Prophylactic Cranial Irradiation Reduces Risk of CNS Metastasis, Improves DFS in Locally Advanced NSCLC

The use of prophylactic cranial irradiation failed to demonstrate a statistically significant improvement in overall survival over observation in patients with locally advanced stage III non–small cell lung cancer; however, the modality did improve disease-free survival and decreased the risk of brain metastasis.

Alexander Sun, MD

Results showed that PCI did not demonstrate a statistically significant improvement in OS over observation among patients with locally advanced stage III disease, thereby failing to meet the study’s primary endpoint (HR, 0.82; 95% CI, 0.63-1.06; P = .12). The estimated median OS was 2.4 years (95% CI, 2.0-2.9) and 2.1 years (95% CI, 1.7-2.7) among patients who underwent PCI and observation, respectively. The 5- and 10-year OS rates were 24.7% and 17.6% with PCI compared with 26.0% and 13.3% for observation, respectively.

“As the incidence of brain metastases rise in patients living longer with improved control of locoregional and distant disease, the need to establish an accepted means of prevention of brain metastases remains important,” lead study author, Alexander Sun, MD, of the Department of Radiation Oncology at the University Health Network’s Princess Margaret Cancer Centre, said in a press release.“Researchers need to identify the appropriate patient population and a safe intervention on future trials.”

In the trial, patients were randomized to observation or PCI at 2 Gy/fraction at 5 days per week, reaching a maximum dose of 30 Gy. Patients were followed 6 months after starting radiation, and every 6 months thereafter up to 2 years, after which they were followed annually. Brain imaging with MRI or CT scan was performed at 6 and 12 months from the start of therapy and every year thereafter.

The median age was 61 years and the majority had received platinum doublet chemotherapy. Approximately two-thirds of patients were male (n = 213), and one-third were female (n = 127).

Patients were stratified according to disease stage (IIIA versus IIIB), histologic characteristics (nonsquamous versus squamous), therapy (surgery versus no surgery), age (<60 versus >60 years), and Zubrod performance status (0 versus >0).

A total of 527 deaths and an estimated accrual of 1058 patients were anticipated to detect a 20% reduction in the risk of death with PCI versus observation, with 80% power and a 1-sided P value of .025. However, due to poor accrual, the study was closed early. At the time of analysis, 277 deaths had occurred in 340 evaluable patients, providing approximately 45% power to detect a difference in OS.

Results showed that, at the time of the analysis, there were 300 DFS events and 60 brain metastasis events. Regarding the study’s secondary endpoints, PCI decreased the 5- and 10-year (16.7% and 28.3%%) rate of brain metastases (HR, 0.43; 95% CI, 0.24-0.77; P = .004) and improved 5- (19.0% and 12.6%) and 10-year DFS [(16.1% and 7.5%; (HR, 0.76; 95% CI, 0.59-0.97; P =.03)] among patients with stage III locally advanced disease.

Of the prespecified criteria, Zubrod performance status <0, and age >60 years appeared to be positive prognostic factors in patients who did not have surgery (n = 225). Patients who did not receive surgery had a median OS of 2.3 years with PCI versus 1.9 years with observation (HR, 0.73; 95% CI, 0.54-0.98; P = .04), as well as a lower risk of DFS events (HR, 0.70; 95% CI, 0.52-0.93; P = .01) and development of brain metastasis (HR, 0.34; 95% CI, 0.17-0.68; P = .002). Conversely, patients <60 years and those with nonsquamous histology had higher rates of brain metastasis.

For patients who did undergo surgery (n = 115), there was no difference in OS, DFS, or development of brain metastasis between arms. However, a multivariable analysis found age ≥60 years and stage IIIB cancers to be poor prognostic factors, resulting in an increased risk of death. Additionally, those with nonsquamous disease had a higher risk of developing brain metastasis.

Regarding patients with nonsquamous histology (n = 225), the use of PCI resulted in a significant decrease in the risk of brain metastasis (HR, 0.43; 95% CI, 0.24-0.78; P = .01) and improved DFS (HR, 0.72; 95% CI, 0.53-0.98; P = .04). For those with squamous histology (n = 115), there was no difference in OS and DFS between arms.

Most adverse events (AEs) were acute in nature; there were 6 cases of grade 3 treatment-related AEs in the PCI arm. These included fatigue, hematologic, ataxia, depression, and headache. However, 5 patients in the PCI arm experienced late onset grade 3 AEs, including soft tissue necrosis and neurocognitive deficits.

“The challenge in the future is to exploit the therapeutic ratio of benefits versus risks,” the study authors wrote in the article. “Patients most likely to benefit from PCI are those at highest risk of developing brain metastases. These patients would include those treated without surgery or with poor risk features such as nonsquamous cancer, young age, and high-volume disease.”

These data will be compiled in a meta-analysis of similarly designed randomized studies as part of an ongoing international effort to detect an OS benefit with PCI for patients with locally advanced NSCLC.


  1. Sun A, Hu C, Wong S, 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 ahead of print March 14, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.7220.
  2. NRG Oncology (2019). Prophylactic cranial irradiation improves disease-free survival and brain metastasis rates for locally advanced non—small cell lung cancer. Published March 19, 2019. Accessed March 19, 2019.


The use of prophylactic cranial irradiation (PCI) failed to demonstrate a statistically significant improvement in overall survival (OS) over observation in patients with locally advanced stage III non—small cell lung cancer (NSCLC); however, the modality did improve disease-free survival (DFS) and decreased the risk of brain metastasis, according to long-term follow-up of the phase III RTOG 0214 trial.