NCOG-03. PREDICTORS OF NEUROLOGIC DEATH IN PATIENTS WITH BRAIN METASTASES

BACKGROUND Neurologic death (ND), defined as intracranial disease progression with accompanying neurologic symptoms in the absence of life-threatening systemic disease, is the most serious consequence of intracranial disease among patients with brain metastases (BMs). Data indicating which factors are predictive of this outcome remain limited, however. Determining which patients are at increased risk of ND will guide improved care and further research aimed at preventing ND. METHODS We identified 1,218 patients with newly diagnosed BMs managed at Brigham and Women’s Hospital from 2008-2015. Demographic and tumor characteristics for patients experiencing ND, non-neurologic death, and who were alive at last follow up were analyzed by univariable and multivariable Fine and Gray competing risks regression to identify predictors of ND, with non-neurologic death serving as a competing risk. RESULTS In multivariable analysis, ND was associated with number of BMs (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% CI 1.01-1.02, p< 0.001) and three primary tumor sites (with non-small cell lung cancer as the reference): melanoma (HR 4.67, 95% CI 3.27-6.68, p< 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47-3.68, p< 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28-3.82, p=0.005). Additionally, among patients with breast primaries, HER2+ tumors displayed increased risk of ND relative to the reference subtype (HR+/HER2-) in univariable analysis (HR 2.41, 95% CI 1.00-5.84, p=0.05). A reduced risk of ND was found in patients with Karnofsky performance status of 90-100 versus 30-80 (HR 0.67, 95% CI 0.48-0.95, p=0.03) and progressive extracranial disease (HR 0.50, 95% CI 0.38-0.67, p< 0.001). CONCLUSION Patients with melanoma, small cell lung cancer, gastrointestinal, and HER2+ breast cancer primaries, in addition to those with greater intracranial versus extracranial disease burdens, are at increased risk of ND. Future research into novel intracranial approaches should focus on these groups of patients.

Anaesthetic management of a patient undergoing magnetic resonance imaging with suspected intracranial disease

Seizing patients with suspected intracranial disease are relatively common within the veterinary profession. Veterinary nurses will be familiar with some of the most common challenges these patients present while hospitalised, however to determine the cause and severity of disease, general anaesthesia is often required. This article will discuss some of the specific considerations during the peri-anaesthetic period of a seizing patient undergoing magnetic resonance imaging, including recommendations for future practice.

Paediatric primary cough headache with internal jugular phlebectasia

Primary cough headaches (PCHs) are mainly observed in people aged >40 years, but cough-induced headaches are potentially symptomatic in children. We report a case of a child diagnosed with PCH without an intracranial disease. A 7-year-old boy presented with cough due to pertussis and powerful cough-induced headaches. No brain abnormalities were detected, but the right side of his neck was observed to swell. Echo examination confirmed right internal jugular vein dilatation during a Valsalva manoeuvre, and the patient was diagnosed with PCH with internal jugular phlebectasia. PCHs are normally reported in adults, but they can also occur in children. PCHs and internal jugular vein abnormalities may be related. Thus, tests assessing internal jugular vein morphology and function should be considered for PCH cases.

Emergency department visits and inpatient hospitalizations among older patients with brain metastases: A dual population- and institution-level analysis

Background Older patients with brain metastases (BrM) commonly experience symptoms that prompt acute medical evaluation. We characterized emergency department (ED) visits and inpatient hospitalizations in this population. Methods We identified 17,789 and 361 Medicare enrollees diagnosed with BrM using the Surveillance, Epidemiology, and End Results-Medicare database (2010-2016) and an institutional database (2007-2016), respectively. Predictors of ED visits and hospitalizations were assessed using Poisson regression. Results The institutional cohort averaged 3.3 ED visits/1.9 hospitalizations per person-year, with intracranial disease being the most common reason for presentation/admission. SEER-Medicare patients averaged 2.8 ED visits/2.0 hospitalizations per person-year. For patients with synchronous BrM (N=7,834), adjusted risk factors for ED utilization and hospitalization, respectively, included: male sex (rate ratio [RR]=1.15 [95% CI=1.09-1.22], p<0.001; RR=1.21 [95% CI=1.13-1.29], p<0.001); African American vs. white race (RR=1.30 [95% CI=1.18-1.42], p<0.001; RR=1.25 [95% CI=1.13-1.39], p<0.001); unmarried status (RR=1.07 [95% CI=1.01-1.14], p=0.02; RR=1.09 [95% CI=1.02-1.17], p=0.01); Charlson co-morbidity score >2 (RR=1.27 [95% CI=1.17-1.37], p<0.001; RR=1.36 [95% CI=1.24-1.49], p<0.001); and receipt of non-stereotactic vs. stereotactic radiation (RR=1.44 [95% CI=1.34-1.55, p<0.001; RR=1.49 [95% CI=1.37-1.62, p<0.001). For patients with metachronous BrM (N=9,955), ED visits and hospitalizations were more common after vs. before BrM diagnosis (2.6 vs. 1.2 ED visits per person-year; 1.8 vs. 0.9 hospitalizations per person-year, respectively; RR=2.24 [95% CI=2.15-2.33], p<0.001; RR=2.06 [95% CI=1.98-2.15], p<0.001, respectively). Conclusions Older patients with BrM commonly receive hospital-level care secondary to intracranial disease, especially in select subpopulations. Enhanced care coordination, closer outpatient follow-up, and patient navigator programs seem warranted for this population.

