Intracranial Progression Research Articles

75. PROGRAMMED DEATH RECEPTOR LIGAND ONE EXPRESSION MAY INDEPENDENTLY PREDICT SURVIVAL IN NON-SMALL CELL LUNG CARCINOMA BRAIN METASTASES PATIENTS RECEIVING IMMUNOTHERAPY

BACKGROUNDProgrammed death receptor ligand one (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models.METHODSIn this multi-institutional retrospective cohort study, we identified NSCLC-BM patients treated with PD-1/PD-L1 inhibitors after local BM treatment (radiotherapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess predictive value PD-L1 expression for overall survival (OS) and intracranial progression free survival (IC-PFS).RESULTSForty-eight BM patients with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (HR = 0.44; 95% CI 0.19 – 1.02; p = 0.055). This effect persisted after correcting for lung-graded prognostic assessment (lung-GPA) and other identified potential confounders (HR = 0.24; 95% CI = 0.10 – 0.61; p = 0.002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR = 0.86 per 10% expression, 95% CI 0.77 – 0.98, p = 0.02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR = 0.54, 95% CI 0.26 – 1.14, p = 0.11).CONCLUSIONSIn patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-GPA. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.

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

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

Isolated progression of metastatic lung cancer: Clinical outcomes associated with definitive radiotherapy.

Progressive, metastatic non-small cell lung cancer (NSCLC) often requires the initiation of new systemic therapy. However, in patients with NSCLC that is oligoprogressive (≤3 lesions), local radiotherapy (RT) may allow for the eradication of resistant microclones and, therefore, the continuation of otherwise effective systemic therapy. Patients treated from 2008 to 2019 with definitive doses of RT to all sites of intracranial or extracranial oligoprogression without a change in systemic therapy were identified. Radiographic progression-free survival (rPFS) and time to new therapy (TNT) were measured. Associations between baseline clinical and treatment-related variables were correlated with progression-free survival via Cox proportional hazards modeling. Among 198 unique patients, 253 oligoprogressive events were identified. Intracranial progression occurred in 51% of the patients, and extracranial progression occurred in 49%. In the entire cohort, the median rPFS was 7.9 months (95% CI, 6.5-10.0 months), and the median TNT was 8.8 months (95% CI, 7.2-10.9 months). On adjusted modeling, patients with the following disease characteristics were associated with better rPFS: better performance status (P=.003), fewer metastases (P=.03), longer time to oligoprogression (P=.009), and fewer previous systemic therapies (P=.02). Having multiple sites of oligoprogression was associated with worse rPFS (P<.001). In select patients with oligoprogression, definitive RT is a feasible treatment option to delay the initiation of next-line systemic therapies, which have more limited response rates and efficacy. Further randomized prospective data may help to validate these findings and identify which patients are most likely to benefit.

Whole brain radiotherapy with partial hair-sparing technique-a feasibility study

Introduction: Whole brain radiotherapy (WBRT) is a common palliative treatment for brain metastases from solid tumours. Traditionally, it is given with opposed lateral fields causing total alopecia as hair-bearing scalp skin receives the full dose. Volumetric modulated arc therapy (VMAT) can deliver WBRT with a simultaneous integrated boost (SIB) to larger metastases whilst minimising dose to critical structures such as the hippocampus. This feasibility study aimed to test the hypothesis that a reduced dose to the scalp using a VMAT hair-sparing WBRT protocol would spare scalp hair and reduce alopecia at four weeks post treatment without compromising disease control at three months. Methods: The Hair Spare study (01.07 WBRTMel sub-study SS01.13) was an investigator-initiated, prospective feasibility study. A VMAT hair-sparing WBRT protocol was developed to limit the dose to the scalp to 16 Gray (Gy) in 15 fractions. The primary objective was the rate of alopecia at 4 weeks post RT as measured by CTCAE v4 and clinician and patient perception. Quality of life (QoL) was assessed at baseline, one month and three months post treatment with validated instruments including European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ-C15-PAL+4) plus four additional questions specifically relating to hair, a visual analogue scale (VAS) to measure the perception of hair loss severity, and the total Chemotherapy-Induced Alopecia Distress Scale (CADS). Results: Nine patients with brain metastases from melanoma (6), breast (2) and lung (1) cancer were enrolled at the Mater Sydney Hospital, Crows Nest, Australia. At 4 weeks, 5 patients were evaluable: 4 reported moderate alopecia (CTCAE v4 Grade 2) and 1 reported mild alopecia (CTCAE v4 Grade 1). All 5 wore wigs or scarves to hide hair loss. Any amount of hair loss impacted QoL. Reduced hair loss compared to complete alopecia, as usually found with conventional WBRT, did not translate to a mean improvement in QoL. There was no symptomatic intracranial progression of disease while the patients remained on study. Two patients had MRI at 3 months, and both had evidence of intracranial progression of disease within the volume that had received prescription WBRT dose. From the data collected it seems that VMAT hair-sparing WBRT was well-tolerated. Conclusion: VMAT hair-sparing WBRT partially spared scalp hair at four weeks post WBRT and did not compromise symptomatic disease control during the study. The treating oncologists observed that the hair grew back quicker than with conventional WBRT, and that combined cytotoxic chemotherapy was additive to RT-induced alopecia. However, the study was not optimal in that data collection was hampered by patient availability. The patient population was too unwell to be followed up according to the protocol.

