Intracranial Progression Research Articles

Are oral anticoagulants a risk factor for mild traumatic brain injury progression? A single-center experience focused on of direct oral anticoagulants and vitamin K antagonists.

Mild traumatic brain injury (TBI) in anticoagulated patients is a common challenge for emergency departments because of lack of appropriate epidemiological data and huge management variability for those under oral anticoagulation therapy. Given the discrepancies between guidelines, the aim of the present study was to quantify the association between oral anticoagulant therapy (either vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC)) and the post-traumatic intracranial hemorrhage worsening compared to admission CT scan. We included all consecutive records of patients admitted to our emergency department for mild TBI as chief complaint and with a positive admission CT scan. After statistical univariate comparison, cause-specific hazard ratio (HR) and 95% confidence interval (CI) were determined with the use of Cox proportional hazard model. In the study period, 4667 patients had a CT scan for mild TBI; 439 (9.4%) were found to have intracranial hemorrhage. Among these patients, 299 (68.1%) were prescribed observation and control CT: 46 (15.38%) were on anticoagulant therapy, 23 (50%) on VKA, and 23 (50%) on DOAC. In multivariate analysis, only oral anticoagulation therapy was significantly associated to an increased risk of intracranial hemorrhage progression (HR 2.58; 95% CI 1.411-4.703; p = .002 and HR 1.9; 95% CI 1.004-3.735; p = .0048 for VKA and DOAC, respectively). Surgery was due to isolated subdural hematoma in 87.5% of cases, to subdural hematoma associated with intraparenchymal hemorrhage in 9.38% and to intraparenchymal hemorrhage only in 3.12%; 13 cases (4.35%) deceased in intensive care unit. In our series, anticoagulation was associated to a significant increase in intracranial progression, leaving the question open as to what this implies in current clinical practice; subdural hematoma was the major finding associated to evolution and surgery. Against this background, further studies are needed to clarify patients' management and DOAC safety profile compared to VKA in mild TBI.

Progression of Intracranial Hemorrhage After Chemical Prophylaxis Using Low-Molecular-Weight Heparin in Patients With Traumatic Brain Injury.

Chemical prophylaxis using low-molecular-weight heparin (LMWH) is considered a standard of care for venous thromboembolism in trauma patients. Our center performs a head computed tomography (CT) scan 24 hours after initiation with prophylactic LMWH in the setting of a known traumatic brain injury (TBI). The purpose was to determine the overall incidence of ICH progression after chemoprophylaxis in patients with a TBI. This retrospective study was performed at a Level I trauma center, from 1/1/2014 to 12/31/2017. Study patients were drawn from the institution's trauma registry based on Abbreviated Injury Score codes. 778 patients met all inclusion criteria after initial chart review. The proportion of patients with an observed radiographic progression of intracranial hemorrhage after LMWH was 5.8%. 3.1% of patients had a change in clinical management. Observed radiographic progression after LMWH prophylaxis and the presence of SDH on initial CT, the bilateral absence of pupillary response in the emergency department, and a diagnosis of dementia were found to have statistically significant correlation with bleed progression after LMWH was initiated. Over a 4-year period, the use of CT to evaluate for radiographic progression of traumatic intracranial hemorrhage 24 hours after receiving LMWH resulted in a change in clinical management for 3.1% of patients. The odds of intracranial hemorrhage progression were approximately 6.5× greater in patients with subdural hemorrhage on initial CT, 3.1× greater in patients with lack of bilateral pupillary response in ED, and 4.2× greater in patients who had been diagnosed with dementia.

