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Background: Continuing therapy for aggressive non-small-cell lung cancer (NSCLC) after first-line treatment (FLT) is challenging. The clinical efficacy of second-line chemotherapy (SLCT) for progressive NSCLC is limited. In this metaanalysis, we aim to evaluate the clinical efficacy of the combination of I-125 seeds brachytherapy (ISB) and SLCT in progressive NSCLC after FLT. Methods: The PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases were screened for relevant publications until September 2021. Meta-analyses are conducted by RevMan 5.3 and Stata 12.0. Results: Our meta-analysis encompassed 6 studies (4 retrospective studies and 2 randomized controlled trials), which included 272 patients that underwent ISB with SLCT (combined group) and 257 patients that received SLCT alone (chemotherapy alone group). The complete response (24.7% vs. 7.0%, P < 0.00001), treatment response (65.7% vs. 38.1%, P = 0.0002), and disease control (95.2% vs. 80.4%, P < 0.00001) rates are markedly elevated for patients receiving combined therapy versus those receiving chemotherapy alone. Moreover, pooled progression-free survival (P = 0.0001) and overall survival (P < 0.00001) were remarkably extended for patients that received the combination therapy, while no obvious differences were detected in the pooled myelosuppression (39.0% vs. 30.6%, P = 0.05) and gastrointestinal response (38.5% vs. 35.9%, P = 0.52) rates between 2 groups. Significant heterogeneity was found in the endpoints of the treatment response and progression-free survival. Conclusions: This meta-analysis demonstrated that ISB could enhance the clinical efficacy of SLCT in patients with progressive NSCLC after FLT without inducing major toxic side effects. [ABSTRACT FROM AUTHOR]