Optimal intervention timing for craniocerebral radiotherapy in EGFR mutant lung adenocarcinoma patients with brain metastases

Abstract

Background: Intracranial radiation in combination with EGFR targeted therapy demonstrated signals of superiority to EGFR targeted therapy alone based on several observational studies. The timing based on specific criteria is not clear, and we evaluated the efficacy of intervention timing of craniocerebral radiotherapy (RT) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) on prognosis of patients with EGFR mutant lung adenocarcinoma complicated with brain metastasis.

Methods: In total, 603 patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations were enrolled in this retrospective study between March 2008-September 2023. Propensity score matching (PSM) was conducted to adjust for demographic and clinical covariates and to compare survival differences between the EGFR-TKI plus craniocerebral RT group and the EGFR-TKI only group. Patients were divided into upfront group and delayed group according to timing of craniocerebral RT interventions and analyses. Graded prognostic assessment for lung cancer using molecular markers (Lung molGPA), overall survival (OS), and intracranial progression-free survival (iPFS) were calculated. Kaplan-Meier was used to compare iPFS and OS in different groups.

Results: In our study, the median overall survival (OS) was 48.8 months, and the median intracranial progression-free survival (iPFS) was 14.2 months before PSM. After PSM, the median OS of EGFR-TKIs + craniocerebral RT group and EGFR-TKI only group was 52.0 months and 43.2 months, respectively (p = 0.0363). In total of 417 patients who underwent craniocerebral RT, were enrolled subsequently and divided into groups A (Lung-molGPA 1-2) and B (Lung-molGPA 2.5-4) according to the lung-molGPA score. For group A, the median OS of upfront-group and delay-group was 27 and 42.1 months, respectively (p = 0.0019). For patients in group B, there was no significant difference in OS between the two groups (p = 0.9642).

Conclusion: For patients with craniocerebral metastases of EGFR-mutant lung adenocarcinoma, combination of EGFR-TKIs and craniocerebral RT confers enhanced survival benefits. In patients with lower Lung-molGPA scores, delayed administration of craniocerebral RT is recommended to improve both iPFS and OS.

Keywords: Brain metastasis; Craniocerebral radiotherapy; EGFR-mutant; Lung adenocarcinoma; Lung-molGPA.

Fig. 1

In patients who used first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) cohort: A Overall survival (OS) and (B) intracranial progression-free survival (iPFS) of the cohort before propensity score matching (PSM). C Comparison of OS between the EGFR-TKIs combined with craniocerebral RT group and EGFR-TKI alone group before PSM. (a) OS and (b) iPFS of the cohort after PSM. (c) Comparison of OS between the EGFR-TKIs combined with craniocerebral RT group and EGFR-TKI alone group after PSM

Fig. 2

In patients used first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) cohort: A Comparison of iPFS between the upfront-group and delay-group. B iPFS of patients in group A stratified according to intervention timing of craniocerebral RT. C iPFS of patients in group B stratified according to intervention timing of craniocerebral RT. D Comparison of OS between the upfront-group and delay-group. E OS of patients in group A stratified according to intervention timing of craniocerebral RT. F OS of patients in group B stratified according to intervention timing of craniocerebral RT