EXTH-36. ELECTROCONVULSIVE SEIZURE-INDUCED CHANGES IN THE TUMOR MICROENVIRONMENT PROMOTE SURVIVAL IN GLIOMA-BEARING MICE

Abstract PURPOSE Growing evidence indicates that the neurotransmitters dysregulated in psychiatric disorders are similarly dysregulated in glioblastoma (GBM) biology. GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to augment progression, and catabolize serotonin to drive proliferation and inhibit anti-tumor immunity. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to correct these dysregulations and can additionally improve medication blood-brain barrier (BBB) penetrance. We hypothesized that seizure-induced changes in the glioma microenvironment occur with ECT, slowing tumor progression, increasing BBB permeability, and prolonging overall survival in glioma-bearing mice. METHODS C57BL6 mice were orthotopically injected with CT-2A-Luc mouse glioma cells. Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week. Intracranial progression was monitored via bioluminescent signal from CT-2A-Luc xenografts. BBB permeability was assessed by subjecting mice to ECT or sham treatment immediately following intravenous injection of sodium fluorescein. RESULTS Intracranial progression was maximally reduced in ECT-treated mice relative to sham-treated mice after 17 ECT treatments (ECT radiance 2.6 x 109 photons/second versus sham 4.7 x 109 photons/second, p=0.013), which was further confirmed by both decreased tumor weight and tumor size on histologic evaluation. This translated into an improvement in overall survival from median 29 days in sham-treated mice to 38 days in ECT-treated mice (p=0.0018). Mean seizure duration was 41.8 seconds and positively correlated with overall survival (Pearson coefficient r=0.63, p=0.028). Brain parenchymal uptake of sodium fluorescein was significantly higher in ECT-treated mice (mean relative increase in ECS to sham radiance of 1.47, p< 0.05). CONCLUSION Repeated ECT slows tumor progression and prolongs overall survival in C57BL6 mice bearing CT-2A-Luc xenografts. The BBB is compromised immediately following ECT. ECT merits further oncologic investigation as a potential therapeutic in GBM.

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

Abstract 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.

DDRE-04. EFFECTIVENESS AND SAFETY OF OSIMERTINIB FOR PATIENTS WITH LEPTOMENINGEAL METASTASES FORM NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND the FLAURA study established Osimertinib to be the priority choice for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring mutated epidermal growth factor receptor (EGFR). However, like many previous studies, the FLAURA study excluded patients with symptomatic CNS metastases. Hence, we performed a systematic review and meta-analyses of studies to assess the efficiency and safety of Osimertinib for the treatment of NSCLC with leptomeningeal metastases (LM). METHODS We included studies published between 2010 and 2021 that evaluated the efficacy and toxicity of Osimertinib in NSCLC patients with LM. We searched PubMed, Embase, and oncology meeting abstracts (ASCO, ESMO and WCLC). Primary outcomes were objective response rate (ORR), disease control rate (DCR), any grade 3/4 toxicity rate. We used the random-effects model to generate pooled estimates for proportions. Newcastle-Ottawa Scale (NOS) was used to assess the certainty in the evidence. RESULTS Twelve studies reporting on 367 patients were included in the meta-analysis. Most patients (≥90%) received Osimertinib as at least second line of treatment. The objective response rate was 42% (95% CI, 24%-59%; n = 184), and CNS disease control rate was 90% (95% CI, 85%-94%; n = 154). Intracranial progression free survival and overall survival ranged from 3.7 to 15.6 months, and 11.0 to 18.8 months, respectively. Adverse events were similar with previous studies and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates was acceptable. CONCLUSION This meta-analysis confirmed that for advanced NSCLC with LM harboring EGFR-TKI-sensitizing mutations, Osimertinib showed impressive antitumor activity and acceptable toxicity.

Pre-injury chronic alcohol abuse predicts intracranial hemorrhagic progression, unfavorable clinical outcome, and mortality in severe traumatic brain injury

ABSTRACT Objective We aimed to determine the incidence of pre-injury alcohol abuse in TBI at our neurointensive care unit (NICU), the relation to intracranial hemorrhage evolution, and clinical outcome. Methods Patients with TBI treated at our NICU at Uppsala university hospital, Sweden, 2008–2018, were included. Clinical, radiological, and outcome variables were evaluated. Results Of 844 patients with TBI, 147 (17%) had a history of pre-injury alcohol abuse and these patients were slightly older, but had a similar Charlson co-morbidity index as the other patients. They were more often injured by falls and more frequently developed acute subdural hematomas and cerebral contusions. Their platelets were lower and their IVY bleeding time slightly longer. Patients with pre-injury alcohol abuse more often exhibited an intracranial hemorrhage progression on the second computed tomography. Pre-injury alcohol abuse was an independent predictor of increased mortality (odds ratio = 2.96, p-value = 0.001) and decreased favorable outcome (odds ratio = 0.46, p-value = 0.001) in multiple regression analyses. Conclusions Pre-injury alcohol abuse was common in severe TBI, associated with coagulopathy, worse intracranial hemorrhage/injury evolution, and independently predicted poor clinical outcome. These patients deserve more attention in care and research to address specific challenges including disturbed hemostasis.

