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

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

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.

Body CT and PET/CT Detection of Extracranial Lymphoma in Patients with Newly Diagnosed Central Nervous System Lymphoma

Background We aimed to investigate the detection rate of body CT or PET/CT for sites of extracranial disease in patients with a new pathological diagnosis of CNS DLBCL and to identify factors associated with sites of extracranial disease. Methods An international multicenter cohort study of consecutive immunocompetent patients with a new diagnosis of CNS DLBCL confirmed by brain biopsy who underwent CT and/or PET/CT to evaluate for sites of extracranial disease between 1998 and 2019. The primary outcome was the detection rate of extracranial lymphoma by CT or PET/CT. Subgroup analyses according to age and EBV status were also performed. Logistic regression analyses were performed to determine factors related to sites of extracranial disease. Detection rates of CT and PET/CT were compared. Results 1043 patients were included. The overall detection rate of CT or PET/CT was 2.6% (27/1043). The treatment approach was adjusted in 74% of these patients. Multivariable analysis demonstrated that age>61-years (OR, 3.10; P=.016) and EBV positivity (OR, 3.78; P=.045) were associated with greater odds of extracranial lymphoma. There was no statistically significant difference in detection rate between CT and PET/CT (P=.802). In patients≤61 years old, the false-referral rates were significantly higher than the detection rates (P<.001). Conclusion Our results showed increased odds of extracranial lymphoma in patients with older age or EBV-positive lymphoma. Treatment was adjusted in a majority of patients diagnosed with extracranial lymphoma, thereby supporting the current guidelines for the use contrast-enhanced body CT or PET/CT in patients with newly diagnosed CNS DLBCL.

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?

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% & 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.

Survival Outcomes following LINAC based Stereotactic Radiosurgery/Stereotactic Radiotherapy (SRST) treatment of brain metastases: The Wessex Experience

Aims Since 2016, the University Hospital Southampton NHS Foundation Trust (UHSFT) has been commissioned by NHS England to deliver SRST to brain metastases. At UHSFT, all referrals are discussed at the Wessex Neurosciences multidisciplinary team meeting. Referrals that satisfy the criteria set by NHS England (estimated prognosis greater than 6 months, absence or controlled extracranial disease or potentially controllable extracranial disease with a Karnofsky Performance Status >70%) will be offered SRST. This retrospective study was performed to assess overall survival rates of patients with brain metastases treated with SRST with further tumour subtype analysis. We also benchmarked our results with other SRST centres. Method Retrospective data collection was performed for all the patients who have been treated with SRST. Patients who received SRST to a single metastasis, multiple metastases and/or to the resection cavity between 01/01/2017 to 30/09/2019 were included in this study. All treatment was delivered using a LINAC based SRST platform. Prescription doses ranged from 13.5 Gy to 21 Gy in a single fraction, 21 to 24 Gy in 3 fractions and 25 Gy in 5 fractions. Patients are treated using a stereotactic thermoplastic immobilisation shell and dynamic conformal arc therapy with ExacTrac TM and Cone Beam CT imaging. Dates of death were obtained from the NHS Digital Spine and survival analysis using median overall survival was performed using the Kaplan Meier Method. Results 277 patients were treated between 01/01/17 and 30/9/2019. The median overall survival from the Kaplan Meier Method was shown to be 14.7 months and the 6-month overall survival was 71% for all patients. Sub-group analysis of individual tumour sites showed: lung (n=110) median OS 12.1 months, melanoma (n=58) median OS 26.4 months, breast (n=46) median OS not reached (67% still alive) but 18 months survival was 70%, renal (n=22) median OS 15.4 months and colorectal (n=19) median OS 6 months. “Other” tumour sites (n=22) included patients with ovarian, neuroendocrine, sarcoma, testis, oesophagus, unknown primary and gallbladder which were grouped together due to small patient numbers. 41% of patients treated were alive at the time of analysis. Conclusion Patients with brain metastases treated with SRST at UHFST have similar outcomes compared to other SRST centres. These patients have a median overall survival of 14.7 months. However, 29% of patients analysed did not survive more than 6 months. Further collection and analysis of the data might improve patient selection and their outcomes.

