Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases

Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases | 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 Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases Damla SERÇE UNAT, Şener ARIKAN, Günseli BALCI, Sinem ERMİN, Aydan MERTOĞLU, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5316285/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Introduction: Brain Metastasis (BM) in Non-Small Cell Lung Cancer (NSCLC) is still important reason of morbidity and mortality despite the advances in the cancer treatment. Using Tyrosine Kinase Inhibitors against Epidermal Growth Factor Receptors (EGFR) mutations revolutionized in NSCLC treatment. We investigated whether the presence of EGFR mutation influences survival in patients with Lung Adenocarcinoma with BM. Material and Methods The data of the patients with pathological diagnosis of NSCLC and BM at tertiary hospital were analyzed retrospectively in terms of survival. A total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. After exclusion of patients with lack of data, unknown EGFR mutation status, no brain metastasis and additional malignancy 336 patients were included to the study. Results It is found that EGFR (+) patients were more female dominant (48.6% vs 13.3% p < 0.0001) and were have less history of smoking (%47.2 vs %87.1, p < 0.0001) and were better survival (%79.2 vs %92.8). We found negativity of EGFR increased death risk by 1.700 times (95% CI: 1.323–2.183, p < 0.0001) in univariate analysis and by 1.724 times (95% CI 1.251–2.377, p = 0.0001) in multivariate analysis. When overall survivals have been compared estimated overall survival time of EGFR (-) patients were 10.088 (95% CI 8.571–11.606) months and of EGFR (+) patients were 11.829 months (95% CI 10.336–13.323) (p < 0.001). Conclusion EGFR positivity was associated with survival. Also, survival was significantly longer in EGFR-positive patients with brain metastases diagnosed with NSCLC. Non-small cell lung cancer adenocarcinoma brain metastasis EGFR prognosis Figures Figure 1 Figure 2 1. INTRODUCTION Despite all the developments in the treatment of non-small cell lung cancers (NSCLC), the development of brain metastasis (BM) is still a noble cause of morbidity and mortality ( 1 ). When the rates of BM in NSCLC were evaluated, BM was detected in 7–10% of the patients at the time of diagnosis, and during the follow-up of lung cancer in 25–40% ( 2 ). After BM develops, the prognosis is less than 3 months in patients who do not receive any treatment and around 4.5 months on average with whole brain irradiation ( 3 ). The identification of driver mutations in the pathogenesis of lung cancer and the emerging treatment options for some of them opened a new horizon regarding the treatment of NSCLC. It was observed that the risk of developing BM during the disease in epidermal growth factor receptor ( EGFR ) mutant cases is higher than in non-mutant cases. There are different results in the literature about the prognosis of these cases ( 4 – 6 ). In a previous study, BM was found to be a poor prognostic indicator, and neurological deaths were more common in EGFR mutant cases ( 7 , 8 ). Also, a study that was published reported that EGFR mutation status does not have significant impacts on overall and progression-free survival ( 9 ). On the other hand, studies are reporting better prognosis in EGFR mutant BM cases. EGFR mutation status was reported to be associated with better survival independent of age, functional status, extracranial disease status, and BM count. It was also reported that EGFR mutation status is an independent predictor of response to radiotherapy (RT), and longer survival was detected in patients who received EGFR -tyrosine kinase inhibitor (TKI) treatment after the resection of brain and lung lesions ( 10 ). The purpose of the present study was to investigate the impacts of EGFR mutation status on survival in patients with a diagnosis of lung adenocarcinoma with BM followed in SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital. 2. METHODS The data of patients diagnosed with lung adenocarcinoma pathologically, BM detected by cranial MRI and EGFR mutation analysis at SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital between 01.01.2010–01.02.2021 were analyzed retrospectively in one single center. The study started after the approval of the Medical Specialization Ethics Committee of our hospital, dated 26.03.2021, and numbered 07–16. EGFR mutation analysis was made by DNA extraction and reverse transcriptase polymerase chain reaction (RT-PCR). Samples from tissue and peripheric blood was analyzed with RT-PCR properly. The FDA-approved “Cobas®ฏ EGFR Test” designed to detect forty-two mutations in exons 18–21 of the EGFR gene, including exon 19 deletion, L858R and T790M, was used. The demographic characteristics of the cases and all factors that affected survival were recorded. The thoracic disease progression-free survival was taken as the time from the date of pathological diagnosis to the date of progression of the disease except brain metastasis. The BM progression-free survival was taken as the time from the date of diagnosis of BM to recurrence or progression of brain metastasis. The overall survival (OS)l was taken as the time from the date of diagnosis of BM to the date of death or the date of the last control in patients with ongoing follow-up. Mortality rate was defined as being deceased or survivor at the 01.02.2022 (one year after last date of inclusion period). 3. STATISTICS The data obtained in the study were entered into the database that was created in the SPSS (Statistical Package for Social Sciences) 18.0 program and statistical analyzes were made. The comparisons of the independent groups with the variables that had a normal distribution were made with the “student t ” test and the variables that did not have a normal distribution with the “Mann-Whitney U” test, which is a nonparametric test. The receiver operating characteristic (ROC) analysis was made to calculate the cutoff values for continuous variables affecting the survival and progression process, and the most appropriate cutoff values were determined according to the Youden’s index. The univariate survival and progression-free survival were compared with Kaplan-Meier, log-rank test, and hazard ratios were calculated. The Cox regression analysis was made in the multivariate analysis with the backward stepwise method according to the Wald value. The margin of error for the first type was found to be α:0.05 and the double-tailed test was performed in all statistical comparison tests. If the “ p ” value was less than 0.05, the difference between the groups was considered statistically significant. 4. RESULTS A total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. Among these 2554 patients, 618 were excluded because they were diagnosed with NSCLC, 969 had no brain metastases, 318 had a lack of data, 272 were without EGFR results, and 41 had an additional primary malignancy. The remaining 336 patients were analyzed retrospectively in the study (Fig. 1 ). A total of 266 of the patients were male (79.2%) and the mean age was 60.6 (32–81) and 264 patients (78.6%) out of 336 lung adenocarcinoma cases were EGFR mutation negative. The general characteristics of the patients are given in Table 1 . Table 1 General characteristics of the patients. Variables Total (n = 336) Age (mean ± SD) 60.16 ± 9.12 Gender (n, %) Female Male 70 (20.8) 266 (79.2) EGFR mutation status (n, %) Positive Negative 72 (21.4) 264 (78.6) Targeted Treatment Received Not Received 55 (76.4) 17 (23.6) Type of Targeted Treatment Osimertinib Erlotinib Alectinib Gefitinib Afatinib 6 (10.9) 25 (45.5) 2 (3.6) 9 (16.4) 8 (14.5) EGFR Mutation Type Exon 19 29 (40.3) Exon 20 - S768I 3 (4.2) Exon 21 - L858R 23 (31.9) G719X 5 (6.9) Exon 19 and Exon 20 - T790M 9 (12.5) Exon 20 - T790M and Exon 21 - L858R 3 (4.2) Comorbidity (n, %) Yes No 129 (38.4) 207 (61.6) Additional organ metastasis (n, %) Yes No 271 (80.7) 65 (19.3) Diagnosis stage (n, %) Stage I Stage II Stage III Stage IV 9 (2.7) 6 (1.8) 44 (13.1) 277 (82.4) Systemic chemotherapy (n, %) Received Not received 209 (62.2) 127 (37.8) Number of chemotherapy cures (median, min-max) 6 (1–40) Mortality (n, %) 302 (89.9) Tumor (T) and node (N) status of the primary disease at the time of BM, clinical findings, characteristics of BM, treatments, and their comparison in EGFR (+) and EGFR (-) groups are summarized in Table 2 . Table 2 The characteristics of the brain metastasis and comparison between groups. Variables Total (n = 336) EGFRmut (+) (n = 72) EGFRmut (-) (n = 264) p-value Number of brain metastases (n, %) Single Multiple 130 (38.7 ) 22 (30.6) 108 (40.9) 0.110 206 (61.3) 50 (69.4) 156 (59.1) Brain metastasis symptoms (n, %) Seizures 45 (13.4) 7 (9.7) 38 (14.4) 0.403 Consciousness change 37 ( 11 ) 11 (15.3) 26 (9.8 ) 0.275 Hemiplegia 38 (11.3) 4 (5.6) 34 (12.9) 0.126 Paraplegia 15 (4.5) 2 (2.8) 13 (4.9) 0.747 Headache 49 (14.6) 18 ( 25 ) 31 (11.7) 0.008 Dizziness 37 ( 11 ) 17 (23.6) 20 (7.6) < 0.001 Brain metastasis size (mm) (median, min-max) 16 (2-288) 15 (2–40) 17 (2-288) 0.008 Hemorrhage into brain metastasis (n, %) Yes 8 (6.5) 3 (4.2) 5 (1.9) 0.376 No 328 (93.5) 69 (95.8) 259 (98.1) Rim-type involvement in brain metastasis (n, %) Yes 75 (22.3) 14 (19.4) 61(23.1) 0.616 No 261 (77.7) 58 (80.6) 203 (76.9) Treatment (n, %) Metastasectomy 34 (10.1) 9 (12.5) 25 (9.5) 0.592 Cranial radiotherapy 323 (84.2) 68 (92.6) 255 (96.5) 0.488 Brain metastasis relapse or progression (n, %) Yes 51 (15.2) 9 (12.5) 42 (15.9) 0.475 No 285 (96.1) 63 (87.5) 222 (84.) The variables that could affect survival were compared in the mortality and survivor groups, and their relationship with survival was evaluated and summarized in the Table 3 . Table 3 The comparison of the variables that might affect survival in the surviving and mortality groups. Variable Mortality (n = 302) Survivor (n = 34) p-value Age 60.22 ± 9.30 59.68 ± 7.42 0.743 Gender (n, %) Male Female 244 (80.8) 22 (64.7) 0.049 58 (19.2) 12 (35.3) Comorbidity (n, %) Yes No 112 (37.1) 17 (50) 0.200 190 (62.9) 17 (50) EGFR status (n, %) Positive Negative 57 (18.9) 15 (44.2) 0.001 245 (81.1) 19 (55.8) Performance status (n, %) ECOG 0 ECOG 1-2-3-4 123 (40.7) 27 (79.4) < 0.0001 179 (59.3) 7 (20.6) Diagnostic sequence (n, %) Later brain metastasis 208 (68.9) 23 (67.6) 1 Simultaneous diagnosis 94 (31.1) 11 (32.4) Clinical manifestation due to cranial metastasis (n, %) Yes 179 (59.3) 10 (29.4) 0.002 No 123 (40.7) 24 (70.6) Cranial radiotherapy (n, %) Received Not received 292 (96.7) 31 (91.2) 0.134 10 (3.3) 3 (8.8) Cranial Metastasectomy Yes No 30 (9.9) 4 (11.8) 0.763 272 (90.1) 30 (88.2) Chemotherapy Received 188 (62.3) 21 (61.8) 1 Not received 114 (37.7) 13 (38.2) T status at diagnosis (n, %) T1 T2 T3 T4 41 (13.5) 9 (26.5) 0.164 83(27.5) 10 (29.4) 43 (14.2) 5 (14.7) 135 (44.8) 10 (29.4) N status at diagnosis (n, %) N0 N1 N2 N3 46 (15.2) 13 (38.2) 0.002 34 (11.3) 6 (17.6) 92 (30.5) 9 (26.5) 130 (43.0) 6 (17.6) M status at diagnosis (n, %) M0 M1 50 (16.6) 10 (29.4) 0.105 252 (83.4) 24 (70.6) Additional organ metastasis (n, %) Yes No 251 (83.1) 20 (58.8) 0.002 51 (16.9) 14 (41.2) T status at the time of brain metastasis (n, %) T1 T2, 3, 4 37 (12.3) 11 (32.4) 0.004 265(87.2) 23 (67.6) N status at the time of brain metastasis (n, %) N0 N1 N2 N3 52 (17.2) 12 (35.3) 0.006 30 (9.9) 6 (17.6) 82 (27.2) 10 (29.5) 138 (45.7) 6 (17.6) M status at the time of brain metastasis M1a, M1b M1c 85 (28.1) 17 (50) 0.015 217 (71.9) 17 (50) LDH U/L (median, min-max) 220 (65-2322) 189 (118–1522) 0.009 Albumin g/dL (median, min-max) 3.80 (2-5.1) 4.13 (3.34–5.3) 0.001 NLR (median, min-max) 3.61 (0,24–161) 3.06 (0.18–22.2) 0.213 LDH threshold value U/L (n, %) > 218 ≤ 218 154 (51) 8 (23.5) 0.004 148 (49) 26 (76.5) Total protein threshold g/dL (n, %) > 6.87 ≤ 6.87 142 (47) 21 (61.8) 0.147 160 (53) 13 (38.2) Albumin threshold g/dL (n, %) > 3.96 ≤ 3.96 123 (40.7) 23 (67.6) 0.005 179 (59.3) 11 (32.4) NLR threshold value (n, %) > 4.2 ≤ 4.2 135 (44.7) 10 (29.4) 0.128 167 (55.3) 24 (70.6) ECOG: Eastern Cooperative Oncology Group; Patient performance status score. T: Tumor size, N: Lymph node metastasis, M: Metastasis status. LDH: Lactate dehydrogenase, NLR: Neutrophil/lymphocyte ratio. The comparison of the tumor-node-metastasis (TNM) status, stage, and presence of additional organ metastasis at the time of diagnosis, TNM status at the time of BM, and stage in the mortality and survival groups are given in Table 3 . The characteristics of the laboratory parameters were examined in the mortality and survival groups. The threshold values of parameters were calculated with the Youden’s index. The comparisons made according to these threshold values are given in Table 3 . The relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and their survival was evaluated with univariate analysis. Multivariate analysis was made based on the variables obtained according to univariate analysis results and clinical significance. Multivariate analysis results are given in Table 4 . Table 4 The impacts of the demographic, clinical, and radiological characteristics of patients on mortality according to multivariate analysis. Variables Multivariate Analysis HR (95% CI) p-value Age (> 72 years) 2.1 1.5 - 3.1 19 mm) 1.3 1.0 - 1.7 0.029 Clinical manifestation related to brain metastasis (Yes) 1.5 1.2 - 1.9 0.002 Chemotherapy (Not received) 1.5 1.2 - 1.9 0.002 LDH U/L (> 218) 1.3 1.0 - 1.6 0.042 Stage at diagnosis (Stage IV) 1.5 1.1 - 2.1 0.017 T status at the time of brain metastasis (T II, III, IV) 1.6 1.1 - 2.3 0.016 N status at the time of brain metastasis (N2, 3) 1.4 1.1 - 1.8 0.018 M status at the time of brain metastasis (M1c) 1.9 1.5 - 2.4 < 0.0001 LDH: Lactate dehydrogenase, EGFR (Epidermal Growth Factor Receptor): T: Tumor size, N: Lymph node metastasis, M: Metastasis status, HR: Hazard ratio, CI: Confidence interval. The mean thoracic disease progression-free survival of all patients was found to be 11.199 (9.84–12.55) months. The mean thoracic disease progression-free survival times were 9.72 months (95% CI 8.329–11.111) in the EGFR (-) group and 16.625 months (95% CI 13.185–20.065) in the EGFR (+) group (p < 0.0001). The brain metastasis progression status of the patients was evaluated. Although no recurrence or progression of brain metastasis was detected in 283 patients (84.2%), it was seen in 51 patients (15.2%). Progression-free survival times of 51 patients with relapse/progression in brain metastases were evaluated. The mean brain metastasis recurrence or progression-free survival time was 34.105 months (95% CI: 30.604–37.605). This period was 28.966 (95% CI 29.668–42.662) months in the EGFR (-) Group and 36.165 (95% CI 30.627–43.361) months in the EGFR (+) Group. The mean value of the overall survival time of the patients was found to be 11.83 (95% CI: 10.33–13.32). When overall survival was compared, the mean expected time in the EGFR (-) group was 10.088 (95% CI 8.571–11.606) months, and 11.829 months (95% CI 10.336–13.323) months in the EGFR (+) Group (p < 0.001) (Fig. 2 ). The survival of 72 patients with positive EGFR was evaluated according to their targeted treatment status. 55 patients received targeted treatment; 17 patients did not receive targeted treatment. While the mortality rate was 88.24% in those who did not receive targeted treatment, the mortality rate in those who received targeted treatment was 76.36%. The median expected overall survival was found to be 7.929 months (95% CI: 4.794–11.065) in the no-treatment group, and it was 21.209 months (95% CI: 16.672–25.747) in the group that received targeted treatment. EGFR-positive patients were 4 times more (95% CI: 1.767–9.058) in the group that did not receive targeted treatment than in the group that received the targeted treatment (p = 0.0009) (Fig. 2 ). 5. DISCUSSION In our study, the impacts of EGFR mutation on survival were investigated in patients with lung adenocarcinoma with brain metastases. In the present study, there were 72 (21.4%) patients out of the group of 336 patients in the patient group were found to be EGFR positive, and 55 (76.4%) of this group received targeted treatment. In studies conducted in Türkiye, the EGFR positivity rate ranges between 22–42% ( 12 ). In the present study, the rate of women in EGFR -positive patients was higher than in the EGFR -negative group (48.8%; 13.3%) and the smoking history was less in EGFR -positive patients (47.2%; 87.1%). It is already known that driver mutation positivity is more common in women and non-smokers (varying between 29–66% in the literature) ( 13 , 14 ). It is also known that tumors with EGFR positivity cause a predisposition to metastasis regardless of tumor size, especially brain metastasis when compared to those without EGFR ( 15 , 16 ). In the present study although additional organ metastases were more common in the EGFR -negative group, this difference was not statistically significant. It was found in the present study that EGFR -negative patients had larger brain metastases. In the study of Yeop-shin et al., no correlation was detected between the size of brain metastasis and EGFR positivity ( 17 ). In our study, symptoms such as seizures, changes in consciousness, hemiplegia, paraplegia, and visual impairment symptoms were not associated with EGFR status. However, headache and dizziness complaints were statistically and significantly higher in the EGFR -positive group. Luo D et al. found that intracranial hypertension, paresthesia, aphasia, and distraction were higher in the EGFR -positive group, but not at statistically significant levels ( 18 ). The relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and survival was examined. There are publications in the literature reporting that the female gender is a positive prognostic characteristic in survival ( 19 ). In this study, even though the male gender was found to be a risk factor for death in univariate analysis, it was not found as a risk factor for mortality in multivariate analysis. This can be explained by the fact that male patients were older and had less EGFR positivity than female patients. Age over 72 was found to be a risk factor for mortality in the univariate and multivariate analyses. EGFR mutation is seen at a higher rate in younger patients. Also, age was found to be a factor that negatively affected survival in the EGFR -negative and EGFR -positive NSCLC ( 20 , 21 ). The impacts of co-morbidities on the prognosis of lung cancer are less researched considering the stage and treatment modalities. Although there are publications in the literature reporting a relationship between comorbidity and mortality in lung cancer ( 22 , 23 ), no correlation was detected between comorbidity and survival in our study. Smoking was found to be a factor that increased the risk of mortality in the multivariate analyses in our study like other studies ( 24 ). It is already known that poor performance status (ECOG (Eastern Cooperative Oncology Group ≥ 1) negatively affects survival in NSCLC and all cancer types and tend to be older and more EGFR -negative ( 25 – 27 ). Performance status was found to be statistically and significantly risky for mortality in univariate analysis, but not found to be significantly risky in multivariate analysis in the present study. This change may be occurred by retrospective design of the study. T ≥ 2 or N ≥ 2 disease at the time of diagnosis and at the time of brain metastasis, M1c disease at the time of brain metastasis, presence of additional organ metastases, and Stage IV disease at the time of diagnosis were found to be risky in terms of mortality in univariate analysis. It is already known that active extracranial metastasis is associated with decreased survival in NSCLC patients with brain metastases. Eichler et al. reported that active extracranial metastasis has a poor impact on survival ( 10 ) was supported by the fact that M1c is associated with decreased survival at the time of brain metastasis in the univariate and multivariate analyses. It is already known that the nutritional status of the patient or the presence of cachexia affects the prognosis and survival of lung cancer patients ( 28 ). The total protein and albumin levels were used to measure cachexia in the present study with the threshold values for total protein ≤ 6.87 g/dL and albumin ≤ 3.96 g/dL. No relationship was detected between total protein and survival. As an intracellular enzyme, LDH was shown to be associated with a poor prognostic factor because it shows increased catabolism and mitotic activity ( 29 – 30 ). And NLR level is an indicator of the increased systemic inflammatory response, it was found to be associated with poor prognosis in lung cancer ( 31 ). LDH > 218 U/L and NLR > 4.2 appear to increase the risk of mortality in univariate analysis. It was also seen that having an LDH > 218 U/L increased the risk of mortality in multivariate analysis. In our study it is found that tumor size > 19 mm and the presence of clinical symptoms because of brain metastasis decreased survival in multivariate analysis. It is concordant with other studies ( 32 ). Brain metastasis development during follow-up rather than brain metastasis at the time of diagnosis was found to be a risk factor in terms of mortality in univariate and multivariate analyzes in the present study. In the study of Jünger et al. it was found that time of BM in NSCLC did not affect the mortality ( 32 ). This study contradicts our study in this regard. The impact of chemotherapy and targeted treatment on survival was also examined. Chemotherapy increases survival