WBRT in 2020: Obsolete, or new and improved?
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Conventional whole-brain radiotherapy (WBRT) has changed little and remained an important part of the armamentarium in the management of brain metastases for the better part of the past half century. WBRT is a proven effective therapy but has well-established toxicity, including both short-term effects, such as fatigue and hair loss, as well as long-term effects, which are primarily neurocognitive.
The field of radiation oncology has taken two divergent paths to minimize the associated toxicities of WBRT. One has been to focus on improving WBRT through pharmacologic and technical innovations. Both these approaches were established in large randomized cooperative group trials. The addition of the neuroprotective agent memantine reduced long-term neurocognitive effects of conventional WBRT. In addition to the pharmacologic path, technical improvements were utilized to minimize the dose to the hippocampus while delivering WBRT, which showed reduction in associated neurocognitive toxicity.
The other path taken was to minimize the use of WBRT. This approach was well-established in large, randomized trials for patients with one to three (or four) metastases with stereotactic radiosurgery (SRS) alone and not utilizing WBRT. After the success among patients with limited metastases, the natural evolution of this path was to explore SRS in patients with four or more brain metastases. The recently reported small, randomized phase 3 trial by Li and colleagues showed that for patients with four to 15 brain metastases, SRS alone showed equivalent survival with reduced neurocognitive toxicity. This trial provides the best evidence to date that SRS alone is a preferred alternative to conventional WBRT for patients with four to 15 metastases.
The trial was well-conceived and well-designed but was challenged with slow accrual and small size. It was ultimately closed with the publication of NRG Oncology CC001, the trial that showed hippocampal-avoidant WBRT is superior to conventional WBRT.
Li and colleagues enrolled 72 patients with a median of eight brain metastases. Importantly, only 31 patients were evaluable at 4 months for Hopkins Verbal Learning Test-Revised Total Recall. The majority of patients in the WBRT arm received memantine as part of their therapy, but a significant minority did not. OS appeared similar for both arms, but clearly a small trial with competing causes of death was highly unlikely to report a difference in survival. Like the trials of patients with fewer metastases, because the survival was similar with reduced neurocognitive toxicity, SRS alone is the preferred approach, with the caveats of trial size and use of conventional WBRT.
Thus, the role of conventional, “old-fashioned” WBRT continues to dwindle and really now only exists for patients with poor performance status or limited survival prospects, and even that role is open for debate. However, the question of enhanced WBRT with memantine and hippocampal avoidance remains unanswered. Fortunately, there is an ongoing trial, CCTG CE.7, that is currently accruing and should answer the question of whether to use hippocampal-avoidance WBRT plus memantine or SRS alone for patients with five to 15 brain metastases.
Reference:
Brown PD, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.02767.
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