Low Risk of Traumatic Intracranial Hematoma Expansion with Factor Xa Inhibitors without Andexanet Reversal

Andexanet alfa, a novel anticoagulation reversal agent for factor Xa inhibitors, was recently approved. Traumatic intracranial hemorrhage presents a prime target for this drug. The Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors study established the efficacy of andexanet alfa in reversing factor Xa inhibitors. However, the association between anticoagulation reversal and traumatic intracranial hemorrhage progression is not well understood. The objective of this study was to determine progression rates of patients with traumatic intracranial hemorrhage on factor Xa inhibitors prior to hospitalization who were managed without the use of andexanet alfa. A retrospective cohort study was performed between 2016 and 2019 at a single institution. An institutional traumatic brain injury (TBI) registry was queried. Patients with recorded use of apixaban or rivaroxaban <18 hours before injury were included. The primary study outcome was <35% increase in hemorrhage volume or thickness on repeated head computed tomography (CT) scans. We identified 25 patients meeting the inclusion criteria. Two patients were excluded because of a lack of necessary CT data. Twelve patients (52%) were receiving apixaban, and 11 were (48%) on rivaroxaban. On admission CT scan, 14 patients had subdural hematoma, 6 had traumatic intraparenchymal hemorrhage, and 3 had subarachnoid hemorrhage. Anticoagulation reversal was attempted in 17 patients (74%), primarily using 4-factor prothrombin complex concentrate. Twenty patients (87%) were adjudicated as having excellent or good hemostasis on repeat imaging. Our results indicate that patients on factor Xa inhibitors with complicated mild TBI have a similar intracranial hemorrhage progression rate to patients who are not anticoagulated or anticoagulated with a reversible agent. The hemostatic outcomes in our cohort were similar to those reported after andexanetalfa administration.

Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway

BackgroundThe regulation of vascular smooth muscle cell (VSMC) phenotype plays an important role in intracranial aneurysm (IA) formation and progression. However, the underlying mechanism remains unclear. Metformin is a 5′ AMP-activated protein kinase (AMPK) agonist that has a protective effect on vasculature. The present study investigated whether metformin modulates VSMC phenotype switching via the AMPK/acetyl-CoA carboxylase (ACC) pathway during IA pathogenesis.MethodsAdult male Sprague-Dawley rats (n = 80) were used to establish an elastase-induced IA model. The effects of metformin on AMPK activation and VSMC phenotype modulation were examined. We also established a platelet-derived growth factor (PDGF)-BB-induced VSMC model and analyzed changes in phenotype including proliferation, migration, and apoptosis as well as AMPK/ACC axis activation under different doses of metformin, AMPK antagonist, ACC antagonist, and their combinations.ResultsMetformin decreased the incidence and rupture rate of IA in the rat model and induced a switch in VSMC phenotype from contractile to synthetic through activation of the AMPK/ACC pathway, as evidenced by upregulation of VSMC-specific genes and decreased levels of pro-inflammatory cytokines. AMPK/ACC axis activation inhibited the proliferation, migration, and apoptosis of VSMCs, in which phenotypic switching was induced by PDGF-BB.ConclusionsMetformin protects against IA formation and rupture by inhibiting VSMC phenotype switching and proliferation, migration, and apoptosis. Thus, metformin has therapeutic potential for the prevention of IA.

Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial.

PURPOSEIn the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs.PATIENTS AND METHODSPatients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease.RESULTSThere were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03).CONCLUSIONIn patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Alliance A071701: Genomically guided treatment trial in brain metastases.

TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .

CNS outcomes in EGFR/ALK wild-type NSCLC patients with brain metastases treated with immune checkpoint inhibitors (ICI).

e14505 Background: Anti-tumor lymphocytes activated in response to ICIs may cross the blood brain barrier with effect on brain metastases (BM). Preliminary evidence suggests that ICIs alone are effective for melanoma BMs. However, the ability of ICI to effectively control NSCLC BMs without radiotherapy is controversial. By comparing serial MRIs and patterns of progression in ICI and chemotherapy treated patients, we sought to investigate the role of ICI in BM control in NSCLC patients. Methods: Serial MRIs were reviewed in ICI treated NSCLC patients with known BMs. Eligible patients must have a minimum of one baseline MRI and a follow-up within 3 months of CNS directed treatment. Patients with EGFR/ ALK mutations were excluded. A control cohort of patients who had never received ICIs was selected using the same criteria. The primary outcome was cumulative CNS progression and intracranial progression free survival (iPFS) analyzed using an accelerated failure time model and competing risk analysis. Results: We identified 137 ICI treated NSCLC patients with known BMs. After excluding for patients without serial MRIs, we analyzed 40 ICI treated patients and 39 controls. All patients received upfront radiotherapy or surgery and the modality used was similar (p = 0.13). CNS failure was less common in the ICI group (p = 0.02). ICI treated patients had a trend to longer iPFS in the PD-L1 ≥50% subgroup (p = 0.058). Cumulative incidence of progressive BM at 12 and 24 months were significantly lower in the ICI treated PD-L1 ≥50% subgroup: 19%/19% vs 50%/56% (p = 0.02). Patients in the PD-L1 ≥50% subgroup who achieved a systemic partial response (n = 10) did not experience any CNS events despite extracranial progression in some. Conclusions: Durable CNS disease control is observed with ICIs in NSCLC with PD-L1 ≥50% and demonstrates a high level of concordance with systemic response. The need for radiotherapy in PD-L1 ≥50% disease should be investigated and may be reasonably delayed in asymptomatic patients with small BMs. Importantly, the same trend was not observed in PDL1 &lt; 50% patients and caution is needed in employing this strategy in this subset of patients.

AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .

Programmed Death Receptor Ligand One Expression May Independently Predict Survival in Patients With Non-Small Cell Lung Carcinoma Brain Metastases Receiving Immunotherapy

Programmed death receptor ligand 1 (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models. In this multi-institutional retrospective cohort study, we identified patients with NSCLC-BM treated with PD-1/PD-L1 inhibitors after local BM treatment (radiation therapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess the predictive value of PD-L1 expression for overall survival (OS) and intracranial progression-free survival (IC-PFS). Forty-eight patients with BM with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.19-1.02; P = .055). This effect persisted after correcting for lung-graded prognostic assessment and other identified potential confounders (HR, 0.24; 95% CI, 0.10-0.61; P = .002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR, 0.86 per 10% expression; 95% CI, 0.77-0.98; P = .02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR, 0.54; 95% CI, 0.26-1.14; P = .11). In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-graded prognostic assessment. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.

Research progress on mechanism and dosimetry of brainstem injury induced by intensity-modulated radiotherapy, proton therapy, and heavy ion radiotherapy.

Radiotherapy (RT) is an effective method for treating head and neck cancer (HNC). However, RT may cause side effects during and after treatment. Radiation-induced brainstem injury (BSI) is often neglected due to its low incidence and short survival time and because it is indistinguishable from intracranial tumor progression. It is currently believed that the possible mechanism of radiation-induced BSI includes increased expression of vascular endothelial growth factor and damage of vascular endothelial cells, neurons, and glial cells as well as an inflammatory response and oxidative stress. At present, it is still difficult to avoid BSI even with several advanced RT techniques. Intensity-modulated radiotherapy (IMRT) is the most commonly used therapeutic technique in the field of RT. Compared with early conformal therapy, it has greatly reduced the injury to normal tissues. Proton beam radiotherapy (PBT) and heavy ion radiotherapy (HIT) have good dose distribution due to the presence of a Bragg peak, which not only results in better control of the tumor but also minimizes the dose to the surrounding normal tissues. There are many clinical studies on BSI caused by IMRT, PBT, and HIT. In this paper, we review the mechanism, dosimetry, and other aspects of BSI caused by IMRT, PBT, and HIT.Key Points• Enhanced MRI imaging can better detect radiation-induced BSI early.• This article summarized the dose constraints of brainstem toxicity in clinical studies using different techniques including IMRT, PBT, and HIT and recommended better dose constraints pattern to clinicians.• The latest pathological mechanism of radiation-induced BSI and the corresponding advanced treatment methods will be discussed.

