Immunotherapy Increases Incidence of Radiation Necrosis Following Radiotherapy for Brain Metastases and Specific Immunotherapy Classes May Be More Strongly Implicated than Others

Introduction: Radiation necrosis (RN) is a complication of radiation therapy (RT) for cerebral masses where brain tissue degrades, forming a focal structural lesion regional to the original tumor. Most often occurring 1-2 years following therapy, RN can lead to edema, seizures, and death. Immunotherapy (IT) used concurrently or proximal to RT for the treatment of brain metastases (BM) may increase RN incidence.

Methods: This analysis utilizes TriNetX, an EHR/claims database encompassing numerous healthcare organizations (HCOs), to compare RN incidence in BM patients who received IT within 6 months of RT vs. those who did not. After propensity-score matching for demographic factors and primary tumor site/histology, 2 cohorts comprised 2,098 patients each. The outcome, symptomatic RN, was defined using ICD codes I67.8 and T66. Risk ratios (RR) were calculated.

Results: BM patients who received IT within 6 months of RT were significantly more likely to develop RN at 1 year (RR: 1.43 [1.15-1.79]), 4 years (RR: 1.54 [1.32-1.81]), and overall (RR: 1.61 [1.37-1.89]); all p< 0.0001. Patients given anti-HER2 IT were more likely to develop RN than those who received other immunotherapies regardless of primary site/histology (RR: 1.71 [1.20-2.41], p=0.0023), while no risk difference was appreciated for PD-1/PD-L1 or protein kinase inhibitors compared to other immunotherapies.

Conclusion : In accordance with prior analyses, our data show that immunotherapy increases RN incidence following RT for brain metastases. Many previous analyses examine RN risk conferred by IT for specific primary tumor sites only, or combine multiple. Since primary site may influence RN risk, this propensity-score matched analysis provides evidence that IT increases RN incidence regardless of primary tumor site and other confounding variables, and represents over 4,000 patients across multiple HCOs. RN risk may vary by immunotherapy class, and more study is needed to characterize these differences.