A phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell..

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Author(s): E. M. Gore, K. Bae, S. Wong, J. Bonner, A. Sun, S. Schild, L. E. Gaspar, J. Bogart, M. Werner-Wasik, H. Choy; Medical College of Wisconsin, Milwaukee, WI; Department of Statistics, Radiation Therapy Oncology Group; Division of Neoplastic Diseases, Medical College of Wisconsin, Milwaukee, WI; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL; Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Department of Radiation Oncology, Mayo Clinic Arizona, Scottsdale, AZ; Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, CO; Department of Radiation Oncology, SUNY Health Science Center at Syracuse, Syracuse, NY; Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX
Background: The incidence of central nervous system (CNS) metastases is high in patients with locally advanced non-small cell lung cancer. Brain as an only site of relapse appears increasingly common as loco-regional and extra-cranial systemic treatment improves. There is not standard agreement as to how to address this risk.
Methods: Patients with stage III NSCLC without progression of disease after loco-regional treatment with surgery and/or radiation therapy with or without chemotherapy were eligible. Participants were randomized to prophylactic cranial irradiation (PCI) or observation and stratified by stage (IIIA or B), histology (non-squamous or squamous) and therapy (surgery or no surgery). PCI was delivered once daily at 2Gy per fraction to 30Gy. The primary endpoint of the study was overall survival (OS). Secondary endpoints were disease free survival (DFS) and the impact of PCI on incidence of CNS metastases, neuropsychological function, and quality of life (QoL). Kaplan- Meier estimation with the log-rank test was used for OS and DFS and the logistic regression model was used for calculating the incidence of CNS metastasis.
Results: Total accrual was 356 patients of the targeted 1058 between 9/19/02 and 8/30/07. The study was closed early due to slow accrual. 340 patients were evaluable. One year OS (p=0.86, 75.6 % and 76.9% for PCI and observation) and one year DFS (p=0.11, 56.4% and 51.2% for PCI and observation) were not statistically significantly different. However, CNS metastatic rate at 1 year was statistically significantly different with CNS relapse 7.7% vs. 18% for PCI vs. observation (p=0.004). Logistic regression showed that the patients in the observation arm are 2.52 times more likely to develop CNS metastases than those in the PCI arm (odds ratio=2.52, 95% CI=(1.32-4.80)).
Conclusions: PCI in patients without progressive disease after loco-regional therapy for III NSCLC significantly decreases the rate of CNS metastases. This study did not show a statistically significant difference in OS or DFS. Forthcoming analysis of the impact of PCI on neuropsychological function and QoL will influence the recommendations regarding the standard use of PCI.