The Optimal Sequence of Intracranial Radiotherapy Compared to Systematic TKI for Brain Metastases in Targeted Treatment Era

Abstract

The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity.Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis.Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P<0.001), but no longer median time to OS (35.6 vs. 41.5 months, P = 0.383) and BMSS (66.2 vs. 58.0 months, P = 0.746) after the salvage therapy. RT alone group showed similar IPFS (18.0 months; 95% CI 14.1-22.0 months; P = 0.686) and a trend of lower OS (19.9 months; 95% CI, 17.6 - 22.3 months; P = 0.010), BMSS (44.8 months; 95% CI 30.7 - 58.9 months; P = 0.002) than upfront RT group. Treatment-related grade 3-4 adverse events were rare, and similar hematological toxicities, liver and renal dysfunctions were observed among different groups.Compared to upfront TKI group, upfront RT group got longer median IPFS time in BM patients but no significant OS or BMSS benefit with similar well-tolerated toxicities. TKI group had better OS and BMSS than RT alone group. The best timing of intracranial RT remains to be further verified.S. Yang: None. J. Xiao: None. H. Zhang: None. Q. Liu: None. Y. Zhang: None. X. Chen: None. K. Wang: None. X. Huang: None. Y. Ma: None. R. Zhao: None. N. Bi: None. J. YI: None. S. Wang: None. Y. LI: None.