The Sequence of Intracranial Radiotherapy and Systemic Treatment With Tyrosine Kinase Inhibitors for Gene-Driven Non-Small Cell Lung Cancer Brain Metastases in the Targeted Treatment Era: A 10-Year Single-Center Experience

Abstract

PurposeThe high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients.Patients and MethodsWe retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups.ResultsAmong the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30–0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3–4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups.ConclusionCompared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities.Trial registration IDNCT04832672.

Clinical Management of Patients with Non-Small Cell Lung Cancer, Brain Metastases, and Actionable Genomic Alterations: A Systematic Literature Review

“…The majority of brain metastases reported were located at the cerebral hemispheres and cerebellum. Few studies reported the median time interval between the diagnosis of NSCLC and brain metastases; among those studies that did, the average time to diagnosis was between 1 and 2 years (this average does not include patients who had brain metastases at NSCLC diagnosis) [ 45 , 82 , 88 ]. One Japanese retrospective study noted that the rate and frequency of developing brain metastases were rapid and higher in patients with EGFR mutations than in patients without EGFR mutations [ 99 ].…”

“…In the first-line setting, treatment with upfront WBRT with or without concomitant TKIs resulted in the more favorable clinical outcomes compared with treatment with TKIs only or upfront TKIs followed by WBRT. Three observational studies found that median CNS-PFS was longer in patients who had received earlier or upfront versus no or delayed radiotherapy [ 32 , 68 , 88 ]. Additional observational studies found that EGFR TKIs in combination or sequenced with radiotherapy (WBRT and/or SRS) had longer median CNS-PFS than with EGFR TKI monotherapy [ 24 , 27 , 30 , 34 , 38 , 82 , 98 ].…”

Is it possible to delay stereotactic radiotherapy of brain metastasis of lung cancer?

“…On the other hand, in a more recent retrospective series of 147 patients either EGFR-mutated (n = 94), ALK-positive (n = 52) or both (n = 1) looking speci cally at the role of SRT in combination with targeted therapies, all treated with CNS-penetrant TKI, the use of an early SRT did not improve PFS or time to intra-cranial progression [24]. In 198 patients with a targetable mutation, Yang [25] compared upfront and deferred radiotherapy (nearly 40% were treated with WBRT): they found that deferred RT had a higher rate of brain progression, with no impact on survival, re ecting again the loss of e cacy of medical treatment to prevent the occurrence of new BM during the course of the disease. In our series, only 17 patients had a targetable mutation, with no difference in local control according to treatment line.…”

Analysis of the efficacy of upfront brain radiotherapy versus deferred radiotherapy for EGFR/ALK-positive non-small cell lung cancer with brain metastases: a retrospective study

“…Like our findings, a plethora of research has demonstrated that upfront RT enhances iPFS and OS and increases the rate of BM remission. A retrospective study of 198 eligible patients revealed a significant improvement in iPFS with upfront RT (19.9 vs. 11.1 months, P < 0.001) [ 17 ]. According to Magnuson et al, there were significant differences in OS (46 vs. 30 vs. 25 months, P = 0.001) and iPFS (23 vs. 24 vs. 17 months, p = 0.025) between patients treated with SRS + TKI, WBRT + TKI, or TKI [ 16 ].…”