Neurocognitive Considerations in the Treatment of Brain Metastases

Nicholas F. Marko; Robert J. Weil


Abstract and Introduction


The results of a randomized, controlled trial investigating the neurocognitive effects of stereotactic radiosurgery (SRS), with or without whole-brain radiation therapy (WBRT), to treat brain metastases demonstrated a significant reduction in learning and memory, associated with the addition of WBRT to SRS. The results indicate that SRS monotherapy is an effective and safe initial management strategy for brain metastases.


Up to 30% of cancer patients will develop brain metastases,[1] an event traditionally considered to represent end-stage disease and indicative of a turning point from curative treatment to palliative management. Fortunately, progress in systemic therapy is enabling patients with cancer to live longer after diagnosis of brain metastases, which has focused attention on the long-term sequelae of treatment of central nervous system (CNS) disease. Secondary effects related to neurocognition have come under scrutiny because of physician and patient desires to enhance quality of life (QoL) during cancer therapy.[2]

A recent publication by Chang and colleagues[3] investigated the effects of initial treatment with stereotactic radiosurgery (SRS), either alone or in combination with whole-brain radiation therapy (WBRT) on neurocognitive functions in patients with brain metastases. The authors hypothesized that addition of WBRT to SRS would impair learning and memory function. They tested this by performing a randomized, prospective trial powered to detect a 5-point decline in the Hopkins Verbal Learning Test—Revised (HVLT-R). The study was stopped when accrual of 58 patients sufficiently demonstrated a significant reduction in the HVLT-R score of patients receiving SRS plus WBRT compared with SRS alone. Survival was comparable in both groups, but local control, 12-month tumor recurrence rate, and requirement for salvage therapy were greater for patients in whom initial WBRT was omitted.

Understanding the potential practical implications of the study findings requires a brief review of the evidence regarding inclusion of WBRT to manage brain metastases. Advocates of both approaches agree that local control improves survival in patients with brain metastases.[1,4] Those who favor inclusion of initial WBRT highlight the evidence that demonstrates improved local and distant tumor control with concurrent administration of WBRT (Table 1).[1,3,5–7] With regard to neurocognition, proponents of WBRT argue that increased CNS tumor burden and failure of local and regional control contribute to cognitive decline[8] and that the increased need for salvage therapy in patients not treated with upfront WBRT[3,6,9,10] adversely affects QoL. Conversely, opponents of this strategy argue that improved CNS tumor control need not increase overall survival,[3,9,10] and that routine use of initial WBRT limits therapeutic options at the time of recurrence. Additionally, the limited available evidence suggests that upfront WBRT might adversely affect neurocognition,[3,5] a secondary effect that patients wish to avoid. There remains considerable interest but scant data regarding neurocognitive effects, and it is here that the investigation by Chang and coauthors makes a significant contribution.[3] This study represents the first prospective trial of adjuvant therapy for brain metastases specifically designed with a primary neurocognitive endpoint. The results support the hypothesis that WBRT may cause persistent learning and memory impairment(s).

The findings of Chang and colleagues will help inform treatment decisions regarding the management of patients with brain metastases; however, it is essential to highlight several factors to consider when applying these results clinically. First, Chang et al.[3] and others[5] examined neurocognitive effects of WBRT in patients with a maximum of four metastases and good functional status (Karnofsky performance score [KPS]≥70). Enrollment in these studies is therefore limited to the subsets of patients assigned to Recursive Partitioning Analysis (RPA) class I or II. There are presently no studies that investigate the balance between therapeutic benefit and neurocognitive risk in patients with more than four metastases or with poor functional status (KPS>70, RPA class 3). Other concerns include the relatively small sample size and the large number of patients initially treated only with SRS who subsequently required salvage therapy with surgery. The independent effects of the salvage surgery upon survival and long-term neurocognitive function were not assessed and require further investigation.

Second, the cost of preserving long-term neurocognition by omitting upfront WBRT is a reduction in local and distant control of CNS metastases, which subsequently leads to an increased need for salvage therapy.[3,6,9,10] While investigations by Chang et al.[3] and other researchers[5–7,9] demonstrate that these factors do not seem to adversely affect survival, evidence to the contrary has been reported.[1] Moreover, current literature suggests an inverse relationship between CNS tumor burden and neurocognition,[8] and the QoL and cost-effectiveness implications of increased requirements for salvage therapy remain unknown. Considering all of these factors, we believe that the study findings of Chang and colleagues may be best applied in the context of patient discussions regarding the individualized management strategy of their CNS disease. Patients who strongly associate memory and learning preservation with QoL and who accept the possibility of CNS progression and additional, salvage therapy can now be presented with class I evidence that SRS alone is a reasonable and effective initial strategy to manage their metastatic disease.

Finally, we stress the importance of investigating and reporting the relationships between measured neurocognitive declines and adverse impacts on QoL. While Chang and colleagues make general comments noting that reductions in HVLT-R scores might correlate with increased need for assistance in activities of daily living (ADLs) and that, "neurocognitive function and measure of [ADLs] and QoL are correlated,"[3] they present no empiric QoL data that would describe the actual impact of their observed reduction in HVLT-R score. Objective QoL metrics are essential complements to neurocognitive testing (NCT) results and should be included in future investigations.

In summary, Chang and colleagues have studied the potential effects of upfront WBRT on memory and learning in a small number of patients with brain metastasis. Their analysis of treatment outcomes with SRS with and without WBRT suggest that initial SRS alone is a viable and effective therapeutic option that may be particularly attractive to RPA class I–II patients for whom memory and learning are important components of QoL and who are willing to accept the trade-off of reduced local and distant control rates and increased need for salvage therapy. This study is the most recent in a growing number of CNS therapeutic trials that include neurocognitive metrics, a practice that most clinicians believe is critical, given evidence to suggest more effective management of these patients' primary malignancies. We are optimistic that future trials will continue to include comprehensive NCT (for instance, NCCTG-N0574, and will also track QoL metrics, as both parameters are necessary to inform decisions regarding the individualized, therapeutic strategies in patients with brain metastases.


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