==== Front Transl OncolTransl OncolTranslational Oncology1936-5233Neoplasia Press S1936-5233(18)30195-510.1016/j.tranon.2018.07.003Review articleEfficacy and Safety of Radiotherapy Plus EGFR-TKIs in NSCLC Patients with Brain Metastases: A Meta-Analysis of Published Data Wang Xueyan *1Xu Ye *1Tang Weiqing †1Liu Lingxiang llxlau@163.com*⁎* Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China† Division of Surgery, Guilin Medical University, Guilin, Guangxi, 541000, China⁎ Address all correspondence to: Lingxiang Liu, Lingxiang Liu, 300 Guangzhou Rd, The First Affiliated Hospital of Nanjing Medical University, Department of Oncology, Nanjing, Jiangsu Province, People's Republic of China. llxlau@163.com1 X.W., Y.X., and W.T. contributed equally to this work as first authors. 20 7 2018 10 2018 20 7 2018 11 5 1119 1127 8 5 2018 29 6 2018 2 7 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background: The role of radiotherapy (RT) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains controversial. Therefore, we conducted a meta-analysis to comprehensively evaluate the efficacy and safety of RT plus EGFR-TKIs in those patients. Materials and Methods: Relevant literatures published between 2012 and 2017 were searched. Objective response rate(ORR), disease control rate (DCR), overall survival (OS), intracranial progression-free survival (I-PFS) and adverse events (AEs) were extracted. The combined hazard ratios (HRs) and relative risks (RRs) were calculated using random effects models. Results: Twenty-four studies (2810 patients) were included in the analysis. Overall, RT plus EGFR-TKIs had higher ORR (RR = 1.32, 95%CI: 1.13–1.55), DCR (RR = 1.12, 95%CI: 1.04–1.22), and longer OS (HR = 0.72, 95%CI: 0.59–0.89), I-PFS (HR = 0.64, 95%CI: 0.50–0.82) than monotherapy, although with higher overall AEs (20.2% vs 11.8%, RR = 1.34, 95% CI: 1.11–1.62). Furthermore, subgroup analyses found concurrent RT plus EGFR-TKIs could prolong OS (HR = 0.69, 95%CI: 0.55–0.86) and I-PFS (HR = 0.57, 95%CI: 0.44–0.75). Asian ethnicity and lung adenocarcinoma (LAC) patients predicted a more favorable prognosis (HR = 0.69,95%CI: 0.54–0.88, HR = 0.66, 95%CI: 0.53–0.83, respectively). Conclusion: RT plus EGFR-TKIs had higher response rate, longer OS and I-PFS than monotherapy in NSCLC patients with BM. Asian LAC patients with EGFR mutation had a better prognosis with concurrent treatment. The AEs of RT plus EGFR-TKIs were tolerated. ==== Body Introduction Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide [1]. Approximately 80% of lung cancers were diagnosed non-small cell lung cancer (NSCLC). About 40% of NSCLC patients developed brain metastasis (BM) during the course of diseases, and 10%–25% of advanced NSCLC patients had BM at initial diagnosis, the risk even higher in those with epidermal growth factor receptor (EGFR) mutation [2], [3]. The median overall survival (OS) remains disappointing, less than 3 months, for untreated BM patients [4]. Whole-brain radiotherapy (WBRT) has long been a standard therapy for NSCLC with multiple BMs, providing symptom palliation and prolonging survival [5]. Moreover, stereotactic radiosurgery (SRS) has emerged as a principal alternative treatment for oligo-brain metastasis, allowing for precise tumor targeting with minimal invasive [6], [7]. Currently, EGFR tyrosine kinase inhibitors (TKIs) have been recognized as the first-line treatment for advanced NSCLC patients with EGFR mutation-positive [8], [9], [10]. Gefitinib and erlotinib can be able to cross the blood–brain barrier (BBB) after disrupted by brain radiotherapy (RT) [11], [12]. Particularly, RT and EGFR TKIs might have synergistic anti-tumor effect, with sustained clinical efficacy and favorable safety [13], [14], [15]. However, the role of RT combined with EGFR-TKIs for NSCLC patients with BM remains controversial [16], [17]. Therefore, we performed the meta-analysis to comprehensively evaluate the efficacy and safety of RT plus EGFR-TKIs in those patients. Materials and Methods Search Strategy and Selection Criteria Relevant literatures, published between January 1, 2012 and November 28,2017 from PubMed, EMBASE, Web of Science, Google Scholar, and Cochrane Library were collected, using the terms “lung cancer”, “lung neoplasms”, “lung tumor”, “brain metastasis”, “brain neoplasms” “radiotherapy”, and “tyrosine kinase inhibitors”. To be included in the analysis, each study had to fulfill the following criteria: (1) histologically or cytologically confirmed NSCLC and had been diagnosed with one or more BMs by imaging modalities; (2) prospective or retrospective studies; (3) treatment-naive to the BMs; (4) combination therapy: RT (WBRT, SRS or three-dimensional conformal radiotherapy) combined with EGFR-TKIs; monotherapy: EGFR-TKIs alone or RT ± chemotherapy(CT); (5) only the latest and most complete article was included if duplicate studies were from the same population; (6) full text articles in English or Chinese language were available. Two reviewers independently determined study eligibility, disagreements were resolved by consensus. Data Extraction Two investigators conducted independently with the standardized forms according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The following data were collected from each study: first author, year of publication, source of patients, trial phase, histology, number of patients, median ages, number of female, intervention methods, outcomes and adverse events (AEs). In addition, the result was double-checked by a third reviewer and discrepancies were settled by group discussion. Methodological Assessment Two reviewers independently assessed the quality of the included literatures according to The Cochrane Handbook for Systematic Reviews (Version 5.1.0), based on the following criteria: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; (7) other bias. We evaluated methodological quality as low, unclear or high risk of bias. Literatures were defined as low risk of bias (A) when all criteria were assessed as low risk; defined as moderate risk of bias (B) or high risk of bias (C) when one or more criteria were assessed as unclear risk or high risk, respectively. Definition of Outcomes and Comparisons The primary outcomes were the OS and I-PFS, then stratified by monotherapy, treatment sequence, ethnicity, histologic type and published year. The effective value of OS and I-PFS were determined by the combination of hazard ratio (HR) and 95% confidence interval (CI), if the CI included 1, then the HR was nonsignificant. For time-to-event data, if a direct report of HR and 95% CI was not possible, estimated value was derived indirectly from other presented data using the methods proposed by Tierney et al. [18]. Furthermore, objective response rate(ORR), disease control rate (DCR) and AEs were estimated by relative risk (RR). Response rate was calculated using the Response Evaluation Criteria in Solid Tumors. Complete remission: all tumor lesions completely disappeared and normalization of tumor marker level. Partial response: at least a 30% decrease in the sum of the longest diameters (LD) of target lesions. Progressive disease: at least a 20% increase in the smallest sum of the LD of target lesions or the appearance of one or more new lesions. Stabilized disease: neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. AEs were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Statistical analysis χ2 and I2 tests were used to test the statistical heterogeneity