Intracranial Progression Research Articles

Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma.

Purpose/Objectives Combination BRAF(vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited.We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis.DF was defined as any new intracranial lesions.Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of thediameters of thefive largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308,p<0.02). Two (20%) patients eventually received stereotactic radiosurgery, and 2 (20%) received whole-brain radiotherapy for intracranial progression. Conclusion Although patients withBRAF-mutant melanoma with BM had fair local control on BRAF plus MEK inhibitors, the competing risk of death and distant intracranial and extracranial progression was high. Patients with larger brain metastases may benefit from local therapy.

Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer.

Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4m) compared to those with progressive or stable/responding ECD (48.8m and 71.5m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9m) versus stable/responding (36.6m) or isolated intracranial relapse (28.4m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

Radiotherapy for Secondary CNS Lymphoma: Patterns of Utilization and Clinical Outcomes

Introduction: Secondary CNS lymphoma (SCNSL) is a challenging clinical scenario observed in 2-5% of non-Hodgkin lymphoma patients, without well-defined standard of care. We sought to understand the indications and outcomes of patients with SCNSL referred for radiotherapy (RT) at a tertiary cancer center. Methods: We analyzed 93 consecutive patients with SCNSL of aggressive B cell histology who received brain RT at Memorial Sloan Kettering Cancer Center between 1999-2021. Overall survival (OS) was estimated using the Kaplan-Meier method. Time to intracranial progression was estimated for patients with brain imaging at least 30 days after treatment start using competing risk analysis with death as a competing risk. Outcomes were considered from the start of RT. Patients were further analyzed by treatment intent and by the presence of leptomeningeal disease (LMD), defined radiographically or by cerebrospinal fluid analysis. Results: Median age was 63 (interquartile range [IQR]: 51-70). 9% of patients had CNS involvement at initial diagnosis. Histologies included diffuse large B cell (76%), mantle cell (7%), post-transplant lymphoproliferative disorder (7%), Burkitt (5%), Richter's transformed CLL (4%), lymphoblastic lymphoma (1%). 55% of patients received R-CHOP and 12% received R-EPOCH as initial therapy, and 25% received CNS prophylaxis. 21 (23%) patients received RT as their initial SCNSL treatment. Of the 72 (77%) patients who received CNS-directed systemic therapy for SCNSL prior to brain RT, 88% received a methotrexate (MTX)-based regimen. Median time interval between MTX and RT was 32 days (IQR: 15 - 82). 86 (92%) of patients received whole brain (WBRT) and 7 (8%) received partial brain RT. Median RT dose was 30 Gy (IQR: 23.4-30). 3 patients received craniospinal irradiation (CSI). Median OS for the entire cohort was 2.9 months. Median OS differed by RT treatment intent as follows: consolidation after complete response to systemic therapy (61.7 months, n=8), RT bridging to hematopoietic cell transplantation (HCT) (not reached, n=7), RT bridging to CAR-T (5.7 months, n =3), RT salvage after progression or intolerance of systemic therapy (2.5 months, n = 54), RT as initial SCNSL treatment typically in an emergency or palliative setting (1.2 months, n=21) (p < 0.0001). Across the full cohort, median OS was longer for patients without evidence of LMD at the time of RT (6.3 vs. 1.7 months, p < 0.0001). Among patients with LMD at SCNSL diagnosis, those who cleared LMD by the time of RT had longer median OS than those with persistent LMD (8.3 vs. 2.2 months, p = 0.014). The estimated 3-year risk of intracranial failure after salvage RT was 35 ± 11% for patients without LMD and was not evaluable for patient with LMD at salvage as all patients' treatment failed or the patients died by 4 months. Conclusion: SCNSL remains a clinical challenge and patients referred for brain RT have overall poor prognosis. However, the subset of patients who receive RT as consolidation or bridge to HCT can achieve long term survival. The presence of LMD at RT is prognostic for inferior survival. For SCNSL patients without LMD, intracranial disease control after salvage RT is possible. Alternate treatment strategies including broader consideration of CSI for persistent LMD are warranted. Further identification of clinical, anatomic, and molecular subtypes of SCNSL that impact treatment response will help to clarify optimal treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CNSC-04. CEREBROSPINAL FLUID-DERIVED CIRCULATING TUMOR DNA IS SUPERIOR TO PLASMA IN NSCLC PATIENTS WITH CNS PROGRESSION