The Optimal Sequence of Intracranial Radiotherapy Compared to Systematic TKI for Brain Metastases in Targeted Treatment Era

The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity.Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis.Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P<0.001), but no longer median time to OS (35.6 vs. 41.5 months, P = 0.383) and BMSS (66.2 vs. 58.0 months, P = 0.746) after the salvage therapy. RT alone group showed similar IPFS (18.0 months; 95% CI 14.1-22.0 months; P = 0.686) and a trend of lower OS (19.9 months; 95% CI, 17.6 - 22.3 months; P = 0.010), BMSS (44.8 months; 95% CI 30.7 - 58.9 months; P = 0.002) than upfront RT group. Treatment-related grade 3-4 adverse events were rare, and similar hematological toxicities, liver and renal dysfunctions were observed among different groups.Compared to upfront TKI group, upfront RT group got longer median IPFS time in BM patients but no significant OS or BMSS benefit with similar well-tolerated toxicities. TKI group had better OS and BMSS than RT alone group. The best timing of intracranial RT remains to be further verified.S. Yang: None. J. Xiao: None. H. Zhang: None. Q. Liu: None. Y. Zhang: None. X. Chen: None. K. Wang: None. X. Huang: None. Y. Ma: None. R. Zhao: None. N. Bi: None. J. YI: None. S. Wang: None. Y. LI: None.

Characterizing Seizure-Induced Changes in the Glioma Microenvironment

Growing evidence indicates that the neurotransmitters dysregulated in psychiatric disorders are similarly dysregulated in glioblastoma (GBM) biology. Patients with psychiatric disorders are classically thought of having excessive glutamate (major depression, bipolar depression), excessive dopamine (mania, psychosis), and/or insufficient serotonin (major depression, anxiety). Analogously, GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to activate the hypoxic response and augment progression, and catabolize serotonin to drive proliferation. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to treat severe cases of depression, mania, psychosis, and catatonia. ECT has been shown to decrease extracellular glutamate and glutamate receptor expression in vivo and increase blood-brain barrier (BBB) permeability. ECT, then, may have previously unexplored oncologic value. We hypothesized that seizure-induced changes in the glioma microenvironment occur with ECT, increasing permeability of the BBB, slowing tumor progression, and prolonging overall survival in glioma-bearing mice.C57BL6 mice were orthotopically injected with CT-2A-Luc mouse glioma cells. Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week until survival endpoints were reached. Seizure duration and rates of tonic hindlimb extension were recorded. Intracranial progression was monitored via bioluminescent signal from CT-2A-Luc xenografts. BBB permeability was assessed by subjecting mice to ECT or sham treatment immediately following tail vein injection of sodium fluorescein. Mice were saline perfused and brains were harvested for fluorescent spectroscopy.Intracranial progression was maximally reduced in ECT-treated mice relative to sham-treated mice after 17 treatments (mean sham radiance 4.7 × 109 photons/s versus mean ECT radiance 2.6 × 109 photon/s, P = 0.013). This translated into an improvement in overall survival from median 29 days in sham-treated mice to 34.5 days in ECT-treated mice (P = 0.0018). Mean seizure duration was 41.8 seconds and positively correlated with overall survival (Pearson coefficient r = 0.63, P = 0.028). Tonic hindlimb extension occurred in 68% of seizures and positively correlated with overall survival (Pearson coefficient r = 0.72, P = 0.0078). Brain parenchymal uptake of sodium fluorescein was significantly higher in ECT-treated mice, with a mean relative increase in ECS to sham radiance of 1.47 (P < 0.05).Repeated ECT slows tumor progression and prolongs overall survival in C57BL6 mice bearing CT-2A-Luc xenografts. The BBB is compromised immediately following ECT. ECT merits further oncologic investigation as a potential therapeutic in GBM.T. Sita: None. L. Hurley: None. C. Dussold: None. S. Sachdev: None. R. Stupp: Research Grant; CarThera, Paris. Consultant/ad hoc advisor for research protocol development; GT Medical Technologies, Insightec; Northwest Biotherapeutics. Scientific Advisory Board; CranioVation, TriAct, Hemispherian. IDMC of an ongoing clinical trial; Celularity. A. Stegh: None.

