Predictors of Adverse Radiation Effect in Brain Metastasis Patients Treated With Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy

Purpose Immune checkpoint inhibitor (ICI) therapy has recently been found to improve survival in patients with a number of cancers, including those with metastatic disease. There is an association of adverse radiation effect (ARE) in patients with brain metastases who have been treated with stereotactic radiosurgery (SRS) and ICIs. Methods and Materials Single-institution retrospective review identified 1118 brain metastases treated with SRS between 2013 and 2018 that had received ICI therapy and 886 metastases that did not receive ICI. Toxicity grading was done via the Common Terminology Criteria for Adverse Events v4.0 grading criteria. Cumulative incidence of ARE was estimated using competing risks methodology; univariate and multivariable regression models were generated to estimate the subdistribution hazard (sHR) of ARE. Results Two-year cumulative incidence of ARE was 4.5% and 2.1% in patients treated with and without ICI, respectively (Gray’s P = .004). Of the 52 metastases exhibiting ARE during the follow-up period, ARE severity by Common Terminology Criteria for Adverse Events v4 was grade 1 in 14 patients, grade 2 in 15, grade 3 in 9, and grade 4 in 14. There were no grade 5 events. Factors associated with an increased sHR of ARE on univariate analysis included ICI, metastasis volume, SRS dose, prescription isodose line, cavity-directed SRS, and V12. Multivariable analysis revealed prescription isodose line (sHR 0.95, P < .01) and ICI (sHR 2.58, P < .01) as significant predictors of ARE. Increasing V12 was associated with a rapidly increasing risk of adverse radiation effect in patients who received ICI. Conclusions Our findings suggest that patients receiving ICI have an increased risk of ARE after radiosurgery for brain metastases, with large metastases being at particularly high risk. Immune checkpoint inhibitor (ICI) therapy has recently been found to improve survival in patients with a number of cancers, including those with metastatic disease. There is an association of adverse radiation effect (ARE) in patients with brain metastases who have been treated with stereotactic radiosurgery (SRS) and ICIs. Single-institution retrospective review identified 1118 brain metastases treated with SRS between 2013 and 2018 that had received ICI therapy and 886 metastases that did not receive ICI. Toxicity grading was done via the Common Terminology Criteria for Adverse Events v4.0 grading criteria. Cumulative incidence of ARE was estimated using competing risks methodology; univariate and multivariable regression models were generated to estimate the subdistribution hazard (sHR) of ARE. Two-year cumulative incidence of ARE was 4.5% and 2.1% in patients treated with and without ICI, respectively (Gray’s P = .004). Of the 52 metastases exhibiting ARE during the follow-up period, ARE severity by Common Terminology Criteria for Adverse Events v4 was grade 1 in 14 patients, grade 2 in 15, grade 3 in 9, and grade 4 in 14. There were no grade 5 events. Factors associated with an increased sHR of ARE on univariate analysis included ICI, metastasis volume, SRS dose, prescription isodose line, cavity-directed SRS, and V12. Multivariable analysis revealed prescription isodose line (sHR 0.95, P < .01) and ICI (sHR 2.58, P < .01) as significant predictors of ARE. Increasing V12 was associated with a rapidly increasing risk of adverse radiation effect in patients who received ICI. Our findings suggest that patients receiving ICI have an increased risk of ARE after radiosurgery for brain metastases, with large metastases being at particularly high risk.