Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001.

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.

• Authors: Paul D Brown, Vinai Gondi, Stephanie Pugh, Wolfgang A Tome, Jeffrey S Wefel, Terri S Armstrong, Joseph A Bovi, Cliff Robinson, Andre Konski, Deepak Khuntia, David Grosshans, Tammie L S Benzinger, Deborah Bruner, Mark R Gilbert, David Roberge, Vijayananda Kundapur, Kiran Devisetty, Sunjay Shah, Kenneth Usuki, Bethany Marie Anderson, Baldassarre Stea, Harold Yoon, Jing Li, Nadia N Laack, Tim J Kruser, Steven J Chmura, Wenyin Shi, Snehal Deshmukh, Minesh P Mehta, Lisa A Kachnic, for NRG Oncology
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 38 Issue 10 Pg. 1019-1029 (04 01 2020) ISSN: 1527-7755 [Electronic] United States
• PMID: 32058845 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Antiparkinson Agents
• Memantine

Topics

• Antiparkinson Agents (therapeutic use)
• Brain Neoplasms (drug therapy, radiotherapy, secondary)
• Chemoradiotherapy
• Cognition (radiation effects)
• Cognition Disorders (etiology, prevention & control)
• Female
• Hippocampus (radiation effects)
• Humans
• Male
• Memantine (therapeutic use)
• Middle Aged
• Progression-Free Survival
• Proportional Hazards Models
• Quality of Life
• Radiation Injuries (etiology, prevention & control)
• Radiotherapy Planning, Computer-Assisted (methods)
• Radiotherapy, Intensity-Modulated (adverse effects, methods)