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Clinical Trial
. 2020 Apr 1;38(10):1019-1029.
doi: 10.1200/JCO.19.02767. Epub 2020 Feb 14.

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

Paul D Brown  1 , Vinai Gondi  2 , Stephanie Pugh  3 , Wolfgang A Tome  4 , Jeffrey S Wefel  5 , Terri S Armstrong  6 , Joseph A Bovi  7 , Cliff Robinson  8 , Andre Konski  9 , Deepak Khuntia  10 , David Grosshans  5 , Tammie L S Benzinger  8 , Deborah Bruner  11 , Mark R Gilbert  6 , David Roberge  12 , Vijayananda Kundapur  13 , Kiran Devisetty  14 , Sunjay Shah  15 , Kenneth Usuki  16 , Bethany Marie Anderson  17 , Baldassarre Stea  18 , Harold Yoon  19 , Jing Li  5 , Nadia N Laack  1 , Tim J Kruser  20 , Steven J Chmura  21 , Wenyin Shi  22 , Snehal Deshmukh  3 , Minesh P Mehta  23 , Lisa A Kachnic  24 ; for NRG Oncology
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Clinical Trial

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

Paul D Brown et al. J Clin Oncol. .

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.

Trial registration: ClinicalTrials.gov NCT02360215.

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Figures

FIG 1.
FIG 1.
Several-fold reduction in radiation dose to hippocampi (yellow) using (A) hippocampal avoidant whole-brain radiotherapy (HA-WBRT) v (B) conventional WBRT.
FIG 2.
FIG 2.
CONSORT diagram. HA, hippocampal avoidance; HVLT-R, Hopkins Verbal Learning Test-Revised; RT, radiotherapy; WBRT, whole-brain radiotherapy.
FIG 3.
FIG 3.
Kaplan-Meier graph showing time to cognitive failure. HA, hippocampal avoidance; WBRT, whole-brain radiotherapy.
See this image and copyright information in PMC

Comment in

References

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    1. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. JAMA. 2016;316:401–409. - PMC - PubMed

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