Comparing Cognitive Decline after Radiotherapy for Brain Metastases: A Meta-Analysis of Prospective Trials

Abstract

The incidence of brain metastases continues to rise due to improved systemic therapies and expanded screening efforts. Whole-brain radiation therapy (WBRT) has been a long-utilized therapy. However, its association with early cognitive decline has led to the development of stereotactic radiosurgery (SRS), the addition of Memantine (WBRT+M), and hippocampal avoidance (HA-WBRT); as efforts to mitigate the development of neurocognitive deficits. We conducted a meta-analysis to quantify and compare the proposed benefits of these therapies. A PICOS/PRISMA/MOOSE selection protocol was utilized to select prospective trials published between 2009 and 2019 to reflect modern therapy. Weighted random effects meta-analyses were conducted, where the DerSimonian and Laird method was used to calculate between study variance. WBRT was compared to SRS, WBRT+M, and HA-WBRT using meta-regression and the Wald-type test, where the null hypothesis was rejected for p<0.05. Heterogeneity was assessed using the I2 statistic and Cochran’s Q-Test. Five randomized prospective trials consisting of 1,005 patients (442 WBRT, 207 SRS, 256 WBRT+M, and 100 HA-WBRT) were selected. Median patient age was 62 years WBRT, 61 SRS, 63 WBRT+M, and 61 HA-WBRT. The most common definition of cognitive failure was a failure or at least 1 standard deviation decrease on any cognitive test, and was assessed at the first follow-up period, which was at 3 or 4 months post-treatment. For WBRT, cognitive failure rates ranged from 51.9%-59.6%, under the random effects model the summary effect size was 53.2% (95% Confidence Interval [CI]: 48.5%-57.8%). For WBRT+M, 43.7% (95% CI: 37.7%-49.8%) of patients experienced cognitive failure at 3 months. For HA-WBRT, 33.3% (95% CI: 28.6%-52%) of patients experienced cognitive failure at 4 months. For SRS, cognitive failure rates ranged from 20%-24%, the summary effect size was 20.9% (95% CI: 15.7%-26.7%). When comparing to WBRT, SRS (p<0.0001), WBRT+M (p=0.016), and HA-WBRT (p=0.0003) had statistically lower rates of cognitive failure. No heterogeneity was noted for each of the outcomes (I2=0% and Q-Test p>0.05). Summary effect sizes for total intracranial control rates at the first follow-up were: 87.4% (95% CI: 73.4%-96.7%) WBRT, 77.2% (95% CI: 70.8%-83.1%) SRS, and 63% (95% CI: 57%-68.8%) WBRT+M. Total intracranial failure rates were not reported for HA-WBRT. Stereotactic radiosurgery results in the lowest rate of neurocognitive dysfunction following treatment for brain metastases. In patients with brain metastases who may benefit from WBRT over SRS, WBRT with the addition of memantine and/or hippocampal avoidance is associated with a decreased risk of neurocognitive dysfunction.