Abstract Introduction Central nervous system (CNS) metastases are devastating neurologic complications. However, the clinical value of cerebrospinal fluid (CSF) as liquid biopsy medium in EGFR-mutated or ALK-rearranged patients with brain metastases (BM) or leptomeningeal metastases (LM) remains unclear. Patients and Methods We retrospectively analyzed the gene map of 14/48 NSCLC-BM patients and 34/48 NSCLC-LM patients. Compare the clinical predictive value of CSF and matched plasma (PLA) for patients with single CNS progression (cohort 1) or intracranial progression simultaneously with extracranial disease progression (cohort 2). Circulating cell-free tumor DNA (ctDNA) in CSF and matched PLA underwent next-generation sequencing targeting 168 cancer-relevant genes. Results For patients with single CNS progression, the mutation rate of major driver genes is much higher than the rate in matched PLA. Besides, CSF also demonstrated higher levels of potential prognostic markers in comparison with matched PLA samples, showing EGFR-amp presented more than two times the rate compared to matched PLA, and the detection rate of TBX3, PTEN were almost double the rate in CSF than paired PLA samples. In addition, poor outcomes associated with makers including CDKN2A/B, PIK3CA/G, CDK4/6, and MET showed exclusively in CSF samples.Almost all mutations identified in the PLA could detect in matched CSF samples in NSCLC-LM patients with both intracranial and extracranial disease progression. In addition, detection rates of driver mutations, consisting of EGFR or ALK are much higher in CSF compared to matched PLA, and these potential survival marker genes like CDK4/6, CDKN2A/B, EGFR-amp, MET, and PIK3CA identified uniquely in CSF samples. Conclusion CSF is more comprehensive in genomic mutation profile than matched PLA in NSCLC -LM regardless of single intracranial progression or intracranial progression simultaneously with extracranial evolution.

TMIC-01. STAT3 EXPRESSION IN BRAIN METASTASES FROM BREAST CANCER: CORRELATIONS WITH DIFFERENT MOLECULAR SUBTYPES AND CLINICAL OUTCOME

Abstract BACKGROUND STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer (BC) may favor a pro-metastatic environment. MATERIAL AND METHODS Eighty-five BM specimens from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical, molecular data, and intracranial progression (i-PFS) were retrospectively retrieved. RESULTS Median age was of 54 years (range 30–81). Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). 15/68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. 56/68 (82.4%) showed positive staining of pSTAT3, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, 21/68 (30.9%%) with 1, and 12/68 (17.6%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 – 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC. CONCLUSION pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.

BIOM-01. GENOMIC ALTERATIONS IN ALK FUSION-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS WITH BRAIN METASTASES

Abstract PURPOSE Brain metastases (BM) are common in patients with anaplastic lymphoma kinase fusion-positive NSCLC (ALK+ NSCLC). We characterized the genomics of patients with ALK+ NSCLC BM treated with alectinib with or without local therapy to identify correlations of co-mutations with CNS-specific outcomes. METHODS We retrospectively reviewed ALK+ NSCLC patients with BMs who received alectinib for the definitive treatment of BM from 1/2012 and 5/2021. Genomic characteristics of 27 specimens from 27 patients were assessed with MSK-IMPACT, a 505-gene next-generation sequencing (NGS)-based tumor sequencing assay with &amp;gt;700x coverage. Intracranial progression-free survival (iPFS) and overall survival (OS) from BM diagnosis were analyzed using standard statistical methods. RESULTS The median age at BM diagnosis was 57 years (range 25-83). Median iPFS was 1.94 years (95%CI: 1.58- not reached) and median OS was 6.08 years (95%CI: 1.7– not reached). All patients received alectinib for the treatment of brain metastases (78% as 1st-line TKI) and 22% received local therapy. The most frequently altered co- alterations were CDKN2A (48%), TP53 (22%), MAP2K4 (15%), SMARCA4 (11%), CREBBP (11%), and ATM (7%). CDKN2A alterations were more common in patients with intracranial progression (64% vs 31%). MAP2K4 alterations were enriched in metastatic samples (p = 0.028, q = 0.113). SMARCA4 co- alterations were associated with inferior OS (HR: 8.76, 95%CI = 1.74-44.2, p= 0.009) and trended toward association with iPFS but was insignificant (HR: 3.25, 95%CI = 0.83-12.4, p=0.089). We identified missense ALK alterations in CSF from a patient who acquired resistance to alectinib and had leptomeningeal progression (G1269A, I1171T, L1108P). CONCLUSION This study is the first analysis of CNS specific outcomes with detailed genomic annotation for ALK+ NSCLC patients who received definitive alectinib for BM. Further investigation into the role of CNS-penetrant TKIs and the genomic alterations predictive of CNS failure are needed.

