What is the role of memantine (memantine) after whole brain radiation therapy (WBRT)?

Memantine After Whole Brain Radiation Therapy (WBRT)

Memantine should be administered during and for 24 weeks following WBRT to reduce cognitive decline in patients with brain metastases. 1

Mechanism and Evidence

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that helps protect against neurocognitive toxicity associated with WBRT. The evidence supporting its use comes from:

• The RTOG 0614 trial, which evaluated memantine versus placebo in patients receiving WBRT, showing:
  • Significantly longer time to cognitive decline (hazard ratio 0.78, p=0.01) 1, 2
  • Better preservation of executive function at 8 and 16 weeks 2
  • Improved processing speed and delayed recognition at 24 weeks 2
  • Lower probability of cognitive function failure at 24 weeks (53.8% vs 64.9%) 2

Administration Protocol

• Start memantine within 3 days of initiating WBRT 2
• Use a 4-week uptitration period 1
• Continue for a total of 24 weeks 1, 2
• Standard dosing regimen reaches 20 mg/day 2

Enhanced Protection with Hippocampal Avoidance

Recent evidence shows that combining memantine with hippocampal-avoiding WBRT (HA-WBRT) provides superior cognitive protection:

• The NRG CC001 trial demonstrated that HA-WBRT plus memantine significantly:
  • Preserved patient-reported quality of life 1
  • Prevented cognitive decline throughout follow-up 1, 3
  • Reduced symptom burden at 6 and 12 months 3
  • Decreased symptom interference with daily activities 3

Clinical Implementation Considerations

Despite strong evidence supporting memantine use with WBRT, implementation in clinical practice remains suboptimal:

• Population-based studies show strikingly low rates of memantine prescription (only 2.2% of eligible patients) 4
• Usage increased from 1.1% to 5.14% after publication of RTOG 0614 but remains inadequate 4

Patient Selection

Memantine should be considered for all patients receiving WBRT for brain metastases, particularly:

• Patients with good performance status who are expected to survive long enough to experience radiation-induced cognitive effects 1
• Patients undergoing WBRT for multiple brain metastases 1
• Patients receiving prophylactic cranial irradiation (PCI) 1

Caveats and Pitfalls

• Memantine alone was not active when combined with standard WBRT, but showed benefit when combined with hippocampal-avoiding WBRT 1
• The primary endpoint of the RTOG 0614 trial (delayed recall at 24 weeks) showed improvement but did not reach statistical significance (p=0.059), likely due to significant patient loss during follow-up 2
• Despite evidence supporting its use, memantine remains significantly underutilized in clinical practice 4

Conclusion

For patients undergoing WBRT for brain metastases, memantine should be administered during and for 24 weeks following radiation to reduce the risk of cognitive decline. When feasible, combining memantine with hippocampal-avoiding WBRT provides optimal neurocognitive protection.