Scott Floyd

PURPOSE: Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Prophylactic antiepileptic drugs are no longer routinely used in current SRS practice, owing to a perceived low overall frequency of new-onset seizures and potential side effects of medications. It is nonetheless desirable to prevent unwanted side effects following SRS. Risk factors for new-onset seizures after SRS have not been well established. As such, we aimed to characterize variables associated with increased seizure risk. METHODS AND MATERIALS: Patients treated with SRS for newly diagnosed brain metastases between 2013 and 2016 were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected. RESULTS: The cohort consisted of 305 patients treated with SRS without prior seizure history. Median age and baseline Karnofsky Performance Scale score were 64 years (interquartile range, 55-70) and 80 (interquartile range, 80-90), respectively. Twenty-six (8.5%) patients developed new-onset seizures within 3 months of SRS. There was no association between new-onset seizures and median baseline Karnofsky Performance Scale score, prior resection, or prior whole brain radiation therapy. There were significant differences in the combined total irradiated volume (12.5 vs 3.7 cm3, P < .001), maximum single lesion volume (8.8 vs 2.8 cm3, P = .003), lesion diameter (3.2 vs 2.0 cm, P = .003), and number of lesions treated (3 vs 1, P = .018) between patients with and without new-onset seizures, respectively. On multivariate logistic regression, total irradiated volume (odds ratio, 1.09 for every 1-cm1 increase in total volume; confidence interval, 1.02-1.17; P = .016) and pre-SRS neurologic symptoms (odds ratio, 3.08; 95% confidence interval, 1.19-7.99; P = .020) were both significantly correlated with odds of seizures following SRS. CONCLUSIONS: Our data suggest that larger total treatment volume and the presence of focal neurologic deficits at presentation are associated with new-onset seizures within 3 months of SRS. High-risk patients undergoing SRS may benefit from counseling or prophylactic antiseizure therapy.

PURPOSE: Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. METHODS: A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). RESULTS: In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). CONCLUSION: OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

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 &lt; 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.

Purpose. This work introduces and evaluates a method for accurate in-vitro measurement of fluorescent cell burden in complex 3D-culture conditions.Methods.The Fluorescent Cell Burden (FCB) method was developed to analyze the burden of 4T1 mCherry-expressing cells grown in an organotypic co-culture model of brain metastasis using 400μm rat brain slices. As a first step, representative simulated image-data accurately reflecting the 4T1 experimental data, but with known ground truth burden, were created. The FCB method was then developed in the CellProfiler software to measure the integrated intensity and area of the colonies in the simulated image data. Parameters in the pipeline were varied to span the experimentally observed range (e.g. of cell colony size) and the result compared with simulation ground truth to evaluate and optimize FCB performance. The optimized CellProfiler pipeline was then applied to the original 4T1 tumor cell images to determine colony growth with time, and re-applied with upper and lower bound parameters to determine uncertainty estimates.Results.The FCB method measured integrated intensity across 10 simulated images with an accuracy of 99.23% ± 0.75%. When colony density was increased by increasing colony number to 450, 600, and 750, the FCB measurement was 98.68%, 100.9%, 97.6% and 113.5% of the true value respectively. For the increasing number of cells plated on the rat brain slices, the integrated intensity increased nearly linearly with cell count except for at high cell counts, where it is hypothesized that shadowing from clumped cells causes a sub-linear relationship.Conclusion. The FCB method accurately measured an integrated fluorescent light intensity to within 5% of ground truth for a wide range of simulated image data spanning the range of observed variability in experimental data. The method is readily customizable to in-vitro studies requiring estimation of fluorescent tumor cell burden.

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.