Contributions of previous whole-brain radiation therapy, cumulative intracranial tumor volume, and repeat radiosurgery to adverse radiation effects following stereotactic radiosurgery for brain metastasis.

FLAIR hyperintensity extending beyond a cerebral quadrant (FEQ+) after stereotactic radiosurgery (SRS) for brain metastases (BM) was a recently established imaging biomarker for steroid-dependent adverse radiation effects (ARE). In this study, we investigated the clinical and treatment‑related variables associated with the development of FEQ + ARE following SRS. Exploratory analyses were conducted in an initial cohort of 214 consecutively treated patients with 1,106 SRS‑treated brain metastases and subsequently validated in an independent cohort of 149 consecutively treated patients comprising 708 SRS‑treated lesions from a second institution. In the discovery cohort, 62 of 214 patients (29%) developed FEQ + ARE after SRS. On univariate analysis, the likelihood of FEQ + ARE increased with prior whole-brain radiation therapy (pWBRT; OR 4.97, p < 0.001), cumulative intracranial tumor volume (CITV; OR 1.02, p = 0.018), and the number of repeat SRS courses (OR 1.32, p = 0.049). These associations remained robust in multivariate modeling adjusted for follow-up duration. Variance analysis indicated that pWBRT accounted for the largest share of risk. These findings were confirmed in an independent cohort of 149 patients using a pre-specified multivariate model. In this validation cohort, 56 patients (38%) developed FEQ + ARE after SRS. The odds of FEQ + ARE were 22.2 (p = 0.006), 1.18 (p = 0.007), and 2.04 (p = 0.045) for pWBRT, CITV, and repeat SRS, respectively. Variance analysis again showed that pWBRT accounted for the largest share of FEQ + ARE risk. Across two institutional cohorts of consecutively treated patients with > 1,800 SRS-treated BM, prior WBRT, repeat radiosurgery, and higher cumulative intracranial tumor volume were consistently associated with the development FEQ + ARE.