Lower Incidence of Brain Metastases Observed With Early Detection Screening in Lung Cancer

Early detection of primary lung cancer using low-dose computed tomography screening was associated with a lower risk of brain metastases after PLC diagnosis vs other methods

Early detection of primary lung cancer (PLC) using low-dose computed tomography (LDCT) screening was associated with a lower risk of brain metastases after PLC diagnosis vs other methods, according to findings from an analysis of the National Lung Screening Trial (NLST; NCT00047385) that were published in the Journal of Thoracic Oncology.

The 3-year incidence of brain metastases was 6.5% in patients whose PLC was detected with LDCT compared with 11.9% in those whose PLC was detected by other means (cause-specific HR, 0.53; P = .001). The percentages were adjusted for age at PLC diagnosis, disease stage and histology, and smoking status.

Notably, the reduction in brain metastases in patients whose PLC was detected by LDCT was observed across subgroups, including those with early-stage PLC (HR, 0.47; P = .002) and those who underwent surgery (HR = 0.37; P = .001).

These findings were reflected by a complete-case sensitivity analysis (HR, 0.58; 95% CI, 0.39-0.85; P = .005).

“PLCs detected using LDCT screening are at reduced risk of developing [brain metastases] after [lung cancer] diagnosis on the basis of a large population-based cohort study. This reduction in risk for [brain metastases] among LDCT screen-detected [lung cancers]—which persisted in subgroup analyses of patients with early-stage PLC and those who underwent surgery for PLC—may not be fully explained by stage shift nor curative treatment for PLC,” lead study author Chloe C. Su, a PhD student in Epidemiology and Clinical Research at Stanford Medical School, and co-authors wrote in the study publication.

The brain is one of the most common sites of metastasis among patients with lung cancer. Around 10% of patients with lung cancer present with brain metastases, and another 40% of patients will develop brain metastases over the course of their disease. Notably, patients with lung cancer and brain metastases have a markedly poor survival of approximately 3 to 4 months after brain metastases diagnosis. Conversely, patients with asymptomatic or well-controlled brain metastases have increased survival vs those with active central nervous system involvement.

“Early detection of brain metastases could help patients leverage better treatments that have minimal neurologic side effects and maximize their quality of life,” wrote Su and co-authors.

The NLST revealed a 20% reduction in PLC mortality with early lung cancer detection by LDCT screening. As a result of these findings, for those at a high risk of developing lung cancer, annual LDCT screening is recommended by the United States Preventive Services Task Force.

However, it remains unknown whether early PLC detection via LDCT confers a lower risk of subsequent metastatic progression, such as the development of brain metastases.

The prospective, population-based, randomized NLST comprised a cohort of 53,452 individuals between 55- and 74 years of age with a high risk of developing PLC.

This analysis excluded 51,394 patients from the full cohort who did not develop lung cancer, as well as an additional 556 patients who had missing statuses of brain metastasis (n = 555) or who had brain metastases at lung cancer diagnosis (n = 1). As such, the analysis cohort comprised 1502 patients.

Beyond the 9.5% of patients (n = 143) who developed brain metastases, 38.6% (n = 580) died and 51.9% (n = 779) had censored information. The median interquartile range (IQR) follow-up was 2.5 years (range, 0.8-4.9) in the overall population and 1 year (range, 0.6-1.8) among those with brain metastases.

Most patients’ PLC was detected by non-LDCT screening (n = 880; 58.6%). Additionally, most patients were randomized to the CT arm (n = 849; 56.5%) vs the radiograph arm.

Patients were a mean age of 65.9 years when diagnosed with PLC. The majority of patients were female (n = 881; 58.7%) and White (n = 1375; 91.5%).

The mean tumor lesion size was 28.4 mm. Most patients had stage I, II, or III disease (n = 1153; 76.8%), adenocarcinoma (n = 628; 41.8%), and disease located in the upper lung lobes (n = 881; 58.7%).

Additionally, most patients were current smokers (n = 893; 59.5%) who began smoking at a mean age of 16.1 years. Patients who quit smoking did so at a mean age of 58.1 years. The mean pack-years was 65.3, and the mean number of years smoked was 44.2.

Patients had a mean body mass index of 26.9. Most patients previously underwent surgery (n = 826; 55%) but did not receive prior chemotherapy (n = 906; 60.3%), radiation therapy (n = 1140; 75.9%), or other treatments (n = 1400; 93.2%).

Brain MRIs were not done in 76.6% of patients (n = 1150). Patients who received a brain MRI did so at a median of 10 days after diagnosis. Of patients who developed brain metastases, the median time from brain MRI to development of brain metastases was 292 days (IQR, 187-452).

Further results from a propensity score matching analysis reflected a similar pattern regarding the association between brain metastases risk and the mode of PLC detection (HR, 0.58; 95% CI, 0.37-0.92; P = .021).

A subset of patients (n = 552) was analyzed to further evaluate potential reasons for why LDCT-detected PLC conferred a reduced risk of brain metastases. These patients were randomized to the LDCT arm and had available imaging data.

The analysis revealed that lung nodules detected via LDCT screening were larger in bidimensional nodule diameter at screening and were more likely to have spiculated vs smooth or poorly defined margins. However, lesions were smaller in size at the time of pathologic diagnosis in the nodules detected by LDCT vs those detected during intervals between LDCT screening rounds.

Another subset of patients with stage I, LDCT-detected PLC who developed brain metastases (n = 12) was compared with a subset of patients with stage I disease who did not develop brain metastases (n = 350). The results showed that patients who developed brain metastases had a faster rate of growth vs those who did not develop brain metastases (6.4 mm vs 3.6 mm per month, respectively). However, this finding was not statistically significant.

“The reduction in [brain metastases] risk may be because of a potentially different tumor biology of the tumors detected by LDCT screening that are less aggressive and slow growing, which needs to be confirmed by further investigation,” concluded Su and co-authors.


  1. Su CC, Wu JT, Neal JW, et al. Impact of low-dose computed tomography screening for primary lung cancer on subsequent risk of brain metastases. J Thorac Oncol. Published online June 2, 2021. Accessed June 28, 2021. doi:10.1016/j.jtho.2021.05.010