Anlotinib in Combination With Whole Brain Radiotherapy for Advanced Non-Small-Cell Lung Cancer With Brain Metastases Progressive or Developed After at Least One Lines of Prior Treatment

Intracranial metastasis failed to standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. Post Hoc analysis of a phase III randomized control trial (ALTER0303) has demonstrated that anlotinib can benefit patients with advanced NSCLC with brain metastases (BM) and is highly potent in the management of intracranial lesions. Here we report results of a comparative analysis of survival in patients with NSCLC with BM receiving whole brain radiotherapy (WBRT) with and without anlotinib, for whom intracranial disease had progressed or developed after at least one lines of prior systematic therapy.From 2019 to 2020, a total of 96 patients of NSCLC in our institution with BM failed to at least one lines of systematic treatment met inclusion criteria for the study. Patients were treated with concurrent anlotinib and WBRT followed by anlotinib consolidation (an-WBRT group) or WBRT with other regimens at the discretion of the treating physician (WBRT group) at intracranial progression. Overall survival (OS) and intracranial progression-free survival (iPFS) were measured from the date of brain progression.The median lines of prior therapy are both 2 for an-WBRT and WBRT groups. The median OS for the an-WBRT (n = 26) and WBRT (n = 70) cohorts was 12.8 and 14.3 months, respectively (P = 0.82). The an-WBRT group has a longer iPFS than WBRT group (HR, 0.33; 95% CI, 0.21-0.65), with median iPFS of 8.1 months and 4.0 months respectively.This retrospective analysis demonstrated that the combination of anlotinib and WBRT is associated with better iPFS than WBRT in NSCLC patients with intracranial metastasis failed to standard systematic treatment. Randomized, prospective studies are needed to further validate these findings.C. Kong: None. X. Zhu: None. M. Jiang: None. X. Song: None. P. Qian: None. J. Zhu: None. J. Xu: None. X. He: None.

Brain Metastases in Metastatic Cutaneous Melanoma: Patterns of Care and Clinical Outcomes in the Era of Immunotherapy and Targeted Therapy

Immune checkpoint inhibitors (CPIs) and BRAF inhibitors (BIs) are standard treatments for metastatic melanoma and have intracranial activity against melanoma brain metastases (MBMs). However, optimal use of CPI/BI with radiation therapy (RT) is not well established. This study evaluates the current practice pattern of how these systemic therapies are chosen and combined with either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for MBMs. The study also examines if upfront SRS+CPI results in superior intracranial control (IC) than upfront SRS without CPI or upfront CPI/BI followed by salvage RT.Patients with MBMs who received their first course of intracranial RT with between 1/2014 and 12/2019 at a tertiary cancer center were retrospectively reviewed. Patients with leptomeningeal disease and MBMs from non-cutaneous melanoma were excluded. Prior exposure before MBM diagnosis and concomitant use of CPIs/BIs within 3 months of RT were evaluated. Binary logistic regression was performed to determine predictors of SRS or CPI use. Cox regression analysis was used to assess the association with IC, which was calculated from the time of MBM diagnosis to the first intracranial progression after upfront MBM treatment.A total of 123 patients with MBMs with a median age of 61 (IQR: 51-69) were identified, and 55% were BRAF-mutant. There were 75 patients (61%) with 1-4 MBMs, 31 patients (25%) with 5-10 MBMs, and 17 (14%) patients with > 10 MBMs. Before MBM diagnosis, 30% had prior CPI and 18% had prior BI. For the upfront MBM treatment, 64% received SRS (66% with CPI and 23% with BI), 27% received WBRT (42% with CPI and 30% with BI), 9% received upfront CPI/BI. The baseline characteristics were balanced between the patients who received upfront SRS and upfront CPI/BI except patients who received upfront CPI/BI were more likely to have a BRAF mutation (82% vs. 49%, P = 0.04). The median follow-up was 8.7 mo (IQR: 2.8-22) for all patients and 32 mo (IQR: 18-45) for living patients. For patients who received upfront CPI/BI, 73% underwent salvage SRS and 27% with salvage WBRT at a median of 5.7 mos [IQR: 3.0-7.7] after MBM diagnosis. Fewer number of MBMs, higher KPS, and craniotomy were significant predictors of SRS use on multivariable logistic regression. For the upfront SRS cohort, treatment after 2016, BRAF-wild type status, and prior CPI exposure were associated with higher likelihood of concomitant CPI use with SRS. After adjusting for the number of MBMs, upfront SRS+CPI was associated with higher IC than upfront SRS without CPI (HR: 0.43, 95% CI: 0.22-0.84, P = 0.02). Upfront SRS+ CPI also trended towards a higher IC than upfront CPI/BI with salvage RT (HR: 0.54, 95% CI: 0.27-1.1, P = 0.07) after adjusting for the number of MBMs.Upfront SRS with concomitant CPI was the most frequently used approach to treat newly diagnosed favorable MBMs and may yield superior IC than upfront SRS without CPI or upfront CPI/BI.R. Chin: None. K. Chen: None. C.D. Abraham: None. C.G. Robinson: Research Grant; Varian. Consultant; Varian, AstraZeneca, EMD Serono. Advisory Board; Radialogica. Stock Options; Radialogica. S.M. Perkins: I serve on the Medical Advisory Committee for Mevion Medical Systems and receive compensation for this role.; Mevion Medical Systems. T.M. Johanns: None. L.F. Hernandez-Aya: None. J.W. Keller: None. J. Dowling: None. K. Rich: None. M. Chicoine: None. A.H. Kim: None. G.P. Dunn: None. G. Ansstas: None. J. Huang: None.