Patterns of Failure after Stereotactic Radiosurgery vs. Whole Brain Radiotherapy for Resected Brain Metastases: Central Imaging Review of the N107C/CEC.3 (Alliance) Phase III Clinical Trial

<h3>Purpose/Objective(s)</h3> Whole brain radiotherapy (WBRT) has historically been the main instrument to decrease intracranial progression after resection of brain metastases. The previously reported NCCTG N107C/CEC.3 (Alliance) randomized phase III clinical trial of WBRT vs. stereotactic radiosurgery (SRS) demonstrated that overall survival did not significantly differ between arms, while SRS was associated with less cognitive decline than WBRT. However, the initial analysis also showed that local tumor bed control (LC) was significantly worse with SRS than WBRT, with an unexpectedly low 12-month LC rate of 60.5% in patients receiving post-operative SRS. To further investigate LC, a central imaging review was performed. <h3>Materials/Methods</h3> In N107C/CEC.3, 194 patients were randomized to SRS (n=98) or WBRT (n=96). SRS dose was dependent on resection cavity volume and ranged from 12 Gy to 20 Gy all in a single fraction, and WBRT dose was 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. For this analysis, patients with local failure (LF) or leptomeningeal failure that had imaging available were centrally reviewed by two radiation oncologists to verify pattern of failure. Patient and treatment characteristics were assessed for association with updated outcomes after central review using Cox proportional hazards, Pearson's chi-square, or Kruskal-Wallis tests. <h3>Results</h3> Seventy-three patients with LF or leptomeningeal failure determined by their local site were centrally reviewed. After adding patients with no LF or leptomeningeal failure, 185 (95% of total enrolled) patients were included in this analysis as 9 patients with LF did not have imaging available for central review. Of 59 patients initially determined to have LF, 20 were determined on central review to be free of LF. Accordingly, after central review post-operative SRS was no longer associated with significantly lower rates of LC than WBRT (79.2% vs. 86.5% 12-month LC, respectively, p=0.099). After central review, the interrelated variables of tumor diameter, target volume, and prescription dose were associated with risk of LF. Patients with resection cavities > 3 cm had higher rates of LF than those with smaller cavities (23.5% vs. 12.6% 12-month LF rate, respectively; p=0.010). Larger target volume was associated with increased risk of LF (HR: 1.05, 95% CI: 1.01 – 1.09, p=0.008), while higher prescription dose was associated with lower risk of LF (HR: 0.81, 95% CI: 0.67 – 0.96, p=0.018). <h3>Conclusion</h3> In contrast to the initial report, after central review SRS was not associated with significantly higher rates of LF than WBRT. Patients with larger surgical cavities had higher rates of LF, though it is unclear whether this is related to cavity size, biology, or radiation dose. Randomized data comparing single to multifraction SRS in larger surgical cavities is awaited.

Right Sided Sphenoid Fungal Sinusitis Presenting with Contralateral Abducens Paralysis: A Rare Case Report

Abstract Isolated sphenoid sinus disease can be difficult to diagnose and treat due to the non-specificity of their symptoms and to the likelihood that these pathologies can present late with complications. For these reasons, significant delays in the diagnosis and treatment of the patient may happen. In addition, due to the proximity of the sphenoid sinus to vital structures such as the optic nerve, internal carotid artery, cavernous sinus and cranial nerves, any delay in treatment has the potential to lead to catastrophic outcomes, which is why swift diagnosis and early treatment are of the essence. In the differential diagnosis of isolated sixth cranial nerve palsy, sphenoid sinus pathologies must be kept in mind and the patients worked up with CT and/or MRI. Swift diagnosis and treatment before intracranial progression occurs could prevent severe complications. In our case report, we present a patient with isolated right sphenoid sinus aspergilloma (fungus ball) presenting with hemicranial headache and contralateral 6th cranial nerve involvement. In the literature, ipsilateral 6th cranial nerve involvement secondary to sphenoid sinusitis has been commonly reported, however so far only two cases of contralateral cranial nerve involvement have been reported, therefore our case represents a very rare presentation of a rare pathology. The patient has been operated with an endoscopic transnasal approach and in her postoperative follow up, lateral gaze function of the left eye has been observed to be significantly improved. Our case underlines the importance of considering sphenoid sinus aspergillomas in the differential diagnosis of patients presenting with unexplained cranial nerve pathologies, especially in the presence of headache, and the importance of early radiological studies and early operative treatment in these patients.

