Immune checkpoint inhibitors (ICIs) are recommended to treat advanced non-small-cell lung cancer (NSCLC), whereas brain radiotherapy (RT) is the mainstream therapy for patients with brain metastases (BMs). This systematic review and meta-analysis investigated whether the combination of brain RT and ICIs would generate a synergistic effect without unacceptable toxicity to treat NSCLC with BMs. Literature searching was performed in PubMed, Embase, Web Of Science, and The Cochrane Library up to December 20, 2020. Heterogeneity, sensitivity analysis, forest plots, and publication bias were analyzed using Stata 15.0. Nineteen studies were included. In the comparison of the brain RT+ICIs arm and brain RT alone arm, the pooled effect size (ES) for overall survival (OS) (hazard ratio [HR] = 0.77; 95% confidence interval [CI] 0.71-0.83; I² = 0; P < .001; n = 4) and grade 3-4 neurological adverse events (AEs) (risk ratio [RR] = 0.91; 95% CI 0.41-2.02; I² = 26.5; P = .809; n = 4) indicated that the brain RT+ICIs model had significantly better systemic efficacy and similar neurological AEs compared with brain RT alone for NSCLC. Concurrent RT+ICIs were identified as the optimal model, which achieved the best efficacy without significantly increased AEs compared with sequential RT+ICIs. Combined ICIs and brain RT exhibited favorable efficacy and acceptable toxicity for NSCLC patients with BMs, among which, the concurrent model might be the optimal option. Our results could guide the design of future randomized controlled trials and clinical practice.

Purpose: Whilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer.Methods and Materials: From January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables.Results: With a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004).Conclusions: Treatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.