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.

Distribution of brain metastases: low-risk metastasis areas may be avoided when treating with whole-brain radiotherapy

“…Radiation damage to the hippocampus is a key factor leading to cognitive decline [11]. The NRG-CC001 trial [12] reported that WBRT with hippocampal sparing could decrease neurocognitive toxicity compared with traditional WBRT. As the incidence of BMs within 5 mm around the hippocampus is only 4.7 to 8.6% [13][14][15], the limitation of the radiotherapy dose in the hippocampal area can decrease the neurocognitive toxicity related to WBRT without decreasing the intracranial tumor control rate [16].…”

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

“…A variety of measures have been attempted to minimize the radiation dose to the hippocampus in clinical trials. A phase III clinical trial (NRG Oncology CC001, NCT02360215) showed that combined treatment with hippocampal avoidance whole-brain radiotherapy (HA-WBRT) and memantine was better than combined treatment with WBRT plus memantine in preserving cognitive function and patient-reported symptoms in patients with brain metastases [45]. The second ongoing phase III trial, NRG Oncology-CC003 (NCT02635009), is assessing the effects of WBRT with or without HA-WBRT in treating patients with limited-stage or extensive-stage small-cell lung cancer.…”

An Easy-To-Use Survival Score Compared to Existing Tools for Older Patients with Cerebral Metastases from Colorectal Cancer

“…Moreover, at least at one time point with significantly better results regarding executive function, processing speed, and delayed recognition was found in the memantine group. In a recently published phase III trial of 518 patients receiving whole-brain irradiation, hippocampus-sparing and memantine were combined and compared to memantine without sparing of the hippocampi [11]. The combined approach resulted in better preservation of cognitive function without impairing cerebral progression-free survival and overall survival.…”

“…In patients expected to have longer survival times, outcomes can be improved with doses > 30 Gy [8]. Moreover, the modern approaches of hippocampus-sparing and addition of memantine can significantly reduce neurocognitive decline, an important late toxicity of whole-brain-irradiation [9][10][11]. The risk of experiencing this late toxicity increases with time, and therefore, gains importance in longer-term survivors.…”