Value of Repeat CT Brain in Mild Traumatic Brain Injury Patients with High Risk of Intracerebral Hemorrhage Progression.

192 patients with MTBI and ICH were treated between November 2019 to December 2020 at a single level II trauma center. The Glasgow Coma Scale (GCS) was used to classify MTBI, and initial head CT was performed according to the Canadian CT head rule. Patients with a higher risk of ICH progression, including the elderly (≥65 years old), patients on antiplatelets or anticoagulants, or patients with an initial head CT that revealed EDH, contusional bleeding, or SDH > 5 mm, and multiple ICH underwent a repeat head CT within 12 to 24 h later. Data regarding types of intervention, length of stay in the hospital, and outcome were collected. The risk of further neurological deterioration and readmission rates were compared between these two groups. All patients were followed up in the clinic after one month or contacted via phone if they did not return. 189 patients underwent scheduled repeated head CT, 18% had radiological intracranial bleed progression, and 82% had no changes. There were no statistically significant differences in terms of intervention rate, risk of neurological deterioration in the future, or readmission between them. Repeat head CT in mild TBI patients with no neurological deterioration is not recommended, even in patients with a higher risk of ICH progression.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Prognostic Model for Intracranial Progression after Stereotactic Radiosurgery: A Multicenter Validation Study.

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan−Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1−11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1−17.1 months) and 7.6 months (95% CI 6.4−9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Characteristics of Patients Who Survived More than 5 Years after Diagnosis of Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> Patients with melanoma brain metastases (mBM) have historically demonstrated poor overall survival (OS). However, the prognosis of metastatic melanoma has improved dramatically in the era of immunotherapy. At our institution, we have a substantial cohort of patients who received intracranial RT and survived more than five years after diagnosis of mBM. We performed a descriptive study to characterize this cohort. <h3>Materials/Methods</h3> Patients who received intracranial RT for mBM at our institution were identified retrospectively. Those with OS greater than five years after diagnosis of mBM were included. Patient, disease, and treatment characteristics were collected. Kaplan-Meier analysis was used to estimate OS and intracranial progression-free survival (iPFS). Patients with histologically proven radiation necrosis (RN) were identified. <h3>Results</h3> Forty-five patients with 127 mBM at diagnosis received RT between 2006 and 2017 and survived more than 5 years. The median age at mBM diagnosis was 59 years (range, 32 to 73), and 69% were male. The primary tumor was cutaneous in 76% and unknown in 24%. BRAF V600 mutations were identified in 51% of patients. The median number of mBM at diagnosis was 2 (range, 1 to 14), and the median largest dimension was 2.3 cm (range, 0.3 to 5.4). Thirty-one mBM (24%) in 27 patients (60%) were resected prior to RT. Forty patients (89%) had stereotactic radiosurgery and 5 patients (11%) had whole brain RT as their initial RT modality. At mBM diagnosis, 31% had no evidence of disease (NED) extracranially. Most patients (91%) received immunotherapy. This was delivered concurrently with RT (47%), prior to RT (16%), or after RT (33%). At a median of 85 months of follow-up, 9 patients (20%) were deceased, including only 2 with clear evidence of intracranial progression, and 31 (69%) were alive and NED. Median OS was 156 months. Intracranial progression was observed in 19 patients (42%) at a median of 134 months. Histologically proven RN was identified in 11 patients (24%). <h3>Conclusion</h3> To our knowledge, these 45 patients constitute the largest report of mBM patients with OS exceeding 5 years. Most of this cohort was alive and NED at the time of analysis. The burden of intracranial disease at diagnosis was low, and a third of patients had no extracranial disease. Nearly all patients received immunotherapy, of whom half had immunotherapy concurrent with RT. Nearly half of patients who survived more than 5 years did so despite having intracranial progression after initial RT for their mBM. Nearly a quarter of patients had histologically proven RN, suggesting an enhanced immune response to RT in this cohort. Prior studies suggest a correlation between RN and increased intracranial response to RT. Future efforts should characterize the post-treatment radiographic features and other correlatives that differentiate this cohort from the general population with mBM. These results demonstrate an astounding outcome in some patients with limited volume mBM treated in the modern era.