when compared to patients who cannot receive chemotherapy ( 33 ). In the present study, patients who did not receive chemotherapy had a higher risk of mortality in both univariate and multivariate analyses. Cranial metastasectomy is beneficial in selected patients (especially in those with brain metastases without lymph node involvement) ( 34 ). In the present study, cranial metastasectomy reduced mortality risk in univariate analysis, but this impact was not detected in multivariate analysis, which may be because of the number of patients who underwent cranial metastasectomy. Radiotherapy was not found to be associated with the risk of mortality in the present study. This result is similar to the results of the study conducted by Jiang et al. that investigated the impacts of radiotherapy on survival in EGFR -positive patients ( 35 ). When the survival rates of the patients were examined, the thoracic disease progression-free survival time (9.7 months to 16.6 months) and the brain metastasis recurrence or progression-free survival time (29.0 months to 36.2 months) were statistically and significantly longer in the EGFR -positive group. Unlike our study, no difference was reported between progression-free survival times in Luo et al.’s study ( 18 ). Similar to our study, disease progression-free survival time was found to be longer in the EGFR -positive group than in the KRAS -positive or EGFR -negative groups in the study of Cadranel et al. ( 36 ). In the present study, the mean OS time of the patients was found to be 11.8 (95% CI: 10.3–13.3) months. These results are similar to the OS times of metastatic NSCLC (19, 54). There are studies suggests that EGFR positivity is associated with better outcome ( 37 ). In the study of Eichler et al., EGFR mutation was found to be one of the prognostic factors affecting survival along with performance status, age, and the prevalence of extracranial disease ( 10 ). In the present study, it was found that EGFR positivity was associated with prolonged survival, and this relationship was also significant in multivariate analysis. In this way, it was found that EGFR mutation status is a factor affecting survival as much as age, additional organ metastasis at the time of brain metastasis, and smoking history. Among EGFR -positive patients who received EGFR treatment appears to significantly improve survival (mean survival 21.2 vs. 7.9 months). The risk of mortality of patients who were EGFR positive and did not receive EGFR treatment was four times higher than the other group. It was observed during Stage III drug trials that treatments for EGFR prolonged progression-free survival but did not have a statistically significant impact on OS. In studies in which real-life data were evaluated, these agents were also found to provide advantages in OS, which was also explained by the addition of patients with advanced age, poor performance status, and rare EGFR mutation, which were excluded in real-life Stage III studies ( 37 ). Data loss occurred in the present study because of its retrospective nature. Also, the number of patients in this single-center study remained at a certain level. These two situations are the limitations of the study. 6. CONCLUSION NSCLC, which has advanced brain metastases, is a difficult disease to manage and has a high mortality rate. The discovery of driver mutations in NSCLC classification and treatment changed treatment radically. Publications report that EGFR mutation has positive prognostic values in NSCLC patients with BM. The impact of EGFR positivity on survival in patients diagnosed with NSCLC with brain metastases was examined in the study. Advanced age (age > 72), poor performance status at the time of diagnosis (ECOG > 0), smoking history, development of brain metastases in the follow-up, brain metastasis size (> 19 mm), neurological clinical presence because of brain metastasis, not receiving Chemotherapy, and LDH > 218 U/L had negative prognostic value and decreased survival. EGFR positivity was found to be associated with prolonged survival and was found to be a prognostic factor in multivariate analysis in the present study. It was shown in the present study that patients who received targeted treatment had significantly longer survival among EGFR -positive patients. This area must be supported by prospective and multicenter studies. Declarations Conflict of interest : There is no conflict of interest with any financial organization regarding the material discussed in the manuscript. The manuscript is written with contributions of all authors. And the manuscript is approved by all authors. Funding: This scientific publication has received no financial support. Additionally, there are no conflicts of interest, and the authors have not received any personal financial support. AUTHOR CONTRUBITIONS DSU made prominent contributions to the concept of work. DSU also made significant contributions to the collection of data and writing process. SA made significant contributions to the interpretation of data and reviewed the paper. OK made important contributions to the interpretation and collection of data. GB played a role in the writing and editing processes. SE made significant contributions to the collection of data. AM played a vital role in the conception of work, interpretation of data and reviewing of paper. All authors have approved the submitted version of the manuscript. References Langer CJ, Mehta MP. 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Relationship between Epidermal Growth Factor Receptor Gene Mutations and Clinicopathological Features in Patients with Non-Small Cell Lung Cancer in Western Türkiye. Asian Pacific J Cancer Prev [Internet]. 2013 [cited 2022 Mar 6];14(6):3705–9. Available from: http://dx.doi.org/10.7314/APJCP.2013.14.6.3705 Scaglia NC, Chatkin JM, Pinto JA, Tsukazan MTR, Wagner MB, Saldanha AF. Role of gender in the survival of surgical patients with nonsmall cell lung cancer. Ann Thorac Med. 2013 Jul;8(3):142. Visbal AL, Williams BA, Nichols FC, Marks RS, Jett JR, Aubry MC, et al. Gender differences in non–small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg. 2004 Jul;78(1):209–15. Guan J, Chen M, Xiao N, Li L, Zhang Y, Li Q, et al. EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan. Med Oncol. 2016 Jan;33(1):1–8. Ho-Pun-Cheung A, Assenat E, Bascoul-Mollevi C, Bibeau F, Boissiãre-Michot F, Cellier D, et al. EGFR and HER3 mRNA expression levels predict distant metastases in locally advanced rectal cancer. Int J Cancer. 2011 Jun;128(12):2938–46. Shin D-Y, Il Na I, Hyeon Kim C, Park S, Baek H, Hyun Yang S. EGFR Mutation and Brain Metastasis in Pulmonary Adenocarcinomas. Vol. 9, Journal of Thoracic Oncology. 2014. Luo D, Ye X, Hu Z, Peng K, Song Y, Yin X, et al. EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumor Biol [Internet]. 2014 Nov 7 [cited 2020 Dec 26];35(3):2437–44. Available from: https://link.springer.com/article/10.1007/s13277-013-1323-9 Inoue A, Yoshida K, Morita S, Imamura F, Seto T, Okamoto I, et al. Characteristics and overall survival of EGFR mutation-positive non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. Jpn J Clin Oncol. 2016 May;46(5):462–7. Zheng R, Guo D, Dong Y, Wang M, Hu M, Ren Y. Prognostic Factors in Patients with Brain Metastases of Lung Adenocarcinoma with the Surveillance Epidemiology and End Results Database Running title: Prognostic factors in patients with brain metastases of lung adenocarcinoma Email addresses. Sacher AG, Dahlberg SE, Heng J, Mach S, Jänne PA, Oxnard GR. Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non–Small-Cell Lung Cancer. JAMA Oncol. 2016 Mar;2(3):313–20. Dutkowska AE, Antczak A. Comorbidities in lung cancer. Adv Respir Med. 2016;84(3):186–92. Janssen-Heijnen MLG, Schipper RM, Razenberg PPA, Crommelin MA, Coebergh JWW. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: A population-based study. Lung Cancer. 1998 Aug 1;21(2):105–13. Kawaguchi T, Takada M, Kubo A, Matsumura A, Fukai S, Tamura A, et al. Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: A comprehensive analysis of 26,957 patients with NSCLC. J Thorac Oncol. 2010;5(5):620–30. Dall’Olio FG, Maggio I, Massucci M, Mollica V, Fragomeno B, Ardizzoni A. ECOG performance status ≥2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors—A systematic review and meta-analysis of real world data. Lung Cancer. 2020 Jul;145:95–104. Alghamdi HI, Alshehri AF, Farhat GN. An overview of mortality & predictors of small-cell and non-small cell lung cancer among Saudi patients. J Epidemiol Glob Health. 2018 Mar;7:S1–6. Waqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018 Jul;19(4):e373. Clinically relevant determinants of body composition, function, and nutritional status as mortality predictors in lung cancer patients | Elsevier Enhanced Reader. Eckart A, Struja T, Kutz A, Baumgartner A, Baumgartner T, Zurfluh S, et al. Relationship of Nutritional Status, Inflammation, and Serum Albumin Levels During Acute Illness: A Prospective Study. Am J Med. 2020 Jun;133(6):713-722.e7. Jurisic V, Radenkovic S, Konjevic G. The Actual Role of LDH as Tumor Marker, Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:115–24. Cedrés S, Torrejon D, Martínez A, Martinez P, Navarro A, Zamora E, et al. Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clin Transl Oncol. 2012 Nov;14(11):864–9. Jünger ST, Schödel P, Ruess D, Ruge M, Brand JS, Wittersheim M, et al. Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments. Cancers (Basel). 2020 Dec;12(12):1–10. Kosmidis P. Chemotherapy in NSCLC: Historical review. Lung Cancer. 2002;38(3 SUPPL.):19–22. Bex A. Integrating metastasectomy and stereotactic radiosurgery in the treatment of metastatic renal cell carcinoma. EJC Suppl. 2013 Sep;11(2):192-203. doi: 10.1016/j.ejcsup.2013.07.017. PMID: 26217128; PMCID: PMC4041303. Jiang T, Su C, Li X, Zhao C, Zhou F, Ren S, et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol. 2016 Oct;11(10):1718–28. Cadranel J, Mauguen A, Faller M, Zalcman G, Buisine MP, Westeel V, et al. Impact of Systematic EGFR and KRAS Mutation Evaluation on Progression-Free Survival and Overall Survival in Patients with Advanced Non–Small-Cell Lung Cancer Treated by Erlotinib in a French Prospective Cohort (ERMETIC Project—Part 2). J Thorac Oncol. 2012 Oct 1;7(10):1490–502. Li WY, Zhao TT, Xu HM, Wang ZN, Xu YY, Han Y, et al. The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: A systematic review and meta-analysis. Vol. 19, BMC Cancer. BioMed Central Ltd.; 2019. Lu S, Shih JY, Jang TW, Liam CK, Yu Y. Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence. Adv Ther. 2021 May;38(5):2038–53. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Jan, 2025 Reviews received at journal 13 Jan, 2025 Reviewers agreed at journal 07 Jan, 2025 Reviewers agreed at journal 07 Jan, 2025 Reviews received at journal 13 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers invited by journal 01 Nov, 2024 Editor assigned by journal 30 Oct, 2024 Submission checks completed at journal 28 Oct, 2024 First submitted to journal 23 Oct, 2024 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. 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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-5316285","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":371132920,"identity":"ff2dc2fc-731c-4f97-bbb7-6d2c4e3ac685","order_by":0,"name":"Damla SERÇE UNAT","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYNACNgYGPgbmA0CWhAzxWtgY2BJAWnhI0cJjAGIS1iLf3vvww4cyu2g29jOfX92oseBhYD98dAM+LQZnjhtLzjiXnNvGk7vNOucY0GE8aWk38GqRSGNj5m1jzm1jyN1mnMMG1CLBY4ZXi/z8Z2zMf9vqc9v43zwzzvlHhBaGG2xszIxth3PbJHKYHwNJwloMzqQxS/acOw5U/MyMObdPgoeNkF/k248xfvhRVp3bz5/8+HPOtzo5fvbDx/A7DAmwSYBJYpWDAPMHUlSPglEwCkbByAEA5iVCIKjELFcAAAAASUVORK5CYII=","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Damla","middleName":"SERÇE","lastName":"UNAT","suffix":""},{"id":371132921,"identity":"0d332f52-c382-41f6-8bcf-f8cbdaf27bce","order_by":1,"name":"Şener ARIKAN","email":"","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Şener","middleName":"","lastName":"ARIKAN","suffix":""},{"id":371132922,"identity":"24dee516-41c1-4337-bd86-b3ff1f375a41","order_by":2,"name":"Günseli BALCI","email":"","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Günseli","middleName":"","lastName":"BALCI","suffix":""},{"id":371132923,"identity":"a81e6b78-54ed-404b-8113-e7b82fb6412f","order_by":3,"name":"Sinem ERMİN","email":"","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sinem","middleName":"","lastName":"ERMİN","suffix":""},{"id":371132924,"identity":"80a4232a-8f54-40c5-afab-a07d304cf882","order_by":4,"name":"Aydan MERTOĞLU","email":"","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Aydan","middleName":"","lastName":"MERTOĞLU","suffix":""},{"id":371132925,"identity":"48e1b128-1927-46d2-bf2a-28c9adaaa57c","order_by":5,"name":"Ozgur KIRBIYIK","email":"","orcid":"","institution":"Izmir Health Sciences University, Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ozgur","middleName":"","lastName":"KIRBIYIK","suffix":""}],"badges":[],"createdAt":"2024-10-23 06:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5316285/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5316285/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67849397,"identity":"51ce07d7-77c2-4cd3-bd2e-77b3c8ea4387","added_by":"auto","created_at":"2024-10-30 10:14:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108136,"visible":true,"origin":"","legend":"\u003cp\u003ePatient group flow chart.\u003c/p\u003e","description":"","filename":"figure1BMlungadenocaJPEGversion.png","url":"https://assets-eu.researchsquare.com/files/rs-5316285/v1/6ab7e435654cf74e72bddcc7.png"},{"id":67847908,"identity":"53b675e3-5e96-49b6-a37f-3a8587d9fbc9","added_by":"auto","created_at":"2024-10-30 10:06:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55028,"visible":true,"origin":"","legend":"\u003cp\u003eOverall Survival Probabilities of Patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA: \u003c/strong\u003eOS following brain metastasis diagnosis according to EGFR mutation status. B: OS according to the targeted therapy status.\u003c/p\u003e","description":"","filename":"figure2BMlungadenocaJPEGversion.png","url":"https://assets-eu.researchsquare.com/files/rs-5316285/v1/e73f0e37335183b17a5c32a1.png"},{"id":67850104,"identity":"20885854-cba6-40b5-b01e-863eeebdfcb0","added_by":"auto","created_at":"2024-10-30 10:22:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1161009,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5316285/v1/b69b34a5-af2a-4658-ad05-df336ea5bc74.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eDespite all the developments in the treatment of non-small cell lung cancers (NSCLC), the development of brain metastasis (BM) is still a noble cause of morbidity and mortality (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). When the rates of BM in NSCLC were evaluated, BM was detected in 7\u0026ndash;10% of the patients at the time of diagnosis, and during the follow-up of lung cancer in 25\u0026ndash;40% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). After BM develops, the prognosis is less than 3 months in patients who do not receive any treatment and around 4.5 months on average with whole brain irradiation (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The identification of driver mutations in the pathogenesis of lung cancer and the emerging treatment options for some of them opened a new horizon regarding the treatment of NSCLC. It was observed that the risk of developing BM during the disease in epidermal growth factor receptor (\u003cem\u003eEGFR\u003c/em\u003e) mutant cases is higher than in non-mutant cases. There are different results in the literature about the prognosis of these cases (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a previous study, BM was found to be a poor prognostic indicator, and neurological deaths were more common in \u003cem\u003eEGFR\u003c/em\u003e mutant cases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Also, a study that was published reported that \u003cem\u003eEGFR\u003c/em\u003e mutation status does not have significant impacts on overall and progression-free survival (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). On the other hand, studies are reporting better prognosis in \u003cem\u003eEGFR\u003c/em\u003e mutant BM cases. \u003cem\u003eEGFR\u003c/em\u003e mutation status was reported to be associated with better survival independent of age, functional status, extracranial disease status, and BM count. It was also reported that \u003cem\u003eEGFR\u003c/em\u003e mutation status is an independent predictor of response to radiotherapy (RT), and longer survival was detected in patients who received \u003cem\u003eEGFR\u003c/em\u003e-tyrosine kinase inhibitor (TKI) treatment after the resection of brain and lung lesions (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe purpose of the present study was to investigate the impacts of \u003cem\u003eEGFR\u003c/em\u003e mutation status on survival in patients with a diagnosis of lung adenocarcinoma with BM followed in SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003eThe data of patients diagnosed with lung adenocarcinoma pathologically, BM detected by cranial MRI and \u003cem\u003eEGFR\u003c/em\u003e mutation analysis at SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital between 01.01.2010\u0026ndash;01.02.2021 were analyzed retrospectively in one single center. The study started after the approval of the Medical Specialization Ethics Committee of our hospital, dated 26.03.2021, and numbered 07\u0026ndash;16.\u003c/p\u003e \u003cp\u003e \u003cem\u003eEGFR\u003c/em\u003e mutation analysis was made by DNA extraction and reverse transcriptase polymerase chain reaction (RT-PCR). Samples from tissue and peripheric blood was analyzed with RT-PCR properly. The FDA-approved \u0026ldquo;Cobas\u0026reg;ฏ EGFR Test\u0026rdquo; designed to detect forty-two mutations in exons 18\u0026ndash;21 of the \u003cem\u003eEGFR\u003c/em\u003e gene, including exon 19 deletion, L858R and T790M, was used.\u003c/p\u003e \u003cp\u003eThe demographic characteristics of the cases and all factors that affected survival were recorded.\u003c/p\u003e \u003cp\u003e \u003cem\u003eThe thoracic disease progression-free survival\u003c/em\u003e was taken as the time from the date of pathological diagnosis to the date of progression of the disease except brain metastasis. \u003cem\u003eThe BM progression-free survival\u003c/em\u003e was taken as the time from the date of diagnosis of BM to recurrence or progression of brain metastasis. The \u003cem\u003eoverall survival (OS)l\u003c/em\u003e was taken as the time from the date of diagnosis of BM to the date of death or the date of the last control in patients with ongoing follow-up. Mortality rate was defined as being deceased or survivor at the 01.02.2022 (one year after last date of inclusion period).\u003c/p\u003e"},{"header":"3. STATISTICS","content":"\u003cp\u003eThe data obtained in the study were entered into the database that was created in the SPSS (Statistical Package for Social Sciences) 18.0 program and statistical analyzes were made. The comparisons of the independent groups with the variables that had a normal distribution were made with the \u0026ldquo;student \u003cb\u003et\u003c/b\u003e\u0026rdquo; test and the variables that did not have a normal distribution with the \u0026ldquo;Mann-Whitney U\u0026rdquo; test, which is a nonparametric test. The receiver operating characteristic (ROC) analysis was made to calculate the cutoff values for continuous variables affecting the survival and progression process, and the most appropriate cutoff values were determined according to the Youden\u0026rsquo;s index. The univariate survival and progression-free survival were compared with Kaplan-Meier, log-rank test, and hazard ratios were calculated. The Cox regression analysis was made in the multivariate analysis with the backward stepwise method according to the Wald value. The margin of error for the first type was found to be α:0.05 and the double-tailed test was performed in all statistical comparison tests. If the \u0026ldquo;\u003cb\u003ep\u003c/b\u003e\u0026rdquo; value was less than 0.05, the difference between the groups was considered statistically significant.\u003c/p\u003e"},{"header":"4. RESULTS","content":"\u003cp\u003eA total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. Among these 2554 patients, 618 were excluded because they were diagnosed with NSCLC, 969 had no brain metastases, 318 had a lack of data, 272 were without EGFR results, and 41 had an additional primary malignancy. The remaining 336 patients were analyzed retrospectively in the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 266 of the patients were male (79.2%) and the mean age was 60.6 (32\u0026ndash;81) and 264 patients (78.6%) out of 336 lung adenocarcinoma cases were EGFR mutation negative. The general characteristics of the patients are given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003eGeneral characteristics of the patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;336)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.16\u0026thinsp;\u003cb\u003e\u0026plusmn;\u003c/b\u003e\u0026thinsp;9.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e266 (79.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEGFR\u003c/b\u003e \u003cb\u003emutation status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e264 (78.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTargeted Treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003cp\u003eNot Received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (76.