By Arya Amini, MD, and Chad G. Rusthoven, MD
Posted: August 19, 2020
Approximately 10% of patients diagnosed with metastatic NSCLC present with brain metastases, and another 30% develop brain metastases during the course of their illness.1 Traditionally, the treatment for brain metastases included surgery, whole-brain radiotherapy (WBRT), or stereotactic radiosurgery (SRS). Due to neurocognitive effects from WBRT, SRS has now emerged as first-line therapy in many patients with limited brain metastases. Ongoing trials are evaluating the definition of “limited,” which may evolve from the current clinical thresholds ranging from four or fewer to 10 or fewer lesions.2 An ongoing randomized phase III clinical trial is comparing SRS to WBRT in patients with five to 15 brain metastases (NCT03550391).3 In patients who are not candidates for SRS, WBRT is still the “standard” and is typically used in patients with numerous brain metastases not amenable to SRS and/or those presenting with leptomeningeal disease. To counteract the potential neurocognitive side effects from WBRT, hippocampal sparing and memantine are viable options for these patients and should be considered, on the basis of randomized data.4 Lastly, in patients with one or more lesions causing current or impending mass effect and symptoms, or in settings where tissue confirmation is needed, surgery should be considered.
Revisiting the Gold Standard
SRS has emerged as the gold standard for limited brain metastases after multiple randomized trials demonstrated improved cognition and quality of life compared to strategies incorporating WBRT. There has been a growing interest, however, in parallel strategies involving systemic therapy upfront with radiation deferred. Despite the improved side-effect profile of SRS compared to WBRT, SRS can nevertheless pose certain risks, including central nervous system (CNS) necrosis, and can be associated with cognitive and quality-of-life effects when numerous lesions are treated. Therefore, potentially delaying or avoiding radiation may have its benefits. Whereas historically, chemotherapy had low CNS penetration and objective response rates (ORRs), novel agents have been introduced in the past decade with clinically meaningful intracranial response rates in advanced NSCLC. These include EGFR TKI agents such as third-generation osimertinib, which has shown encouraging ORRs and reduction in CNS progression compared to first- and second-generation EGFR TKIs.5 ALK inhibitors have demonstrated similarly encouraging CNS ORRs in the range of 60% to 80%. Pembrolizumab, a PD-1 inhibitor, has been approved for treatment in metastatic NSCLC without targetable mutations, on the basis of phase III randomized data demonstrating improved OS compared to chemotherapy.6-8 In a single-arm, phase II study in patients with metastatic NSCLC with at least one untreated brain metastasis receiving pembrolizumab alone, the CNS response rate approximated 30%.9 Additional data suggest that when combining pembrolizumab with chemotherapy, CNS response rates increase to approximately 40%.10
Although the improved CNS response rates with newer agents are encouraging, there is currently a paucity of high-level evidence to ensure that the outcomes achieved with an initial strategy of systemic therapy alone are equivalent to systemic therapy plus tumor-directed radiation across various clinical settings. Moreover, SRS has traditionally been combined with the most effective systemic therapies available, and the emergence of newer agents with increased CNS activity does not necessarily preclude the benefit of durable local tumor control achieved with SRS. Although the growing interest in a strategy of first-line systemic therapy alone is underscored by ongoing trials enrolling patients with untreated asymptomatic brain metastases (EA516/ S1709 INSIGNA; NCT03793179),11 there are also data suggesting inferior outcomes when upfront radiation is omitted in favor of TKIs alone. Additional analyses suggest potential synergy between radiation and immune checkpoint inhibitors, especially in those with larger lesions potentially causing mass effect or in neurologically critical locations.12,13
Collaborative Decision Making
In a rapidly evolving field, where the development of new therapies with enhanced CNS activity has outpaced clinical trial efforts to evaluate systemic agents with and without brain radiation, our institutions have taken a multidisciplinary approach involving input from both medical oncologists and radiation oncologists. In patients with NSCLC with targetable molecular alterations, such as EGFR and ALK, who have asymptomatic but extensive brain metastases that would normally require WBRT, our groups will often favor a strategy of a CNS-active TKI alone with close clinical and brain MRI monitoring. In some cases, this strategy can lead to “downstaging,” where patients who previously may have required WBRT at presentation can subsequently undergo SRS to isolated deposits of residual disease. In patients who are candidates for upfront SRS, strategies instituting TKIs alone or TKI plus SRS may be reasonable, depending on the clinical scenario. However, early radiation or surgery is usually preferred for tumors that are: symptomatic; have poor prognostic characteristics such as larger size, significant edema, or impending mass effect; or are located in eloquent and higher-risk areas (e.g., in the brainstem or near optic pathways). In patients without targetable mutations, it is important to note that the response rates to immunotherapy are generally lower than those observed with CNS-active TKIs for targetable NSCLC mutations; thus, the threshold to forgo early radiation should be higher in these patients, and close monitoring remains imperative.
Multidisciplinary input and close monitoring are essential particularly when using systemic therapy alone upfront.
In the coming years, prospective trials are needed to assess the optimal timing of radiation for patients with brain metastases who are candidates for CNS-active systemic therapies, to determine whether SRS can be safely delayed without affecting neurocognitive function, quality of life, and survival. In the meantime, early local therapy for brain metastases remains the gold standard, and as such, multidisciplinary input and close monitoring are essential, particularly when using upfront systemic therapy alone. ✦
About the Authors: Dr. Amini is with the Department of Radiation Oncology, City of Hope National Medical Center. Dr. Rusthoven is an associate professor in the Department of Radiation Oncology at the University of Colorado Cancer Center.
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