Early experience with hippocampal avoidance whole brain radiation therapy and simultaneous integrated boost for brain metastases.

Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. A total of 32 patients (median age, 63.5years, range 45.3-78.8years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30Gy with SIB to 37.5Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4months and 19.6months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

Outcomes according to initial and subsequent therapies following intracranial progression in patients with EGFR-mutant lung cancer and brain metastasis.

In patients with epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach. Here, we investigated the clinical outcomes according to the use of upfront RT as well as the subsequent therapy following intracranial progression. This single-centre retrospective study included a total of 173 patients who were treated with EGFR-TKI alone (TKI alone group) or with upfront whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) followed by EGFR-TKI (RT plus TKI group). Clinical outcomes according to initial and subsequent therapies following intracranial progression were analysed. There was no significant difference in OS according to the use of upfront RT (TKI alone group, 24.5 months vs. WBRT group, 20.0 months vs. SRS group, 17.8 months; P = 0.186). Intracranial progression was found in 35 (32.7%) of 107 patients in the TKI alone group. Among them, 19 patients who received salvage RT had the better prognosis than others [median overall survival (OS); 28.6 vs. 11.2 months; P = 0.041]. In the RT plus TKI group, 12 (18.1%) of the 66 patients experienced intracranial progression and 3 of them received salvage RT (median OS; 37.4 vs. 20.0 months; P = 0.044). In multivariate analysis, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS. In conclusion, using EGFR-TKI alone for brain metastasis in EGFR-mutant lung cancer patients showed outcomes comparable to those using upfront RT followed by EGFR-TKI. Patients who could not receive salvage RT following intracranial progression had the worst survival regardless of the type of initial treatment.

Relationship between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute Traumatic Brain Injury Patients: A CENTER-TBI Study.

Failure of cerebral autoregulation has been linked to unfavorable outcome after traumatic brain injury (TBI). Preliminary evidence from a small, retrospective, single-center analysis suggests that autoregulatory dysfunction may be associated with traumatic lesion expansion, particularly for pericontusional edema. The goal of this study was to further explore these associations using prospective, multi-center data from the Collaborative European Neurotrauma Effectiveness Research in TBI (CENTER-TBI) and to further explore the relationship between autoregulatory failure, lesion progression, and patient outcome. A total of 88 subjects from the CENTER-TBI High Resolution ICU Sub-Study cohort were included. All patients had an admission computed tomography (CT) scan and early repeat scan available, as well as high-frequency neurophysiological recordings covering the between-scan interval. Using a novel, semiautomated approach at lesion segmentation, we calculated absolute changes in volume of contusion core, pericontusional edema, and extra-axial hemorrhage between the imaging studies. We then evaluated associations between cerebrovascular reactivity metrics and radiological lesion progression using mixed-model regression. Analyses were adjusted for baseline covariates and non-neurophysiological factors associated with lesion growth using multi-variate methods. Impairment in cerebrovascular reactivity was significantly associated with progression of pericontusional edema and, to a lesser degree, intraparenchymal hemorrhage. In contrast, there were no significant associations with extra-axial hemorrhage. The strongest relationships were observed between RAC-based metrics and edema formation. Pulse amplitude index showed weaker, but consistent, associations with contusion growth. Cerebrovascular reactivity metrics remained strongly associated with lesion progression after taking into account contributions from non-neurophysiological factors and mean cerebral perfusion pressure. Total hemorrhagic core and edema volumes on repeat CT were significantly larger in patients who were deceased at 6 months, and the amount of edema was greater in patients with an unfavourable outcome (Glasgow Outcome Scale-Extended 1-4). Our study suggests associations between autoregulatory failure, traumatic edema progression, and poor outcome. This is in keeping with findings from a single-center retrospective analysis, providing multi-center prospective data to support those results.

