The impact of tumor biology on survival and response to radiation therapy among patients with non-small cell lung cancer brain metastases

Purpose: To investigate the natural history and response to radiation therapy among ALK-rearranged, EGFR-mutated, wild-type adenocarcinoma, and squamous cell non-small cell lung cancer (NSCLC) brain metastases.

Methods and materials: Patients with NSCLC brain metastasis diagnosed from 1989 through 2014 at a single tertiary-care institution were included. The primary outcome was overall survival, whereas secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. Cox proportional hazards regression was used to model overall survival; multivariate competing risks regression was used to model secondary outcomes.

Results: Within the study period, 1920 patients presented with 6312 brain metastases. Squamous histology was associated with poorer median survival compared with adenocarcinomas (5.4 vs 8.8 months, P < .01). Median survival was greatest among ALK+ patients (49.2 months), followed by EGFR+ (20.3 months), and wild-type adenocarcinomas (10.0 months, P < .01). Treatment with estimated glomerular filtration rate inhibitors (hazard ratio [HR], 0.66; P < .01) and vascular endothelial growth factor antibodies (HR, 0.65; P < .01) increased survival independent of mutational status. Among 2056 lesions treated with stereotactic radiosurgery, the 12-month cumulative incidence of local failure was significantly greater among squamous cell carcinomas relative to adenocarcinomas (15% vs 10%, HR, 1.26; P = .04). Patients with ALK+ metastases experienced higher rates of local failure (10%; HR, 2.00; P = .05), distant failure (39%; HR, 2.94; P < .01), and radiation necrosis (18%; HR, 5.77; P < .01), whereas EGFR+ patients experienced the lowest rates of local failure (5%; HR, 0.46; P = .04) and distant failure (3%; HR, 0.13; P = .04).

Conclusions: Advances in precision medicine have increased survival among select patients with NSCLC. In the present investigation, ALK+ and EGFR+ status were associated with improved survival. However, patients with ALK+ metastases have poor intracranial control relative to EGFR+ metastases, possibly because of limited intracranial penetration of crizotinib compared with estimated glomerular filtration rate inhibitors. Future investigations are warranted to determine the optimal management of ALK+ brain metastases with the introduction of second-generation ALK inhibitors.