro.2019.06.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan L, Fan X, Wang L et al (2023) Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the magnetic resonance imaging era. Cancer Med 12:2484\u0026ndash;2492. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cam4.5082\u003c/span\u003e\u003cspan address=\"10.1002/cam4.5082\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto K, Nakajima Y, Minakami S et al (2024) Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the modern magnetic resonance imaging era may be omitted: a propensity score-matched analysis. J Radiat Res 65:805\u0026ndash;812. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/jrr/rrae087\u003c/span\u003e\u003cspan address=\"10.1093/jrr/rrae087\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy A, Le P\u0026eacute;choux C, Mistry H et al (2019) Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer Patients: Secondary Findings From the Prospective Randomized Phase 3 CONVERT Trial. J Thorac Oncol 14:294\u0026ndash;297. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jtho.2018.09.019\u003c/span\u003e\u003cspan address=\"10.1016/j.jtho.2018.09.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo D, Jing W, Zhu H et al (2018) Clinical value of carcinoembryonic antigen for predicting the incidence of brain metastases and survival in small cell lung cancer patients treated with prophylactic cranial irradiation. Cancer Manag Res 10:3199\u0026ndash;3205. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/cmar.S175043\u003c/span\u003e\u003cspan address=\"10.2147/cmar.S175043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManapov F, Kl\u0026ouml;cking S, Niyazi M et al (2012) Primary tumor response to chemoradiotherapy in limited-disease small-cell lung cancer correlates with duration of brain-metastasis free survival. J Neurooncol 109:309\u0026ndash;314. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11060-012-0894-4\u003c/span\u003e\u003cspan address=\"10.1007/s11060-012-0894-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYonemori K, Sumi M, Fujimoto N, Ito Y, Imai A, Kagami Y, Ikeda H (2005) Pro-gastrin-releasing peptide as a factor predicting the incidence of brain metastasis in patients with small cell lung carcinoma with limited disease receiving prophylactic cranial irradiation. Cancer 104:811\u0026ndash;816. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cncr.21238\u003c/span\u003e\u003cspan address=\"10.1002/cncr.21238\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSas-Korczyńska B, Korzeniowski S, W\u0026oacute;jcik E (2010) Comparison of the effectiveness of late and early prophylactic cranial irradiation in patients with limited-stage small cell lung cancer. Strahlenther Onkol 186:315\u0026ndash;319. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00066-010-2088-3\u003c/span\u003e\u003cspan address=\"10.1007/s00066-010-2088-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, Spigel DR, Cho BC et al (2024) Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med 391:1313\u0026ndash;1327. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2404873\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2404873\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePin Y, Paix A, Todeschi J, Antoni D, Proust F, No\u0026euml;l G (2020) Brain metastasis formation and irradiation by stereotactic radiation therapy combined with immunotherapy: A systematic review. Crit Rev Oncol Hematol 149:102923. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.critrevonc.2020.102923\u003c/span\u003e\u003cspan address=\"10.1016/j.critrevonc.2020.102923\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaisana E, Casc\u0026atilde;o R, Alvoeiro M et al (2025) Immunotherapy in lung cancer brain metastases. NPJ Precis Oncol 9:130. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41698-025-00901-0\u003c/span\u003e\u003cspan address=\"10.1038/s41698-025-00901-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRios-Hoyo A, Arriola E (2023) Immunotherapy and brain metastasis in lung cancer: connecting bench side science to the clinic. Front Immunol 14:1221097. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2023.1221097\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2023.1221097\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters S, Pujol JL, Dafni U et al (2022) Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4\u0026ndash;12 STIMULI trial. Ann Oncol 33:67\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.annonc.2021.09.011\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2021.09.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRudin CM, Brambilla E, Faivre-Finn C, Sage J (2021) Small-cell lung cancer. Nat Rev Dis Primers 7:3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41572-020-00235-0\u003c/span\u003e\u003cspan address=\"10.1038/s41572-020-00235-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePesch B, Kendzia B, Gustavsson P et al (2012) Cigarette smoking and lung cancer\u0026ndash;relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 131:1210\u0026ndash;1219. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ijc.27339\u003c/span\u003e\u003cspan address=\"10.1002/ijc.27339\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorres-Dur\u0026aacute;n M, Curiel-Garc\u0026iacute;a MT, Ruano-Ravina A et al (2021) Small-cell lung cancer in never-smokers. ESMO Open 6:100059. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.esmoop.2021.100059\u003c/span\u003e\u003cspan address=\"10.1016/j.esmoop.2021.100059\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Jiang T, Li W et al (2018) Characterization of never-smoking and its association with clinical outcomes in Chinese patients with small-cell lung cancer. Lung Cancer 115:109\u0026ndash;115. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.lungcan.2017.11.022\u003c/span\u003e\u003cspan address=\"10.1016/j.lungcan.2017.11.022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun JM, Choi YL, Ji JH et al (2015) Small-cell lung cancer detection in never-smokers: clinical characteristics and multigene mutation profiling using targeted next-generation sequencing. Ann Oncol 26:161\u0026ndash;166. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/annonc/mdu504\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mdu504\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShenker RF, McTyre ER, Ruiz J et al (2017) The Effects of smoking status and smoking history on patients with brain metastases from lung cancer. Cancer Med 6:944\u0026ndash;952. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cam4.1058\u003c/span\u003e\u003cspan address=\"10.1002/cam4.1058\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu SY, Xing F, Sharma S et al (2020) Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J Exp Med 217. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1084/jem.20191131\u003c/span\u003e\u003cspan address=\"10.1084/jem.20191131\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8542471/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8542471/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate the impact of immunotherapy on survival and brain metastasis (BM) risk in patients with limited-stage small cell lung cancer (LS-SCLC) undergoing prophylactic cranial irradiation (PCI), and to analyze related prognostic factors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on 103 LS-SCLC patients who received PCI between February 2016 and July 2024. Patients were categorized into immunotherapy (n\u0026thinsp;=\u0026thinsp;42) and non-immunotherapy (n\u0026thinsp;=\u0026thinsp;61) groups. The Kaplan-Meier method and Cox proportional hazards models were used for survival and prognostic analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median overall survival (mOS) for the entire cohort was 32.0 months (95% CI: 26.8\u0026ndash;37.2). The immunotherapy group demonstrated significantly prolonged mOS (38.0 vs. 27.0 months, p\u0026thinsp;=\u0026thinsp;0.019) and a lower 3-year BM rate (10.8% vs. 31.7%, p\u0026thinsp;=\u0026thinsp;0.035) compared to the non-immunotherapy group. Subgroup analysis revealed that patients receiving immunotherapy before-PCI (n\u0026thinsp;=\u0026thinsp;27) had more pronounced OS benefit (mOS: 40.0 vs. 27.0 months, p\u0026thinsp;=\u0026thinsp;0.007) and lower BM risk (3-year BM rate: 7.7% vs. 31.7%, p\u0026thinsp;=\u0026thinsp;0.018) than the non-immunotherapy group. Multivariate analysis identified immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.48, p\u0026thinsp;=\u0026thinsp;0.008), no smoking history (HR\u0026thinsp;=\u0026thinsp;0.46, p\u0026thinsp;=\u0026thinsp;0.004), and the presence of extracranial metastasis (HR\u0026thinsp;=\u0026thinsp;1.92, p\u0026thinsp;=\u0026thinsp;0.012) as independent factors for OS. Immunotherapy (HR\u0026thinsp;=\u0026thinsp;0.25, p\u0026thinsp;=\u0026thinsp;0.019) and no smoking history (HR\u0026thinsp;=\u0026thinsp;0.20, p\u0026thinsp;=\u0026thinsp;0.008) were independent protective factors against BM.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFor LS-SCLC patients receiving PCI, early integration of immunotherapy, particularly before PCI, effectively reduces the incidence of brain metastasis and significantly improves survival. Smoking history remains a significant adverse prognostic factor in clinical management.\u003c/p\u003e","manuscriptTitle":"Immunotherapy Improves Survival and Reduces Brain Metastasis Risk in Limited- Stage Small Cell Lung Cancer Patients Receiving Prophylactic Cranial Irradiation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 00:57:44","doi":"10.21203/rs.3.rs-8542471/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"326761d1-0b7e-40c6-93d8-72ffcbac2050","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T00:38:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 00:57:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8542471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8542471","identity":"rs-8542471","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}