Brain metastases treated with radiosurgery or hypofractionated stereotactic radiotherapy: outcomes and predictors of survival.

To assess treatment outcome and prognostic factors associated with prolonged survival in patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HFSRT). This study retrospectively reviewed 200 patients with 324 BM treated with one fraction (15-21Gy) or 5-10 fractions (25-40Gy) between January 2010 and August 2016. 26.5% of patients received whole brain radiotherapy (WBRT) and 25% initial surgery. Demographics, prognostic scales, systemic and local controls, patterns of relapse and rescue, toxicity, and cause of death were analyzed. A stratified analysis by primary tumor was done. Median overall survival (OS) was 8months from SRS/HFSRT. Breast cancer patients had a median OS of 17months, followed by renal (11months), lung (8months), colorectal (5months), and melanoma (4months). The univariate analysis showed improved OS in females (p 0.004), RPA I-II (p < 0.001) initial surgery (p < 0.001), absence of extracranial disease (p 0.023), and good disease control (p 0.002). There were no differences in OS or local control between SRS and HFSRT or in patients receiving WBRT. Among 44% of brain recurrences, 11% were in field. 174 patients died, 10% from confirmed intracranial progression. SRS and HSFRT are equally effective and safe for the treatment of BM, with no exceptions among different primary tumors. Disease control, surgery, age, and prognostic scales correlated with OS. However, the lack of survival benefit regarding WBRT might become logical evidence for its omission in a subset of patients.

Abstract OT3-10-02: A breast cancer trainees research collaborative group prospective study of treatment and outcomes related to central nervous system disease secondary to breast cancer in the United Kingdom

Abstract Introduction: Breast cancer brain metastasis (BCBM) is a particular feature of HER2-positive and triple negative breast cancer (BC) and is becoming more common. This reflects the improved survival of patients living with metastatic breast cancer as well as increased cross-sectional imaging of the central nervous system with magnetic resonance imaging (1). The development of BCBM on the background of adequately controlled extracranial disease is an increasingly prevalent clinical scenario. BCBM causes significant morbidity and mortality; unfortunately the efficacy of systemic treatment is extremely limited and, at present, no systemic therapies are specifically approved for the treatment of BCBM (2). Basic and translational research to understand the pathophysiology of BCBM remains limited by a lack of access to annotated clinical material. Such research is needed if preventative and novel treatment strategies are to be developed. Moreover, there is currently a lack of basic contemporaneous information regarding the incidence and management of BCBM in the UK, how it may vary across the country and its impact on patient outcomes. Finally, clinical studies have been hampered by a lack of a central resource to aid feasibility work and to identify potentially eligible patients. Study design: PRIMROSE will use the trainee collaborative model to establish an observational prospective UK cohort of newly diagnosed BCBM. Data collected will include routine clinico-pathological information, prior adjuvant and metastatic treatment as well as BCBM-related information including presentation, management and outcome. Anonymised data will be collated in a secure central REDCap database. All hospitals in the UK will be eligible to register patients driven by trainees from all specialties via the UK Breast Cancer Trainees Research Collaborative Group (BCTRCG) network. Eligibility criteria: Inclusion criteria: male or female patients aged &amp;gt;16 years of age, with histologically and/or cytologically confirmed BC with involvement of the brain parenchyma. There are no formal exclusion criteria. Patients with leptomeningeal disease will be registered, with data being collected in a separate project (PRIMROSE-LMD). Aims: The overarching objectives include defining the prevalence, management and outcome of BCBM in the UK. Endpoints: *Primary Endpoint: Overall survival from initial diagnosis of CNS involvement. Secondary Endpoints will include: 1. Time to initial CNS involvement from initial diagnosis of MBC; 2. Therapeutic interventions for management of CNS disease; 3. Time to intracranial tumour progression (for each line of therapy given for CNS disease); 4. Overall survival from MBC diagnosis; 5. Cause of death: progressive CNS disease versus progressive disease at other sites. *Information will be presented for the whole cohort as well as by breast cancer subtype Patient accrual: Patient accrual is due to commence in July 2019 and continue will for 2 years in the first instance. There is no predefined target accrual. Contact information: Study lead: Prof Carlo Palmieri; c.palmieri@liverpool.ac.uk

