Clinical Factors Associated With 30-Day Mortality Among Patients Undergoing Radiation Therapy for Brain Metastases.

Purpose: Existing brain metastasis prognostic models do not identify patients at risk of very poor survival after radiation therapy (RT). Identifying patient and disease risk factors for 30-day mortality (30-DM) after RT may help identify patients who would not benefit from RT. Methods and Materials: All patients who received stereotactic radiosurgery (SRS) or whole-brain RT (WBRT) for brain metastases from January 1, 2017, to September 30, 2020, at a single tertiary care center were included. Variables regarding demographics, systemic and intracranial disease characteristics, symptoms, RT, palliative care, and death were recorded. Thirty-day mortality was defined as death within 30 days of RT completion. The Kaplan-Meier method was used to estimate median overall survival. Univariate and multivariable logistic regression models were used to assess associations between demographic, tumor, and treatment factors and 30-DM. Results: A total of 636 patients with brain metastases were treated with either WBRT (n = 117) or SRS (n = 519). The most common primary disease types were non-small cell lung (46.7%) and breast (19.8%) cancer. Median survival time was 6 months (95% CI, 5-7 months). Of the 636 patients, 75 (11.7%) died within 30 days of RT. On multivariable analysis, progressive intrathoracic disease (hazard ratio [HR], 4.67; 95% CI, 2.06-10.60; P = .002), progressive liver and/or adrenal metastases (HR, 2.20; 95% CI, 1.16-3.68; P = .02), and inpatient status (HR, 4.51; 95% CI, 1.78-11.42; P = .002) were associated with dying within 30 days of RT. A higher Karnofsky Performance Status (KPS) score (HR, 0.95; 95% CI, 0.93-0.97; P < .001), synchronous brain metastases at time of initial diagnosis (HR, 0.45; 95% CI, 0.21-0.96; P = .04), and outpatient palliative care utilization (HR, 0.45; 95% CI, 0.20-1.00; P = .05) were associated with surviving more than 30 days after RT. Conclusions: Multiple factors including a lower KPS, progressive intrathoracic disease, progressive liver and/or adrenal metastases, and inpatient status were associated with 30-DM after RT. A higher KPS, brain metastases at initial diagnosis, and outpatient palliative care utilization were associated with survival beyond 30 days. These data may aid in identifying which patients may benefit from brain metastasis-directed RT.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases.

Importance: Clinical 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). Objective: To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. Design, Setting, and Participants: This 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. Exposures: Non-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 Measures: The 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. Results: This 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 Relevance: The 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.

Systemic Therapy Type and Timing Effects on Radiation Necrosis Risk in HER2+ Breast Cancer Brain Metastases Patients Treated With Stereotactic Radiosurgery.

Background: There is a concern that HER2-directed systemic therapies, when administered concurrently with stereotactic radiosurgery (SRS), may increase the risk of radiation necrosis (RN). This study explores the impact of timing and type of systemic therapies on the development of RN in patients treated with SRS for HER2+ breast cancer brain metastasis (BCBrM). Methods: This was a single-institution, retrospective study including patients >18 years of age with HER2+ BCBrM who received SRS between 2013 and 2018 and with at least 12-month post-SRS follow-up. Presence of RN was determined via imaging at one-year post-SRS, with confirmation by biopsy in some patients. Demographics, radiotherapy parameters, and timing ("during" defined as four weeks pre- to four weeks post-SRS) and type of systemic therapy (e.g., chemotherapy, HER2-directed) were evaluated. Results: Among 46 patients with HER2+ BCBrM who received SRS, 28 (60.9%) developed RN and 18 (39.1%) did not based on imaging criteria. Of the 11 patients who underwent biopsy, 10/10 (100%) who were diagnosed with RN on imaging were confirmed to be RN positive on biopsy and 1/1 (100%) who was not diagnosed with RN was confirmed to be RN negative on biopsy. Age (mean 53.3 vs 50.4 years, respectively), radiotherapy parameters (including total dose, fractionation, CTV and size target volume, all p>0.05), and receipt of any type of systemic therapy during SRS (60.7% vs 55.6%, p=0.97) did not differ between patients who did or did not develop RN. However, there was a trend for patients who developed RN to have received more than one agent of HER2-directed therapy independent of SRS timing compared to those who did not develop RN (75.0% vs 44.4%, p=0.08). Moreover, a significantly higher proportion of those who developed RN received more than one agent of HER2-directed therapy during SRS treatment compared to those who did not develop RN (35.7% vs 5.6%, p=0.047). Conclusions: Patients with HER2 BCBrM who receive multiple HER2-directed therapies during SRS for BCBrM may be at higher risk of RN. Collectively, these data suggest that, in the eight-week window around SRS administration, if HER2-directed therapy is medically necessary, it is preferable that patients receive a single agent.

