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Original Investigation
March 14, 2019

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

Author Affiliations
  • 1Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 2NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
  • 3Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 4Medical College of Wisconsin, Milwaukee
  • 5Cleveland Clinic Foundation, Cleveland, Ohio
  • 6Michigan Cancer Research Consortium CCOP, Ann Arbor
  • 7University of Maryland Medical System, Baltimore
  • 8University of Rochester, Rochester, New York
  • 9University of Colorado, Denver
  • 10University of Texas Southwestern Medical Center, Dallas
JAMA Oncol. 2019;5(6):847-855. doi:10.1001/jamaoncol.2018.7220
Key Points

Question  Does prophylactic cranial irradiation (PCI) improve survival in patients with locally advanced non–small cell lung cancer (LA-NSCLC) compared with observation alone?

Findings  In this prospective randomized phase 3 clinical trial including 340 evaluable patients with LA-NSCLC, PCI decreased the 5- and 10-year rate of brain metastases and improved 5- and 10-year disease-free survival, but did not improve overall survival compared with observation alone.

Meaning  Although this study did not meet its primary end point of overall survival, the long-term results reveal many important PCI findings, which will benefit future trials.


Importance  Brain metastasis (BM) rates are high in locally advanced non–small cell lung cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in LA-NSCLC, a survival advantage has not yet been shown.

Objective  To determine if PCI improves survival in LA-NSCLC.

Design, Setting, and Participants  Radiation Therapy Oncology Group (RTOG) 0214 was a randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study took place at 291 institutions in the United States, Canada, and internationally. Of 356 patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340 patients were randomized.

Intervention for Clinical Trials  Observation vs PCI.

Main Outcomes and Measures  The primary outcome was overall survival (OS). The secondary end points were disease-free survival (DFS) and incidence of BM.

Results  Of the 340 total participants, mean (SD) age was 61 years; 213 of the participants were men and 127 were women. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The OS for PCI was not significantly better than observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5- and 10-year rates, 24.7% and 17.6% vs 26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5- and 10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43; 95% CI, 0.24-0.77; P = .003; 5- and 10-year rates, 16.7% vs 28.3% for PCI vs observation) were significantly different. Patients in the PCI arm were 57% less likely to develop BM than those in the observation arm. Younger patients (<60 years) and patients with nonsquamous disease developed more BM. On multivariable analysis, PCI was associated with decreased BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical arm suggests that PCI effectively prolongs OS, DFS, and BM.

Conclusions and Relevance  In patients with stage III LA-NSCLC without progression of disease after therapy, PCI decreased the 5- and 10-year rate of BM and improved 5- and 10-year DFS, but did not improve OS. Although this study did not meet its primary end point, the long-term results reveal many important findings that will benefit future trials. Identifying the appropriate patient population and a safe intervention is critical.

Trial Registration  ClinicalTrials.gov identifier: NCT00048997