Prophylactic Cranial Irradiation-Related Lymphopenia Affects Progression-Free Survival in Patients With Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> In view of anti-tumor immunosuppression, lymphopenia during radiotherapy was shown to be related to adverse outcome of small-cell lung cancer patients (SCLC). However, the relationship between treatment related lymphopenia and efficacy of prophylactic cranial irradiation (PCI) for SCLC is not fully understood. We hypothesize that PCI related lymphopenia is associated with rapid brain metastasis and inferior survival. <h3>Materials/Methods</h3> Limited-stage small cell lung cancer (LS-SCLC) with PCI were included in this study, and clinicopathological variables, and the lowest lymphocyte counts during treatment were retrospectively collected in. Severe Lymphopenia was defined as the lowest absolute lymphocyte count < 500 cells/mm³ during PCI. Univariate logistic regression was performed to evaluate the risk factors of PCI-related lymphopenia. Progression-free survival overall (PFSO) was defined from the date of PCI to the date of disease progression (both intracranial and extracranial). PFS_I was defined from the date of PCI to the intracranial progression, and PFS_E, was defined from the date of PCI to the date of extracranial progression. Log-rank test and Cox-Proportional Hazards were performed for univariate and multivariate survival analysis. <h3>Results</h3> A total of 153 LS-SCLC patients with PCI were enrolled in this study, and 34 (22.2%) of them experience severe lymphopenia. Logistic regression showed that none of age, gender, ECOG PS, RT techniques was associated with PCI-related lymphopenia. The median follow-up was 10.9 months. And patients experienced severe lymphopenia during treatment were found to have inferior PFS_I (median PFS_I: 22.6 vs.NR months, <i>P</i> = 0.012). And multivariate analysis found that severe lymphopenia was the only significant risk factor for intracranial progression. However, sever lymphopenia during PCI was not the prognostic factors for PFSO and PFS_E of LS-SCLC patients receiving PCI (median PFSO: 14.4 vs. 15.8 months, <i>P</i> = 0.218; median PFS_E: NR vs. 33.6 months, <i>P</i> = 0.532; respectively). <h3>Conclusion</h3> Severe lymphopenia during prophylactic cranial irradiation was the risk factor for intracranial progression in LS-SCLC patients receiving PCI, but not for PFSO and extracranial progression.

Initial Report of Clinical Outcomes and Acute Toxicities Following Reirradiation of Primary Brain Tumors

