Paul D Brown1, Vinai Gondi2, Stephanie Pugh3, Wolfgang A Tome4, Jeffrey S Wefel5, Terri S Armstrong6, Joseph A Bovi7, Cliff Robinson8, Andre Konski9, Deepak Khuntia10, David Grosshans5, Tammie L S Benzinger8, Deborah Bruner11, Mark R Gilbert6, David Roberge12, Vijayananda Kundapur13, Kiran Devisetty14, Sunjay Shah15, Kenneth Usuki16, Bethany Marie Anderson17, Baldassarre Stea18, Harold Yoon19, Jing Li5, Nadia N Laack1, Tim J Kruser20, Steven J Chmura21, Wenyin Shi22, Snehal Deshmukh3, Minesh P Mehta23, Lisa A Kachnic24. 1. Mayo Clinic, Rochester, MN. 2. Northwestern Medicine Cancer Center Warrenville and Northwestern Medicine Proton Center, Warrenville, IL. 3. NRG Oncology Statistics and Data Management Center, Philadelphia, PA. 4. Montefiore Medical Center, Albert Einstein College of Medicine, The Bronx, NY. 5. The University of Texas MD Anderson Cancer Center, Houston, TX. 6. National Cancer Institute Center for Cancer Research, Bethesda, MD. 7. Froedtert & the Medical College of Wisconsin, Milwaukee, WI. 8. Washington University in St Louis, St Louis, MO. 9. Chester County Hospital, West Chester, PA. 10. East Bay Radiation Oncology Center, Eden Medical Center, Castro Valley, CA. 11. Winship Cancer Institute of Emory University, Atlanta, GA. 12. CHUM-Hôtel-Dieu de Montréal, Montreal, Quebec, Canada. 13. Saskatoon Cancer Center, Saskatoon, Saskatchewan, Canada. 14. Wayne State University, Karmanos Cancer Institute, Detroit, MI. 15. ChristianaCare National Cancer Institute Community Oncology Research Program, Newark, DE. 16. University of Rochester, Rochester, NY. 17. University of Wisconsin Hospitals and Clinics, Madison, WI. 18. University of Arizona Medical Center-University Campus, Tucson, AZ. 19. Heartland Cancer Research National Cancer Institute Community Oncology Research Program, Decatur, IL. 20. Northwestern Memorial Hospital, Chicago, IL. 21. The University of Chicago Comprehensive Cancer Center, Chicago, IL. 22. Thomas Jefferson University Hospital, Philadelphia, PA. 23. Miami Cancer Institute, Miami, FL. 24. Vanderbilt University Medical Center, Ingram Cancer Center, Nashville, TN.
Abstract
PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.
PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.
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