Expanding the Definition of Oligometastatic in Lung Adenocarcinoma

Abstract

The term oligometastatic is defined as having up to 3 metastatic lesions at the time of diagnosis. More recent studies have incorporated up to 5 metastatic sites, though patients with >3 metastatic areas were highly under-represented in these trials. Current ongoing trials are looking to expand the definition of oligometastatic to 10 sites or less, however presently there is limited data in the modern setting to suggest patients with more than 5 metastatic sites have similar oncologic outcomes to those with 5 or less sites of disease. The purpose of this study is to evaluate oncologic outcomes based on the number of metastatic sites at the time of diagnosis in patients with lung adenocarcinoma. A retrospective analysis of metastatic lung adenocarcinoma patients with known Epidermal Growth Factor Receptor (EGFR) status who underwent treatment from 2009 to 2018 at our institution was performed. All patients included underwent upfront staging with body positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) brain imaging; number of metastatic sites was counted individually. Overall survival (OS) was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing OS. Additional variables included in the analysis were age, gender, race, smoking history, presence of brain metastases, pleural disease, and number of oligometastatic sites. Among the 429 adenocarcinoma patients included, the breakdown of total number of upfront metastases were as follows: 1-3 (40.8%), 4-5 (13.3%), 6-10 (17.2%), 11-20 (11.0%), >20 (17.7%). Median OS was as follows: 1-3 (34 mo; 95% confidence interval [CI], 22-46 mo), 4-5 (22 mo; 95% CI, 16.9-27.1), 6-10 (23 mo; 95% CI, 13.7-32.3), 11-20 (33 mo; 95% CI, 23.6-42.4), >20 (22 mo; 95% CI, 12.9-31.1) (log-rank p=0.055). Under multivariate analysis including all patients, presence of >20 metastatic sites (hazard ratio [HR] 1.84; 95% CI, 1.24-2.72; p=0.002) was associated with worse OS, with no differences in OS seen in patients with 4-5 (HR 1.26; p=0.301), 6-10 (HR 1.43; p=0.067), and 11-20 sites (HR 1.15; p=0.562) (reference 1-3 sites). On subset multivariate analysis of EGFR mutation-positive patients, having >20 metastatic sites (HR 2.55; 95% CI, 1.50-4.33; p=0.001) was again associated with worse OS, with no differences seen in patients with 4-5 (HR 1.02; p=0.955), 6-10 (HR 1.51; p=0.179), and 11-20 sites (1.02; p=0.964) (reference 1-3 sites). The definition of oligometastatic disease will continue to evolve with future studies in the era of better systemic therapies and more refined radiation techniques. In our patient population, specifically those with EGFR mutation-positive disease, there appears to be relatively similar survival differences in patients with up to 20 metastatic sites, suggesting the potential benefit for more aggressive local therapies in these individuals. For patients with >20 metastatic sites, outcomes continue to be poor.