Despite rapid advancements in targeted therapeutics and increasingly conformal radiation techniques, limited data exist regarding reirradiation of primary brain tumors. Herein, we provide an initial report of our institutional experience with reirradiation of primary brain tumors, hypothesizing that reirradiation can be delivered safely in select patients with acceptable oncologic outcomes and toxicities.With IRB approval (828228), we retrospectively reviewed patients who received at least 2 courses of radiation for primary brain tumors at our institution between 2010-2020. Factors prompting study exclusion included: 1) diagnosis of brain metastases, 2) age < 18 years, and 3) follow-up < 2 months. Primary outcomes were intracranial progression free (PFS), and overall survival (OS). Secondary outcomes were acute toxicities, classified as ≤3 months from the start of radiation. Cohort characteristics were analyzed using descriptive statistics and survival estimates were generated using the Kaplan-Meier method.We identified 45 patients (Median (IQR) age-at-reirradiation, 46 (35-38) years; Men, N = 29; Women, N = 16) who met study inclusion criteria. Median follow-up was 7.6 (2.1-13.9) months. Gliomas were the most common diagnosis (N = 33), including 61% glioblastoma. Thirty-eight patients underwent initial surgical resection (GTR, 38%; STR, 47%). Median dose during the initial radiation course was 5940 Gy in 33 fractions. Median interval to reirradiation was 1.8 (0.8-3.1) years. Overall, 75% of patients received reirradiation with IMRT (median dose/fraction, 3500 cGy/10), while 25% patients received SRS (median dose/fraction, 2100 cGy/). Median intracranial PFS was 5.7 months and median OS was 9.6 months. Acute grade ≥3 toxicities occurred in 5 patients and included anorexia (N = 1), cognitive disturbance (N = 1), headache (N = 1), fatigue and aphasia (N = 1), and urinary incontinence (N = 1).In this single-institution series, reirradiation of primary brain tumors was safe and effective with acceptable clinical outcomes and low rates of severe acute toxicities. Additional data on dosimetric details and late toxicities are forthcoming.J. Wei: None. P. Santos: None. R.A. Lustig: None. G. Kurtz: None. J.F. Dorsey: None. J.E. Shabason: None. M. Alonso-Basanta: Travel Expenses; Varian, IBA.

Population-Based Analysis of Outcomes for Patients With Brain Metastases From Epidermal Growth Factor Receptor Mutation Positive Non-Small Cell Lung Cancer Treated With Tyrosine Kinase Inhibitor Alone or Combined With Radiotherapy

With modern therapies, the median survival of patients with brain metastases (BrM) from non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutation (EGFRm) may exceed 1-2 years. BrM directed therapies must therefore carefully balance treatment efficacy and late toxicity. Although some tyrosine kinase inhibitors (TKI) exhibit intracranial activity, there is no level-one evidence to support up-front treatment of BrM using TKI without radiotherapy (RT). This study aimed to compare the outcomes of patients with BrM from EGFRm NSCLC treated with initial RT and TKI, versus TKI alone.All patients who received a TKI (gefitinib, erlotinib, afatinib, or osimertinib) in British Columbia for NSCLC between January 2010 to 2018 were identified in a provincial pharmacy database. Patients were then screened for pathologic diagnosis of EGFRm, and radiologic diagnosis of BrM. These patients were categorized as receiving either TKI alone or RT with TKI for treatment of their BrM. Patients who received RT were cross-referenced with a provincial RT database to determine radiotherapy prescriptions and were classified as having received whole brain (WBRT) with TKI or stereotactic RT/radiosurgery (SRS) with TKI. Patients were excluded if they discontinued TKI after RT or ever received surgery for BrM. Overall survival (OS) and intracranial progression free survival (iPFS) were calculated from the date of BrM diagnosis using Kaplan-Meier analysis. Log rank test was used for comparison between groups, and Cox proportional hazards model was used for multivariate analysis.A total of 167 patients were included for analysis with a median follow up of 45 months. Median OS was 19 months with WBRT (n = 76), 21 months with SRS (n = 45), and 6 months with TKI alone (n = 46), P < 0.01. In patients who had WBRT, iPFS was better than in those having TKI alone [HR 4.68 (2.07-10.56); P < 0.01] or SRS [HR 2.43 (1.20-4.91); P < 0.01]. On multivariate analysis: advanced age, worse performance status, presence of extracranial metastasis, greater than 10 B.M. and type of treatment (TKI alone versus RT with TKI) were associated with inferior OS.This study showed that compared to treatment with TKI alone, the addition of RT for BrM is associated with an improved OS in patients with EGFRm NSCLC. These results are complementary to the growing body of retrospective data suggesting an inferior survival associated with TKI alone compared to RT with TKI for treatment of BrM in patients with EGFRm NSCLC. Prospective studies are required to further guide the best approach to managing this patient population.T. Kong: None. A. Nichol: None. C. Ho: None. A. Benny: None. N. Chooback: None. I.M. Fraser: None. L. Gondara: None. S. Lefresne: None.