of different studies, no heterogeneity was considered when I2< 50% and P > .1, then the fixed-effects model was used. Otherwise, the random effects model was applied (I2> 50% and P < .1). Z test was used to determine the significance of the pooled HR or RR, and P < .05 was considered statistically significant. Publication bias were assessed by Egger's regression and Begg's funnel plot [19], [20], whereas P < .1 was set as statistical significance. Sensitivity analysis was performed to determine the influence of each study regarding overall effective size. OS and I-PFS were calculated using effect variables; ORR, DCR and AEs (Grade ≥ 3) were analyzed using dichotomous variables. Statistical computations were all performed with STATA Version 12.0 (Stata Corporation LP, College Station, TX). All p values were two sided. Results Trial Flow Literature search process was depicted in Figure 1. We identified 186 potentially relevant abstracts, and then 119 were excluded for the following reasons: 68 no target interventions; 27 single-arm studies; 13 reviews and 11 cases reports. Finally, after carefully reading the full-text, 24 studies were included in the analysis. The characteristics of these 24 studies were shown in Table 1.Figure 1 Flow chart of studies included in the meta-analysis. Figure 1Table 1 Main characteristics of 24 included studies Table 1First Author Year S of Pts Trial phase Histology NP (C/M) MA (C/M, years) Female (C/M) Combination therapy Treatment sequence Monotherapy Outcomes AEs SQ Zhu [21] 2017 CN Ret LAC 67/66 56/56 37/35 WBRT/SRS + TKI (gefitinib/erlotinib) Concurrent TKI (gefitinib/erlotinib) OS, I-PFS N B Fan [13] 2017 CN Ret LAC 56/41 56/59 34/20 WBRT/SRS + icotinib Sequential icotinib OS, I-PFS, ORR, DCR N B Doherty [22] 2017 CA Ret NSCLC 157/27 59/65 111/14 WBRT/SRS+ TKI Concurrent TKI OS, I-PFS, ORR, ORR N B Wang [23] 2016 CN Ret NSCLC 37/161 NA NA WBRT/SRS + TKI Sequential WBRT/SRS + CT OS, I-PFS, ORR, DCR Y B Jiang [16] 2016 CN Ret NSCLC 51/116 NA 26/62 WBRT+TKI (gefitinib/ erlotinib/icotinib) Concurrent TKI OS, I-PFS, DCR, ORR N B Chen [24] 2016 CN Ret LAC 53/79 52/52 29/52 WBRT+TKI Concurrent TKI OS, I-PFS, ORR N B Byeon [25] 2016 KR Ret NSCLC 59/62 60/60 36/47 WBRT/SRS + TKI (gefitinib/erlotinib) Sequential TKI (gefitinib/erlotinib) OS, DCR, ORR, I-PFS, ex-PFS N B Xiang [26] 2015 CN Ret NSCLC 39/96 NA NA WBRT+TKI Concurrent WBRT±CT OS N C Wang [27] 2015 CN Pro NSCLC 37/36 61/62 12/13 3D-RT + gefitinib Concurrent 3D-RT + VMP OS, ORR, DCR Y B Liu [28] 2015 CN Ret NSCLC 35/15 46.3/47.5 18/8 WBRT+TKI Concurrent WBRT ORR, DCR N C Liu [29] 2015 CN Ret LAC 62/34 54/54 NA WBRT/SRS + TKI Sequential TKI ± CT OS, I-PFS N C Kim [30] 2015 KR Ret NSCLC 18/13 55/56 12/10 SRS + TKI Concurrent SRS OS, I-PFS Y B Lee [14] 2014 UK II NSCLC 40/40 61.3/62.2 25/29 WBRT+ erlotinib Concurrent WBRT+ placebo OS, I-PFS Y A Cai [31] 2014 CN Ret NSCLC 104/178 65/65 42/60 WBRT/SRS + TKI Concurrent WBRT/SRS OS, I-PFS, ex-PFS N B Zhuang [15] 2013 CN II LAC 23/31 60/63 13/18 WBRT +erlotinib Concurrent WBRT OS, I-PFS, ex-PFS, ORR, DCR Y B Zhou [32] 2013 CN Ret NSCLC 36/22 NA 21/11 WBRT+TKI Concurrent WBRT+CT ORR, DCR Y C Sperduto [17] 2013 MC III NSCLC 41/44 61/64 NA WBRT/SRS + TKI Concurrent WBRT/SRS OS Y B Liu [33] 2013 CN Pro NSCLC 52/52 54/51 23/25 WBRT/SRS + TKI Concurrent WBRT/SRS ORR, DCR Y B Fan [34] 2013 CN Ret NSCLC 75/135 57/57 32/36 WBRT/SRS + TKI Concurrent RT ± CT OS N B Cai [35] 2013 CN Pro NSCLC 65/92 66/66 25/29 WBRT+TKI Concurrent WBRT OS, I-PFS, ORR, DCR Y B Zeng [36] 2012 CN Ret NSCLC 45/45 56/52 24/26 WBRT+ gefitinib Concurrent gefitinib OS, I-PFS, ORR, DCR Y B Pesce [37] 2012 SL II NSCLC 16/43 57/63 7/16 WBRT+TKI Concurrent WBRT+TMZ OS Y B Wu [38] 2012 CN Pro NSCLC 35/18 