Clinical outcomes in patients (pts) with a history of central nervous system (CNS) metastases receiving talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 EMBRACA trial.

1090 Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase (PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR [95% CI] 0.54 [0.41-0.71]; P < 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR [95% CI] 0.32 [0.15-0.68]; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio [95% CI] 8.95 [1.86-52.26]; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 [15.0%] TALA and 20/144 [13.9%] PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio [95% CI] 0.78 [0.13-5.80]; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR [95% CI] 0.67 [0.37-1.2]; P = 0.1936 [stratified log-rank test]). In the safety population ([n = 43, TALA]; [n = 19, PCT]), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .[Table: see text]

Validation of the Updated Renal Graded Prognostic Assessment (GPA) for patients with renal cancer brain metastases treated with Gamma Knife radiosurgery

Introduction: Prognosis of patients with brain metastasis (BM) from renal cell carcinoma (RCC) is relevant for treatment decisions and can be estimated with the Renal Graded Prognostic Assessment (GPA). The aim of this study is to validate the updated version of this instrument in a cohort treated with Gamma Knife radiosurgery (GKRS) without prior local intracerebral therapy. Methods: Between 2007 and 2018, 100 RCC patients with BM were treated with GKRS. They were categorized according to the updated Renal GPA. Overall survival (OS), intracranial disease progression and intracranial local failure were estimated using the Kaplan-Meier method and risk factors were identified with Cox proportional hazard regressions. Results: Median OS was 10.4 months. Median OS for GPA categories 0.0-1.0 (10%), 1.5-2.0 (13%), 2.5-3.0 (37%) and 3.5-4.0 (31%) was 2.9, 5.5, 8.1 and 20.4 months, respectively. Karnofsky performance status <90, serum hemoglobin ≤12.5 g/dL, age >65 years and time from primary diagnosis to brain metastasis <1 year were significantly related with shorter survival, while presence of extracranial disease, the volume and total number of BM had no impact on OS. A total count of >4 BM was the only predictive factor for intracranial disease progression, while none of the investigated factors predicted intracranial local failure. Conclusions: This study confirms the updated Renal GPA in an independent cohort as a valuable instrument to estimate survival in patients with BM from RCC treated with GKRS.

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab

Background: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. Methods: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). Results: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%. Conclusion: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

13. MANAGEMENT OF BRAIN METASTASES FROM SMALL CELL LUNG CANCER USING SRS

PURPOSE/OBJECTIVE(S) The management of brain metastases in patients with SCLC has become controversial in the MRI era. We examine our institutional experience treating patients with SCLC with stereotactic radiosurgery. We hypothesize that an SRS strategy in well-selected patients with close MRI surveillance will result in acceptable tumor control, and without disproportionate future neurological symptoms associated with intracranial disease. MATERIALS/METHODS Patients with a diagnosis of high grade neuroendocrine lung cancer who had undergone SRS between 2013 and 2019 were identified and divided into two groups: SRS-primary and SRS-salvage. SRS-primary was defined as patients who, at time of SRS, had not received previous PCI or WBRT. SRS-salvage was defined as patients who had received previous PCI or WBRT. Primary outcome was intracranial progression free survival. Secondary outcomes included overall survival and neurologic symptom free survival (N-SFS), defined as time to development of neurologic symptoms attributed disease. RESULTS Twenty patients were identified with median follow-up of 14.1 months. 11 patients were identified as SRS-primary, 9 as SRS-salvage. Among SRS-primary, median PFS and OS were 6.1 months (range 0.9 – 14.5 months) and 15.6 months (4.1–43.5) respectively. N-SFS was 11.2 months (range 3.6–40.0). 3 of 11 patients developed neurological symptoms attributable to disease. 3 underwent salvage SRS and 2 salvage WBRT. None died from intracranial disease. Among SRS-salvage, median PFS following PCI/WBRT was 9.8 months (range 1.8 – 23.6 months) and OS following salvage SRS 5.5 months (range 1.1 – 27.8 months). 3 of 9 patients developed further brain metastases post-SRS. 1 patient died from intracranial disease. CONCLUSION Among well-selected patients followed with MRI surveillance, our data suggest SRS as primary management of brain metastases from SCLC may be reasonable. Symptomatic intracranial disease was uncommon after SRS, and no patients undergoing upfront SRS died from intracranial disease. Prospective data are required to validate these results.