Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non–small cell lung cancer patients with brain metastases

Abstract

OBJECTIVE Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non–small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations. METHODS Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses. RESULTS The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97). CONCLUSIONS Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.

State-of-the-Art Molecular Oncology of Lung Cancer in Taiwan

“…The addition of stereotactic radiosurgery (SRS) to EGFR-TKI therapy has been reported to improve intracranial tumor control and provide a potential benefit of preventing neurological deficits and seizures. [63] The combined use of Gamma Knife radiosurgery and EGFR-TKI was shown to have the most significant effect on prolonging survival time after SRS in patients with EGFR-mutant lung cancer and brain metastasis [64]. A prospective study showed that the supernatant of cerebrospinal fluid (CSF) in patients with EGFR-mutant NSCLC and leptomeningeal metastasis (LM) is a valuable specimen for EGFR mutation testing, demonstrating that the detection rates of EGFR mutations and T790M in cell-free DNA (cfDNA) of CSF were 68.8%, and 14.6%, respectively.…”

EGFR mutant status and tyrosine-kinase inhibitors affect the GKRS outcomes for NSCLC brain metastases

“…Chiou et al reported that combined therapy was superior to TKIs alone in terms of tumor control, but not overall survival. They also discussed the synergistic effects of combined therapy in cases of EGFR-positive NSCLC 7 . In 2016, Zhang et al reported no signi cant difference between TKIs alone and combined therapy in terms of median OS 24 .…”

“…Taken together, it appears that in EGFR mutant patients, GKRS is effective for local tumor control and TKIs is effective for overall survival and new brain metastasis. Thus, combining radiosurgery with TKIs should be the preferred treatment for EGFR-mutant patients 7,25,26 .…”

“…Systemic treatment for BMs includes conventional chemotherapy, TKIs, and/or immunotherapy. The sequence of local treatment and systemic medication remains an issue of controversy; however, recent research has indicated that the outcomes of upfront GKRS are superior to those of upfront EGFR-TKI therapy [3][4][5][6] , and combined treatment appears to be the best choice 7 . Several studies have reported that in non-symptomatic patients with NSCLC oligo-BMs, GKRS is the preferred rst-line treatment 8,9 , as it provides superior tumor control with fewer complications than other local BM treatments, such as WBRT 6,10,11 .…”

Combined BBB-penetrant tyrosine kinase inhibitor and intracranial radiotherapy versus BBB-penetrant tyrosine kinase inhibitor alone for the treatment of EGFR-mutated non-small cell lung cancer patients with brain metastases

“…Intracranial radiation therapy, such as whole brain radiotherapy (WBRT) and gamma-knife radiosurgery (GKRS), is the conventional approach to treating brain metastasis. Combining target therapies with GKRS or WBRT has been shown to promote intracranial tumor control beyond what can be achieved using the target therapy alone [11][12][13]. In one study on 280 patients with EGFR-mutated NSCLC and brain metastases, Chiou et al reported that in terms of cumulative tumor control, a combination therapy involving TKI plus GKRS outperformed TKI alone.…”