Three-staged stereotactic radiosurgery for brain metastases: a single institution experience

Abstract Aims Stereotactic radiosurgery (SRS) using the Leksell Gamma Knife system is a commonly used modality for the treatment of brain metastases (BMs). As the size of the target volume (TV) increases, so too does the dose of radiation delivered to surrounding healthy tissue. Large BMs are therefore a contraindication to the use of SRS. Critical organs adjacent to the TV may also be a contraindication to SRS. Staged SRS was proposed as a novel method of delivering three SRS treatments at a reduced radiation dose with a gap of two weeks between each session as a way of shrinking the TV. This allows treatment of TVs otherwise considered untreatable with standard, single-fraction SRS. Little data exists in the literature as to its efficacy. The objective of this study was to evaluate the efficacy of this novel approach and to identify factors which may predict treatment failure. Method A retrospective analysis was undertaken at a single, tertiary Gamma Knife centre. All patients who underwent treatment of their BMs with three-staged Gamma Knife SRS from January 2014 to December 2020 were identified and included. Patient demographics and primary cancer status was ascertained. SRS treatment details for each lesion were collected, including TV, dose and dosimetric data. The percentage reduction in volume of the TVs between the first and second stage, the second and third stage and the first and third stage were calculated. Follow-up data was collected to include follow-up imaging, further intracranial treatments received and survival status. The percentage reduction in volume between each stage was demonstrated on box-and-whisker plots. Statistical significance in reduction in TV between each stage was ascertained by paired samples T-tests. Correlation between initial TV size and percentage reduction post-SRS was determined by a correlation coefficient. Differences were deemed significant with p-values &amp;lt;0.05. Results 12 patients with 14 staged BMs were identified and included. The median age was 61.5 (range 45-79). Seven had a primary malignancy of breast cancer, five non-small cell lung cancer, one melanoma and one colorectal. Median follow-up was 140.5 days (range 10-821). Median TV was 7.44cc (range 1.14-21.53). All TVs received 10Gy at each stage. The median percentage reduction in size of the TV was 7.41% between 1st-2nd stage (range -16.0-42.49%, p-value 0.06), 19.47% between 2nd-3rd stage (range -5.38-53.53%, p-value &amp;lt;0.01) and 24.25% between 1st-3rd stage (range 10.69-68.67%, p-value &amp;lt;0.01). The correlation coefficient between initial TV size and percentage reduction post-SRS was -0.41 (p-value 0.07). 13/14 lesions showed a partial response on first follow-up scan post-SRS, 1/14 lesions showed a mixed response. One patient died 184 days from completion of treatment but without intracranial progression. Two patients had salvage intracranial surgery, 154 and 536 days from completion of treatment respectively. Conclusion Three-staged Gamma Knife is shown to be effective at shrinking the TV and can therefore be used to treat lesions otherwise considered unsuitable for SRS. The presence of extra-cranial metastases did not predict for poor outcomes. Though local control with SRS is thought to diminish with increasing TV size, all staged lesions showed a reduction in size between first and last treatment, and no significant effect was seen between initial TV size and percentage reduction in TV. No patients experienced disease progression on first follow up scan, with 13 of 14 lesions showing disease response. There were only two cases of intracranial progression, with one occurring 536 days post-SRS. Though limited by small numbers and short median follow up period, our data demonstrate encouraging results for three-stage SRS for lesions otherwise unsuitable for single fraction treatment, and should lead to further study.

Stereotactic radiosurgery combined with immune checkpoint inhibition for the treatment of melanoma brain metastases is associated with high levels of extracranial disease control and survivorship - an abscopal effect?

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% &amp; 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.

The Sequence of Intracranial Radiotherapy and Systemic Treatment With Tyrosine Kinase Inhibitors for Gene-Driven Non-Small Cell Lung Cancer Brain Metastases in the Targeted Treatment Era: A 10-Year Single-Center Experience.

PurposeThe high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients.Patients and MethodsWe retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups.ResultsAmong the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30–0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3–4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups.ConclusionCompared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities.Trial registration IDNCT04832672.

