Does Hippocampal-Avoidance Whole-Brain Radiotherapy for Brain Metastases Meaningfully Change Current Practice?

TO THE EDITOR: Gondi et al 1 report a single-arm Radiation Therapy Oncology Group phase II multi-institutional study of hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) in patients with brain metastases (BM; RTOG 0933). The trial end point was the change in the Hopkin’s Verbal Learning Test-Revised (HVLT-R), a test of working memory, at prespecified end points (2, 4, and 6 months after radiotherapy). In an accompanying editorial, Suh 2 suggests that HA-WBRT as a treatment for BM generates hypotheses rather than being practice changing. Several points regarding the study warrant discussion. What was not clear from the study by Gondi et al was the number of patients with BM who were screened before study entry. Without a denominator, it is difficult to assess how many patients would be eligible for HA-WBRT. Stated another way, how applicable is HAWBRT to the population of patients with BM? A second issue addressed in part by Suh 2 is that of competing BM treatments wherein the majority of patients with BM are currently treated with stereotactic radiotherapy either as a primary treatment and increasingly disregarding the number of BM or as a secondary treatment—for example, immediately after resection or as a boost therapy after WBRT. 3 Consequently, the role of WBRT only as a treatment for BM has markedly diminished, based in part on concerns regarding delayed or late radiotherapy CNS injury negatively impacting both cognition and quality of life. The issue of end points in BM trials continues to evolve, and increasing attention is focused on cognition because of negative effects of CNS-directed treatment. Gondi et al 1 selected as a primary end point a change in the HVLT-R, partly on the basis of results of a small underpowered randomized trial by Chang et al. 4 Gondi et al compared results of the current trial with a previous trial of prophylactic WBRT in limited-stage small-cell lung cancer and demonstrated an improvement in memory preservation with HA-WBRT. What is less clear is how relevant HVLT-R is as a primary measure of BM treatment effectiveness? As noted in the majority of BM trials, overall survival with polymetastastic BM is 4 to 7 months with the overwhelming majority of patients dying as a result of progressive systemic disease suggesting that overall survival is not reflective of success of BM-directed treatment. Consequently, the emphasis on cognitive outcomes after treatment of BM has become the newest end point in recent BM trials. A pertinent question is whether memory alone reflects cognitive outcome after CNS-directed treatment rather than an aggregate neurocognitive assessment (the HVLT-R, Trail Making Test Parts A and B, and the Controlled Oral Word Association Test) and symptom burden tool as is commonly done for gliomas. 5 The impact of radiotherapy on frontal executive function may be as germane as working memory with respect to both activities of daily living and quality of life in patients with brain tumors. Finally, issues of cost effectiveness of CNS-directed therapies have not been addressed in BM trials. 6 The cost of stereotactic radiation therapy and HA-WBRT are several-fold higher than WBRT and neither therapy is associated with a significant improvement in overall survival when compared with WBRT. Furthermore in instances of treatment with stereotactic radiation therapy (increasingly the most common modality of therapy for patients with BM), more frequent surveillance (ie, brain magnetic resonance imaging and neurologic assessment) is required because of a higher incidence of distant brain recurrence, which results in neurologic deterioration in the majority of patients. The authors are to be congratulated for performing an innovative radiotherapy trial in BM that, like many novel therapies, raises more questions than answers.