John H. Suh, MD
Department of Radiation Oncology
Taussig Cancer Institute
Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center
After its initial publication in the 1950s,1
the use of whole-brain radiation therapy (WBRT) for patients with brain metastases became the treatment of choice for this population given its wide availability, ease of delivery, and effectiveness in providing palliation. In addition, the historically poor outcomes for the vast majority of patients with brain metastases fostered the routine use of WBRT and promulgated the nihilistic view that toxicities related to WBRT were inconsequential given the dismal outcomes and lack of effective systemic therapies for patients with extracranial metastases.
Currently, the major treatment alternative to WBRT is stereotactic radiosurgery (SRS), which allows for the delivery of precisely focused, highly targeted radiation to multiple intracranial tumors. In addition, SRS has distinct advantages over surgical resection, including the ability to treat multiple and deep-seated intracranial lesions in an outpatient setting.2
Now, based on randomized phase III studies demonstrating superior neurocognitive preservation and duration of functional independence without the addition of WBRT to SRS,3,4
the adoption of SRS alone has greatly escalated and has become the standard primary and adjuvant treatment of choice at many medical centers. As part of its Choosing Wisely campaign, the American Society of Radiation Oncology (ASTRO) has recommended against the routine addition of adjuvant WBRT to SRS for patients with limited brain metastases.5
However, despite the fervent advocacy of SRS alone, the addition of WBRT clearly improves local control, decreases distant brain failure, minimizes the need for salvage therapies such as surgery, and, most importantly, decreases neurologic death.4
Yet, given the growing data against WBRT, one may question whether this therapy should be abandoned as an antiquated and toxic treatment for the majority of patients with brain metastases. Alternatively, novel approaches may potentially mitigate the neurocognitive toxicities of WBRT, which would support its role as a valuable treatment modality.
Two recent clinical trials, RTOG 0614 and RTOG 0933, provide some insight on how one can improve the therapeutic ratio of WBRT.
RTOG 0614: Adding to WBRT
This phase III trial randomized 554 patients to WBRT with or without memantine, an N-methyl- D-aspartate receptor antagonist traditionally used for mild-to-moderate dementia in patients with Alzheimer disease.6 The trial tested the hypothesis that memantine could act as a neuroprotectant by minimizing the neurocognitive effects of WBRT.
Results from the study demonstrated less decline in the Hopkins Verbal Learning Test Revised Delayed Recall (HVLT-R DR) in the memantine arm (P
= .059). Although this difference was not statistically significant, which was possibly a result of only 35% statistical power given the limited number of analyzable patients at 24 weeks, the memantine arm was nevertheless associated with superior cognition over time, with delayed time to cognitive decline and reduced rates of decline in memory, executive function, and processing speed.
RTOG 0933: Minimizing WBRT Exposure
Based on the hypothesis that injury to the neural stem cells of the subgranular zone of the hippocampal dentate gyrus leads to the early cognitive decline following radiation therapy in preclinical studies, modern radiation planning techniques were explored to minimize exposure to this compartment of the hippocampus.7,8
The RTOG 0933 study was a phase II trial of hippocampal avoidance (HA) WBRT intended to reduce the long-term effects of WBRT on neurocognition. 9
The primary endpoint of the trial was the HVLT-R DR at 4 months using a historical control from a comprehensive radiation sensitizer study in which patients received conventional WBRT.10
To facilitate high-quality assurance, central rapid review was conducted in real time to ensure that stringent planning and contouring guidelines were followed.