PurposeThe optimal treatment strategy following local recurrence after stereotactic radiosurgery (SRS) remains unclear. While upfront SRS has been extensively studied, few reports focus on outcomes after retreatment. Here, we report the results following a second course of SRS for local recurrence of brain metastases previously treated with SRS.MethodsUsing institutional database, patients who received salvage SRS (SRS2) following in-field failure of initial SRS (SRS1) for brain metastases were identified. Radionecrosis and local failure were defined radiographically by MRI following SRS2. The primary endpoint was defined as the time from SRS2 to the date of all-cause death or last follow-up [overall survival (OS)]. The secondary endpoints included local failure-free survival (LFFS) and radionecrosis-free survival, defined as the time from SRS2 to the date of local failure or radionecrosis, or last follow-up, respectively.ResultsTwenty-eight patients with 32 brain metastases were evaluated between years 2004 and 2015. The median interval between SRS1 and SRS2 was 9.7 months. Median OS was 22.0 months. Median LFFS time after SRS2 was 13.6 months. The overall local control rate following SRS2 was 84.4%. The 1- and 2-year local control rates are 88.3% (95% CI, 76.7–100%) and 80.3% (95% CI, 63.5–100%), respectively. The overall rate of radionecrosis following SRS2 was 18.8%. On univariate analysis, higher prescribed isodose line (p = 0.033) and higher gross tumor volume (p = 0.015) at SRS1 were associated with radionecrosis. Although not statistically significant, there was a trend toward lower risk of radionecrosis with interval surgical resection, fractionated SRS, lower total EQD2 (<50 Gy), and lack of concurrent systemic therapy at SRS2.ConclusionIn select patients, repeat LINAC-based SRS following recurrence remains a reasonable option leading to long-term survival and local control. Radionecrosis approaches 20% for high risk individuals and parallels historic values.

BackgroundNon‐small cell lung cancer (NSCLC) harboring kinase‐domain mutations in epidermal growth factor receptors (EGFR) has been observed to be sensitive to ionizing radiation (IR). We explore Rad51‐dependent homologous recombination (HR) DNA repair in regulating radiosensitivity in two NSCLC cell lines with different EGFR mutation status.Methods NSCLC cell lines, wild‐type EGFR A549 and mutant EGFR H820 with an in‐frame deletion in exon 19 of EGFR (ΔE746–E750), were cultured. Radiosensitivity was estimated by colony forming assay. Rad51 expression was evaluated by quantitative real time‐polymerase chain reaction and Western‐blot. Lentiviral small hairpin ribonucleic acid‐Rad51 and ΔE746–E750 deletion mutant EGFR were constructed and transfected into cells. Flowcytometry assay was used to analyze DNA double strand breaks, cell cycle alterations, and apoptosis.Results A549 had a higher survival factor (SF)2 (0.66 vs. 0.44) and lower α/β value (4.07 vs. 9.01). Compared with the A549 cell, the H820 cell exhibited defective arrest in the S‐phase, a higher rate of G2/M accumulation, early apoptosis, and residual γ‐H2AX. Downregulated Rad51 expression decreased SF2 (0.42 vs. 0.31) and increased the α/β ratio (7.51 vs. 10.5), G2/M accumulation, early apoptosis, and γ‐H2AX in two cell lines. H820 had a low IR‐induced Rad51 expression and nuclear translocation. Exogenous expression of the ΔE746–E750 deletion mutant EGFR caused the A549 cell to become more radiosensitive.ConclusionsAn EGFR mutated NSCLC cell line is sensitive to IR , which is correlated with reduced IR‐induced Rad51 expression and nuclear translocation. The signaling pathway of EGFR maintaining Rad51 protein levels maybe a novel lung cancer therapeutic target to overcome radioresistance.

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