Reply to M.C. Chamberlain

regard to the safety of HA-WBRT, previous work by Gondi et al 4 evaluating 1,133 metastases in 371 patients revealed perihippocampal lesions in 8.6% of patients. Moreover, only 4.5% of patients who developed intracranial progression in Radiation Therapy Oncology Group trial RTOG 0933 progressed in the hippocampal-avoidance area. 2 Therefore, for the vast majority of patients undergoing WBRT, HA would be associated with a low risk of compromising intracranial disease control. Next, patients with a good performance status (Karnofsky performance status 70) and favorable long-term prognosis would likely benefit most from this technique and were specifically enrolled onto this trial. As a result of advancements in imaging techniques, better availability of and access to health care resources, and improvement in systemic therapies, we suspect that the proportions of these patients with favorable risk will continue to increase. Another concern raised addresses the role of HA-WBRT in the current era of stereotactic radiosurgery (SRS) given that focal therapies are quickly becoming the primary and adjuvant treatment of choice for patients with brain metastases. The updated National Cancer Center Network 2015 guidelines recommend either WBRT or SRS alone as primary treatment options for patients with multiple lesions ( 3 lesions). Despite the increasing adoption of primary SRS, randomized phase III trials have clearly demonstrated that the addition of WBRT improves local control and distant brain failure, minimizes the need for salvage therapies, and most importantly, decreases neurologic death. 5 Therefore, HA-WBRT may offer an attractive alternative treatment, especially in patients with a high probability of distant intracranial failure, with a reduced risk for neurocognitive deterioration. Over time, cooperative group trials in patients with brain metastases have transitioned from evaluating survival as the primary end point to focus on neurocognitive metrics. This was clearly fueled by additional analyses of the trials by Chang et al 6 and Kocher et al, 7 which demonstrated a decline in the Hopkin’s Verbal Learning TestRevised results and cognitive functioning, respectively, in patients who underwent WBRT. To compare their work with the previous research in this domain, Gondi et al 2 specifically evaluated a change in results measured by the Hopkin’s Verbal Learning Test-Revised as the primary end point for RTOG 0933. This decision was also supported by previous research by Li et al 8 who determined that memory function, unlike other neurocognitive domains, continued to decline after WBRT despite tumor shrinkage. Although a more complete battery of tests would be interesting to analyze, choosing the specific test that has been uniquely linked to neurocognitive deterioration after WBRT and used in previous studies has the advantage of being feasible and practical for study. Ultimately, the discovery of a reliable biomarker that correlates with neurocognitive functioning would allow survival to also be a recognized end point in future trials. In the current era of value-based care, cost-effectiveness studies are clearly needed when multiple treatment options exist. 9 In one of the few studies on this topic, Lal et al 10 used the economic data from the trial by Chang et al 6 to demonstrate the cost effectiveness and cost utility of primary SRS with observation when compared with SRS with WBRT. Although SRS with observation was associated with a higher cost, it was also associated with a higher effectiveness and cost effectiveness, even when considering additional salvage therapies, with a gain of cost per life-year well within the standards for other medical therapies. As more experience and economic data are generated in association with HA-WBRT, similar types of analyses will generate useful comparative data. In all, given the scrutiny on costs, future trials