Radiation Necrosis Risk in NSCLC Patients Receiving EGFR TKIs or ALK Inhibitors

Abstract

<h3>Purpose/Objective(s)</h3> Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and anaplastic lymphoma kinase (ALK) inhibitors have become commonplace in the treatment of locally advanced and metastatic NSCLC with activating mutations. The toxicity of stereotactic radiation therapy (SRT) when given concurrently with these drugs remains unclear. The purpose of this study was to determine the incidence of radiation necrosis (RN) in patients receiving these targeted therapies (TGT). <h3>Materials/Methods</h3> We retrospectively reviewed metastatic NSCLC patients who received EGFR TKI or ALK inhibitor at our institution. Patients with brain metastases treated with SRT with a minimum of 6 months post-SRT follow up were included for analysis, and demographic, oncologic, radiation and imaging records were reviewed. RN diagnosis was based upon the radiologist interpretation, radiation oncologist progress notes, or pathology reports after resection. Local recurrence was defined radiographically or histologically. Biologically effective dose was calculated using the linear quadratic equation using an α/β of 3 (BED3) and 10 (BED10). <h3>Results</h3> Thirty-nine patients with 161 treated brain lesions fit our inclusion criteria. Most patients were female (76.9%), with a median age of 60 (range 27-73), and were treated to a median of 3 (1-27) lesions per patient. EGFR TKI or ALK inhibitor was administered in the 2-week interval surrounding SRT (TGT+) for 116 of 161 lesions, and 28 of 116 (24.1%) developed evidence of RN (21 symptomatic, 18.1%). Among the 45 lesions where TKI or ALK inhibitor was not given in the 2-week interval surrounding SRT (TGT-), one case of RN (2.2%) was identified. Most symptomatic RN lesions (67%) resolved with therapy. Local control among TGT+ and TGT- lesions was 93.1% and 97.7% respectively (p=0.08). The odds for developing RN were higher for TGT+ than TGT- treatments (OR=14; 95%CI 1.8-106). In 19 out of 116 TGT+ lesions, TGT was either held during SRT or initiated within 2 weeks following SRT, and the RN rate was not lower than for SRT where TGT was administered concurrently (26.3% vs 23.7%, p=0.4). Among TGT+ lesions, there was no difference in number of TKIs received prior to, during, or after SRT for those with or without RN. There was no association of prescribed BED3 or BED10 with the development of RN. Lesions that developed RN were more likely to be treated with osimertinib than those without RN (46% vs 23%, p=0.02). <h3>Conclusion</h3> Patients receiving SRT with EGFR TKI or ALK therapy 2 weeks before or after SRT are at higher risk of RN. This risk does not appear to diminish when holding TGT during SRT or delaying TGT initiation until after SRT. Special attention should be given to patients receiving SRT with osimertinib therapy as our data suggest that they are at higher risk of developing RN. Future work will focus on identification of unique dosimetric and temporal factors that may be predictive of RN in patients taking these targeted agents.