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (23.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of Targeted Treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eOsimertinib\u003c/p\u003e \u003cp\u003eErlotinib\u003c/p\u003e \u003cp\u003eAlectinib\u003c/p\u003e \u003cp\u003eGefitinib\u003c/p\u003e \u003cp\u003eAfatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (10.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (45.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (16.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (14.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEGFR Mutation Type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (40.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 20 - S768I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 21 - L858R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (31.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG719X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 19 and Exon 20 - T790M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExon 20 - T790M and Exon 21 - L858R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (38.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e207 (61.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdditional organ metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e271 (80.7)\u003c/p\u003e \u003cp\u003e65 (19.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiagnosis stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eStage I\u003c/p\u003e \u003cp\u003eStage II\u003c/p\u003e \u003cp\u003eStage III\u003c/p\u003e \u003cp\u003eStage IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (2.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (13.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e277 (82.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSystemic chemotherapy (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003cp\u003eNot received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e209 (62.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 (37.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of chemotherapy cures (median, min-max)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMortality (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e302 (89.9)\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\u003eTumor (T) and node (N) status of the primary disease at the time of BM, clinical findings, characteristics of BM, treatments, and their comparison in EGFR (+) and EGFR (-) groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eThe characteristics of the brain metastasis and comparison between groups.\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" 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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;336)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eEGFRmut\u003c/em\u003e (+) (n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eEGFRmut\u003c/em\u003e (-) (n\u0026thinsp;=\u0026thinsp;264)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eNumber of brain metastases (n, %)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 (38.7 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (30.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108 (40.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e206 (61.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156 (59.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis symptoms (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (13.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsciousness change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (9.8 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.275\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemiplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.747\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis size (mm) (median, min-max)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (2-288)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (2\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (2-288)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemorrhage into brain metastasis (n, %)\u003c/b\u003e\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.376\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e328 (93.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (95.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e259 (98.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRim-type involvement in brain metastasis (n, %)\u003c/b\u003e\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (22.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61(23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.616\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e261 (77.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e203 (76.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.592\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCranial radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e323 (84.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (92.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e255 (96.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.488\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrain metastasis relapse or progression (n, %)\u003c/b\u003e\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.475\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e285 (96.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e222 (84.)\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\u003eThe variables that could affect survival were compared in the mortality and survivor groups, and their relationship with survival was evaluated and summarized in the Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\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\u003eThe comparison of the variables that might affect survival in the surviving and mortality groups.\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMortality (n\u0026thinsp;=\u0026thinsp;302)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvivor (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.22\u0026thinsp;\u0026plusmn;\u0026thinsp;9.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.68\u0026thinsp;\u0026plusmn;\u0026thinsp;7.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.743\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e244 (80.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (64.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (35.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidity (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.200\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e190 (62.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEGFR\u003c/b\u003e \u003cb\u003estatus (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (18.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (44.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245 (81.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (55.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePerformance status (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eECOG 0\u003c/p\u003e \u003cp\u003eECOG 1-2-3-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (20.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiagnostic sequence (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLater brain metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e208 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimultaneous diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 (31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (32.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical manifestation due to cranial metastasis (n, %)\u003c/b\u003e\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e123 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (70.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCranial radiotherapy (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003cp\u003eNot received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e292 (96.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (91.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCranial Metastasectomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e272 (90.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (88.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e188 (62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (38.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT status at diagnosis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003cp\u003eT2\u003c/p\u003e \u003cp\u003eT3\u003c/p\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.164\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83(27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN status at diagnosis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003cp\u003eN1\u003c/p\u003e \u003cp\u003eN2\u003c/p\u003e \u003cp\u003eN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (38.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 (30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (26.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 (43.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eM status at diagnosis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eM0\u003c/p\u003e \u003cp\u003eM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (16.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252 (83.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (70.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdditional organ metastasis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e251 (83.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (58.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (41.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT status at the time of brain metastasis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003cp\u003eT2, 3, 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e265(87.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (67.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN status at the time of brain metastasis (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003cp\u003eN1\u003c/p\u003e \u003cp\u003eN2\u003c/p\u003e \u003cp\u003eN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138 (45.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eM status at the time of brain metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eM1a, M1b\u003c/p\u003e \u003cp\u003eM1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e217 (71.