Twenty years ago, Patchell and colleagues1 demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.
With advances in surgical technique, some have questioned the need for WBRT. Emerging data have highlighted the adverse cognitive effects of WBRT, leading to trials of postoperative stereotactic radiosurgery (SRS), hypothesized to yield equivalent local control but higher risk of distant brain relapse compared with WBRT, and in theory providing an appropriate balance between intracranial control and cognition.
Mahajan and colleagues2 reported on a single-institution randomized trial of observation versus SRS for patients who underwent resection of 1–3 brain metastases. SRS yielded no overall survival or neurologic death benefit but reduced the 12-month surgical bed relapse rate from 57% to 29% (P = 0.015), confirming that adjuvant SRS yields modest surgical bed control benefit without improving survival.
Brown and colleagues3 reported results from a multi-institutional phase III trial (N107C) of SRS versus WBRT for patients undergoing resection of one brain metastasis. This trial was more reflective of community-based neurosurgical and radiosurgical practices. There was no survival difference between the modalities. WBRT yielded a 20% improvement in 12-month surgical bed control (SRS 60% vs WBRT 80%, P = 0.00068). Overall intracranial control (37% vs 72% at 12 months, P < 0.0001) and median time to any intracranial progression (6.4 vs 27.5 mo) also favored WBRT. The trade-off of these benefits from WBRT was an approximate 3-week shortening in median cognitive deterioration-free survival (3.7 mo for SRS vs 3 mo, P = 0.00068) and a 33% increase in 6-month cognitive deterioration (one standard deviation decline in at least one cognitive test).
Collectively, these studies suggest that following resection for brain metastasis, SRS relative to observation yields no overall survival or neurologic death benefit but diminishes surgical bed failure; and, relative to WBRT, does not improve survival, decreases surgical bed control and time to intracranial failure, but improves time to and incidence of cognitive decline. Therefore, treatment selection requires a comprehensive and balanced discussion of trade-offs with patients.
Importance of Intracranial Control
To understand the role of postoperative radiotherapy, it helps to reevaluate the role for resection in brain metastasis. Resection is frequently reserved for larger and/or symptomatic lesions and has been shown to prolong overall survival in appropriately selected patients (ie, single/oligo-brain metastases, limited extracranial disease, and good performance predicting favorable prognosis).4,5 In such patients, durable intracranial control (offered by resection) can translate into meaningful survival prolongation that appropriately counterbalances the potential risks of operative morbidity and delay in systemic therapy.
In this select group of patients with favorable prognosis, the role of postoperative radiotherapy should be held to the same standard: Optimize intracranial control in a manner that meaningfully translates into survival impact but appropriately counterbalances treatment-associated risks. Patchell et al1 demonstrated that postoperative WBRT led to a meaningful reduction in neurologic death. Mahajan and colleagues2 demonstrated reduction in neurologic death with postoperative SRS, but this was not statistically significant (P = 0.13). N107C3 lacks a comparison of the rates of neurologic cause of death between WBRT and SRS, and therefore one has to rely on alternative data sources, such as the multicenter trial by Kepka et al6 that observed a 35% higher rate of neurologic death following SRS compared with WBRT at 2 years (P = 0.015).
Thus, in patients for whom surgical resection is likely to meaningfully impact survival, optimizing intracranial control with adjuvant radiotherapy also contributes to this benefit. The decision on modality (SRS or WBRT) involves a trade-off. SRS as a strategy to avoid WBRT yields an approximate 3-week benefit in median time to cognitive deterioration-free survival, with trade-off of 20% loss in 12-month tumor bed control, 21-month shortening in time to any intracranial failure, and absence of benefit in preventing neurologic death.
Neuroprotective Strategies During WBRT
During the latter stages of accrual to N107C, two seminal studies testing the potential cognitive preservation benefits of neuroprotective strategies during WBRT were published. In RTOG 0614, a multi-institutional phase III trial, memantine during WBRT reduced the probability of cognitive dysfunction at 6 months by 11% and led to better preservation of executive function, processing speed, and delayed recognition.7 In RTOG 0933, a multi-institutional phase II trial, memory preservation was observed following conformal avoidance of the hippocampus during WBRT for patients with brain metastases.8 A phase III trial of WBRT with memantine with or without hippocampal avoidance (NRG CC001) is currently ongoing. Based on the results of RTOG 0614 and pending the results of NRG CC001, the trade-off between intracranial control and cognitive effects of WBRT may require reexamination.
Leptomeningeal Dissemination
An unintended consequence of resection is the risk of iatrogenic leptomeningeal dissemination (LMD) that is not adequately prevented with postoperative SRS. Mahajan et al observed a 12-month risk of LMD following resection of 16% in the observation arm and 28% in the SRS arm, comparable to previously published estimates.9,10 LMD after resection can significantly impact the management of these patients, often requiring either WBRT or intrathecal chemotherapy or both, and potentially compromising survival, cognitive function, and quality of life.
Emerging data have demonstrated a reduction in the risk of LMD with the use of preoperative, as opposed to postoperative, SRS based on the principle that preoperative SRS may preemptively sterilize microscopic disease that seeds the cerebrospinal fluid during resection.10 A randomized trial of pre- versus postoperative SRS for resectable brain metastases at high risk for developing LMD is currently seeking approval from the Cancer Therapy Evaluation Program.
Conclusion
These recently published seminal studies are valuable contributions to our understanding of the role of adjuvant radiotherapy following resection for brain metastasis, and underscore that the choice of WBRT or SRS requires a detailed and comprehensive discussion with patients on the trade-off between intracranial control and cognition.
References
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