Abstract OT3-10-01: Phase Ib study of stereotactic radiation and nivolumab in the management of metastatic breast cancer with brain metastases

Abstract Background:Patients with breast cancer brain metastases represent a poor prognosis cohort with a high unmet clinical need. Standard-of-care treatments for patients with breast cancer brain metastases include local treatments, such as surgical resection and radiation treatment modalities that include stereotactic radiosurgery (SRS) or whole brain radiotherapy. Numerous pre-clinical studies have provided evidence to combine radiation therapy with immune checkpoint inhibition to improve response rates. The evidence is strongest for short course, hypofractionated radiation regimens. We hypothesize treatment with nivolumab and SRS will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone. Trial Design:The study is designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Treatment will be initiated with a dose of nivolumab (480 mg IV) that will be repeated every 4 weeks. The initial dose of nivolumab will be followed 1 week later by SRS at sites of brain metastases or post-operative cavities. Patients will be allowed to continue endocrine and HER2-targeted therapies if brain metastases progression was noted on these agents.Eligibility:Eligible patients include those ≥18, ECOG ≤2 with ≤10 breast cancer brain metastases of all subtypes eligible for stereotactic radiation. Specific Aims:The primary objective is to evaluate the safety and feasibility of nivolumab and SRS to sites of brain metastases. Secondary objectives include evaluation of intracranial progression free survival (PFS), extracranial PFS, overall survival, local control, and distant brain control. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, mutation burden, TCR repertoire etc.) for association with clinical benefit.Statistical Methods:Safety and feasibility will be monitored by a 3 + 3 design followed by a dose expansion phase. Patient Accrual:This study is open with 4 patients enrolled at the time of submission. A total of 12 patients will be enrolled.Contact Information:Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT03807765. Citation Format: Kamran A Ahmed, Youngchul Kim, Avan J. Armaghani, John A. Arrington, Jimmy J. Caudell, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Sungjune Kim, Loretta Loftus, Timothy J. Robinson, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Nam D. Tran, H. Michael Yu, Hyo S. Han. Phase Ib study of stereotactic radiation and nivolumab in the management of metastatic breast cancer with brain metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-10-01.

Cost-effectiveness of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.

Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with whole-brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM. A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]) from the Chinese healthcare perspective. When considering progression as intracranial progression and overall progression, respectively, the incremental cost-effectiveness ratio was $14882.64/QALY and $13484.21/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34521.42/QALY for intracranial progression and $36562.63/QALY for overall progression; net benefit: -$8407.36 for intracranial progression and -$9836.41 for overall progression). One-way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18000/QALY, icotinib could be cost-effective. Icotinib was cost-effective compared with WBI with or without chemotherapy.

Systemic therapy following craniotomy in patients with a solitary breast cancer brain metastasis

PurposeTo describe practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM).MethodsA multi-institutional retrospective review of consecutive patients undergoing resection of a single BCBM without extracranial metastases was performed to describe subtype-specific postoperative outcomes and assess the impact of types of ST on site of recurrence, progression-free survival (PFS), and overall survival (OS).ResultsForty-four patients were identified. Stratified estimated survival was 15, 24, and 23 months for patients with triple negative, estrogen receptor positive (ER+), and HER2+ BCBMs, respectively. Patients receiving postoperative ST had a longer median PFS (8 versus 4 months, adjusted p-value 0.01) and OS (32 versus 15 months, adjusted p-value 0.21). Nine patients (20%) had extracranial progression, 23 (52%) had intracranial progression, three (8%) had both, and nine (20%) did not experience progression at last follow-up. Multivariate analysis showed that postoperative hormonal therapy was associated with longer OS (HR 0.26; 95% CI 0.08–0.89; p = 0.03) but not PFS (HR 0.35, 95% CI 0.08–1.47, p = 0.15) in ER+ patients. Postoperative HER2-targeted therapy was not associated with longer OS or PFS in HER2+ patients.ConclusionsDisease progression occurred intracranially more often than extracranially following resection of a solitary BCBM. In ER+ patients, postoperative hormonal therapy was associated with longer OS. Postoperative HER2-targeted therapy did not show survival benefit in HER2+ patients. These results should be validated in larger cohorts.