NA NA WBRT+TKI Concurrent WBRT ORR, DCR N B Fu [39] 2012 CN Ret NSCLC 38/123 NA NA WBRT+TKI Concurrent WBRT ORR, DCR Y C Abbreviations: NP, number of patients; MA, median ages; S of Pts, source of patients; C/M, combination therapy/monotherapy; AEs: adverse events; SQ: study quality; CN, China; KR, Korea; CA, Canada; UK, the United Kingdom; MC, Multicenter; SL, Switzerland; Ret: retrospective; Pro: prospective; NSCLS: non-small cell lung cancer; LAC, lung adenocarcinoma; TKI, tyrosine kinase inhibitor; WBRT, whole brain radiotherapy; SRS, stereotactic radiosurgery; 3D-CRT, three-dimensional conformal radiotherapy; TMZ, temozolomide; CT, chemotherapy; OS, overall survival; I-PFS, intracranial progression-free survival; ex-PFS, extracranial progression-free survival; ORR, objective response rate; DCR, disease control rate; N, no mention in the paper; Y, have mentioned in the paper; NA, not available. Study Characteristics Totally, 2810 patients with BM from 24 studies were enrolled in the analysis. RT plus EGFR-TKIs was performed in 1241 (44.2%) patients, while EGFR-TKIs alone in 470 (16.8%) patients, and RT ± CT in 1099 (39%) patients. In addition, 8 prospective studies [14], [15], [17], [27], [33], [35], [37], [38] (665 patients, 23.7%) including one phase III [17] and three phase II [14], [15], [37] clinical trials and 16 retrospective studies (2145 patients, 76.3%) were included. 20 studies (2402 patients, 85.5%) were conducted among Asian while 4 studies [14], [17], [22], [37] (408 patients, 14.5%) among non-Asian and 8 studies [13], [14], [16], [21], [24], [25], [29], [30] (857 patients,30.5%)were performed exclusively in patients with EGFR mutations. As for the intervention methods, 8 studies (1020 patient, 36.3%) were conducted with WBRT/SRS plus TKIs versus TKIs alone [13], [16], [21], [22], [24], [25], [29], [36], one study (73 patients, 2.6%) with 3D-CRT plus TKIs/VM-26 (teniposide) [27], the other 15 studies (1717 patients, 61.1%) with WBRT/SRS plus TKIs versus WBRT/SRS ± CT. As far as the treatment sequence, 4 study arms (214 patients, 7.6%) were provided with sequential treatment [13], [23], [25], [29], while 20 study arms (1027 patients, 36.5%) with concurrent treatment. The clinical characteristics of 2810 patients were summarized in Table A1 (Appendix). Assessment of Study Quality We evaluated the 24 studies using the seven aspects mentioned above, the risk of bias in this analysis were shown in Figure 2, while the details in Figure S1. Four studies were with random allocation [14], [17], [27], [37], while two with the methods discussion [17], [37]. One study concealed the allocation and blinding method [15]. All of the articles applied the intention-to-treat analysis. Finally, 1/24 studies received quality scores of A, while 18/24 of B and 5/24 of C, as shown in Table 1. Meta-Analysis of Objective Response Rate and Disease Control Rate ORR and DCR were assessed respectively in 16 studies [13], [15], [16], [22], [23], [24], [25], [27], [28], [30], [32], [33], [35], [36], [37], [38], [39]. The overall ORR was 64.0% (13.0%–85.7%) in combination therapy and 40.5% (14.4–78.0%) in monotherapy; the overall DCR was 82.7% (27.9%–98.2%) in combination therapy and 71.9% (31.3–97.6%) in monotherapy. Random effects models were used to pool the RR in both ORR and DCR due to the statistical heterogeneity (I2 = 61.6%,P = .001; I2 = 65.9%, P = .000, respectively). As a result, combination therapy resulted in higher ORR (RR = 1.32, 95%CI: 1.13–1.55, P = .000) and DCR (RR = 1.12, 95%CI: 1.04–1.22, P = .005) than monotherapy. However, subgroup analysis of combination therapy versus TKIs alone showed no improvement in both ORR (RR = 1.25, 95%CI: 0.99–1.56, P = .057, Figure 3A) and DCR (RR = 1.10, 