Development of Brain Metastases in Patients With Non–Small Cell Lung Cancer and No Brain Metastases at Initial Staging Evaluation: Cumulative Incidence and Risk Factor Analysis

Abstract

<b>BACKGROUND.</b> Although established guidelines give indications for performing staging brain MRI at initial diagnosis of non-small cell lung cancer (NSCLC), guidelines are lacking for performing surveillance brain MRI for patients without brain metastases at presentation. <b>OBJECTIVE.</b> The purpose of this study is to estimate the cumulative incidence of and risk factors for brain metastasis development in patients with NSCLC without brain metastases at initial presentation. <b>METHODS.</b> This retrospective study included 1495 patients with NSCLC (mean [± SD] age, 65 ± 10 years; 920 men and 575 women) without brain metastases at initial evaluation that included brain MRI. Follow-up brain MRI was ordered at the discretion of the referring physicians. MRI examinations were reviewed in combination with clinical records for brain metastasis development; patients not undergoing MRI were deemed to have not had metastases develop through last clinical follow-up. The cumulative incidence of brain metastases was determined, with death considered a competing risk, and was stratified by clinical stage group, cell type, and epidermal growth factor receptor (<i>EGFR</i>) gene mutation status. Univariable and multivariable Cox proportional hazards regression analyses were performed. <b>RESULTS.</b> A total of 258 of 1495 patients (17.3%) underwent follow-up brain MRI, and 72 (4.8%) had brain metastases develop at a median of 12.3 months after initial diagnosis of NSCLC. Of the 72 patients who had metastases develop, 44.4% had no neurologic symptoms, and 58.3% had stable primary thoracic disease. The cumulative incidence of brain metastases at 6, 12, 18, and 24 months after initial evaluation was 0.6%, 2.1%, 4.2%, and 6.8%, respectively. Cumulative incidence at 6, 12, 18, and 24 months was higher (<i>p</i> < .001) in patients with clinical stage III-IV disease (1.3%, 3.9%, 7.7%, and 10.9%, respectively) than in those with clinical stage I-II disease (0.0%, 0.8%, 1.2%, and 2.6%, respectively), and it was higher (<i>p</i> < .001) in patients with <i>EGFR</i> mutation-positive adenocarcinoma (0.7%, 2.5%, 6.3%, and 12.3%, respectively) than in those with <i>EGFR</i> mutation-negative adenocarcinoma (0.4%, 1.8%, 2.9%, and 4.4%, respectively). Among 1109 patients with adenocarcinoma, independent risk factors for the development of brain metastasis were clinical stage III-IV (hazard ratio [HR], 9.39; <i>p</i> < .001) and <i>EGFR</i> mutation-positive status (HR, 1.78; <i>p</i> = .04). The incidence of brain metastasis over the study interval was 8.7% among patients with clinical stage III-IV disease and 17.4% among those with <i>EGFR</i> mutation-positive adenocarcinoma. <b>CONCLUSION.</b> Clinical stage III-IV and <i>EGFR</i> mutation-positive adenocarcinoma are independent risk factors for brain metastasis development. <b>CLINICAL IMPACT.</b> For patients with clinical stage III-IV disease or <i>EGFR</i> mutation-positive adenocarcinoma, surveillance brain MRI performed 12 months after initial evaluation may be warranted.