Prognostic Model for Intracranial Progression after Stereotactic Radiosurgery: A Multicenter Validation Study.

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan−Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1−11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1−17.1 months) and 7.6 months (95% CI 6.4−9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Application of TG-218 action limits to SRS and SBRT pre-treatment patient specific QA.

AAPM TG-218 provides recommendations for standard IMRT pre-treatment QA without giving specifics for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). In light of this, our purpose is to report our experience with applying TG-218 recommendations to a large multicenter clinical SRS and SBRT program for a range of diverse clinical pre-treatment QA systems. Pre-treatment QA systems included Delta4 (Scandidos), Portal Dosimetry (Varian Medical Systems), ArcCHECK (SunNuclear), and SRS MapCHECK (SunNuclear). Plans were stratified by technique for each QA system, and included intracranial and extracranial IMRT and VMAT (total QA cases n=275). Gamma analysis was re-analyzed with spatial/dose criteria combinations ranging from 1 to 3 mm and 1% to 4%, and action and tolerance limits were calculated per plan type and compared to the "universal" TG-218 action limit of 90%. The analysis indicated that spatial tolerance criteria could be tightened to 1 mm while still maintaining an in-control QA process for all QA systems evaluated.

Comprehensive radiation and imaging isocenter verification using NIPAM kV-CBCT dosimetry.

PURPOSE: To develop and demonstrate a comprehensive method to directly measure radiation isocenter uncertainty and coincidence with the cone-beam computed tomography (kV-CBCT) imaging coordinate system that can be carried out within a typical quality assurance (QA) time slot. METHODS: An N-isopropylacrylamide (NIPAM) three-dimensional (3D) dosimeter for which dose is observed as increased electron density in kV-CBCT is irradiated at eight couch/gantry combinations which enter the dosimeter at unique orientations. One to three CBCTs are immediately acquired, radiation profile is detected per beam, and displacement from imaging isocenter is quantified. We performed this test using a 5 mm diameter MLC field, and 7.5 and 4 mm diameter cones, delivering approximately 16 Gy per beam. CBCT settings were 1035-4050 mAs, 80-125 kVs, smooth filter, 1 mm slice thickness. The two-dimensional (2D) displacement of each beam from the imaging isocenter was measured within the planning system, and Matlab code developed in house was used to quantify relevant parameters based on the actual beam geometry. Detectability of the dose profile in the CBCT was quantified as the contrast-to-noise ratio (CNR) of the irradiated high-dose regions relative to the surrounding background signal. Our results were compared to results determined by the traditional Winston-Lutz test, film-based "star shots," and the vendor provided machine performance check (MPC). The ability to detect alignment errors was demonstrated by repeating the test after applying a 0.5 mm shift to the MLCs in the direction of leaf travel. In addition to radiation isocenter and coincidence with CBCT origin, the analysis also calculated the actual gantry and couch angles per beam. RESULTS: Setup, MV irradiation, and CBCT readout were carried out within 38 min. After subtracting the background signal from the pre-CBCT, the CNR of the dosimeter signal from the irradiation with the MLCs (125 kVp, 1035 mAs, n = 3), 7.5 mm cone (125 kVp, 1035 mAs, n = 3), and 4 mm cone (80 kVp, 4050 mAs, n = 1) was 5.4, 5.9, and 2.9, respectively. The minimum radius that encompassed all beams calculated using the automated analysis was 0.38, 0.48, and 0.44 mm for the MLCs, 7.5 mm cone, and 4 mm cone, respectively. When determined manually, these values were slightly decreased at 0.28, 0.41, and 0.40 mm. For comparison, traditional Winston-Lutz test with MLCs and MPC measured the 3D isocenter radius to be 0.24 mm. Lastly, when a 0.5 mm shift to the MLCs was applied, the smallest radius that intersected all beams increased from 0.38 to 0.90 mm. The mean difference from expected value for gantry angle was 0.19 ± 0.29°, 0.17 ± 0.23°, and 0.12 ± 0.14° for the MLCs, 7.5 mm cone, and 4 mm cone, respectively. The mean difference from expected for couch angle was -0.07 ± 0.28°, -0.08 ± 0.66°, and 0.04 ± 0.25°. CONCLUSIONS: This work demonstrated the feasibility of a comprehensive isocenter verification using a NIPAM dosimeter with sub-mm accuracy which incorporates evaluation of coincidence with imaging coordinate system, and may be applicable to all SRS cones as well as MLCs.