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH U/L (median, min-max)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e220 (65-2322)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e189 (118\u0026ndash;1522)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlbumin g/dL (median, min-max)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.80 (2-5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.13 (3.34\u0026ndash;5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNLR (median, min-max)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.61 (0,24\u0026ndash;161)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.06 (0.18\u0026ndash;22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.213\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH threshold value U/L (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;218\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e148 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (76.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal protein threshold g/dL (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6.87\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;6.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.147\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (38.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlbumin threshold g/dL (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3.96\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;3.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (59.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (32.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNLR threshold value (n, %)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4.2\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135 (44.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e167 (55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (70.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eECOG: Eastern Cooperative Oncology Group; Patient performance status score.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eT: Tumor size, N: Lymph node metastasis, M: Metastasis status.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eLDH: Lactate dehydrogenase, NLR: Neutrophil/lymphocyte ratio.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe comparison of the tumor-node-metastasis (TNM) status, stage, and presence of additional organ metastasis at the time of diagnosis, TNM status at the time of BM, and stage in the mortality and survival groups are given in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe characteristics of the laboratory parameters were examined in the mortality and survival groups. The threshold values of parameters were calculated with the Youden\u0026rsquo;s index. The comparisons made according to these threshold values are given in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and their survival was evaluated with univariate analysis. Multivariate analysis was made based on the variables obtained according to univariate analysis results and clinical significance. Multivariate analysis results are given in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe impacts of the demographic, clinical, and radiological characteristics of patients on mortality according to multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" 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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eMultivariate Analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHR (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026gt;\u0026thinsp;72 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eEGFR\u003c/em\u003e mutation status (Negative)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history (Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain metastasis diagnosis (Following lung diagnosis)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain metastasis size (\u0026gt;\u0026thinsp;19 mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical manifestation related to brain metastasis (Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy (Not received)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH U/L (\u0026gt;\u0026thinsp;218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.042\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage at diagnosis (Stage IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT status at the time of brain metastasis (T II, III, IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN status at the time of brain metastasis (N2, 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM status at the time of brain metastasis (M1c)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eLDH: Lactate dehydrogenase, \u003cem\u003eEGFR\u003c/em\u003e (Epidermal Growth Factor Receptor): T: Tumor size, N: Lymph node metastasis, M: Metastasis status, HR: Hazard ratio, CI: Confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe mean thoracic disease progression-free survival of all patients was found to be 11.199 (9.84\u0026ndash;12.55) months. The mean thoracic disease progression-free survival times were 9.72 months (95% CI 8.329\u0026ndash;11.111) in the EGFR (-) group and 16.625 months (95% CI 13.185\u0026ndash;20.065) in the EGFR (+) group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eThe brain metastasis progression status of the patients was evaluated. Although no recurrence or progression of brain metastasis was detected in 283 patients (84.2%), it was seen in 51 patients (15.2%). Progression-free survival times of 51 patients with relapse/progression in brain metastases were evaluated. The mean brain metastasis recurrence or progression-free survival time was 34.105 months (95% CI: 30.604\u0026ndash;37.605). This period was 28.966 (95% CI 29.668\u0026ndash;42.662) months in the EGFR (-) Group and 36.165 (95% CI 30.627\u0026ndash;43.361) months in the EGFR (+) Group.\u003c/p\u003e \u003cp\u003eThe mean value of the overall survival time of the patients was found to be 11.83 (95% CI: 10.33\u0026ndash;13.32). When overall survival was compared, the mean expected time in the EGFR (-) group was 10.088 (95% CI 8.571\u0026ndash;11.606) months, and 11.829 months (95% CI 10.336\u0026ndash;13.323) months in the EGFR (+) Group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe survival of 72 patients with positive EGFR was evaluated according to their targeted treatment status. 55 patients received targeted treatment; 17 patients did not receive targeted treatment. While the mortality rate was 88.24% in those who did not receive targeted treatment, the mortality rate in those who received targeted treatment was 76.36%. The median expected overall survival was found to be 7.929 months (95% CI: 4.794\u0026ndash;11.065) in the no-treatment group, and it was 21.209 months (95% CI: 16.672\u0026ndash;25.747) in the group that received targeted treatment. EGFR-positive patients were 4 times more (95% CI: 1.767\u0026ndash;9.058) in the group that did not receive targeted treatment than in the group that received the targeted treatment (p\u0026thinsp;=\u0026thinsp;0.0009) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"5. DISCUSSION","content":"\u003cp\u003eIn our study, the impacts of \u003cem\u003eEGFR\u003c/em\u003e mutation on survival were investigated in patients with lung adenocarcinoma with brain metastases.\u003c/p\u003e \u003cp\u003eIn the present study, there were 72 (21.4%) patients out of the group of 336 patients in the patient group were found to be \u003cem\u003eEGFR\u003c/em\u003e positive, and 55 (76.4%) of this group received targeted treatment. In studies conducted in T\u0026uuml;rkiye, the \u003cem\u003eEGFR\u003c/em\u003e positivity rate ranges between 22\u0026ndash;42% (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study, the rate of women in \u003cem\u003eEGFR\u003c/em\u003e-positive patients was higher than in the \u003cem\u003eEGFR\u003c/em\u003e-negative group (48.8%; 13.3%) and the smoking history was less in \u003cem\u003eEGFR\u003c/em\u003e-positive patients (47.2%; 87.1%). It is already known that driver mutation positivity is more common in women and non-smokers (varying between 29\u0026ndash;66% in the literature) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is also known that tumors with EGFR positivity cause a predisposition to metastasis regardless of tumor size, especially brain metastasis when compared to those without EGFR (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In the present study although additional organ metastases were more common in the \u003cem\u003eEGFR\u003c/em\u003e-negative group, this difference was not statistically significant.\u003c/p\u003e \u003cp\u003eIt was found in the present study that \u003cem\u003eEGFR\u003c/em\u003e-negative patients had larger brain metastases. In the study of Yeop-shin et al., no correlation was detected between the size of brain metastasis and \u003cem\u003eEGFR\u003c/em\u003e positivity (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, symptoms such as seizures, changes in consciousness, hemiplegia, paraplegia, and visual impairment symptoms were not associated with \u003cem\u003eEGFR\u003c/em\u003e status. However, headache and dizziness complaints were statistically and significantly higher in the \u003cem\u003eEGFR\u003c/em\u003e-positive group. Luo D et al. found that intracranial hypertension, paresthesia, aphasia, and distraction were higher in the \u003cem\u003eEGFR\u003c/em\u003e-positive group, but not at statistically significant levels (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and survival was examined. There are publications in the literature reporting that the female gender is a positive prognostic characteristic in survival (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In this study, even though the male gender was found to be a risk factor for death in univariate analysis, it was not found as a risk factor for mortality in multivariate analysis. This can be explained by the fact that male patients were older and had less \u003cem\u003eEGFR\u003c/em\u003e positivity than female patients.\u003c/p\u003e \u003cp\u003eAge over 72 was found to be a risk factor for mortality in the univariate and multivariate analyses. \u003cem\u003eEGFR\u003c/em\u003e mutation is seen at a higher rate in younger patients. Also, age was found to be a factor that negatively affected survival in the \u003cem\u003eEGFR\u003c/em\u003e-negative and \u003cem\u003eEGFR\u003c/em\u003e-positive NSCLC (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe impacts of co-morbidities on the prognosis of lung cancer are less researched considering the stage and treatment modalities. Although there are publications in the literature reporting a relationship between comorbidity and mortality in lung cancer (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), no correlation was detected between comorbidity and survival in our study.