95%CI: 0.93–1.29, P = .254, Figure 3B) in NSCLC patients with BM.Figure 2 Quality and bias risk assessment of 24 included studies. Figure 2Figure 3 Meta-analysis of RT plus EGFR-TKIs versus monotherapy in NSCLC patients with BM for ORR (A), DCR (B), OS (C), I-PFS (D) and subgroup-analysis of monotherapy. Abbreviations: RT = radiotherapy; EGFR-TKIs = epidermal growth factor receptor tyrosine kinase inhibitors; NSCLC = non-small cell lung cancer; BM = brain metastasis; ORR = objective response rate; DCR = disease control rate; OS = overall survival; I-PFS = intracranial progression-free survival. Figure 3 Meta-Analysis of Overall Survival and Intracranial progression-free survival The OS was evaluated in 19 studies (2384 patients, 85%) [13], [14], [15], [16], [17], [21], [22], [23], [24], [25], [26], [27], [29], [30], [31], [34], [35], [36], [37], and I-PFS was in 13 studies (1570 patients, 56%) [13], [14], [15], [16], [21], [22], [24], [25], [29], [30], [31], [35], [36] including the extracranial progression-free survival (ex-PFS) in three (457 patients, 16%) of them [15], [25], [31]. Random effects models were used to pool the HR in both OS and I-PFS based on the heterogeneity values (I2 = 67.1%, P = .000; I2 = 75.5%, P = .017, respectively). As a result, combination therapy resulted in longer OS (HR = 0.72, 95%CI: 0.59–0.89, P = .002, Figure S2 A) and I-PFS (HR =0.64, 95%CI: 0.50–0.82, P = .000) than monotherapy, except for ex-PFS (HR = 0.64, 95%CI: 0.35–1.15, P = .133)(Figure S2 B). However, the subgroup analysis of combination therapy versus TKIs alone showed no improvement in OS (HR = 0.78, 95%CI: 0.59–1.03, P = .08, Figure 3C), although prolonged I-PFS (HR = 0.67, 95%CI: 0.45–0.98, P = .04, Figure 3D) was found in NSCLC patients with BM. Moreover, when the analysis was limited to EGFR mutations, no improvement was found in combination therapy for OS (HR 0.85, 95%CI: 0.66–1.08, P = .125, Figure S3 A) and I-PFS (HR 0.79, 95%CI: 0.60–1.05, P = .100, Figure S3 B), regardless of concurrent vs. sequential treatment, RT plus TKI vs. TKI alone/RT ± CT. We also conducted multiple subgroup analyses, shown in Table 2. As for concurrent versus sequential treatment, we found that concurrent RT plus EGFR-TKIs could significantly prolong OS (HR = 0.69, 95%CI: 0.55–0.86, P = .001) and I-PFS (HR = 0.57, 95%CI: 0.44–0.75, P = .000) in NSCLC patients with BM. Moreover, sequential treatment could not improve both of them (HR = 0.99, 95% CI:0.75–1.32, P = .959; HR = 0.95, 95% CI: 0.62–1.46, P = .822, respectively) (Figure 4, A and B). Furthermore, better OS (HR = 0.66, 95%CI: 0.53–0.83, P = .000, Figure 4C) and I-PFS (HR = 0.67, 95%CI: 0.52–0.86, P = .001, Figure 4D) were found in Asian NSCLC patients with BM. Lung adenocarcinoma (LAC) patients with BM had favorable prognosis, with HR 0.69 (95%CI: 0.54–0.88, P = .003, Figure 4E) and 0.58 (95%CI: 0.43–0.76, P = .000, Figure 4F) for OS and I-PFS respectively. Recent published year (2015–2017) showed no improvement in OS (HR = 0.78, 95%CI: 0.60–1.02, P = .071, Figure S4 A), although prolonged I-PFS was found (HR = 0.68, 95%CI: 0.47–0.99, P = .000) (Figure S4 B). As for prognostic factors from included patients, symptomatic brain metastases (P = .003), No of BMs >3 (P = .000), extracranial metastases (P = .000), brainstem metastases (P = .000), KPS <70 (P = .000), ECOG PS >1 (P = .000) were poor prognostic factors. However, female (P = .000), age< 65 years old (P = .000), never smoking (P = .000), EGFR exon 19 deletion (P = .001) were good prognostic factors (Figure S5). Adverse Events The AEs were analyzed in 12 studies (1150 patients, 40.9%) [14], [15], [17], [23], [27], [30], [32], [33], [35], [36], [37], [39]. The overall incidence rate of AEs was higher in the