Updated, long-term results from the prospective, randomized, multicenter, phase 3 NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0214 trial (ClinicalTrial.gov Identifier: NCT00048997) in patients with locally advanced non-small cell lung cancer (NSCLC) without progression of disease following definitive locoregional therapy showed no significant difference in overall survival (OS) between the patients randomly assigned to receive prophylactic cranial irradiation (PCI) therapy or observation (P =.12). The findings from this study were published online in JAMA Oncology.

Although primary, definitive multimodality therapy (ie, irradiation and/or surgery with or without chemotherapy) has extended the lives of patients with stage IIIA/IIIB, nonmetastatic NSCLC, this improvement in OS has been accompanied by an apparent increase in the likelihood of developing brain metastases.

The large NRG Oncology/RTOG 0214 study was designed to evaluate whether OS of these patients is increased with PCI therapy compared with observation alone following definitive primary therapy. Secondary end points included assessments of PCI on disease-free survival (DFS) and development of brain metastasis.

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Patients were stratified by disease stage (IIIA or IIIB), disease histology (squamous or nonsquamous), and primary therapy (surgery vs no surgery). Of the 340 patients randomly assigned to a study arm, 163 and 177 from the PCI (2 Gy/fraction for 5 days/week for 3 weeks for a total 30 Gy dose) and observation arms, respectively, were available for analysis. Median follow-up was 2.1 years for all patients, and 9.2 years for living patients.

In this study, the OS of patients was not significantly improved with PCI compared with observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P =.12).  Respective 5- and 10-year survival rates for these 2 study arms were 24.7% and 17.6% for patients receiving PCI vs 26.0% and 13.3% for patients randomly assigned to observation.

However, a significant DFS benefit was observed for patients treated with PCI compared with those receiving observation alone (HR, 0.76; 95% CI, 0.59-0.97; P =.03).

Furthermore, respective 5- and 10-year DFS rates were 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation, respectively. In addition, the incidence of brain metastasis was significantly decreased in patients receiving PCI compared with observation (hazard ratio= 0.43; 95% CI, 0.24-0.77; P = .003), with respective 5- and 10-year rates of 16.7% vs 28.3% and 16.7% vs 28.3% for PCI vs observation.

Grade 3 acute PCI-related adverse events occurred in 4% of patients receiving this treatment, and included fatigue, ataxia, headache, and a hematologic adverse event. Grade 4 acute PCI-related depression occurred in 1 patient. Grade 3 late PCI-related adverse events occurred in 3% of patients.

Because this study was terminated early due to poor accrual, this analysis was only approximately 45% powered to detect a change in OS. Although subgroup analyses were limited due to the low number of patients, on multivariate analysis, an OS benefit (as well as a DFS benefit and fewer brain metastases) for PCI was observed in the subgroup including patients who did not receive surgery (P =.04).

In conclusion, the authors wrote that “it is very unlikely that a single definitive study with and without PCI for NSCLC will ever be completed, although establishing an accepted means of prevention of brain metastasis remains important.”


  1. Sun A, Hu C, Wong SJ, et al. Prophylactic cranial irradiation vs observation in patients with locally advanced non-small cell lung cancer: A long-term update of the NRG Oncology/RTOG 0214 phase 3 randomized clinical trial [published online March 14, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.7220