\u003c/p\u003e \u003cp\u003eSmoking was found to be a factor that increased the risk of mortality in the multivariate analyses in our study like other studies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is already known that poor performance status (ECOG (Eastern Cooperative Oncology Group\u0026thinsp;\u0026ge;\u0026thinsp;1) negatively affects survival in NSCLC and all cancer types and tend to be older and more \u003cem\u003eEGFR\u003c/em\u003e-negative (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Performance status was found to be statistically and significantly risky for mortality in univariate analysis, but not found to be significantly risky in multivariate analysis in the present study. This change may be occurred by retrospective design of the study.\u003c/p\u003e \u003cp\u003eT\u0026thinsp;\u0026ge;\u0026thinsp;2 or N\u0026thinsp;\u0026ge;\u0026thinsp;2 disease at the time of diagnosis and at the time of brain metastasis, M1c disease at the time of brain metastasis, presence of additional organ metastases, and Stage IV disease at the time of diagnosis were found to be risky in terms of mortality in univariate analysis.\u003c/p\u003e \u003cp\u003eIt is already known that active extracranial metastasis is associated with decreased survival in NSCLC patients with brain metastases. Eichler et al. reported that active extracranial metastasis has a poor impact on survival (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) was supported by the fact that M1c is associated with decreased survival at the time of brain metastasis in the univariate and multivariate analyses.\u003c/p\u003e \u003cp\u003eIt is already known that the nutritional status of the patient or the presence of cachexia affects the prognosis and survival of lung cancer patients (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The total protein and albumin levels were used to measure cachexia in the present study with the threshold values for total protein\u0026thinsp;\u0026le;\u0026thinsp;6.87 g/dL and albumin\u0026thinsp;\u0026le;\u0026thinsp;3.96 g/dL. No relationship was detected between total protein and survival.\u003c/p\u003e \u003cp\u003eAs an intracellular enzyme, LDH was shown to be associated with a poor prognostic factor because it shows increased catabolism and mitotic activity (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). And NLR level is an indicator of the increased systemic inflammatory response, it was found to be associated with poor prognosis in lung cancer (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). LDH\u0026thinsp;\u0026gt;\u0026thinsp;218 U/L and NLR\u0026thinsp;\u0026gt;\u0026thinsp;4.2 appear to increase the risk of mortality in univariate analysis. It was also seen that having an LDH\u0026thinsp;\u0026gt;\u0026thinsp;218 U/L increased the risk of mortality in multivariate analysis.\u003c/p\u003e \u003cp\u003eIn our study it is found that tumor size\u0026thinsp;\u0026gt;\u0026thinsp;19 mm and the presence of clinical symptoms because of brain metastasis decreased survival in multivariate analysis. It is concordant with other studies (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBrain metastasis development during follow-up rather than brain metastasis at the time of diagnosis was found to be a risk factor in terms of mortality in univariate and multivariate analyzes in the present study. In the study of J\u0026uuml;nger et al. it was found that time of BM in NSCLC did not affect the mortality (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). This study contradicts our study in this regard.\u003c/p\u003e \u003cp\u003eThe impact of chemotherapy and targeted treatment on survival was also examined. Chemotherapy increases survival when compared to patients who cannot receive chemotherapy (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In the present study, patients who did not receive chemotherapy had a higher risk of mortality in both univariate and multivariate analyses. Cranial metastasectomy is beneficial in selected patients (especially in those with brain metastases without lymph node involvement) (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In the present study, cranial metastasectomy reduced mortality risk in univariate analysis, but this impact was not detected in multivariate analysis, which may be because of the number of patients who underwent cranial metastasectomy. Radiotherapy was not found to be associated with the risk of mortality in the present study. This result is similar to the results of the study conducted by Jiang et al. that investigated the impacts of radiotherapy on survival in \u003cem\u003eEGFR\u003c/em\u003e-positive patients (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhen the survival rates of the patients were examined, the thoracic disease progression-free survival time (9.7 months to 16.6 months) and the brain metastasis recurrence or progression-free survival time (29.0 months to 36.2 months) were statistically and significantly longer in the \u003cem\u003eEGFR\u003c/em\u003e-positive group. Unlike our study, no difference was reported between progression-free survival times in Luo et al.\u0026rsquo;s study (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Similar to our study, disease progression-free survival time was found to be longer in the \u003cem\u003eEGFR\u003c/em\u003e-positive group than in the \u003cem\u003eKRAS\u003c/em\u003e-positive or \u003cem\u003eEGFR\u003c/em\u003e-negative groups in the study of Cadranel et al. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study, the mean OS time of the patients was found to be 11.8 (95% CI: 10.3\u0026ndash;13.3) months. These results are similar to the OS times of metastatic NSCLC (19, 54). There are studies suggests that \u003cem\u003eEGFR\u003c/em\u003e positivity is associated with better outcome (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). In the study of Eichler et al., \u003cem\u003eEGFR\u003c/em\u003e mutation was found to be one of the prognostic factors affecting survival along with performance status, age, and the prevalence of extracranial disease (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In the present study, it was found that \u003cem\u003eEGFR\u003c/em\u003e positivity was associated with prolonged survival, and this relationship was also significant in multivariate analysis. In this way, it was found that \u003cem\u003eEGFR\u003c/em\u003e mutation status is a factor affecting survival as much as age, additional organ metastasis at the time of brain metastasis, and smoking history.\u003c/p\u003e \u003cp\u003eAmong \u003cem\u003eEGFR\u003c/em\u003e-positive patients who received \u003cem\u003eEGFR\u003c/em\u003e treatment appears to significantly improve survival (mean survival 21.2 vs. 7.9 months). The risk of mortality of patients who were \u003cem\u003eEGFR\u003c/em\u003e positive and did not receive \u003cem\u003eEGFR\u003c/em\u003e treatment was four times higher than the other group. It was observed during Stage III drug trials that treatments for \u003cem\u003eEGFR\u003c/em\u003e prolonged progression-free survival but did not have a statistically significant impact on OS. In studies in which real-life data were evaluated, these agents were also found to provide advantages in OS, which was also explained by the addition of patients with advanced age, poor performance status, and rare \u003cem\u003eEGFR\u003c/em\u003e mutation, which were excluded in real-life Stage III studies (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eData loss occurred in the present study because of its retrospective nature. Also, the number of patients in this single-center study remained at a certain level. These two situations are the limitations of the study.\u003c/p\u003e"},{"header":"6. CONCLUSION","content":"\u003cp\u003eNSCLC, which has advanced brain metastases, is a difficult disease to manage and has a high mortality rate. The discovery of driver mutations in NSCLC classification and treatment changed treatment radically. Publications report that \u003cem\u003eEGFR\u003c/em\u003e mutation has positive prognostic values in NSCLC patients with BM. The impact of \u003cem\u003eEGFR\u003c/em\u003e positivity on survival in patients diagnosed with NSCLC with brain metastases was examined in the study. Advanced age (age\u0026thinsp;\u0026gt;\u0026thinsp;72), poor performance status at the time of diagnosis (ECOG\u0026thinsp;\u0026gt;\u0026thinsp;0), smoking history, development of brain metastases in the follow-up, brain metastasis size (\u0026gt;\u0026thinsp;19 mm), neurological clinical presence because of brain metastasis, not receiving Chemotherapy, and LDH\u0026thinsp;\u0026gt;\u0026thinsp;218 U/L had negative prognostic value and decreased survival. \u003cem\u003eEGFR\u003c/em\u003e positivity was found to be associated with prolonged survival and was found to be a prognostic factor in multivariate analysis in the present study. It was shown in the present study that patients who received targeted treatment had significantly longer survival among \u003cem\u003eEGFR\u003c/em\u003e-positive patients. This area must be supported by prospective and multicenter studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e: There is no conflict of interest with any financial organization regarding the material discussed in the manuscript.\u003c/p\u003e\n\u003cp\u003eThe manuscript is written with contributions of all authors. And the manuscript is approved by all authors.\u003c/p\u003e\n\u003cp\u003eFunding: This scientific publication has received no financial support. Additionally, there are no conflicts of interest, and the authors have not received any personal financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRUBITIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDSU made prominent contributions to the concept of work. DSU also made significant contributions to the collection of data and writing process. SA made significant contributions to the interpretation of data and reviewed the paper. OK made important contributions to the interpretation and collection of data. GB played a role in the writing and editing processes. SE made significant contributions to the collection of data. AM played a vital role in the conception of work, interpretation of data and reviewing of paper. All authors have approved the submitted version of the manuscript.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLanger CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005 Sep;23(25):6207\u0026ndash;19. \u003c/li\u003e\n\u003cli\u003eSchuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer. 2004 Aug;45(SUPPL. 2):S253\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eMehta MP, Rodrigus P, Terhaard CHJ, Rao A, Suh J, Roa W, et al. 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[cited 2020 Dec 26]. Available from: https://link.springer.com/article/10.1007/s13277-013-1323-9\u003c/li\u003e\n\u003cli\u003eEichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010 Nov;12(11):1193\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eMcGranahan T, Nagpal S. A Neuro-oncologist\u0026rsquo;s Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer. Curr Treat Options Oncol [Internet]. 