combination therapy than monotherapy (20.2% vs 11.8%, RR = 1.34, 95% CI: 1.11–1.62; P = .003) with random effects models due to the heterogeneity (P = .000, I2 = 45.0%). The most common AEs in combination therapy versus monotherapy were rash (42.2% vs 6.7%, RR = 6.72, 95%CI: 1.62–27.86; P = .009), dry skin (15.9% vs 1.4%, RR = 8.16, 95%CI: 1.51–44.17; P = .015) and diarrhea (19.6% vs 7.8%, RR = 2.17, 95%CI: 1.13–4.15; P = .020), as shown in Table 3 and Figure S6. Test of Heterogeneity and Sensitivity Analysis The heterogeneity was found with the systemic analysis of OS (I2 = 67.1%, χ2 = 54.79, P = .000) and I-PFS (I2 = 74.1%, χ2 = 41.92, P = .000). More importantly, no heterogeneity was detected in the subgroup analysis of non-Asian and sequential treatment for OS. The statistical heterogeneity was reduced after the subgroup analyses for OS (RT + TKI vs TKI, Asian, LAC, published year 2015–2017) and I-PFS (RT + TKI vs RT ± CT, Asian, sequential treatment and published year 2012–2014) (Table 2). Therefore, the most important sources of heterogeneity were different ethnicity, treatment sequence and histologic types.Table 2 HR Value of OS and I-PFS in Subgroups Analyses According to Monotherapy, Treatment Sequence, Ethnicity, Histology and Published Year Table 2 NS NP HRs(95%CI) P Heterogeneity Test χ2 I2 P OS 19 2384 0.72(0.59,0.89) 0.002 54.79 67.1% 0.000 RT + TKI vs TKI 8 1020 0.78(0.59,1.03) 0.080 12.34 43.3% 0.090 RT + TKI vs RT ± CT 11 1364 0.69(0.52, 0.92) 0.011 40.73 75.4% 0.000 Concurrent 11 1872 0.69(0.55, 0.86) 0.001 44.78 68.7% 0.000 Sequential 4 512 0.99 (0.75, 1.32) 0.959 3.00 0.0% 0.392 Asian 15 1976 0.66(0.53, 0.83) 0.000 42.29 66.9% 0.000 Non-Asian 4 408 1.04 (0.79, 1.38) 0.769 2.95 0.0% 0.399 LAC 5 512 0.69(0.54, 0.88) 0.003 4.10 2.4% 0.393 NSCLC 14 1872 0.75(0.57, 0.97) 0.031 50.69 74.4% 0.000 2015–2017 11 1367 0.78 (0.60, 1.02) 0.071 22.68 55.9% 0.012 2012–2014 8 1017 0.66(0.48, 0.90) 0.009 26.89 74.0% 0.000 I-PFS 13 1624 0.64(0.50, 0.82) 0.000 41.92 71.4% 0.000 RT + TKI vs TKI 8 1020 0.67(0.45, 0.98) 0.040 32.33 78.4% 0.000 RT + TKI vs RT ± CT 5 604 0.60(0.47, 0.77) 0.000 6.55 38.9% 0.162 Concurrent 10 1310 0.57(0.44, 0.75) 0.000 29.32 69.3% 0.001 Sequential 3 314 0.95(0.62, 1.46) 0.822 3.87 48.3% 0.145 Asian 11 1360 0.67(0.52, 0.86) 0.001 31.40 68.2% 0.001 Non-Asian 2 264 0.50 (0.16, 1.56) 0.235 9.17 89.1% 0.002 LAC 5 512 0.58(0.43, 0.76) 0.000 5.14 22.1% 0.274 NSCLC 8 1112 0.68(0.48, 0.96) 0.028 35.47 80.3% 0.000 2015–2017 8 961 0.68(0.47, 0.99) 0.044 31.20 77.6% 0.000 2012–2014 5 663 0.59(0.45, 0.77) 0.000 7.20 44.4% 0.126 Abbreviations: NS, number of studies; NP, number of patients; HRs, hazard ratios; CI, confidence interval. Figure 4 Subgroup analysis of OS and I-PFS in concurrent and sequential treatment (A and B), Asian and non-Asian (C and D), LAC and NSCLC (E and F), respectively. Abbreviations: OS = overall survival; I-PFS = intracranial progression-free survival; LAC = Lung adenocarcinoma; NSCLC = non-small cell lung cancer. Figure 4Table 3 Stratified Analysis of the Reported Overall Adverse Events in the 12 Included Studies Table 3Adverse event NS NP Incidence rate(%) RRs (95%CI) P Heterogeneity test Treatment group Control group χ2 I2 P headache 6 470 22(0–35.4) 21.4(10–31.8) 1.13(0.81,1.58) 0.469 4.79 0.0% 0.481 fatigue 5 576 20.5(0–44.2) 12.7(1.9–46.5) 1.07(0.74,1.50) 0.721 1.95 0.0% 0.744 dizziness 3 242 25.5(5.6–47.8) 19.1(0–21.7) 1.51(0.80,2.83) 0.200 2.70 26.0% 0.259 rash 8 763 42.2(20–44.4) 6.7(0–44.4) 6.71(1.62,27.86) 0.009 55.84 87.5% 0.000 dry skin 2 134 15.9(2.5–39.1) 1.4(0–3.3) 8.16(1.51,4.17) 0.015 0.54 0.0% 0.462 mucositis 2 113 5.1(4.3–6.3) 1.4(0–3.2) 2.85(0.36, 2.29) 0.319 0.68 0.0% 0.409 nausea & vomiting 8 903 26(0–51.9) 17.3(0–48.1) 1.14(0.90, 