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.
Highlights
As systemic therapies have improved, brain metastases (BM) have been increasingly reported as one of the most common clinical events and causes of mortality in patients with advanced malignancies, especially those with lung cancer
A total of 198 patients were included in the study (Figure 1): 94 (47.5%) patients first received target therapy followed by RT, and 104 patients first received RT followed by target therapy (57, 28.8%) or concurrent RT and target therapy (47, 23.7%)
BM, brain metastases; Karnofsky performance score (KPS), Karnofsky Performance Score; tyrosine kinase inhibitors (TKIs), tyrosine kinase inhibitor; RT, radiation therapy; whole-brain therapy (WBRT), whole brain radiotherapy; SRS, stereotactic radiosurgery; hypofractionated stereotactic RT (HFSRT), hypofractionated stereotactic radiotherapy; CI, confidence interval; HR, hazard ratios. was the factor nearly influencing brain metastasisspecific survival (BMSS) (Supplementary Table S2)
Summary
As systemic therapies have improved, brain metastases (BM) have been increasingly reported as one of the most common clinical events and causes of mortality in patients with advanced malignancies, especially those with lung cancer. A few clinical studies reported that single-agent EGFR- tyrosine kinase inhibitors (TKIs) showed promising results in TKI treatmentnaive patients [2, 3]. A few multi-target anti-angiogenesis agents have shown good response rates in clinical studies [6, 7]. It remains unclear whether it is reasonable enough to defer RT until the intracranial progression is noted in patients on TKIs based on the aforementioned results, considering potential RT toxicity. In the era of targeted therapy, the optimal timing of intracranial RT and TKI treatment in patients with BM remains to be further confirmed
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