ImportanceClinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS).ObjectiveTo determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course.Design, Setting, and ParticipantsThis multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022.ExposuresNon-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus.Main Outcomes and MeasuresThe primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach.ResultsThis study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations.Conclusions and RelevanceThe results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.
To determine the prognostic significance of neurologic symptoms at progression for patients with brain metastases (BM) undergoing stereotactic radiosurgery (SRS), all patients completing an initial course of SRS between 1/2015 and 12/2020 were identified across two institutions. Intracranial progression (ICP) was recorded, with symptomatic ICP (SICP) defined as new/worsening neurologic symptoms without another etiology. Overall survival (OS), freedom from ICP (FFICP), and freedom from symptomatic ICP (FFSICP) were assessed via Kaplan-Meier method. For FFSICP, patients were censored at time of death or asymptomatic ICP. Logistic regression models tested parameter association to neurologic symptoms. Cox proportional hazard models tested parameters impacting FFICP and FFSICP. Among 1383 patients, median age was 63.4 years, 54.8% were female, and 45.6% had KPS ≥90. Common primary sites were non-small cell lung (48.7%), breast (14.7%), and melanoma (8.5%). 46.9% had oligometastatic disease (≤5 foci), and 53.4% had >1 BM. 26.1% patients had prior surgical resection, and 10.3% had WBRT. With a median follow up of 8.7 months, 504 (36%) and 194 (14%) experienced asymptomatic and symptomatic ICP respectively. OS was worse for patients experiencing SICP (median 10.2 vs 17.9 months, p<0.001). Among patients with ICP, SICP was associated with total treated tumor volume (per-ml, OR 1.01, 95% CI 1.00-1.02), while those with more recent MRI imaging and post-SRS systemic therapy was associated with asymptomatic ICP. Patients who received post-SRS chemotherapy (HR 0.64, 95% CI 0.45-0.90), immunotherapy (HR 0.49, 95% CI 0.34-0.71), or targeted therapy (HR 0.49, 95% CI 0.33-0.73) had better FFSCIP. Worse FFSCIP was associated with melanoma (HR 2.56, 95% CI 1.49-4.38), and greater than 2 BMs (HR 2.24, 95% CI 1.56-3.22). SICP is prognostic for OS, and is associated with melanoma, no systemic therapy post-SRS, and greater number of BMs. These data further support the use of SICP as a meaningful clinical endpoint.
2013 Background: 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). Methods: 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. Results: 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. Conclusions: 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.
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