1.40) 0.266 4.65 0.0% 0.703 anorexia 2 134 19(5–43.5) 15.5(7.5–25.8) 1.58 (0.50, 4.5) 0.397 1.61 37.7% 0.205 diarrhea 8 816 19.6(5–42.2) 7.8(0–37.8) 2.16 (1.13, 4.15) 0.020 12.27 42.9% 0.092 constipation 2 134 17.5(2.5–17.5) 11.3(0–25.8) 1.74 (0.83, 3.63) 0.141 0.12 0.0% 0.725 pneumonitis 3 327 9.3(0–30.4) 4.9(0–22.6) 1.78 (0.32, 9.92) 0.510 3.72 46.3% 0.155 dyspnea 2 139 28.6(12,5–35) 18.1(0–37.5) 2.32(0.19,28.83) 0.512 3.03 67.0% 0.082 leucopenia/neutropenia 5 541 13.6(0–28.9) 16.8(8.7–25) 0.90 (0.50, 1.61) 0.722 5.75 30.5% 0.218 anemia 5 562 7.4(0–15.2) 7.3(5–10.9) 0.93 (0.35, 2.49) 0.889 6.19 35.3% 0.186 thrombocytopenia 3 325 5.2(0–8.7) 9.3(6.5–14.7) 0.70 (0.19, 2.5) 0.586 3.04 34.2% 0.219 myelosuppression 2 219 18.7(0–27.8) 8.2(6.5–9.1) 0.29 (0.08, 1.07) 0.064 2.32 56.8% 0.128 transaminases 3 171 3.4(0–5) 9.4(7.7–10) 2.15 (0.75, 6.17) 0.155 2.17 7.8% 0.338 myopathy 2 111 8.1(5.3–11) 11.9(8.3–31.8) 0.43 (0.10, 1.83) 0.253 0.16 0.0% 0.693 overall 12 1150 20.2(0–51.9) 11.8(0–46.5) 1.34 (1.10,1.62) 0.003 127.26 45.0% 0.000 Abbreviations: NS, number of studies; NP, number of patients; RRs, risk rates; CI, confidence interval. Furthermore, the results of sensitivity analysis regarding OS and I-PFS were relatively stable, and excluded each of the study did not influence the overall effective size. Thus, there were no potential and important bias factors associated with interventions (Figure S7). Publication Bias The Begg's funnel plot and Egger's regression test were applied for detecting publication bias in the meta-analysis. No funnel plot asymmetry was found for OS and I-PFS (Begg's test, P = .944, P = .428; Egger's test, P = .474, P = .631, respectively). Therefore, there was no evidence of significant publication bias in the analysis (Figure S8). Discussion BM is a common complication of lung cancer and associated with poor outcomes. Patients with driver mutations may have a higher incidence of BM due to the prolonged survival with targeting agents [40], [41]. RT, including WBRT and SRS, has long been recognized as a standard therapy in NSCLC patients with BM, even when the patients have asymptomatic or single-brain metastasis [42], [43], [44]. Moreover, EGFR-TKIs such as gefitinib and erlotinib, which have the possibility of crossing the BBB and competing with adenosine triphosphate, could enhance radiosensitization [45], [46]. Hence, RT combined with EGFR-TKIs seems to be promising strategy for NSCLC patients with BM. Previously, one meta-analysis [47] enrolled only eight publications, and another update [48] had issues involved in 1/15 studies. Therefore, we comprehensive analysis of 24 studies with different monotherapy, treatment sequence, ethnicity, histologic type and published year for both OS and I-PFS. Besides, the stratified analyses for overall AEs were also been performed. As a result, we present more precise update information about the efficacy and safety of RT plus EGFR-TKIs in NSCLC patients with BM. This meta-analysis showed that combination therapy produced higher ORR and DCR, with longer OS and I-PFS than monotherapy in NSCLC patients with BM. The common AEs of EGFR-TKIs which were tolerated, were rash, dry skin and diarrhea. As for subgroup analyses, we found that combination therapy versus TKIs alone showed no improvement in OS, ORR and DCR, although prolonged I-PFS was found. Thus, the increased efficacy of combination therapy was interpreted cautiously by the TKI therapy. Furthermore, concurrent RT plus EGFR-TKIs could prolong the OS and I-PFS while sequential treatment had no improvement. Then, it confirmed the synergistic effect of RT and EGFR-TKIs [3], [31], [46]. Additionally, a larger retrospective study had demonstrated that upfront RT, especially SRS, and