Evaluating the Utility of EQ5D-5L in Patients with Brain Metastases: Secondary Analysis of NRG-CC001

<h3>Purpose/Objective(s)</h3> EuroQoL EQ5D has become the preferred preference-based tool used in oncology clinical trials to assess patient health states following different interventions. It allows for an efficient measure of patient quality-of-life (QoL) that can be used to calculate quality-adjusted life years required to perform cost-effectiveness analyses. NRG-CC001 established the neuroprotective effect of hippocampal avoidant-whole brain radiotherapy (HA-WBRT) plus memantine over WBRT plus memantine in patients with brain metastases. EQ5D results, collected as part of patient reported outcomes, demonstrated no differences between study arms. Although EQ5D was used in this trial, it is unknown if this tool is sensitive to QoL changes experienced by patients with brain metastases. The primary objective of this study was to assess the utility of EQ5D in reflecting neurocognitive function (NCF) changes in this patient population. <h3>Materials/Methods</h3> We performed a post hoc analysis of NRG-CC001 trial data, focusing on EuroQoL EQ5D measures. We used independent sample t-tests to assess mean differences of EQ5D index and visual analog scale (VAS) score changes from baseline (at 2, 4, and 6 months) between patients who experienced NCF failure and those who did not. We also compared mean changes in EQ5D for patients who experienced intracranial progression to those without intracranial progression. <h3>Results</h3> EQ5D index score and VAS score changes between those patients who had NCF failure and those that had intact NCF showed no statistically significant differences at 2, 4, and 6 months (Table). When stratifying by age (<=61, >61), education (<= high school, >high school), and KPS (70, >70), there was no significant EQ5D difference by treatment arm or by NCF change. There was a trend towards significance when assessing changes in EQ5D index and VAS score at 4 months (p=0.06 and 0.05, respectively), and a significant correlation at 6 months for VAS score change (p=0.04) based on progression of disease versus not. <h3>Conclusion</h3> EQ5D was not sensitive to changes in NCF following whole brain radiation therapy for patients with brain metastases, but was sensitive to changes in intracranial progression. Given that NCF is well-established as a patient-centric outcome measure following brain radiation, the results of this study challenge the routine use of EQ5D in brain metastases clinical trials that are focused on preventing NCF failure. There is an urgent need to identify preference-based health status measures that are sensitive to changes in NCF and can be utilized in clinical trials for patients with brain metastases.

Optimal Treatment Strategy of Radiotherapy and Crizotinib for Patients with Brain Metastasis from ALK-Rearranged Non-Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Radiotherapy and anaplastic lymphoma kinase (ALK) inhibitors are treatment options for brain metastasis (BM) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). This study aimed to find the optimal treatment strategy for patients with BM from ALK-rearranged NSCLC. <h3>Materials/Methods</h3> Between 2012 and 2017, consecutive patients with BM from ALK-rearranged NSCLC treated with crizotinib and radiotherapy in our institution were reviewed and enrolled into the study. Patients were treated with sequential radiotherapy and crizotinib (upfront radiotherapy or crizotinib followed by the other at intracranial progression), or concurrent radiotherapy and crizotinib. The cumulative incidence of intracranial progression free survival (iPFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the log-rank test was used to analyze differences between the groups. A two-sided p value ≤ 0.05 were considered statistically significant. <h3>Results</h3> Totally 41 patients were enrolled, including 24 (58.5%) with sequential treatment and 17 (41.5%) with concurrent treatment. The diagnosis-specific graded prognostic assessment (DS-GPA) score was 0-2 in 25 (60.1%) patients and > 2 in 16 (39.0%) patients, respectively. There were 13(31.7%), 17 (41.5%), and 11 (26.8%) patients treated with stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and WBRT with simultaneous in-field boost (SIB), respectively. The median iPFS and OS in all patients were 33.5 (95% CI 30.8-36.2) months and 63.9 (95% CI 46.0-81.9) months, respectively. There was no significant difference of iPFS or OS between the sequential treatment group and the concurrent treatment group. However, in DS-GPA scores of 0-2, the iPFS was longer in the sequential treatment group than concurrent treatment group (67.9 months vs.32.6 months, <i>P</i>=0.045), but the difference of OS was not significant between the two groups (38.9 months vs. 32.6 months, <i>P</i>=0.829). Moreover, the median iPFS of patients receiving SRS, WBRT alone, and WBRT with SIB was 33.5 months, 43.6 months, and 63.9 months (P=0.047). The corresponding median OS was not reached, 26.0 months, and 67.9 months, respectively (<i>P</i><0.001). <h3>Conclusion</h3> For patients with BM from ALK-rearranged NSCLC in our study, sequential crizotinib and brain radiotherapy for patients with DS-GPA score of 0-2 achieve better iPFS. In addition, WBRT with SIB achieves the best iPFS.

