Intracranial Progression Research Articles

Osimertinib in advanced EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases: an open-label, 3-arm, phase II pilot study.

BackgroundOsimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported.MethodsIn this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513.ResultsThe iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature.ConclusionOsimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

Non-Hodgkin Lymphoma Causing Hypopituitarism Can Imaging Help Diagnosis and Management?

Non-Hodgkin lymphomas of the hypothalamus and pituitary are rare. They usually remain clinically silent until onset of compressive features affecting surrounding structures. When symptomatic, patients most commonly present with diabetes insipidus, headaches, ophthalmoplegia and/or bilateral hemianopia.We report a case of a 67-year-old Caucasian female with a history of B-cell lymphoma in complete remission. She presented with left oculomotor nerve palsy and was subsequently found to have a sellar/suprasellar mass lesion on MRI. Alongside hypocortisolism and hypogonadotropic hypogonadism, she developed transient diabetes insipidus during her illness. Her clinical course was characterized by rapid intracranial progression of the sellar mass. MR spectroscopy suggested a diagnosis of lymphoma. Diagnostic biopsy confirmed high-grade diffuse large B-cell CNS lymphoma; this changed the definitive management from surgical excision to chemotherapy. Despite treatment, she succumbed to her illness within 7 months of initial presentation.This case highlights the aggressive nature of CNS lymphomas and the need for a high index of suspicion in an unusual presentation of sellar/suprasellar mass lesions.LEARNING POINTSNovel imaging techniques such as MR spectroscopy might help to differentiate some brain tumours from pituitary macroadenomas, but these are not diagnostic.Tissue diagnosis with biopsy and histopathology is the gold standard for deciding management of pituitary fossa mass lesions with atypical presentation.

MET-6 Neoadjuvant fractionated stereotactic radiotherapy followed by piecemeal resection for metastatic brain tumor

BACKGROUND: Large brain metastases which require resection are treated with surgery followed by whole brain radiation therapy or postoperative stereotactic radiosurgery (SRS). Recently a novel strategy using neoadjuvant stereotactic radiosurgery (Na-SRS) followed by surgery was reported, demonstrating lower rates of postoperative leptomeningeal dissemination (LMD) and symptomatic radiation necrosis (RN). We treated with neoadjuvant fractionated stereotactic radiotherapy (Na-fSRT) followed by surgery for large brain metastasis with piecemeal resection. METHODS: Twelve patients received Na-fSRT followed by surgery between July 2019 and April 2021. Na-fSRT dose was based on lesion size and was standard dosing. Surgery generally followed within 7 days after radiotherapy. RESULTS: The mean age was 68 years (51–79). Sixteen men and five women. Mean follow-up period was 8.5 months (1–24.9). Primary were lung; 10 (NSCLC; 9, SCLC (recurrence); 1), esophagus; 3, colon; 2, melanoma; 2, kidney; 2 (recurrence1), uterus body; 1, and liver; 1. The median maximum tumor diameter was 3.6 cm (2.6–4.9). Median PTV, GTV volume were 21.7ml, 15.5ml, respectively. The median fSRT dose was 30Gy/5fr, and the median time from fSRT to surgery was 4 days (1–7). As preoperative adverse event, intracranial hypertension and partial seizure grade 2 (CTCAE ver.5) were occurred, but controlled with steroid and osmotic diuretics and anticonvulsant. Grade 3 and more adverse events were not occurred. Gross total removal was performed in 95.2%. Event cumulative incidence as follows: cavity local recurrence 4.8% (subtotal removal case); distant brain failure 33%; LMD 4.8%; and symptomatic RN 0%. The median intracranial progression free survival was 7 months, and median overall survival was 8.4 months. CONCLUSIONS: Na-fSRT followed by piecemeal resection is safety and feasible, and may have therapeutic value for deep large brain metastasis and eloquent lesion. Further prospective investigations in multi-institutional settings are warranted.

Abstract P230: A phase 1/2 study of BLU-945, a highly potent and selective inhibitor of epidermal growth factor receptor (EGFR) resistance mutations, in patients with EGFR-mutant non-small cell lung cancer (NSCLC)

Abstract BACKGROUND Activating EGFR mutations such as exon 19 deletion (ex19del) and L858R mutations, exon 19 insertions (ex19ins), and point mutations L861Q, G719X, and S768I are oncogenic drivers in lung adenocarcinoma, the most common NSCLC subtype. Although EGFR-targeted therapies, including first-, second-, and third-generation tyrosine kinase inhibitors (TKIs), have improved outcomes in patients (pts) with EGFR-mutant (EGFRm) NSCLC, resistance to these drugs is inevitable. BLU-945 is an investigational fourth-generation EGFR TKI designed to suppress both activating and on-target resistance EGFR mutations, such as C797S and T790M. Preclinical data showed BLU-945 has nanomolar potency against EGFRm/T790M double and EGFRm/T790M/C797S triple mutants with >450-fold selectivity for these mutants over wild-type EGFR in biochemical and cellular assays, and demonstrated robust preclinical antitumor activity, including in intracranial tumors harboring these mutations, providing the therapeutic rationale for BLU-945 clinical development. METHODS BLU-945-1101 (NCT04862780) is an international, open-label, first-in-human, phase 1/2 study designed to evaluate safety, tolerability, and antitumor activity of BLU-945 in pts with EGFRm NSCLC. Key eligibility criteria include adults with pathologically confirmed metastatic NSCLC with an activating EGFR mutation per local assessment (including ex19del or L858R); Eastern Cooperative Oncology Group performance status 0–2; and previous treatment with ≥1 EGFR-targeted TKI. Pts with asymptomatic brain metastases and on stable doses of corticosteroids are eligible. Key exclusion criteria are any additional known primary driver alterations, including but not limited to pathologic aberrations of EGFR exon 20 (insertions), KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET. Phase 1 primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D), and safety. The phase 2 primary endpoint is overall response rate (ORR) by RECIST 1.1. Phase 1 secondary endpoints include ORR, duration of response (DOR), pharmacokinetics (PK), and pharmacodynamics (PD); phase 2 secondary endpoints include DOR, disease control rate (DCR), clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), time to intracranial progression and intracranial response rate, PK, PD, and safety. Phase 1 dose escalation (N≈60) will be conducted using Bayesian optimal interval design. In the phase 2 dose expansion (N≈61), pts will be enrolled into 3 groups based on mutation profile and treated at the RP2D: primary group 1 for pts with EGFR T790M and C797S (n≈37); exploratory group 2 for pts with EGFR T790M but not C797S (n≈12); exploratory group 3 for pts with EGFR C797S but not T790M (n≈12). Group 1 will use Simon’s 2-stage design to test the null hypothesis of ORR ≤20% against a 1-sided alternative of ≥40%. Pts may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia. Citation Format: David Spigel, Koichi Goto, D. Ross Camidge, Yasir Elamin, Adrianus J. de Langen, Natasha B. Leighl, Anna Minchom, Zofia Piotrowska, David Planchard, Karen Reckamp, Faris Albayya, Jennifer Green, Sean Kim, Melinda Louie-Gao, Renata Sawtell, Alena Zalutskaya, Byoung Chul Co. A phase 1/2 study of BLU-945, a highly potent and selective inhibitor of epidermal growth factor receptor (EGFR) resistance mutations, in patients with EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P230.

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.