Pretreatment Clinical Parameters Associated with Intracranial Progression Burden Following an Initial Stereotactic Radiosurgery Course in a Multi-Institutional Brain Metastases Cohort

Abstract

While brain metastasis (BM) velocity is a valuable prognostic metric at time of intracranial progression (ICP), pre-SRS risk factors for post-SRS high-burden intracranial progression (ICP) remain poorly characterized. We hypothesized that pre-SRS clinical parameters are associated with subsequent high-burden (ICP), defined as either ≥5 (ICP5) or new/progressive ≥11 BMs (ICP11). All patients completing an initial SRS course for BMs at two institutions from 1/2015-12/2020 were retrospectively identified. Patients with prior whole brain radiation therapy (WBRT) and/or BM resection were eligible. Demographic and clinical parameters were collected. ICP was defined as any radiographic concern for distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP were estimated via the Kaplan Meier method. Cox models assessed association between parameters and freedom from ICP5 and ICP11. We identified 1383 patients completed SRS, with a median follow up of 8.7 months. Patients were 54.8% female, 45.6% with KPS ≥90, and a median of 63.4 years old. Primary tumor types included non-small cell lung (48.7%), breast (14.7%), and melanoma (8.5%). 46.9% had oligometastatic disease (≤5 metastatic foci: including BMs) at SRS, and 53.4% underwent SRS for >1 BM. 10.3% of patients had undergone prior WBRT and 26.1% surgical resection. 555 patients (40.1%) experienced ICP following SRS, of whom 72.6% had 1-4, 11.5% had 5-10, and 15.9% had ≥11 new/progressive BMs. Among patients with ICP, 6-month freedom from ICP was 35.5% (95% CI: 31.1-40.5%) for those with 1-4 BMs at time of ICP, 29.7% (95% CI: 20.4-43.3%) for 5-10 BMs, and 20.5% (95% CI: 13.5-30.1%) for ≥11 BMs (p = 0.016). Respective 12-month OS rates were 56.8% (95% CI: 52.1-61.9%), 46.0% (95% CI: 35.1-60.1%), and 38.7% (95% CI: 29.4-50.9%; p<0.001). Neurologic symptoms at time of ICP were observed in 21.1% of patients with 1-4 BMs, 28.1% with 5-10 BMs, and 50.0% with new/progressive ≥11 BMs (p<0.001). On multivariable analysis, superior freedom from high-burden ICP was associated with the following pre-SRS parameters: oligometastatic burden (ICP5: HR 0.68, 95% CI: 0.47-0.99; ICP11: 0.59; 95% CI: 0.36-0.97), no prior immunotherapy (ICP11: HR 0.57, 95% CI: 0.34-0.57), and a single BM at time of initial SRS (1 vs 2 BM, ICP 5: HR 0.51, 95% CI: 0.31-0.82; ICP11: HR 0.45, 95% CI: 0.24-0.84), while primary tumor type was not associated with ICP5 or ICP11. Pre-SRS parameters including polymetastatic burden, prior receipt of immunotherapy, and >1 BM were associated with post-SRS high-burden ICP. High burden ICP developed earlier following SRS completion and was associated with higher rates of neurologic decline and inferior OS.