CNS Outcomes in ALK Fusion Positive NSCLC Patients with BM Who Received Alectinib with or without Local Therapy

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) are common in patients (pts) with anaplastic lymphoma kinase (<i>ALK</i>) fusion positive non-small cell lung cancer (NSCLC). <i>ALK</i>-rearrangements are observed in approximately 5% of NSCLC patients. Alectinib is a highly selective, central nervous system (CNS)-penetrant tyrosine kinase inhibitor which may allow patients with BMs to defer local therapy (LT) such as surgery, stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). We characterized the CNS outcomes in pts with <i>ALK</i> fusion positive NSCLC BM treated with alectinib with or without LT. <h3>Materials/Methods</h3> We retrospectively reviewed <i>ALK</i> fusion-positive NSCLC pts with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. CNS response rates (RR) were assessed via modified Response Assessment in Neuro-Oncology (RANO)-BM criteria. Surgically resected lesions were excluded from this analysis. A complete response (CR) was defined as complete disappearance of the lesion and a partial response (PR) was defined as a >30% decrease in size relative to baseline. Intracranial progression (iPFS) was analyzed using the Kaplan-Meier (KM) method with log-rank test, with death factored in as a competing risk. <h3>Results</h3> We identified 39 pts with <i>ALK</i> fusion positive NSCLC who initiated alectinib at BM diagnosis: 27 pts received alectinib only and 12 pts received alectinib and upfront LT including surgical resection (<i>n</i> = 2, 17%), comprehensive surgical resection followed by SRS (<i>n</i> = 2, 17%), SRS 4 (<i>n</i> = 4, 33%) or WBRT (<i>n</i> = 4; 33%). Alectinib was first-line therapy for 26 (67%) pts and second-line therapy for 12 (31%) pts. Median follow-up from BM diagnosis was 50.6 months (IQR 33.3-56.7). Patients treated with alectinib and LT were more likely to have pre-treatment neurologic symptoms (83% vs 33%), larger median BM size (median 12 mm vs 5 mm), and BM > 1 cm in size (83% vs 30%) compared to pts who received alectinib only. Despite these negative factors, there were no differences between both groups with regards to iPFS (TKI only, HR 1.31, 95% CI 0.55-3.11; p=0.54). A total of 28 and 55 lesions were assessed for CNS RR in the alectinib + LT and alectinib only groups, respectively. At 6-months, the CNS RR were 46% (PR) and 54% (CR) vs. 19% (PR) and 74% (CR) in the alectinib + LT and alectinib only groups, respectively. <h3>Conclusion</h3> To our knowledge, this study represents the largest yet reported series of alectinib-treated NSCLC BM with detailed patient and lesion-level CNS-specific outcomes. Despite the fact that patients with <i>ALK</i> fusion positive NSCLC treated with alectinib + LT had larger BM and a greater likelihood of pre-treatment neurologic symptoms, the iPFS was similar between the patients treated with alectinib only and alectinib + LT. With newer generation TKIs which may have CNS penetrance, further prospective studies are required to identify which patients are most likely to benefit from the addition of LT to <i>ALK</i>-directed therapy.