Efficacy and Safety of a Second Course of Stereotactic Radiation Therapy for Locally Recurrent Brain Metastases: A Systematic Review

Recent advances in cancer treatments have increased overall survival and consequently, local failures (LFs) after stereotactic radiotherapy/radiosurgery (SRS/SRT) have become more frequent. LF following SRS or SRT may be treated with a second course of SRS (SRS2) or SRT (SRT2). However, there is no consensus on whenever to consider reirradiation. A literature search was conducted according to PRISMA guidelines. Analysis included 13 studies: 329 patients (388 metastases) with a SRS2 and 135 patients (161 metastases) with a SRT2. The 1-year local control rate ranged from 46.5% to 88.3%. Factors leading to poorer LC were histology (melanoma) and lack of prior whole-brain radiation therapy, large tumor size and lower dose at SRS2/SRT2, poorer response at first SRS/SRT, poorer performance status, and no controlled extracranial disease. The rate of radionecrosis (RN) ranged from 2% to 36%. Patients who had a large tumor volume, higher dose and higher value of prescription isodose line at SRS2/SRT2, and large overlap between brain volume irradiated at SRS1/SRT1 and SRS2/SRT2 at doses of 18 and 12 Gy had a higher risk of developing RN. Prospective studies involving a larger number of patients are still needed to determine the best management of patients with local recurrence of brain metastases

P14.29 The treatment of melanoma brain metastases with stereotactic radiosurgery concurrently with immune checkpoint inhibition is associated with improved extracranial disease control and overall survival compared to the overall metastatic melanoma cohort - a synergistic effect reaching beyond local control?

BACKGROUND Melanoma brain metastases (MBM) are an increasingly common referral to the neuro-oncology MDT in the context of lengthening survivorship of metastatic melanoma (MM) patients in the immunotherapy era. Stereotactic radiosurgery (SRS) and immune checkpoint inhibition (ICI) are both effective in the management of MBM and, when combined, 12-month local control rates of >85% and overall survival (OS) >80% have been reported.[4,5] Recent local analysis of patients treated at our tertiary SRS referral centre has revealed even greater outcomes in this patient cohort. This study aimed to compare the outcomes of patients with MBM treated with concurrent SRS and ICI compared to the overall metastatic melanoma cohort, to elucidate whether the addition of SRS to ICI may improve disease control outside of the brain as well as within. MATERIAL AND METHODS A retrospective analysis of our local SRS database and an ARIA ePrescribing database search was performed to identify a cohort of patients treated with concurrent SRS and ICI for MBM, as well as a control cohort of MM patients who received ICI alone, over a 4 year period until February 2020. The primary endpoints were the extracranial progression free survival (PFS) and overall survival (OS) at 12 months. Secondary endpoints were the median PFS (mPFS) and OS (mOS). Kaplan-Meier curves and survival statistics were generated using SPSS v26. RESULTS A total of 34 MBM from 19 patients were identified in the SRS+ICI group and there were 200 patients in the control group. The minimum follow up was 12 months. The median patient age, duration of ICI and use of combination ICI favoured the SRS+ICI group. The number of sites of extracranial disease pre-ICI and overall anti-PD-1 usage was well matched. In the SRS+ICI group, there were no cases of extracranial progression and no deaths within 12 months. In the control group, the 12-month PFS and OS rates were 50.5% and 77.5% respectively. In terms of mPFS, this was not reached (estimated 37.6 months) in the SRS+ICI group, versus 13.4 months in the control group (log rank test, p=0.001). In terms of mOS, this was not reached in the SRS+ICI group, versus 55.8 months in the control group (log rank test, p=0.016). CONCLUSION We demonstrate improved extracranial disease control and survivorship amongst metastatic melanoma patients who develop brain metastases and are treated with concurrent SRS and ICI compared to those who do not. The outcomes of our control cohort are comparable to the 4-year follow up of the CheckMate 067 trial (n=945),[6] which strengthens the validity of the statistical comparisons made in this study. The improved extracranial disease control seen when SRS and ICI are combined in the treatment of MBM questions whether an abscopal effect may be at play, and therefore further accents the utility of SRS in MBM beyond that of local control alone. This could influence management in cases of borderline decisions for SRS.