Radiologic and Clinical Outcomes of Stereotactic Radiosurgery for Intraventricular Metastases

The optimal management of intraventricular metastases remains debatable. The aim of this study is to define the safety and efficacy of Gamma-Knife radiosurgery in the treatment of intraventricular metastases. This retrospective, single-center study involved patients that were treated with stereotactic radiosurgery (SRS) for intraventricular metastases. The study end points included SRS-related toxicity, local and distal intracranial tumor control, as well as the incidence of post-treatment hydrocephalus and leptomeningeal dissemination. Factors associated with radiologic and clinical outcomes were also analyzed. The cohort included 17 consecutive patients who underwent stereotactic radiosurgery for treatment of 41 intracranial metastases, of which 23 were primary intraventricular (intraventricular metastasis). Median overall survival from primary tumor diagnosis and from SRS treatment were 28 and 5 months, respectively. With a median radiological follow-up of 3 (interquartile range 3) months, 7 patients (41.18%) experienced overall intracranial disease progression, whereas 7 (27.27%) intraventricular metastases progressed radiologically. Four (23.53%) and 3 (17.65%) patients developed hydrocephalus and leptomeningeal dissemination post-SRS, respectively. Four patients (23.53%) died due to intracranial disease progression. SRS offers a reasonable chance of local tumor control for patients with intraventricular brain metastasis. However, the risk of hydrocephalus and leptomeningeal spread of disease is not inconsequential and merits close follow-up for patients with brain metastasis involving the ventricular system.

P59.01 Clinical Characteristics of Patients With MET Amplification-Positive NSCLC After EGFR-TKI Therapy

Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. View Large Image Figure ViewerDownload Hi-res image Download (PPT) Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by exon 21 mutation (39.2%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (mPFS of 1st/2nd generation TKI cohort, 7.0 vs. 10.4 months, p = 0.003, PFS of 3rd generation TKI cohort, 7.2 vs. 11.0 months, p=0.163). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

P14.03 Shifting trends and entity-specific aspects in patients with brain metastasis: real-life analysis from 6031 individuals over an observation period of 30 years

Abstract BACKGROUND We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning. MATERIAL AND METHODS 6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry. RESULTS The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p&amp;lt;0.001). Synchronous diagnosis of BM and primary tumor was more frequently observed in lung cancer and CUP patients compared to breast cancer patients (p&amp;lt;0.001). An increasing fraction of patients presented with asymptomatic BM (1986–1999: 20.2% vs. 2010–2020: 30.4%; p&amp;lt;0.001), specifically in lung cancer (p&amp;lt;0.001), melanoma (p&amp;lt;0.001) and renal cell cancer (p=0.004). A decrease of neurosurgical procedures (1986–1999: 39.3% vs. 2010–2020: 20.4%) and an increase of radiation treatments (1986–1999: 56.5% vs. 2010–2020: 73.0%) and systemic therapies (1986–1999: 0.6% vs. 2010–2020: 2.4%; p&amp;lt;0.001) was observed. Furthermore, median overall survival significantly increased across entities (1986–1999: 5 months vs. 2010–2020: 7 months; p=0.001). Intracranial progression as the cause of death increased across entities (p&amp;lt; 0.001). The prognostic DS-GPA (Hazard ratio [HR] 1.42; p&amp;lt; 0.001) and the Lung-molGPA (HR 1.67; p&amp;lt;0.001) could be validated. CONCLUSION We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.

Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study

Introduction Osimertinib is effective for relapsed T790M-positive patients with brain metastases. The high brain permeability suggests that also such patients without T790M could benefit. Therefore, we evaluated the effect of osimertinib on brain metastases in both T790M-positive and -negative patients. Methods The TREM-study was an investigator-initiated phase II, single-arm, multi-institutional clinical trial conducted in Northern Europe. Patients with resistance to prior EGFR-TKIs received osimertinib until radiological progression, unacceptable toxicity or death. Baseline brain scans were performed in patients with known or suspected brain metastases and repeated every 8–12 weeks. We assessed intracranial efficacy in patients with baseline brain metastases. Results Brain metastases were detected in 48/199 patients at baseline. Of these, 63% were T790M-positive, 27% -negative and 10% had unknown T790M-status. The majority (73%) of the patients had received prior whole brain radiotherapy and additionally 8% had received stereotactic radiosurgery (SRS). Brain scans were available for review for 42 patients. The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively. The estimated risk of CNS progression was 0.8% at 6 months and 6% at 12 months for T790M-positive patients, and 14% and 17% at 6 and 12 months, respectively, for the T790M-negative. Conclusion This subgroup analysis confirms CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.