Serum Tumor Marker Response Predicts Survival and Intracranial Control after Radiation Therapy for Germ Cell Tumor Brain Metastases

<h3>Purpose/Objective(s)</h3> Patients with brain metastases (BM) from germ cell tumors (GCT) demonstrate poor overall survival (OS). However, multimodality treatment enables durable disease control in some patients. Serum tumor markers including beta-human chorionic gonadotropin (β-HCG) and alpha-fetoprotein (AFP) are used to evaluate response to systemic therapy. However, their utility in assessing the efficacy of intracranial radiation therapy (RT) is unclear. We evaluated whether changes in β-HCG and AFP after RT for GCT BM predict OS and freedom from intracranial progression (iPFS). <h3>Materials/Methods</h3> Patients with GCT BM who received intracranial RT at our institution were identified retrospectively. At least one β-HCG or AFP value before and after RT was required for inclusion. Serum tumor marker values were obtained prior to RT and 1 month after RT. Univariate and multivariate Cox regression analyses evaluated changes in β-HCG and AFP as predictors of OS and iPFS. Patients with normal tumor markers prior to RT were excluded from analyses. <h3>Results</h3> Sixty-two male patients who received RT between 2002 and 2021 were included. Median age was 30 years (range, 2 to 61). The primary tumor was testicular in 81% and mediastinal in 15%. Histology was seminoma in 10%. At diagnosis, the median number of BM was 2, and the median largest diameter was 1.8 cm. Initial RT included whole brain radiation therapy in 55%, stereotactic radiosurgery in 34%, and both in 10%. 31% had resection preceding RT. Most patients had extracranial disease (79%) and received chemotherapy within a month of RT (66%). During RT, radiographic progression of extracranial disease occurred in 34% of patients. Median OS and iPFS were 20.6 and 27.7 months, respectively. Among 41 patients with baseline β-HCG above the normal range, β-HCG decreased at 1 month after RT in 51%. Patients with decreased β-HCG, versus those with increased β-HCG, had significantly better OS (median not reached versus 5.4 months) and iPFS (median not reached versus 4.7 months). These correlations remained significant on multivariate analysis, controlling for largest BM diameter and RT modality (OS: HR = 13, 95% CI = [4.6, 37], p = 1 × 10⁻⁶; iPFS: HR = 6.4, 95% CI = [2.2, 19], p = 6 × 10⁻⁴). These correlations also remained significant whether or not patients had extracranial disease progression during RT (p < 0.05). Among 20 patients with baseline AFP above the normal range, AFP decreased at 1 month after RT in 75%. Likewise, decreased AFP was correlated with better OS on univariate regression (p = 0.04). <h3>Conclusion</h3> To our knowledge, this is the first study to evaluate changes in serum tumor markers as predictors of outcomes after RT for GCT BM. Decrease in β-HCG one month after RT was associated with better OS and iPFS on multivariate analysis, and likewise, decrease in AFP was associated with better OS on univariate analysis. These data indicate that post-RT β-HCG and AFP levels are useful predictors of outcomes in patients with GCT BM.

Impact of ATM Mutations on Brain Metastasis Control and Radionecrosis in Non-Small Cell Lung Cancer Patients Undergoing SRS

<h3>Purpose/Objective(s)</h3> While Ataxia Telangectasia Mutated gene (ATM) variants have been associated with improved local control after radiation, adverse radiation events have been reported following conventional radiotherapy for extracranial tumors. It remains unknown whether ATM variants affect rates of radiation necrosis (RN) and local intracranial progression (LIP) following stereotactic radiosurgery (SRS) for brain metastases. We questioned whether pathologic ATM variants increase rates of RN and/or decrease rates of LIP following SRS for brain metastasis in non-small cell lung cancer (NSCLC) patients. <h3>Materials/Methods</h3> Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified at our institution. RN and LIP were determined by either biopsy or multi-disciplinary serial MRI review. Cumulative incidence of RN and LIP were estimated via the Kaplan Meier method. Cox proportional hazards testing was performed for variant classification (not detected [ND] vs variant of unknown significance [VUS] or pathogenic variant [PV]). A power analysis estimated that 34 events would need to be observed to detect a >4-fold hazard ratio for event. <h3>Results</h3> 541 patients completed SRS for brain metastasis secondary to NSCLC, of which 260 completed molecular profiling. Comprehensive Genomic Profiling (CGP) was performed on cell free circulating tumor DNA (61%), primary tumor (17%), extracranial metastasis (17%), and brain tumor (18%), including ≥2 sites for 33 (13%) patients. Availability of CGP data was significantly associated with more recent year of SRS completion (2018-20, 64% vs 2015-17, 25%; p<0.001), younger age at brain metastasis diagnosis (64.8 years [IQR 57.1-72.8] vs 67.8 years [IQR 59.6-72.8]; p=0.036), no prior tobacco use (22% vs 10%; p<0.001), adenocarcinoma histology (84% vs 73%; p=0.002), and metastatic disease at initial diagnosis (73% vs 63%; p=0.017). ATM variants were identified in 36 cases (13.8%; 13 PV, 23 VUS). For all patients with CPG, RN incidence was 4.9% (95% CI 1.6 – 8.2%) at 6 months and 9.9% (95% CI 4.8 - 15.0%) at 12 months and LIP was 5.4% (95% CI 2.4 – 8.4%) at 6 months and 9.8% (5.5 – 14.1%) at 12 months. For patients with ATM variants, RN incidence was 5.3% (0.0 - 15.3%) at both 6 and 12 months, with 2 total RN events at 5.7 months and 13.9 months following SRS, respectively; LIP was 3.1% (0.0 - 9.1%) at both 6 and 12 months, with one total LIP event at 2.0 months following SRS (P=0.46 and P=0.26 for RN and LIP, respectively). <h3>Conclusion</h3> We did not detect significant differences in RN or LIP risk following SRS for NSCLC brain metastases associated with ATM variants. These results suggest that at this time, ATM status should not inform SRS use when otherwise indicated for NSCLC brain metastases. This dataset additionally allowed us to estimate the number of patients needed to detect a given magnitude of relative risk for RN or LIP associated with a given variant. These data can inform future studies as CGP data accumulate.

