Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery

Abstract

Objective : Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC. Methods : We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27). Results : The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5-27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004). Conclusion : GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.

Efficacy and Safety of Combined Brain Stereotactic Radiotherapy and Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with Brain Metastases

“…This was based on an approximation of the half-lives of the PD-1 pathway inhibitors used. This is consistent with other studies that stated that the patients received RT within 1 month before or after IT as the concurrent ‘RT + IT’ group [ 16 ], except Chen et al [ 34 ] and Lee et al [ 17 ], who defined the time interval as two weeks, and Imber et al [ 38 ], who defined the time interval as two months. In addition, we excluded patients who had received chemotherapy within one month following SRT in order to be sure that regional outcomes would only be the result of the interaction between SRT and IT, and that chemotherapy had no impact on the intracranial response.…”

“…Most of the included studies have shown that the combination of RT and IT increased OS and regional PFS compared to RT alone, without inducing more brain necrosis (BN). Moreover, Lee et al recently reported the outcomes of 77 patients with BM from NSCLC who received IT alone ( n = 26), IT with concurrent Gamma Knife radiosurgery (GKS) within 14 days ( n = 24), or IT with non-concurrent GKS ( n = 27) [ 17 ]. OS, regional, and local PFS were higher in the group receiving IT and GKS compared to the “IT alone” group.…”

Immunotherapy in NSCLC Patients With Brain and Leptomeningeal Metastases

“…Similar positive results in terms of clinical outcomes and tolerability were reported in other retrospective series ( 40 , 41 ). According to the majority of retrospective studies, a period between 4 weeks and 1 months before or after immunotherapy could be defined as the cutoff to differentiate a concurrent or sequential treatment approach ( 42 ).…”

Efficacy and Safety of Combined Brain Radiotherapy and Immunotherapy in Non-Small-Cell Lung Cancer With Brain Metastases: A Systematic Review and Meta-Analysis

“…As shown in Figure 1 , a total of 2009 records were searched in the databases. After reviewing all the records for the title, abstract, or full text, a total of 19 records [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] , comprising 15 full text articles and 4 conference abstracts, with 16,405 patients, were included for further analysis ( Table 1 ). Among them, 15,411 patients had NSCLC.…”

“…The sequential group could be further divided into the brain RT prior subgroup and brain RT after subgroup, represented as RT → ICIs and ICIs → RT, respectively. The definition of the time interval between brain RT and ICIs in the concurrent group differed between studies, the majority of studies 18 , 21 , 22 , 24 , 30 , 32 , 33 stated that the patients received RT within 4 weeks or 1 month before or after ICIs as the concurrent RT + ICIs group, except Chen et al 17 and Lee et al 31 , who defined the time interval as 2 weeks, and Imber et al 16 , who defined the time interval as 2 months.…”