2017 Apr 1 [cited 2022 Feb 19];18(4):22. Available from: /pmc/articles/PMC5385200/\u003c/li\u003e\n\u003cli\u003eUnal OU, Oztop I, Calibasi G, Baskin Y, Koca D, Demir N, et al. Relationship between Epidermal Growth Factor Receptor Gene Mutations and Clinicopathological Features in Patients with Non-Small Cell Lung Cancer in Western T\u0026uuml;rkiye. Asian Pacific J Cancer Prev [Internet]. 2013 [cited 2022 Mar 6];14(6):3705\u0026ndash;9. Available from: http://dx.doi.org/10.7314/APJCP.2013.14.6.3705\u003c/li\u003e\n\u003cli\u003eScaglia NC, Chatkin JM, Pinto JA, Tsukazan MTR, Wagner MB, Saldanha AF. Role of gender in the survival of surgical patients with nonsmall cell lung cancer. Ann Thorac Med. 2013 Jul;8(3):142.\u003c/li\u003e\n\u003cli\u003eVisbal AL, Williams BA, Nichols FC, Marks RS, Jett JR, Aubry MC, et al. Gender differences in non\u0026ndash;small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002. Ann Thorac Surg. 2004 Jul;78(1):209\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eGuan J, Chen M, Xiao N, Li L, Zhang Y, Li Q, et al. EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan. Med Oncol. 2016 Jan;33(1):1\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eHo-Pun-Cheung A, Assenat E, Bascoul-Mollevi C, Bibeau F, Boissi\u0026atilde;re-Michot F, Cellier D, et al. EGFR and HER3 mRNA expression levels predict distant metastases in locally advanced rectal cancer. Int J Cancer. 2011 Jun;128(12):2938\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003eShin D-Y, Il Na I, Hyeon Kim C, Park S, Baek H, Hyun Yang S. EGFR Mutation and Brain Metastasis in Pulmonary Adenocarcinomas. Vol. 9, Journal of Thoracic Oncology. 2014.\u003c/li\u003e\n\u003cli\u003eLuo D, Ye X, Hu Z, Peng K, Song Y, Yin X, et al. EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumor Biol [Internet]. 2014 Nov 7 [cited 2020 Dec 26];35(3):2437\u0026ndash;44. Available from: https://link.springer.com/article/10.1007/s13277-013-1323-9 \u003c/li\u003e\n\u003cli\u003eInoue A, Yoshida K, Morita S, Imamura F, Seto T, Okamoto I, et al. Characteristics and overall survival of EGFR mutation-positive non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. Jpn J Clin Oncol. 2016 May;46(5):462\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eZheng R, Guo D, Dong Y, Wang M, Hu M, Ren Y. Prognostic Factors in Patients with Brain Metastases of Lung Adenocarcinoma with the Surveillance Epidemiology and End Results Database Running title: Prognostic factors in patients with brain metastases of lung adenocarcinoma Email addresses.\u003c/li\u003e\n\u003cli\u003eSacher AG, Dahlberg SE, Heng J, Mach S, J\u0026auml;nne PA, Oxnard GR. Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non\u0026ndash;Small-Cell Lung Cancer. JAMA Oncol. 2016 Mar;2(3):313\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eDutkowska AE, Antczak A. Comorbidities in lung cancer. Adv Respir Med. 2016;84(3):186\u0026ndash;92.\u003c/li\u003e\n\u003cli\u003eJanssen-Heijnen MLG, Schipper RM, Razenberg PPA, Crommelin MA, Coebergh JWW. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: A population-based study. Lung Cancer. 1998 Aug 1;21(2):105\u0026ndash;13.\u003c/li\u003e\n\u003cli\u003eKawaguchi T, Takada M, Kubo A, Matsumura A, Fukai S, Tamura A, et al. Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: A comprehensive analysis of 26,957 patients with NSCLC. J Thorac Oncol. 2010;5(5):620\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eDall\u0026rsquo;Olio FG, Maggio I, Massucci M, Mollica V, Fragomeno B, Ardizzoni A. ECOG performance status \u0026ge;2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors\u0026mdash;A systematic review and meta-analysis of real world data. Lung Cancer. 2020 Jul;145:95\u0026ndash;104.\u003c/li\u003e\n\u003cli\u003eAlghamdi HI, Alshehri AF, Farhat GN. An overview of mortality \u0026amp; predictors of small-cell and non-small cell lung cancer among Saudi patients. J Epidemiol Glob Health. 2018 Mar;7:S1\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eWaqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018 Jul;19(4):e373.\u003c/li\u003e\n\u003cli\u003eClinically relevant determinants of body composition, function, and nutritional status as mortality predictors in lung cancer patients | Elsevier Enhanced Reader.\u003c/li\u003e\n\u003cli\u003eEckart A, Struja T, Kutz A, Baumgartner A, Baumgartner T, Zurfluh S, et al. Relationship of Nutritional Status, Inflammation, and Serum Albumin Levels During Acute Illness: A Prospective Study. Am J Med. 2020 Jun;133(6):713-722.e7.\u003c/li\u003e\n\u003cli\u003eJurisic V, Radenkovic S, Konjevic G. The Actual Role of LDH as Tumor Marker, Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:115\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eCedr\u0026eacute;s S, Torrejon D, Mart\u0026iacute;nez A, Martinez P, Navarro A, Zamora E, et al. Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer. Clin Transl Oncol. 2012 Nov;14(11):864\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eJ\u0026uuml;nger ST, Sch\u0026ouml;del P, Ruess D, Ruge M, Brand JS, Wittersheim M, et al. Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments. Cancers (Basel). 2020 Dec;12(12):1\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eKosmidis P. Chemotherapy in NSCLC: Historical review. Lung Cancer. 2002;38(3 SUPPL.):19\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eBex A. Integrating metastasectomy and stereotactic radiosurgery in the treatment of metastatic renal cell carcinoma. EJC Suppl. 2013 Sep;11(2):192-203. doi: 10.1016/j.ejcsup.2013.07.017. PMID: 26217128; PMCID: PMC4041303.\u003c/li\u003e\n\u003cli\u003eJiang T, Su C, Li X, Zhao C, Zhou F, Ren S, et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol. 2016 Oct;11(10):1718\u0026ndash;28.\u003c/li\u003e\n\u003cli\u003eCadranel J, Mauguen A, Faller M, Zalcman G, Buisine MP, Westeel V, et al. Impact of Systematic EGFR and KRAS Mutation Evaluation on Progression-Free Survival and Overall Survival in Patients with Advanced Non\u0026ndash;Small-Cell Lung Cancer Treated by Erlotinib in a French Prospective Cohort (ERMETIC Project\u0026mdash;Part 2). J Thorac Oncol. 2012 Oct 1;7(10):1490\u0026ndash;502.\u003c/li\u003e\n\u003cli\u003eLi WY, Zhao TT, Xu HM, Wang ZN, Xu YY, Han Y, et al. The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: A systematic review and meta-analysis. Vol. 19, BMC Cancer. BioMed Central Ltd.; 2019.\u003c/li\u003e\n\u003cli\u003eLu S, Shih JY, Jang TW, Liam CK, Yu Y. Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence. Adv Ther. 2021 May;38(5):2038\u0026ndash;53.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-bronchology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Bronchology](https://ejb.springeropen.com/)","snPcode":"43168","submissionUrl":"https://submission.nature.com/new-submission/43168/3","title":"The Egyptian Journal of Bronchology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-small cell lung cancer, adenocarcinoma, brain metastasis, EGFR, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-5316285/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5316285/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eBrain Metastasis (BM) in Non-Small Cell Lung Cancer (NSCLC) is still important reason of morbidity and mortality despite the advances in the cancer treatment. Using Tyrosine Kinase Inhibitors against Epidermal Growth Factor Receptors (EGFR) mutations revolutionized in NSCLC treatment. We investigated whether the presence of EGFR mutation influences survival in patients with Lung Adenocarcinoma with BM.\u003c/p\u003e\u003ch2\u003eMaterial and Methods\u003c/h2\u003e \u003cp\u003eThe data of the patients with pathological diagnosis of NSCLC and BM at tertiary hospital were analyzed retrospectively in terms of survival. A total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. After exclusion of patients with lack of data, unknown EGFR mutation status, no brain metastasis and additional malignancy 336 patients were included to the study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIt is found that EGFR (+) patients were more female dominant (48.6% vs 13.3% p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and were have less history of smoking (%47.2 vs %87.1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and were better survival (%79.2 vs %92.8). We found negativity of EGFR increased death risk by 1.700 times (95% CI: 1.323\u0026ndash;2.183, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in univariate analysis and by 1.724 times (95% CI 1.251\u0026ndash;2.377, p\u0026thinsp;=\u0026thinsp;0.0001) in multivariate analysis. When overall survivals have been compared estimated overall survival time of EGFR (-) patients were 10.088 (95% CI 8.571\u0026ndash;11.606) months and of EGFR (+) patients were 11.829 months (95% CI 10.336\u0026ndash;13.323) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEGFR positivity was associated with survival. Also, survival was significantly longer in EGFR-positive patients with brain metastases diagnosed with NSCLC.\u003c/p\u003e","manuscriptTitle":"Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-30 10:06:53","doi":"10.21203/rs.3.rs-5316285/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-27T05:42:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-13T20:14:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82307447865103590832188267665978116862","date":"2025-01-07T14:33:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92533546977048288978373087039814494040","date":"2025-01-07T10:08:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-13T18:50:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"232653922200556674633212929847793003650","date":"2024-11-04T07:00:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-01T11:15:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-30T05:45:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-28T08:54:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Egyptian Journal of Bronchology","date":"2024-10-23T06:38:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-bronchology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Bronchology](https://ejb.springeropen.com/)","snPcode":"43168","submissionUrl":"https://submission.nature.com/new-submission/43168/3","title":"The Egyptian Journal of Bronchology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4be5b961-a1f5-4617-a5e3-1df7e79cb094","owner":[],"postedDate":"October 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-02-13T09:38:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-30 10:06:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5316285","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5316285","identity":"rs-5316285","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}