Hypofractionated Stereotactic Radiotherapy with or without Whole Brain Radiotherapy with Helical Tomotherapy for Multiple Brain Metastases – Long-Term Follow-Up Results of a Phase II Trial

<h3>Purpose/Objective(s)</h3> Multiple brain metastases (BMs) remain a therapeutic challenge. Helical tomotherapy (HT) is a novel technique which has shown favorable dosimetric properties in previous studies. The aim of this single institutional phase II trial was to investigate the feasibility and safety of hypofractionated stereotactic radiotherapy (HFSRT) with or without simultaneous whole brain radiotherapy (WBRT) by HT in treating patients with multiple BMs. <h3>Materials/Methods</h3> Patients with at least 3 BMs were enrolled. The prescribed dose was 40 Gy in 20 fractions for WBRT and 60 Gy in 20 fractions for BMs simultaneously, or only focal HFSRT for the lesions with optimized doses based on tumor volumes and locations. After 2/3 course of radiation, patients received MRI scan, and gross tumor volume (GTV) was re-contoured if the volume of lesion was decreased. An adaptive second phase plan would be made to fulfill the rest of radiotherapy based on the new target. The primary endpoint was intracranial progression free survival (IPFS). The secondary endpoints were local control (LC), overall survival (OS), brain metastasis-specific survival (BMSS) and toxicities. <h3>Results</h3> Between September 2014 and June 2017, 69 patients (male: female=28:41) were enrolled and finally been analyzed. 63.8% of them were non-small cell lung cancer (NSCLC). The median number of lesions was 6 (3- 43) and the median total volume was 18.3 cc (0.4- 93.1 cc). The median follow-up time was 40.1 months. The 1-year LC, IPFS, OS and BMSS rates were 96.4%, 80.5%, 71.0% and 94.6%, respectively. The median survival time was 18.1 months (95% CI, 15.5- 20.7). After 2/3 course of radiation, 23 patients (33.3%) with 111 lesions were re-contoured due to volume decrease. The median GTV decrease rate was 39.7% (1.0%- 89.0%). Only 1 patient (1.4%) had Grade 3 hematological toxicity and the radiation necrosis rate was 2.9%. <h3>Conclusion</h3> Helical tomotherapy was well tolerated and could significantly extend IPFS compared with historical controls in multiple BMs. Large randomized clinical trials are warranted.

A Case of Extracranial Metastasis of Glioblastoma Multiforme Seen on Bone Scintigraphy.

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system in adults. It is known for its devastating intracranial progress thus attributing to its very short survival. Here, we report a case of 37-year-old female with GBM post surgery, chemotherapy and radiotherapy who presented with pain in right hip region. She was referred to our department for evaluation of skeletal metastasis. Tc-99m methylene diphosphonate bone scan revealed an expansile lesion involving the right iliac blade along with extensive lytic bony lesions throughout the axial skeleton.

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis.

Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.