Hippocampal-avoidance whole-brain radiation therapy: a new standard for patients with brain metastases?

The use of whole-brain radiation therapy (WBRT) for brain metastases was first described in the 1950s. Since that time, WBRT has long been considered the treatment of choice, given its wide availability, ease of delivery, and effectiveness in providing palliation for many patients. Numerous phase III trials have also validated its benefit in improving neurologic signs and symptoms for many patients, with median survival times ranging from 3 to 6 months. Because of the poor outcomes for most patients with brain metastases, some physicians developed a nihilistic view of brain metastases and considered the routine use of WBRT as an obvious approach, given the limited treatment options. As a result, the potential toxicities resulting from WBRT were largely dismissed. However, with the many advances in neurosurgery, imaging, medical oncology, and radiation oncology, the outcomes for some patients have greatly improved, particularly for those with favorable prognostic factors. With this improvement in outcomes and the higher expectations of patients and physicians, the routine use of WBRT has been highly scrutinized, considering its potential impact on neurocognitive function (NCF) and quality of life (QOL). As a result, the optimal management of brain metastases remains one of the most controversial areas of oncology, even among experts. Given the improved outcomes for some patients with brain metastases, the impact of WBRT on NCF has recently been an active area of investigation. A comprehensive phase III trial (PCI-P-120-9801) of WBRT versus WBRT plus motexafin gadolinium, a radiation sensitizer, was performed and included a battery of neurocognitive tests. This study of 401 patients demonstrated that the vast majority of patients with brain metastases (90.5%) had some decline in NCF before initiation of treatment. Neurocognitive test scores and global neurocognitive impairment at baseline were correlated with brain tumor volume and also predicted for survival. Further analysis suggested the adverse impact of tumor progression on NCF was greater than the treatment-related effects of WBRT. In addition, recent neurocognitive data from RTOG (Radiation Therapy Oncology Group) 0214, a phase III randomized trial of observation versus prophylactic cranial irradiation (PCI) for patients with non–small-cell lung cancer, have also suggested a negative impact of PCI. In addition to the neurocognitive effects, the impact of WBRT on QOL and functional independence has also been investigated. Although phase III trials of stereotactic radiosurgery (SRS) and WBRT for patients with a limited number of brain metastases ( four) have shown a significant improvement in local and distant brain control with the addition of WBRT to SRS, the decline in Hopkins Verbal Learning Test–Revised (HVLT-R) scores at 4 months and lack of improvement in the duration of functional independence have further decreased the advocacy for WBRT. In addition, the healthrelated QOL (HRQOL) data from the phase III European Organisation for Research and Treatment of Cancer trial of SRS or surgery with or without WBRT have also introduced additional concerns. In this trial, the WBRT arm had a statistically significant detriment in mean global QOL scores at 9 months and also had lower cognitive function at 8 weeks and 1 year; however, this trial did not formally assess patients with a battery of neurocognitive tests and had only a 45% compliance rate at 1 year. On the basis of the results of these studies and the concerns regarding the effects of WBRT on NCF, strategies to mitigate the late effects of WBRT have been actively explored. Omission of WBRT through the use of SRS is emerging as an attractive treatment approach compared with WBRT, given its inherent advantages, including its multidisciplinary approach, single-session outpatient delivery, minimal recovery time, patient convenience, and more rapid initiation of systemic treatments. Technologic advances in treatment delivery and treatment planning have also facilitated the use of SRS alone as the primary treatment for patients with five lesions. Recently, a prospective observational study of SRS alone in 1,194 patients with one to 10 brain metastases suggested no difference in survival or treatment-related adverse events for patients with two to four and five to 10 lesions. To confirm this and other studies, the North American Gamma Knife Consortium will be performing a prospective randomized trial evaluating NCF of SRS versus WBRT for patients with five metastases (ClinicalTrials .gov NCT01731704). Another approach to minimize the neurocognitive effects of WBRT uses memantine, an N-methyl-D-aspartate receptor antagonist, as a potential neuroprotector, which has been used for patients with mild to moderate dementia in Alzheimer’s disease. RTOG 0614 was a double-blind, placebo-controlled phase III trial of WBRT plus memantine versus WBRT plus placebo. This trial randomly assigned 554 patients to WBRT with or without memantine 10 mg initially then JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 34 DECEMBER 1 2014