followed by EGFR-TKIs could prolong OS in NSCLC patients with EGFR mutation and BM [49]. However, it needs to be confirmed by prospective studies. Likewise, Asian LAC patients with BM had an improvement for both OS and I-PFS, which may be ascribed to TKIs. As is known, Asian NSCLC patients had a higher EGFR mutation rate than other ethnicities, with 60% and 10%–15%, respectively [50], [51]. However, the discordant EGFR mutation rate between primary (0%) and brain metastatic tumors (32%) was found [52], [53]. Therefore, molecular mechanisms need to be studied with EGFR-TKIs in the process of BM. Certain limitations must be mentioned in the meta-analysis. Firstly, the 24 included studies did not have high methodological quality. Then, multiple subgroup analyses were performed to increase the reliability of our results. Secondly, several important information such as number of BMs, performance status, EGFR mutation, and extracranial disease control were not consistently reported. But no significant difference was found in each of the included studies. Thirdly, heterogeneity was found in this meta-analysis. Multiple subgroup analyses indicated that different ethnicity, treatment sequence and histologic types may be the major sources of heterogeneity. Last but not least, although the publication bias were not found in this analysis, English and Chinese articles only could not completely avoid language bias. Conclusion Our comprehensive analysis suggested that RT plus EGFR-TKIs resulted in higher response rate, with longer OS and I-PFS than monotherapy in NSCLC patients with BM. Asian LAC patients with EGFR mutation will have a better prognosis with concurrent treatment. The common AEs of EGFR-TKIs were rash, dry skin and diarrhea. Nonetheless, more high quality and large-scale clinical trials are necessary to confirm the efficacy and safety of RT plus EGFR-TKIs in NSCLC patients with BM. The following are the supplementary data related to this article.Table A1 Characteristics of 2810 Included Patients. Abbreviations: KPS = Karnofsky performance score; ECOG = Eastern Cooperative Oncology Group; No of BM = number of brain metastases; EGFR = epidermal growth factor receptor. Table A1 Figure S1 Risk of Bias Summary of 24 Included Studies. Figure S1Figure S2 Meta-Analysis of OS (A) and I-PFS, ex-PFS (B) in 24 Included Studies. Abbreviations: OS = overall survival; I-PFS = intracranial progression-free survival; ex-PFS = extracranial progression-free survival. Figure S2Figure S3 Subgroup Analysis of OS (A) and I-PFS(B) in NSCLC patients with BM and EGFR mutations. Figure S3Figure S4 Subgroup Analysis of OS (A) and I-PFS(B) for Published Year. Abbreviations: OS = overall survival; I-PFS = intracranial progression-free survival. Figure S4Figure S5 Meta-Analysis of Characteristics of Included Patients. Abbreviations: EGFR = epidermal growth factor receptor; KPS = Karnofsky performance score; ECOG = Eastern Cooperative Oncology Group; No of BM = number of brain metastases; Figure S5Figure S6 Meta-Analysis of the Reported Overall Adverse Events(AEs) in the 12 Included Studies. Figure S6Figure S7 Meta-Analysis of Sensitivity Analysis Regarding OS and I-PFS. Abbreviations: OS = overall survival; I-PFS = intracranial progression-free survival. Figure S7Figure S8 Meta-Analysis of Publication Bias Regarding OS and I-PFS. Abbreviations: OS = overall survival; I-PFS = intracranial progression-free survival. Figure S8 Acknowledgments This study is supported by National Natural Science Foundation of China (81472782); Natural Science Foundation of Jiangsu Province (BK20141491); and the project of National Key Research and Development Plan of China (2017YFC1309201). 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