OTHR-10. Diverse survival outcomes of HER2+ Breast Cancer Brain Metastases (BrCBM) presenting with isolated brain relapse compared to those with concurrent extracranial disease

Background In patients with isolated HER2+ BrCBM and no extracranial disease (ECD), there are no consensus guidelines on optimal treatment approaches following CNS-directed therapy. Our goal was to determine the implications of ECD at time of first HER2+ BrCBM on intracranial progression-free survival (PFS1) and overall survival (OS). Methods Retrospective analysis was performed on 77 patients with HER2+ BrCBM who received 1st CNS radiation from 2006–2020. Demographics, dates of metastatic and intracranial diagnosis, ECD status at 1st BrCBM, and outcomes were collected. The primary endpoint was PFS1 defined as time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from 1st CNS radiation and 1st metastatic disease to date of death/last known alive. ECD status was defined by RECIST1.1 from staging scans within 30 days of 1st BrCBM. Results In this patient cohort, 25% (19/77) had isolated brain relapse/no ECD. Median age was 50 years. Most patients (58%) developed first BrCBM during adjuvant or early-line metastatic therapy. All patients with no ECD presented with isolated brain relapse as first metastatic presentation. Patients with concurrent ECD presented with first BrCBM at a median of 16.6m (95% CI: 10.5 to 25.3) after initial metastatic presentation. Median OS from initial metastatic presentation to death was worse for patients with isolated brain relapse (25.3m, 95% CI: 16.8 to 35.3) compared to those with concurrent ECD (49.7m, 95% CI: 43.2 to 62; p=0.01). Median OS from first CNS involvement to death was not statistically different amongst groups. Conclusions Patients with isolated HER2+ BrCBM as their initial metastatic event have substantially worse OS compared to patients with concurrent ECD developing CNS metastases later in their disease course. This population with isolated brain relapse deserves investigation of novel treatment algorithms, including earlier introduction of brain-penetrable HER2-targeted agents.

RADI-09. Clinical factors associated with death after radiotherapy for brain metastases

Introduction It can be challenging to accurately identify patients with brain metastases who have very poor prognosis and are unlikely to benefit from radiation (RT). We characterized factors of patients who died within 30 days of receiving RT for brain metastases. Methods Patients who received whole brain RT (WBRT) or stereotactic radiosurgery (SRS) for brain metastases between 1/1/2017–9/30/2020 at a single institution were identified. Patient, tumor, treatment, and death variables were collected. Characteristics between those who did and did not die within 30 days were compared using the Wilcoxon Rank-Sum or Chi-Square test. Survival was estimated with Kaplan-Meier method. Results 636 patients received WBRT (n=117) or SRS (n=519). Median age was 61. Median survival was 6 months (95% CI 5–7 months). 75 (12%) died within 30 days of RT. Patients who died within 30 days had worse median KPS (50 vs 80, p<0.001). A higher proportion who died within 30 days had innumerable intracranial metastases (45% vs 11%, p<0.001), leptomeningeal disease (16% vs 5%, p<0.001), and higher burden of neurologic symptoms at presentation (seizures (12% vs 4%, p=0.003); cranial neuropathies (32% vs 9%, p<0.001); motor/sensory deficits (51% vs 29%, p<0.001); altered mentation (60% vs 26%, p<0.001); headaches (48% vs 30%, p<0.001); steroid use (68% vs 48%, p<0.001)). Patients who died within 30 days had progressive extracranial disease (intrathoracic: 87% vs 50%; spinal: 57% vs 18%; liver/adrenal: 60% vs 24%), p<0.001. More patients who died within 30 days received inpatient RT (39% vs 4%, <0.001) and did not complete RT (24% vs 1%, p<0.001). Discussion Patients who died within 30 days of RT had worse KPS, intracranial/extracranial disease burden, and neurologic symptoms. Future analyses will assess whether these factors can inform a prognostic model to identify patients with poor prognosis who may be appropriate for supportive care alone.