Strategies to Preserve Cognition in Patients With Brain Metastases: A Review.

Tyler P Robin,Chad G Rusthoven

doi:10.3389/fonc.2018.00415

Abstract

Brain metastases are common to the natural history of many advanced malignancies. Historically, whole brain radiation therapy (WBRT) has played a key role in the management of brain metastases, especially for patients with multiple lesions. However, prospective trials have demonstrated consistent neurocognitive toxicities after WBRT, and various pharmacologic and anatomic strategies designed to mitigate these toxicities have been studied in recent years. Memantine, an NMDA receptor antagonist, taken during and after WBRT improved cognitive preservation in a randomized trial over placebo. Deliberate reductions in radiation dose to the hippocampus, via hippocampal-avoidance (HA)-WBRT, resulted in improved cognition over historic controls in a phase II trial, and follow-up randomized trials are now ongoing to evaluate cognitive outcomes with HA vs. conventional brain radiation techniques. Nevertheless, some of the most promising strategies currently available to reduce the cognitive effects of brain radiation may be found in efforts to avoid or delay WBRT administration altogether. Stereotactic radiosurgery (SRS), involving focused, high-dose radiation to central nervous system (CNS) lesions with maximal sparing of normal brain parenchyma, has become the standard for limited brain metastases (classically 1–3 or 4 lesions) in the wake of multiple randomized trials demonstrating equivalent survival and improved cognition with SRS alone compared to SRS plus WBRT. Today, there is growing evidence to support SRS alone for multiple (≥4) brain metastases, with comparable survival to SRS alone in patients with fewer lesions. In patients with small-cell lung cancer, the routine use of prophylactic cranial irradiation (PCI) for extensive-stage disease has been also been challenged following the results of a randomized trial supporting an alternative strategy of MRI brain surveillance and early salvage radiation for the development of brain metastases. Moreover, new systemic agents are demonstrating increasing CNS penetration and activity, with the potential to offer greater control of widespread and microscopic brain disease that was previously only achievable with WBRT. In this review, we endeavor to put these clinical data on cognition and brain metastases into historical context and to survey the evolving landscape of strategies to improve future outcomes.

Highlights

Paradigms for the management of brain metastases are evolving, with increasing treatment options and a greater focus on cognitive preservation
In an effort to mitigate the neurocognitive effects of whole brain radiation (WBRT) and prophylactic cranial irradiation (PCI), both anatomic and pharmacologic strategies have been studied in recent years, including hippocampalavoidance radiation and the concomitant use of the drug memantine for neuroprotection [1, 2]
As prognoses continue to improve for patients with brain metastases, efforts to minimize the cognitive sequelae of therapy will only become increasingly important

Summary

INTRODUCTION

Paradigms for the management of brain metastases are evolving, with increasing treatment options and a greater focus on cognitive preservation. Multiple randomized trials of SRS alone vs SRS plus WBRT for patients with limited metastases have demonstrated that, overall, the addition of WBRT is associated with [1] objective declines in neurocognitive function, [2] improved CNS disease control rates, but [3] no benefit in terms of OS [21,22,23,24,25]. The NCCN CNS and small-cell lung cancer guidelines acknowledge the potential role of memantine to promote cognitive preservation for patients undergoing both WBRT and PCI, the latter has not yet been tested in a randomized control trial [5, 26]. It is important to acknowledge, that there is limited prospective data comparing CNS-penetrant agents to strategies incorporating

Methods

Findings

CONCLUSIONS AND FUTURE DIRECTIONS